Compared with the control values (p<0.05)

Fig. 4. Changes in CRP values when compared to Groups

Fig. 3. Changes in Cortisol values when compared to Groups

In this trial investigating the extent of suppression of the stress response to surgery in patients undergoing general anesthesia + epidural anesthesia achieved with two different local anesthetics relative to the patients only receiving general anesthesia, the intraoperative hemodynamics, intraoperative anesthetic and analgesic agent requirement, the postoperative analgesia quality, the side effects and the recovery were also compared between the groups.

Bupivacaine is commonly used in epidural analgesia owing to its long-lasting effect and the sensory block it achieves that is more marked than the motor block. However, levobupivacaine was reported to be safer with respect to the central nervous system toxicity and cardiotoxicity in addition to exhibiting a local anesthetic effect similar to bupivacaine in the clinical trials. The tendency for sensory block is longer with levobupivacaine relative to bupivacaine. Following epidural administration of levobupivacaine, the duration of the motor block was observed to be shorter than that of the sensory block. Levobupivacaine was reported to be as effective as bupivacaine when combined with morphine or fentanyl in the treatment of postoperative pain. Some trials demonstrated that levobupivacaine exhibited small increases in the sensory block time relative to bupivacaine, in line with the results from this trial. This finding may be attributed to the relatively increased vasoconstrictor effect of levobupivacaine compared to bupivacaine (5-8).

In this trial, there was no difference between Group I and Group II in the time to achieve sensory block at T6. There was no difference between the two groups in the motor block levels measured until the time to achieve sensory block at T6 dermatome. The follow-ups

The Effect of General Anesthesia and General Anesthesia Plus Epidural

analgesia, even if partially.

related to the increase in glucose values.

significant difference compared to the other groups.

higher relative to Groups I and II.

hours relative to Groups I and II.

Levobupivacaine or Bupivacaine on Hemodynami Stress Response and Postoperative Pain 219

administration (18). In this trial, epidural morphine was combined with local anesthetic agents to achieve postoperative analgesia in Groups I and II. Iv morphine was used in Group III. Glucose level was better suppressed in Groups I and II relative to Group III. The trials detected that the cortisol levels increased starting from the skin incision in cases undergoing general anesthesia + epidural analgesia; however, the blood cortisol levels were suppressed relative to the group receiving general anesthesia (19, 20). In another trial (21), epidural + general anesthesia and postoperative morphine administration were claimed to provide a better suppression of the blood cortisol level relative to the general anesthesia + postoperative iv morphine administration. In this trial, the postoperative 1st hour cortisol value was higher in Group III relative to Groups I and II. In all groups, the postoperative 1st hour cortisol value was higher than the control value; the postoperative cortisol value at 24 hours was significantly increased only in Group III. This shows that the cortisol response was better suppressed in the groups receiving epidural anesthesia and postoperative epidural analgesia relative to the group receiving general anesthesia and postoperative iv

Insulin, an anabolic and hypoglycemic hormone decreases following trauma as opposed to glucose and cortisol. This helps to maintain hyperglycemia and protect the metabolic status of the vital organs (22). In this trial, there was no difference between the groups in the insulin values measured preoperatively and in the first and 24th hours postoperatively. The increase in the insulin values in the 24th postoperative hour in Groups I and III may be

Compared to general anesthesia, the increase in TNF-a and CRP levels was observed to be less with general + epidural anesthesia (1). In this trial, the 24th postoperative hour CRP values exhibited an increase compared to the control values in all groups. While there was no statistically significant difference between the groups, the values in Group III were

Chu CPW et al (2) compared general anesthesia followed by iv morphine, and combined spinal epidural anesthesia followed by epidural 1% bupivacaine and 2 µg ml-1 fentanyl, and detected lower VAS scores in the first, 12th and 48th postoperative hours in the group

In this trial, morphine was combined with low-dose local anesthetic in patients using epidural PCA. Iv morphine PCA was used in the general anesthesia group. In the treatment of postoperative pain, the VAS scores were higher during the first hours in Group III relative to Groups I and II (p<0.05). This may result from the postoperative maintenance of analgesia in groups receiving preoperative epidural anesthesia. In the group receiving intravenous morphine PCA, the VAS scores gradually decreased and exhibited no

Enquist et al (3) demonstrated that epidural anesthesia blocking the neural afferent conduction whether combined with general anesthesia or alone resulted in suppression of the stress response to surgery in their trial on the effects of epidural anesthesia at various doses on surgical stress. The blood pressure values were higher during the first postoperative hours in the group of patients receiving epidural + general anesthesia relative to the general anesthesia group with no difference detected between the groups after three hours. In this trial, the MBP values were similarly higher in Group III during the first two

Nabil W. Doss et al (4) compared the thoracic epidural anesthesia and general anesthesia techniques in their trial performed using 0.2% ropivacaine in patients undergoing

receiving epidural anesthesia and postoperative epidural analgesia (p<0.05).

conducted during the 24th postoperative hour revealed a smaller number of patients developing motor block in the group using levobupivacaine.

In the trial by Bader et al (9) where women undergoing cesarean section were administered 0.5% (150 mg) levobupivacaine or bupivacaine at the same dose via epidural anesthesia, the incidence of hypotension was detected to be lower in those receiving levobupivacaine (84.4% levobupivacaine, 100% bupivacaine).

Bardsley et al (10), upon administering 56.1 mg of levobupivacaine and 47.9 mg of bupivacaine via the iv route, and Kopacz and Allen (11), upon accidentally administering 17 ml of 0.75% of levobupivacaine intravenously to a patient, reported that levobupivacaine was safer for achieving direct depression of the myocardial contractility relative to bupivacaine.

In this trial, there was one patient in Group I and four patients in Group II who required intraoperative ephedrine for hypotension, although this was not statistically significant. In Group III, the arterial blood pressure values were higher at various measurement times and required higher anesthetic doses to achieve hemodynamic stability. None of the three groups exhibited EKG changes. The absence of EKG changes in Groups I and II may be attributed to the low concentration of the epidural local anesthetic used.

Luchetti M et al (12) compared epidural + general anesthesia and total intravenous anesthesia in patients undergoing laparoscopic cholecystectomy and reported that the epidural + general anesthesia group did not require intraoperative opioid use, did not exhibit an increase in side effects and had a faster recovery. In our trial, the amount of sevoflurane and remifentanil used was lower in the epidural + general anesthesia groups relative to the general anesthesia group and thus, recovery was faster in Groups I and II relative to Group III; this finding is in line with the literature.

In their trial where they compared general anesthesia combined with epidural anesthesia achieved by 2% lidocaine to general anesthesia alone, Lu CH et al (13) reported that the requirement for volatile anesthetics was lower in the epidural + general anesthesia group, in line with our results.

The stress response can be avoided and the mediator levels can be maintained at the preoperative values by epidural anesthesia administered before surgical stimulation (14). In addition, epidural analgesia achieved by local anesthetics or opioids should also be maintained in the postoperative period to be able to reduce the stress response at the maximum level (15). In this trial, Group I and Group II were administered local anesthetic solution from the epidural space approximately 20 minutes before the surgery. As the sensory block level reached the T6 dermatome, general anesthesia induction was performed and the surgery was initiated. Maintenance of analgesia was achieved by using postoperative epidural PCA. Postoperative iv morphine PCA was used in Group III. As such, suppression of the stress response was observed similarly to these trials (14, 15).

Latterman et al (16) demonstrated that the glucose response was more limited in the patients receiving epidural anesthesia relative to the group undergoing general anesthesia. In this trial, the plasma glucose value showed a limited increase relative to the control value at the 1st and 24th postoperative hours; this increase was slightly more in Group III. None of the groups exhibited an increase in the glucose level above 150 mg dL-1.

The blood glucose level was detected to be lower with postoperative epidural fentanyl administration relative to iv fentanyl administration (17). Again after general anesthesia, the blood glucose level was observed to be better suppressed in association with general anesthesia + paravertebral anesthesia and analgesia versus postoperative iv morphine

conducted during the 24th postoperative hour revealed a smaller number of patients

In the trial by Bader et al (9) where women undergoing cesarean section were administered 0.5% (150 mg) levobupivacaine or bupivacaine at the same dose via epidural anesthesia, the incidence of hypotension was detected to be lower in those receiving levobupivacaine

Bardsley et al (10), upon administering 56.1 mg of levobupivacaine and 47.9 mg of bupivacaine via the iv route, and Kopacz and Allen (11), upon accidentally administering 17 ml of 0.75% of levobupivacaine intravenously to a patient, reported that levobupivacaine was safer for achieving direct depression of the myocardial contractility relative to

In this trial, there was one patient in Group I and four patients in Group II who required intraoperative ephedrine for hypotension, although this was not statistically significant. In Group III, the arterial blood pressure values were higher at various measurement times and required higher anesthetic doses to achieve hemodynamic stability. None of the three groups exhibited EKG changes. The absence of EKG changes in Groups I and II may be

Luchetti M et al (12) compared epidural + general anesthesia and total intravenous anesthesia in patients undergoing laparoscopic cholecystectomy and reported that the epidural + general anesthesia group did not require intraoperative opioid use, did not exhibit an increase in side effects and had a faster recovery. In our trial, the amount of sevoflurane and remifentanil used was lower in the epidural + general anesthesia groups relative to the general anesthesia group and thus, recovery was faster in Groups I and II

In their trial where they compared general anesthesia combined with epidural anesthesia achieved by 2% lidocaine to general anesthesia alone, Lu CH et al (13) reported that the requirement for volatile anesthetics was lower in the epidural + general anesthesia group, in

The stress response can be avoided and the mediator levels can be maintained at the preoperative values by epidural anesthesia administered before surgical stimulation (14). In addition, epidural analgesia achieved by local anesthetics or opioids should also be maintained in the postoperative period to be able to reduce the stress response at the maximum level (15). In this trial, Group I and Group II were administered local anesthetic solution from the epidural space approximately 20 minutes before the surgery. As the sensory block level reached the T6 dermatome, general anesthesia induction was performed and the surgery was initiated. Maintenance of analgesia was achieved by using postoperative epidural PCA. Postoperative iv morphine PCA was used in Group III. As such, suppression of the stress response was observed similarly to these trials (14, 15). Latterman et al (16) demonstrated that the glucose response was more limited in the patients receiving epidural anesthesia relative to the group undergoing general anesthesia. In this trial, the plasma glucose value showed a limited increase relative to the control value at the 1st and 24th postoperative hours; this increase was slightly more in Group III. None of the

The blood glucose level was detected to be lower with postoperative epidural fentanyl administration relative to iv fentanyl administration (17). Again after general anesthesia, the blood glucose level was observed to be better suppressed in association with general anesthesia + paravertebral anesthesia and analgesia versus postoperative iv morphine

attributed to the low concentration of the epidural local anesthetic used.

relative to Group III; this finding is in line with the literature.

groups exhibited an increase in the glucose level above 150 mg dL-1.

developing motor block in the group using levobupivacaine.

(84.4% levobupivacaine, 100% bupivacaine).

bupivacaine.

line with our results.

administration (18). In this trial, epidural morphine was combined with local anesthetic agents to achieve postoperative analgesia in Groups I and II. Iv morphine was used in Group III. Glucose level was better suppressed in Groups I and II relative to Group III.

The trials detected that the cortisol levels increased starting from the skin incision in cases undergoing general anesthesia + epidural analgesia; however, the blood cortisol levels were suppressed relative to the group receiving general anesthesia (19, 20). In another trial (21), epidural + general anesthesia and postoperative morphine administration were claimed to provide a better suppression of the blood cortisol level relative to the general anesthesia + postoperative iv morphine administration. In this trial, the postoperative 1st hour cortisol value was higher in Group III relative to Groups I and II. In all groups, the postoperative 1st hour cortisol value was higher than the control value; the postoperative cortisol value at 24 hours was significantly increased only in Group III. This shows that the cortisol response was better suppressed in the groups receiving epidural anesthesia and postoperative epidural analgesia relative to the group receiving general anesthesia and postoperative iv analgesia, even if partially.

Insulin, an anabolic and hypoglycemic hormone decreases following trauma as opposed to glucose and cortisol. This helps to maintain hyperglycemia and protect the metabolic status of the vital organs (22). In this trial, there was no difference between the groups in the insulin values measured preoperatively and in the first and 24th hours postoperatively. The increase in the insulin values in the 24th postoperative hour in Groups I and III may be related to the increase in glucose values.

Compared to general anesthesia, the increase in TNF-a and CRP levels was observed to be less with general + epidural anesthesia (1). In this trial, the 24th postoperative hour CRP values exhibited an increase compared to the control values in all groups. While there was no statistically significant difference between the groups, the values in Group III were higher relative to Groups I and II.

Chu CPW et al (2) compared general anesthesia followed by iv morphine, and combined spinal epidural anesthesia followed by epidural 1% bupivacaine and 2 µg ml-1 fentanyl, and detected lower VAS scores in the first, 12th and 48th postoperative hours in the group receiving epidural anesthesia and postoperative epidural analgesia (p<0.05).

In this trial, morphine was combined with low-dose local anesthetic in patients using epidural PCA. Iv morphine PCA was used in the general anesthesia group. In the treatment of postoperative pain, the VAS scores were higher during the first hours in Group III relative to Groups I and II (p<0.05). This may result from the postoperative maintenance of analgesia in groups receiving preoperative epidural anesthesia. In the group receiving intravenous morphine PCA, the VAS scores gradually decreased and exhibited no significant difference compared to the other groups.

Enquist et al (3) demonstrated that epidural anesthesia blocking the neural afferent conduction whether combined with general anesthesia or alone resulted in suppression of the stress response to surgery in their trial on the effects of epidural anesthesia at various doses on surgical stress. The blood pressure values were higher during the first postoperative hours in the group of patients receiving epidural + general anesthesia relative to the general anesthesia group with no difference detected between the groups after three hours. In this trial, the MBP values were similarly higher in Group III during the first two hours relative to Groups I and II.

Nabil W. Doss et al (4) compared the thoracic epidural anesthesia and general anesthesia techniques in their trial performed using 0.2% ropivacaine in patients undergoing

The Effect of General Anesthesia and General Anesthesia Plus Epidural

cholecystectomy. Br J Anaesth 1988; 61:160-4.

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Levobupivacaine or Bupivacaine on Hemodynami Stress Response and Postoperative Pain 221

[8] Luchetti M, Palamba R, Sica G, Massa G, Tufano R. Effectiveness and safety of combined

[9] Lu CH, Borel CO, Wu CT, Yeh CC, Jao SW, Chao PC, Wong CS. Combined general-

ARX index in colorectal surgery.Acta Anaesthesiol Scand 2005; 49(8):1063-7. [10] Chernow B, Alexander HR, Smallridge RC, Thompson WR, Cook D, Beardsley D, Fink

[11] Moller IW, Dinesen K, Sondergard S, Knigge U, Kehlet H. Effect of patient-controlled

[12] Lattermann R, Carli F, Wykes L, Schricker T. Epidural Blockade Modifies Perioperative

[13] Salomaki TE, Leppahuoto J, Laitinen JO, Vuolteenaho O, Nuutinen DS. Epidural versus

[14] Engquist A, Fog-Moller F, Christiansen C, Thode J, Vester-Andersen T, Madsen SN.

[15] Naito Y, Tamai S, Shingo K, Shindo K, Matsui T, Segawa H, Nakai Y, Mori K.

anesthesia both combined with epidural anaesthesia. Masui 2000; 49:121-9. [17] Qu DM, Jin YF, Ye TH, Cui YS, Li SQ, Zhang ZY. The effects of general anesthesia

[18] Christensen NJ, Hilsted J, Hegedus L, Madsbad S. Effects of surgical stress and insulin

[19] Christopherson R, Beattie C, Frank SM, Norris EJ, Meinert CL, Gottlieb SO, Yates H,

[20] CPW Chu, JCCM Yap, PP Chen, HH Hung. Postoperative outcome in Chinese patients

[21] Engquist A, Brant MR, Fernandez A. The blocking effect of epidural analgesia on the

and after upper abdominal surgery. Anesthesiology 1992; 77(3):426-31. [16] Hase K, Meguro K. Perioperative stres response in elderly patients for elective

epidural and general anesthesia for laparoscopic cholecystectomy. Reg Anesth

epidural anesthesia decreases the desflurane requirement for equivalent A-line

MP, Lake CR, Fletcher JR. Hormanal responses to graded surgical stress. Arch

analgesia on plasma catecholamine, cortisol and glucose concertrations after

Glucose Production without Affecting Protein Catabolism. Anesthesiology 2002;

intravenous fentanyl for reducing hormonal, metabolic and physiologic responses

Influence of epidural analgesia on the catecholamine and cyclic AMP responses to

Responses of plasma adrenocorticotropic hormone, cortizol and cytokines during

gastrectomy the comparison between isoflurane anesthesia and sevoflurane

combined with epidural anesthesia on the stres response in thoracic surgery.

on cardiovascular function and norepinephrine kinetics. Am J Physiol. 1984;

Rock P, Parker SD, Perler BA, et al. Perioperative morbidity in patients randomized to epidural or general anesthesia for lower extremity vascular surgery. Perioperative ischemia randomized anesthesia trial study group. Anesthesiology

having primary total knee artroplasty under general anaesthesia / intravenous patient-controlled analgesia compared to spinal-epidural anaesthesia / analgesia.

adrenocortical and hyperglisemic responses to surgery. Acta Anaesthesiol Scand

mastectomy and detected higher rates of nausea and vomiting in the general anesthesia group. Regarding hemodynamics, hypertension was more common in the general anesthesia group. The Aldrete recovery scores measured 1, 2 and 3 hours after the operation exhibited significant differences between the groups only in the first hour and were better in the thoracic epidural anesthesia group. In our trial, nausea-vomiting was less and the time of recovery from anesthesia was shorter in Groups I and II relative to Group III.

Morphine-related postoperative complications were most commonly in the form of nauseavomiting, similar to the other trials. There was no significant difference between Groups I and II, and Group III with respect to nausea and vomiting. However, the number of patients with nausea and vomiting was higher in Group III. None of the patients had hypotension that required postoperative rapid fluid replacement or vasopressor agent use. Similarly, none of the patients developed respiratory depression. While there was no difference between the groups in itching, there were more patients with this compliant in Group III. There was no significant difference between the groups in tremor and only one patient in Group II had tremor.

In avoiding stress response, individual differences, the type and duration of surgery, tissue injury in major surgeries, the type of analgesia and the drugs used are also important as well as the method of anesthesia used.

As a result, we concluded that bupivacaine and levobupivacaine used in epidural anesthesia had similar effects, epidural + general anesthesia provided a better intraoperative hemodynamic stability relative to general anesthesia and reduced the requirement for anesthetic agents, provided a faster recovery, resulted in less side effects and achieved a better analgesia, particularly during the first postoperative hours. We believe that the stress response can be better suppressed by epidural + general anesthesia.

#### **5. References**


mastectomy and detected higher rates of nausea and vomiting in the general anesthesia group. Regarding hemodynamics, hypertension was more common in the general anesthesia group. The Aldrete recovery scores measured 1, 2 and 3 hours after the operation exhibited significant differences between the groups only in the first hour and were better in the thoracic epidural anesthesia group. In our trial, nausea-vomiting was less and the time of recovery from anesthesia was shorter in Groups I and II relative to

Morphine-related postoperative complications were most commonly in the form of nauseavomiting, similar to the other trials. There was no significant difference between Groups I and II, and Group III with respect to nausea and vomiting. However, the number of patients with nausea and vomiting was higher in Group III. None of the patients had hypotension that required postoperative rapid fluid replacement or vasopressor agent use. Similarly, none of the patients developed respiratory depression. While there was no difference between the groups in itching, there were more patients with this compliant in Group III. There was no significant difference between the groups in tremor and only one patient in

In avoiding stress response, individual differences, the type and duration of surgery, tissue injury in major surgeries, the type of analgesia and the drugs used are also important as well

As a result, we concluded that bupivacaine and levobupivacaine used in epidural anesthesia had similar effects, epidural + general anesthesia provided a better intraoperative hemodynamic stability relative to general anesthesia and reduced the requirement for anesthetic agents, provided a faster recovery, resulted in less side effects and achieved a better analgesia, particularly during the first postoperative hours. We believe that the stress

[1] Foster RH, Markham A. Levobupivacaine: A review of its pharmacology and use a local

[3] McLeod GA, Burke D. Review Article: Levobupivacaine. Anaesthesia 2001; 56:331-

[4] O' Sullivan EP. Comparison of 0.75 % levobupivacaine with 0.75 % racemic bupivacaine

[5] Bader AM, Tsen LC, Camann WR, Nephew E, Datta S. Clinical effects and maternal and

[6] Bardsley H, Gristwood R, Baker H, Watson N, Nimmo W. A comparison of the

[7] Kopacz DJ, Allen HW. Accidental intravascular injection of 0.75 % levobupivacaine during lumbar epidural anaesthesia. Anaesth Analg 1999; 89:1027-9.

fetal plasma concentrations of 0.5 % epidural levobupivacaine versus bupivacaine

cardiovascular effects levobupivacaine and rac-bupivacaine following intravenous administration to healty volunteers. Br J Clin Pharmacol 1998;

response can be better suppressed by epidural + general anesthesia.

[2] McCellan KJ, Spencer CM. Levobupivacaine. Drugs 1998; 56:355-62.

for peribulbar anaesthesia (letter). Anaesthesia 1999; 54:610.

for cesarean delivery. Anesthesiology 1999; 90:1596-601.

anesthetics. Drugs 2000; 59:531-79.

Group III.

Group II had tremor.

**5. References** 

41.

46(3):245-9.

as the method of anesthesia used.


**11** 

**Propofol and Postoperative Pain:** 

*University Clinical Center of Kosova,* 

*Republic of Kosova* 

**Systematic Review and Meta-Analysis** 

Antigona Hasani, Hysni Jashari, Valbon Gashi and Albion Dervishi

*Department of Anesthesiology and Department of Pediatric Surgery, Prishtina,* 

If an intravenous or inhalator anesthetic, would include in itself all the components of general anesthesia, like hypnoses, analgesia, amnesia etc. it would represent a really ideal

Propofol is the drug of choice for induction and/or maintenance of anesthesia and sedation in the operating room and intensive care unit. It is a short-acting intravenous anaesthetic that features high blood-tissue solubility and allows a rapid induction and rapid emergence. Propofol has γ-aminobutyric acid agonist activity and produces dose dependent central

Analgesic properties of propofol are discussed in many studies, in recent years. However, evidence suggesting that the drug possesses analgesic activity still remains questionable

The objective of this study is to systematically determine the effects of propofol in

We have included double-blind, randomized, and controlled trials in humans, where postoperative analgesic effect of propofol was compared with another anesthetic or non-

The study was carried out according to the methods recommended by the Cochrane Collaboration (Higgins et al., 2009) and written in accordance with the PRISMA statement

Reports of randomized controlled trials were systemically sought using the Cochrane Library, PubMed, Embase, www.clinicaltrials.gov, and hand searching from the reference

Data were analyzed from 25 randomized controlled trials totaling 2033 adults and children. We developed standard data collection sheets to record details of trial design, interventions, and outcome measures for every trial. We extracted information about propofol and control group. Information about number of patients enrolled, type of surgical intervention and side effects, were also noted. Data on postoperative pain relief using pain scores time to first analgesic request and consumption of supplementary analgesics was taken from each

Qualitative analysis of postoperative effectiveness was evaluated by significant difference (*P* < 0.05 as reported in the original investigation) in pain relief using pain scores, time to

nervous system depression resulting in sedation and hypnosis.

for reporting systematic reviews (Liberati et al., 2009, Moher et al., 2009).

**1. Introduction** 

(Fassoulaki, 2011).

postoperative pain.

drug intervention.

lists of identified papers.

report.

anesthetic.

[22] Doss NW, Ipe J, Crimi T, Rajpal S, Cohen S, Fogler RJ, Michael R, Gintautas J. Continuous thoracic epidural anesthesia with 0.2 % ropivacaine versus general anesthesia for perioperative management of modified radical mastectomy. Anesth Analg. 2001; 92(6):1552-7.

## **Propofol and Postoperative Pain: Systematic Review and Meta-Analysis**

Antigona Hasani, Hysni Jashari, Valbon Gashi and Albion Dervishi *University Clinical Center of Kosova, Department of Anesthesiology and Department of Pediatric Surgery, Prishtina, Republic of Kosova* 

#### **1. Introduction**

222 Pain Management – Current Issues and Opinions

[22] Doss NW, Ipe J, Crimi T, Rajpal S, Cohen S, Fogler RJ, Michael R, Gintautas J.

Analg. 2001; 92(6):1552-7.

Continuous thoracic epidural anesthesia with 0.2 % ropivacaine versus general anesthesia for perioperative management of modified radical mastectomy. Anesth

> If an intravenous or inhalator anesthetic, would include in itself all the components of general anesthesia, like hypnoses, analgesia, amnesia etc. it would represent a really ideal anesthetic.

> Propofol is the drug of choice for induction and/or maintenance of anesthesia and sedation in the operating room and intensive care unit. It is a short-acting intravenous anaesthetic that features high blood-tissue solubility and allows a rapid induction and rapid emergence. Propofol has γ-aminobutyric acid agonist activity and produces dose dependent central nervous system depression resulting in sedation and hypnosis.

> Analgesic properties of propofol are discussed in many studies, in recent years. However, evidence suggesting that the drug possesses analgesic activity still remains questionable (Fassoulaki, 2011).

> The objective of this study is to systematically determine the effects of propofol in postoperative pain.

> We have included double-blind, randomized, and controlled trials in humans, where postoperative analgesic effect of propofol was compared with another anesthetic or nondrug intervention.

> The study was carried out according to the methods recommended by the Cochrane Collaboration (Higgins et al., 2009) and written in accordance with the PRISMA statement for reporting systematic reviews (Liberati et al., 2009, Moher et al., 2009).

> Reports of randomized controlled trials were systemically sought using the Cochrane Library, PubMed, Embase, www.clinicaltrials.gov, and hand searching from the reference lists of identified papers.

> Data were analyzed from 25 randomized controlled trials totaling 2033 adults and children. We developed standard data collection sheets to record details of trial design, interventions, and outcome measures for every trial. We extracted information about propofol and control group. Information about number of patients enrolled, type of surgical intervention and side effects, were also noted. Data on postoperative pain relief using pain scores time to first analgesic request and consumption of supplementary analgesics was taken from each report.

> Qualitative analysis of postoperative effectiveness was evaluated by significant difference (*P* < 0.05 as reported in the original investigation) in pain relief using pain scores, time to

Propofol and Postoperative Pain: Systematic Review and Meta-Analysis 225

healthy 70 kg patients. As the age of the patient increases, total body clearance of propofol may decrease. Clearance rates ranging from 1.4 to 2.2 liters per minute in patients 18 to 35 years of age have been reported, in contrast to clearance rates of 1 to 1.8 liters per minute in patients 65 to 80 years of age. The propofol mean total body clearance rate was 2.09 +/- 0.65 1/min (mean SD), the volume of distribution at steady state was 159 +/- 57 I, and the elimination half-life was 116 +/- 34 min. Elderly patients (patients older than 60 yr ) had significantly decreased clearance rates (1.58 +/- 0.42 vs. 2.19 +/- 0.64 1/min), whereas women (vs. men) had greater clearance rates (33 +/- 8 vs. 26 +/- 7 1 kg-1 min-1) and volumes of distribution (2.50 +/- 0.81 vs. 2.05 +/- 0.65 1/kg). Patients undergoing major intraabdominal surgery had longer elimination half-life values (136 +/- 40 vs. 108 +/- 29 min). Patients required an average blood propofol concentration of 4.05 +/- 1.01 µg/ml for major surgery and 2.97 +/- 1.07 g/ml for nonmajor surgery. Blood propofol concentrations at which 50% of patients were awake and oriented after surgery were 1.07 and 0.95 µg/ml, respectively. The metabolic clearance of propofol exceeds hepatic blood flow, which has leaded to suggestion that propofol is also metabolized in extrahepatic sites. Approximately 70% of a dose is excreted in the urine within 24 hours after administration, and 90% is excreted within 5 days. Psychomotor performance returned to baseline at blood propofol concentrations of 0.38-0.43 g/ml (Shafer et al., 1988, White, 1989,

Propofol causes a significant reduction in systemic blood pressure (more than 50% of preoperative level). This increase in blood pressure is a result of decrease in systemic vascular resistance. In addition to arterial vasodilatation, propofol produces venodilation (due both to a reduction in sympathetic activity and to a direct effect on the vascular smooth muscle), which contributes to its hypotensive effect. The fall in cardiac output is manifested

Respiratory depression and apnea are more pronounced with propofol than thiopental. Propofol decreases tidal volume and increases respiratory rate. The ventilatory response to carbon dioxide and hypoxia is also significantly decreased, but propofol does not inhibit hypoxic pulmonary vasoconstriction. Propofol can produce bronchodilation in patients with chronic obstructive pulmonary disease and in patients with acute laryngospasm during

Propofol decreases CMRO2 and CBF, as well as ICP.33 However, when larger doses are administered, the marked depressant effect on systemic arterial pressure can significantly decrease CPP. Cerebrovascular autoregulation in response to changes in systemic arterial pressure and reactivity of the cerebral blood flow to changes in carbon dioxide tension are not affected by propofol. Evidence for a possible neuroprotective effect has been reported in vitro preparations, and the use of propofol to produce EEG burst suppression has been proposed as a method for providing neuroprotection during aneurysm surgery. Its neuroprotective effect may at least partially be related to the antioxidant potential of propofol's phenol ring structure, which may act as a free-radical scavenger, decreasing free-radical induced lipid peroxidation. Recent studies reported that this antioxidant activity may offer many advantages in preventing the hypoperfusion/reperfusion phenomenon that can occur during surgery (Dagal

Propofol produces cortical EEG changes that are similar to thiopental. However, sedative doses of propofol increase â-wave activity analogous to the benzodiazepines. Induction of anesthesia with propofol is occasionally accompanied by excitatory motor activity (so-called nonepileptic myoclonia). In a study involving patients without a history of seizure disorders, excitatory movements following propofol were not associated with EEG seizure activity.

with decrease in heart rate. (Machała & Szebla, 2008; Frolich, 2011).

& Lam, 2009; Girard et al., 2009; Ozturk et al., 2009; Menku et al., 2010).

emergence from anesthesia (Zeller et al., 2005).

Deegan, 1992; Zuppa et al., 2003).

first analgesic request, and consumption of supplementary analgesics between the treatment groups, and by assessment of the clinical importance of observed differences.

Quantitative analyses of combined data were intended by calculation of the number of patients reporting any pain or no pain (pain response rate) between treatment groups.

Each trial was assessed for different measures of internal sensitivity. First, trials were checked for magnitude of pain intensity. Because it is difficult to detect an improvement with low or no pain, it was noted that pain scores were less than 30 mm on a visual analog scale (VAS) or less than moderate pain on a verbal rating scale or similar score. Second, it was noted that a power calculation of the statistical tests was performed. Trials with sample sizes less than 10 patients per treatment group were not considered in the study.

Meta-analyses were carried out by direct comparisons of intervention versus control and indirect comparisons between the networks of interventions shown to be significant individually.

#### **2. Propofol**

Propofol (2,6-diisopropyl phenol) is chemically inert phenolic compound with anesthetic properties. It has high lipid solubility, but is almost insoluble in water. The original preparation contained the solubilizing agent Ctenophore EL (polyethoxylated Castrol oil). Reformulation of the drug in an egg-oil-glycerol emulsion has eliminated hypersensitivity reactions that occurred with the original formulation (Sebel, 1989). The dose of propofol required to induce anesthesia measured by loss of eyelash reflex in 95% of healthy unpremedicated patients was 1.5-2.5 mg/kg. The range of induction times was 22-125 seconds. The rapid loss of consciousness was realized due to the immediate uptake of the lipid – soluble drug by the central nervous system (CNS).Within several minutes of intravenous administration, the plasma concentration of propofol decreases due to the distribution of the drug throughout the body and its uptake by peripheral tissues. As the plasma concentration falls, propofol diffuses from the CNS into the systemic circulation; when bolus doses of the anesthetic are used to induce anesthesia, there is a rapid recovery of full consciousness and awareness. These advantageous properties have contributed to the popularity of propofol as an induction agent for short procedures and day – case surgery (Short, 1999).

Propofol is also indicated for the maintenance of anesthesia computer-assisted continuous infusion and target-controlled infusion of propofol using a monitor of the hypnotic effects of propofol on the brain electroencephalographic Bispectral Index [BIS] monitor; it is possible to create a closed-loop delivery system for improving the titration of propofol during general anesthesia (Kwan, 1989, Singh, 1999).

Infusions of subanesthetic doses of propofol have been used to sedate patients for surgery under regional anesthesia, in diagnostic centers for sedation during gastroenterology and pulmonary medicine procedures, as well as in critical care areas for sedation of ventilatordependent patients as an alternative to benzodiazepines and/or opioid analgesics (Mazurek, 2004).

Propofol is extensively bound to plasma proteins; approximately 97-98% is bound to albumin. After intravenous injection the plasma concentration of propofol decline. The initial fall is extremely rapid (half life 1-3 min), reflecting the distribution of the lipid soluble drug from plasma to tissue.

Approximately 70% of a dose is excreted in the urine within 24 hours after administration, and 90% is excreted within 5 days. Clearance of propofol ranges from 1.6 to 3.4 liters per minute in

first analgesic request, and consumption of supplementary analgesics between the treatment

Quantitative analyses of combined data were intended by calculation of the number of patients reporting any pain or no pain (pain response rate) between treatment groups. Each trial was assessed for different measures of internal sensitivity. First, trials were checked for magnitude of pain intensity. Because it is difficult to detect an improvement with low or no pain, it was noted that pain scores were less than 30 mm on a visual analog scale (VAS) or less than moderate pain on a verbal rating scale or similar score. Second, it was noted that a power calculation of the statistical tests was performed. Trials with sample

Meta-analyses were carried out by direct comparisons of intervention versus control and indirect comparisons between the networks of interventions shown to be significant

Propofol (2,6-diisopropyl phenol) is chemically inert phenolic compound with anesthetic properties. It has high lipid solubility, but is almost insoluble in water. The original preparation contained the solubilizing agent Ctenophore EL (polyethoxylated Castrol oil). Reformulation of the drug in an egg-oil-glycerol emulsion has eliminated hypersensitivity reactions that occurred with the original formulation (Sebel, 1989). The dose of propofol required to induce anesthesia measured by loss of eyelash reflex in 95% of healthy unpremedicated patients was 1.5-2.5 mg/kg. The range of induction times was 22-125 seconds. The rapid loss of consciousness was realized due to the immediate uptake of the lipid – soluble drug by the central nervous system (CNS).Within several minutes of intravenous administration, the plasma concentration of propofol decreases due to the distribution of the drug throughout the body and its uptake by peripheral tissues. As the plasma concentration falls, propofol diffuses from the CNS into the systemic circulation; when bolus doses of the anesthetic are used to induce anesthesia, there is a rapid recovery of full consciousness and awareness. These advantageous properties have contributed to the popularity of propofol as

Propofol is also indicated for the maintenance of anesthesia computer-assisted continuous infusion and target-controlled infusion of propofol using a monitor of the hypnotic effects of propofol on the brain electroencephalographic Bispectral Index [BIS] monitor; it is possible to create a closed-loop delivery system for improving the titration of propofol during

Infusions of subanesthetic doses of propofol have been used to sedate patients for surgery under regional anesthesia, in diagnostic centers for sedation during gastroenterology and pulmonary medicine procedures, as well as in critical care areas for sedation of ventilatordependent patients as an alternative to benzodiazepines and/or opioid analgesics

Propofol is extensively bound to plasma proteins; approximately 97-98% is bound to albumin. After intravenous injection the plasma concentration of propofol decline. The initial fall is extremely rapid (half life 1-3 min), reflecting the distribution of the lipid -

Approximately 70% of a dose is excreted in the urine within 24 hours after administration, and 90% is excreted within 5 days. Clearance of propofol ranges from 1.6 to 3.4 liters per minute in

groups, and by assessment of the clinical importance of observed differences.

sizes less than 10 patients per treatment group were not considered in the study.

an induction agent for short procedures and day – case surgery (Short, 1999).

general anesthesia (Kwan, 1989, Singh, 1999).

soluble drug from plasma to tissue.

individually.

**2. Propofol** 

(Mazurek, 2004).

decrease. Clearance rates ranging from 1.4 to 2.2 liters per minute in patients 18 to 35 years of age have been reported, in contrast to clearance rates of 1 to 1.8 liters per minute in patients 65 to 80 years of age. The propofol mean total body clearance rate was 2.09 +/- 0.65 1/min (mean SD), the volume of distribution at steady state was 159 +/- 57 I, and the elimination half-life was 116 +/- 34 min. Elderly patients (patients older than 60 yr ) had significantly decreased clearance rates (1.58 +/- 0.42 vs. 2.19 +/- 0.64 1/min), whereas women (vs. men) had greater clearance rates (33 +/- 8 vs. 26 +/- 7 1 kg-1 min-1) and volumes of distribution (2.50 +/- 0.81 vs. 2.05 +/- 0.65 1/kg). Patients undergoing major intraabdominal surgery had longer elimination half-life values (136 +/- 40 vs. 108 +/- 29 min). Patients required an average blood propofol concentration of 4.05 +/- 1.01 µg/ml for major surgery and 2.97 +/- 1.07 g/ml for nonmajor surgery. Blood propofol concentrations at which 50% of patients were awake and oriented after surgery were 1.07 and 0.95 µg/ml, respectively. The metabolic clearance of propofol exceeds hepatic blood flow, which has leaded to suggestion that propofol is also metabolized in extrahepatic sites. Approximately 70% of a dose is excreted in the urine within 24 hours after administration, and 90% is excreted within 5 days. Psychomotor performance returned to baseline at blood propofol concentrations of 0.38-0.43 g/ml (Shafer et al., 1988, White, 1989, Deegan, 1992; Zuppa et al., 2003).

Propofol causes a significant reduction in systemic blood pressure (more than 50% of preoperative level). This increase in blood pressure is a result of decrease in systemic vascular resistance. In addition to arterial vasodilatation, propofol produces venodilation (due both to a reduction in sympathetic activity and to a direct effect on the vascular smooth muscle), which contributes to its hypotensive effect. The fall in cardiac output is manifested with decrease in heart rate. (Machała & Szebla, 2008; Frolich, 2011).

Respiratory depression and apnea are more pronounced with propofol than thiopental. Propofol decreases tidal volume and increases respiratory rate. The ventilatory response to carbon dioxide and hypoxia is also significantly decreased, but propofol does not inhibit hypoxic pulmonary vasoconstriction. Propofol can produce bronchodilation in patients with chronic obstructive pulmonary disease and in patients with acute laryngospasm during emergence from anesthesia (Zeller et al., 2005).

Propofol decreases CMRO2 and CBF, as well as ICP.33 However, when larger doses are administered, the marked depressant effect on systemic arterial pressure can significantly decrease CPP. Cerebrovascular autoregulation in response to changes in systemic arterial pressure and reactivity of the cerebral blood flow to changes in carbon dioxide tension are not affected by propofol. Evidence for a possible neuroprotective effect has been reported in vitro preparations, and the use of propofol to produce EEG burst suppression has been proposed as a method for providing neuroprotection during aneurysm surgery. Its neuroprotective effect may at least partially be related to the antioxidant potential of propofol's phenol ring structure, which may act as a free-radical scavenger, decreasing free-radical induced lipid peroxidation. Recent studies reported that this antioxidant activity may offer many advantages in preventing the hypoperfusion/reperfusion phenomenon that can occur during surgery (Dagal & Lam, 2009; Girard et al., 2009; Ozturk et al., 2009; Menku et al., 2010).

Propofol produces cortical EEG changes that are similar to thiopental. However, sedative doses of propofol increase â-wave activity analogous to the benzodiazepines. Induction of anesthesia with propofol is occasionally accompanied by excitatory motor activity (so-called nonepileptic myoclonia). In a study involving patients without a history of seizure disorders, excitatory movements following propofol were not associated with EEG seizure activity.

Propofol and Postoperative Pain: Systematic Review and Meta-Analysis 227

to be due to decreased transmembrane electrical potential and alteration of electron transport across the inner mitochondrial membrane. And, of course pain during injection of

Finally, the favorable pharmacokinetic properties, like short half-life and high clearance rate, minimal side effects and other nonhypnotic positive effects make it safe and usefull in

General anesthetics and propofol modulate the function of the gama (γ)-aminobutyric acid (GABA)A receptors, the inhibitory neurotransmitter receptors in the central nervous system. GABA is the major inhibitory neurotransmitter in the central nervous system, with fast synaptic inhibition mediated by postsynaptic GABAA receptors. GABAA receptors are members of the superfamily of ligand-gated ion channels and are thought to consist of five subunits (α, β, and γ). The GABA-induced chloride current can be potentiated by some general anesthetics. The actions of propofol appear to be mediated by β3-containing GABAA receptors. Specific residue is located within the second transmembrane region of the β3 subunit of the GABAA receptor and has a influence in determining the action of propofol

The hypnotic effect of propofol and probably analgesic effect is related to GABA accumulation and occupation of the GABA receptor. Occupation of receptors produced hyperpolarisation of the postsynaptic cell membrane and neuronal inhibition. Propofol at low concentration enhance the amplitude of response of GABA and prolong the duration of GABA mediated synaptic inhibition. At supraclinical concentrations propofol directly

The analgesic effect of propofol may result as it acts at GABAA receptors (Dong & Xu, 2002). On the other hand, propofol induced potentiation of glycin receptors at the spinal level and might contribute to its antinociceptive actions and general anesthesia (Xu et al., 2004). Spinal (NMDA) receptors were reported to be involved in the antinociceptive action of propofol. Prolonged firing of C-fiber nociceptors causes release of glutamate which acts on N-methyl-D-aspartate (NMDA) receptors in the spinal cord. Activation of NMDA receptors causes the spinal cord neuron to become more responsive to all of its inputs, resulting in central sensitization. NMDA-receptor antagonists can suppress central sensitization. NMDA-receptor activation not only increases the cell's response to pain stimuli, it also decreases neuronal sensitivity to opioid receptor agonists. In addition to preventing central sensitization, co-administration of NMDA-receptor antagonists with an opioid may prevent tolerance to opioid analgesia. Was reported that intrathecal administration of an NMDA receptor agonist inhibited the antinociceptive effect of propofol; in contrast, an NMDA receptor antagonist enhanced the antinociceptive action of propofol (Cheng et al., 2008). These studies demonstrated that propofol has a synergistic action with several nociceptive

transmission cascades including amino acid and opioid systems in the spinal cord.

The above mentioned methods determined the probable way of analgesic action of propofol.

We followed the PRIZMA statement that recommends standards to improve the quality of

propofol which could prevent in several ways (Jalota et al., 2011).

clinical practice.

**3. Analgesic effects of propofol** 

(Krasowski et. Al., 1998; Siegwart et al. 2002).

activate the receptors anion channel.

**4. Methods** 

reporting of meta-analyses.

Propofol appears to possess profound anticonvulsant properties. Propofol has been reported to decrease spike activity in patients with cortical electrodes implanted for resection of epileptogenic foci and has been used successfully to terminate status epilepticus. The duration of motor and EEG seizure activity following electroconvulsive therapy is significantly shorter with propofol than with other IV anesthetics. Propofol produces a decrease in the early components of somatosensory and motor evoked potentials but does not influence the early components of the auditory evoked potentials (Modica et al., 1990).

There is no evidence to suggest that propofol has any significant effects on renal or hepatic function.

Propofol is known to possess direct antiemetic effects. Its use for induction and maintenance of anesthesia has been shown to be associated with a lower incidence of postoperative nausea and vomiting (PONV) when compared to any other anesthetic drug or technique. The precise mechanism of propofol antiemetic effect of propofol has not been elucidated, several mechanisms have been proposed, including a direct depressant effect on the chemoreceptor trigger zone (CTZ), the vagal nuclei, and other centers implicated in PONV (Becker, 2010). A systematic review of PONV following maintenance of anesthesia with propofol or an inhalational anesthetic agent found that patients receiving propofol had a significantly lower frequency of PONV, regardless of induction agent, choice of inhalational agent, use of nitrous oxide, patient age, or use of an opioid (Soppitt et al., 2000). Another systematic review found that propofol may be effective in reducing PONV in the short term, but only when given as a continuous infusion for maintenance of anesthesia and when the PONV event rate is greater than 20% (Eberhart et al., 2006). There is evidence of a relationship between plasma propofol concentration and antiemetic efficacy. Gan et al., 1999, found that a median plasma propofol concentration of 343 ng/mL was associated with a reduction in PV in surgical patients. After a typical induction dose, plasma propofol levels remain above this antiemetic serum concentration threshold for approximately 30 minutes. Therefore, the common practice of selecting propofol for inducing anesthesia because of its antiemetic effects provides little benefit to a patient in terms of reducing the likelihood that the patient will develop PONV during the stay in the postanesthesia care unit and after discharge from the ambulatory surgery center.

Anticonvulsant effect of propofol is always described (Simpson et al., 1988). Theoretically, propofol should be strongly anticonvulsant, as it exhibits both GABAergic effects and persistent sodium current and calcium current blockade. However, a literature search of propofol associated tonic-clonic seizures retrieved more than 500 case reports, of which 81 were analyzed in more detail. The denominator is missing from these case reports, and hence the true incidence is unknown. Among the 172,592 anesthetics analyzed there were 53 generalized convulsions, of which 16 were thought to be primarily due to anesthesia. Fifteen of these cases were attributed to local anesthetic drug error, anti-epileptic drug withdrawal or cerebral anoxia/hypercarbia. This left a single case where the seizure was thought to be due to the anesthetic, propofol, an incidence of 1 per 172,592 anesthetics (Fredman et al, 1994).

Propofol has a remarkable safety profile (Sarani B, Gracias, 2008). Dose dependent hypotension is the commonest complication; particularly in volume depleted patients. Hypertriglyceridemia and pancreatitis are uncommon complications. Allergic complications, which may include bronchospasm, have been reported. High dose propofol infusions have been associated with the "propofol syndrome"; this is a potentially fatal complication characterized by severe metabolic acidosis and circulatory collapse (Murdoch &, Cohen, 1999). This is a rare complication first reported in pediatric patients and believed to be due to decreased transmembrane electrical potential and alteration of electron transport across the inner mitochondrial membrane. And, of course pain during injection of propofol which could prevent in several ways (Jalota et al., 2011).

Finally, the favorable pharmacokinetic properties, like short half-life and high clearance rate, minimal side effects and other nonhypnotic positive effects make it safe and usefull in clinical practice.

#### **3. Analgesic effects of propofol**

226 Pain Management – Current Issues and Opinions

Propofol appears to possess profound anticonvulsant properties. Propofol has been reported to decrease spike activity in patients with cortical electrodes implanted for resection of epileptogenic foci and has been used successfully to terminate status epilepticus. The duration of motor and EEG seizure activity following electroconvulsive therapy is significantly shorter with propofol than with other IV anesthetics. Propofol produces a decrease in the early components of somatosensory and motor evoked potentials but does not influence the early

There is no evidence to suggest that propofol has any significant effects on renal or hepatic

Propofol is known to possess direct antiemetic effects. Its use for induction and maintenance of anesthesia has been shown to be associated with a lower incidence of postoperative nausea and vomiting (PONV) when compared to any other anesthetic drug or technique. The precise mechanism of propofol antiemetic effect of propofol has not been elucidated, several mechanisms have been proposed, including a direct depressant effect on the chemoreceptor trigger zone (CTZ), the vagal nuclei, and other centers implicated in PONV (Becker, 2010). A systematic review of PONV following maintenance of anesthesia with propofol or an inhalational anesthetic agent found that patients receiving propofol had a significantly lower frequency of PONV, regardless of induction agent, choice of inhalational agent, use of nitrous oxide, patient age, or use of an opioid (Soppitt et al., 2000). Another systematic review found that propofol may be effective in reducing PONV in the short term, but only when given as a continuous infusion for maintenance of anesthesia and when the PONV event rate is greater than 20% (Eberhart et al., 2006). There is evidence of a relationship between plasma propofol concentration and antiemetic efficacy. Gan et al., 1999, found that a median plasma propofol concentration of 343 ng/mL was associated with a reduction in PV in surgical patients. After a typical induction dose, plasma propofol levels remain above this antiemetic serum concentration threshold for approximately 30 minutes. Therefore, the common practice of selecting propofol for inducing anesthesia because of its antiemetic effects provides little benefit to a patient in terms of reducing the likelihood that the patient will develop PONV during the stay in the postanesthesia care unit and after

Anticonvulsant effect of propofol is always described (Simpson et al., 1988). Theoretically, propofol should be strongly anticonvulsant, as it exhibits both GABAergic effects and persistent sodium current and calcium current blockade. However, a literature search of propofol associated tonic-clonic seizures retrieved more than 500 case reports, of which 81 were analyzed in more detail. The denominator is missing from these case reports, and hence the true incidence is unknown. Among the 172,592 anesthetics analyzed there were 53 generalized convulsions, of which 16 were thought to be primarily due to anesthesia. Fifteen of these cases were attributed to local anesthetic drug error, anti-epileptic drug withdrawal or cerebral anoxia/hypercarbia. This left a single case where the seizure was thought to be due to

the anesthetic, propofol, an incidence of 1 per 172,592 anesthetics (Fredman et al, 1994).

Propofol has a remarkable safety profile (Sarani B, Gracias, 2008). Dose dependent hypotension is the commonest complication; particularly in volume depleted patients. Hypertriglyceridemia and pancreatitis are uncommon complications. Allergic complications, which may include bronchospasm, have been reported. High dose propofol infusions have been associated with the "propofol syndrome"; this is a potentially fatal complication characterized by severe metabolic acidosis and circulatory collapse (Murdoch &, Cohen, 1999). This is a rare complication first reported in pediatric patients and believed

components of the auditory evoked potentials (Modica et al., 1990).

discharge from the ambulatory surgery center.

function.

General anesthetics and propofol modulate the function of the gama (γ)-aminobutyric acid (GABA)A receptors, the inhibitory neurotransmitter receptors in the central nervous system. GABA is the major inhibitory neurotransmitter in the central nervous system, with fast synaptic inhibition mediated by postsynaptic GABAA receptors. GABAA receptors are members of the superfamily of ligand-gated ion channels and are thought to consist of five subunits (α, β, and γ). The GABA-induced chloride current can be potentiated by some general anesthetics. The actions of propofol appear to be mediated by β3-containing GABAA receptors. Specific residue is located within the second transmembrane region of the β3 subunit of the GABAA receptor and has a influence in determining the action of propofol (Krasowski et. Al., 1998; Siegwart et al. 2002).

The hypnotic effect of propofol and probably analgesic effect is related to GABA accumulation and occupation of the GABA receptor. Occupation of receptors produced hyperpolarisation of the postsynaptic cell membrane and neuronal inhibition. Propofol at low concentration enhance the amplitude of response of GABA and prolong the duration of GABA mediated synaptic inhibition. At supraclinical concentrations propofol directly activate the receptors anion channel.

The analgesic effect of propofol may result as it acts at GABAA receptors (Dong & Xu, 2002). On the other hand, propofol induced potentiation of glycin receptors at the spinal level and might contribute to its antinociceptive actions and general anesthesia (Xu et al., 2004).

Spinal (NMDA) receptors were reported to be involved in the antinociceptive action of propofol. Prolonged firing of C-fiber nociceptors causes release of glutamate which acts on N-methyl-D-aspartate (NMDA) receptors in the spinal cord. Activation of NMDA receptors causes the spinal cord neuron to become more responsive to all of its inputs, resulting in central sensitization. NMDA-receptor antagonists can suppress central sensitization. NMDA-receptor activation not only increases the cell's response to pain stimuli, it also decreases neuronal sensitivity to opioid receptor agonists. In addition to preventing central sensitization, co-administration of NMDA-receptor antagonists with an opioid may prevent tolerance to opioid analgesia. Was reported that intrathecal administration of an NMDA receptor agonist inhibited the antinociceptive effect of propofol; in contrast, an NMDA receptor antagonist enhanced the antinociceptive action of propofol (Cheng et al., 2008). These studies demonstrated that propofol has a synergistic action with several nociceptive transmission cascades including amino acid and opioid systems in the spinal cord.

The above mentioned methods determined the probable way of analgesic action of propofol.

#### **4. Methods**

We followed the PRIZMA statement that recommends standards to improve the quality of reporting of meta-analyses.

Propofol and Postoperative Pain: Systematic Review and Meta-Analysis 229

double-blinding was not a requirement, because adequate blinding was not felt to be possible in most studies. Each study was evaluated independently by authors and

Selected studies included 25 randomised controlled trials that compared the use propofol during anesthesia and any drug or non-drug intervention, or a combination, with an active or inactive control, and reported the response rate and severity of pain after propofol anesthesia.

**VALIDITY SCORE (0-7)** 

2Described and adequate 2 Described and adequate

1 Yes 1 Described but incomplete 2 Described and adequate

Selected studies included 25 randomised controlled trials that compared the use propofol during anesthesia and any drug or non-drug intervention, or a combination, with an active or inactive control, and reported the response rate and severity of pain after propofol anesthesia. The studies included in this review enrolled 1970, male and female patients, 1 to 80 year old, ASA I-III, who underwent surgical or non-surgical treatment resulting in the need for acute pain control. Relevant pain outcomes included number of patients who express pain, pain intensity, time to first analgesic request and supplemental analgesic demand were noted. All included studies had numerical data presented in the text or a table; if data were not presented as such, we extracted the information from the graphs if the scale allowed a

We excluded trials including less than 10 patients and those reporting on chronic pain. Data

Information on number of patients, anesthetics and type of surgery was obtained from each

The data extracted from each of the included trials included: eligibility and exclusion criteria, study design, duration and degree of follow-up, randomization, allocation concealment, blinding, number and characteristics of participants, type of surgery, pain score, time to first analgesic request, and consumption of supplementary analgesics between the propofol and other treatment groups, and by assessment of the side effects

Qualitative analysis of postoperative effectiveness was evaluated by significant difference (*P* < 0.05 as reported in the original investigation) in pain relief using pain scores, time to first analgesic request, and consumption of supplementary analgesics between the treatment

groups, and by assessment of the clinical importance of observed differences.

*Randomisation Double blinding* 

*Concealment of allocation Flow of patients* 

0 None 0 None 1Mentioned 1 Mentioned

0 None 0 None

from animal studies, abstracts, letters or reviews were not considered.

agreement was reached by consensus.

Fig. 2. Modified Oxford Scale

sufficiently precise estimation.

report.

(Table 1, 2 & 3). **Meta analyses** 

#### **Systematic search**

The study was carried out according to the methods recommended by the Cochrane Collaboration and written in accordance with the PRISMA statement for reporting systematic reviews (Higgins et al., 2009 & Liberati et al., 2009).

This systematic review included studies published up to December 2010. We conducted a systemic search of the electronic databasas: PubMed, Cochrane Library, and Embase, www.clinicaltrials.gov, and hand searching from the reference lists of identified papers. We used the search terms "propofol" and ("postoperative analgesia" OR "analgesic effect"). Abstracts and unpublished studies were not considered. The search was limited to clinical trials and randomised controlled trials. Reference lists from identified studies and journals which appeared to be associated with the most retrieved citations were then hand-searched. The trials in languages other than English were not excluded. We prepared a flow diagram to summarize the study selection process according to PRISMA (Jaded et al., 1996) (Figure 1.)*.* 

To minimize data duplication as a result of multiple reporting we compared papers from the same author. In addition, we searched www.clinicaltrials.gov for studies. Two authors (HJ and AD) screened and retrieved reports and excluded irrelevant studies. Relevant data were extracted by one author (VG) and checked by another (AH).

From each study we extracted details on patients' characteristics (adults and children, ASA status, age), type of surgery or no surgery and use of anesthetics in control group (Table 1.). Pain score, pain score method and use of postoperative analgesics, were also noted (Table 2). Side effects were noted in Table 3.

#### **Study selection**

To be considered for the review, the study was evaluated with regard to randomization method, allocation concealment, details of blinding measures, and withdrawals and dropouts using the modied 7-point 4-item Oxford scale (Figure 2) (Dong et al., 2002). This meant that adequate randomization was an absolute requirement for selection. However, double-blinding was not a requirement, because adequate blinding was not felt to be possible in most studies. Each study was evaluated independently by authors and agreement was reached by consensus.

Selected studies included 25 randomised controlled trials that compared the use propofol during anesthesia and any drug or non-drug intervention, or a combination, with an active or inactive control, and reported the response rate and severity of pain after propofol anesthesia.


Fig. 2. Modified Oxford Scale

228 Pain Management – Current Issues and Opinions

The study was carried out according to the methods recommended by the Cochrane Collaboration and written in accordance with the PRISMA statement for reporting

This systematic review included studies published up to December 2010. We conducted a systemic search of the electronic databasas: PubMed, Cochrane Library, and Embase, www.clinicaltrials.gov, and hand searching from the reference lists of identified papers. We used the search terms "propofol" and ("postoperative analgesia" OR "analgesic effect"). Abstracts and unpublished studies were not considered. The search was limited to clinical trials and randomised controlled trials. Reference lists from identified studies and journals which appeared to be associated with the most retrieved citations were then hand-searched. The trials in languages other than English were not excluded. We prepared a flow diagram to summarize the study selection process according to PRISMA (Jaded et al., 1996) (Figure 1.)*.* 

systematic reviews (Higgins et al., 2009 & Liberati et al., 2009).

561 potentially relevant references identified and screened

Excluded by

(330)

(182)

25 articles with usable informations included in this meta-analysis

were extracted by one author (VG) and checked by another (AH).

Side effects were noted in Table 3.

**Study selection** 

Other (24)

review of the abstract

 Other topic, animal Studies, review

Fig. 1. Flow diagram of excluded and included studies according to PRIZMA statement

To minimize data duplication as a result of multiple reporting we compared papers from the same author. In addition, we searched www.clinicaltrials.gov for studies. Two authors (HJ and AD) screened and retrieved reports and excluded irrelevant studies. Relevant data

From each study we extracted details on patients' characteristics (adults and children, ASA status, age), type of surgery or no surgery and use of anesthetics in control group (Table 1.). Pain score, pain score method and use of postoperative analgesics, were also noted (Table 2).

To be considered for the review, the study was evaluated with regard to randomization method, allocation concealment, details of blinding measures, and withdrawals and dropouts using the modied 7-point 4-item Oxford scale (Figure 2) (Dong et al., 2002). This meant that adequate randomization was an absolute requirement for selection. However,

**Systematic search** 

Selected studies included 25 randomised controlled trials that compared the use propofol during anesthesia and any drug or non-drug intervention, or a combination, with an active or inactive control, and reported the response rate and severity of pain after propofol anesthesia.

The studies included in this review enrolled 1970, male and female patients, 1 to 80 year old, ASA I-III, who underwent surgical or non-surgical treatment resulting in the need for acute pain control. Relevant pain outcomes included number of patients who express pain, pain intensity, time to first analgesic request and supplemental analgesic demand were noted. All included studies had numerical data presented in the text or a table; if data were not presented as such, we extracted the information from the graphs if the scale allowed a sufficiently precise estimation.

We excluded trials including less than 10 patients and those reporting on chronic pain. Data from animal studies, abstracts, letters or reviews were not considered.

Information on number of patients, anesthetics and type of surgery was obtained from each report.

The data extracted from each of the included trials included: eligibility and exclusion criteria, study design, duration and degree of follow-up, randomization, allocation concealment, blinding, number and characteristics of participants, type of surgery, pain score, time to first analgesic request, and consumption of supplementary analgesics between the propofol and other treatment groups, and by assessment of the side effects (Table 1, 2 & 3).

#### **Meta analyses**

Qualitative analysis of postoperative effectiveness was evaluated by significant difference (*P* < 0.05 as reported in the original investigation) in pain relief using pain scores, time to first analgesic request, and consumption of supplementary analgesics between the treatment groups, and by assessment of the clinical importance of observed differences.

Propofol and Postoperative Pain: Systematic Review and Meta-Analysis 231

<sup>1988</sup>NE NE p>0.05 p>0.05

<sup>1990</sup>VAS P<0.05 p>0.05 p>0.05

<sup>1991</sup>laser power meter NS NE NE

<sup>1991</sup>VAS NS NS NS

<sup>1994</sup>VAS P<0.05 NS NS

<sup>1995</sup>VAS NS NS NS

<sup>1996</sup>VAS NS NE NE

<sup>1996</sup>VAS NS NS NS

<sup>1966</sup>VAS P<0.05 NE NE

<sup>1997</sup>OPDS NS NS NS

<sup>1998</sup>VAS P<0.05 for Iso P<0.05 for Iso P<0.05 for Iso

<sup>2001</sup>VAS P<0.05 P<0.05 P<0.05

<sup>2001</sup>NRS NE P<0.05 P<0.05

<sup>2003</sup>VAS P<0.05 P<0.05 P<0.05

<sup>2003</sup>VAS NS NS NS

<sup>2003</sup>VNRS NS NS NS

<sup>2008</sup>NAS p<0.01 p<0.01 p<0.01

<sup>2008</sup>VAS NS NS NS

<sup>2009</sup>FPS NS NE NE

<sup>2010</sup>NRS P<0.05 NE NE

<sup>2010</sup>VAS P=0.01 NS NS

<sup>2010</sup>CHEOPS P<0.05 P<0.05 P<0.05

<sup>2010</sup>VAS P> 0.001 P> 0.001 P> 0.001 NS - no significant difference between treatment groups or no significant difference in favor of the treatment; *P*<0.05 - significant difference between treatment groups in favor of the treatment; NE - not evaluated.

2005 VAS P<0.05 more pain with

**Time to First Analgesic Request**

P<0.001 NE NE

propofol NE NE

**Supplemental Analgesic Demand** 

**References Pain Score Method Pain Score** 

tibial pressure algesimetry

Briggs et al. 1982

Doze et al.

Borgeat et al.

Anker-Møller et al.

Van Hemelrijck etal.

Petersen-Felix et al.

Hendolin et al.

Jellish et al.

Eriksson et al.

Zacny et al.

Davis et al.

Boccara et al.

Ozkose et al.

Hand et al.

Hofer et al.

Coolong et al

Frölich et al.

Cheng et al.

Hasani et al.

Tan et al.

Pieters et al.

Shin et al.

Fassoulaki et al.

Bandschapp et al.

Table 2. Details of study included.

Mukherjee et al.


VS-Validity Score (Modified Oxford Scale)

NS - no significant difference between treatment groups or no significant difference in favor of the treatment; P< 0.05 - significant difference between treatment groups in favor of the treatment; NE - not evaluated.

Table 1. Details of study included.

<sup>1982</sup>3 Propofol Thiopentone 40 Gynecologic procedures

<sup>1988</sup>4 Propofol thiopental/isoflurane 120 Abdominal surgery

<sup>1990</sup>4 Propofol thiopental/halothane 40 ENT surgery

et al. 1991 4 Propofol desflurane 92 gynecological

<sup>1994</sup>5 Propofol thiopental/isoflurane 41 uvuloplasty

1996 5 desflurane propofol 90 gynecological

<sup>1966</sup>3 propofol fentanyl 12 ice-cold water

1998 5 propofol isoflurane 40 cosmetic

2001 6 Propofol,/fentanyl sevoflurane/isofl &

remifentanyl

al. 2003 6 propofol,fentanyl,

2010 7 propofol &

Table 1. Details of study included.

VS-Validity Score (Modified Oxford Scale)

<sup>1997</sup>5 reifentanil alfentanil/isofl/prop 129 strabismus surgery

<sup>2001</sup>3 propofol intralipids 48 tourniquet pain

2003 7 propofol sevoflurane 305 gynaecologic or

<sup>2005</sup>4 propofol placebo 80 thermal pain

<sup>2003</sup>4 propofol thiopental 84 laparascopic procedures

<sup>2008</sup>7 propofol isoflurane 80 open uterine surgery

<sup>2009</sup>5 propofol halothane 83 abdominal surgery

al. 2010 7 propofol intralipid/saline 14 electrical stimulation

<sup>2010</sup>7 propofol sevoflurane 42 adenotonsillectomy

sevoflurane and

NS - no significant difference between treatment groups or no significant difference in favor of the treatment; P< 0.05 - significant difference between treatment groups in favor of the treatment; NE - not evaluated.

2010 6 propofol sevoflurane 80 gynecological

al. 2008 7 sevofl/desfl propofol 105 gynecological operations

et al. 1991 4 Propofol thiopental/saline 19 laser stimulation

<sup>1995</sup>5 Propofol thiopental/isoflurane 102 middle ear surgery

et al. 1996 2 Propofol alfentanyl 12 electric/laser/acoustical

**Patients Type of Intervention** 

laparascopy

stimulation

laparascopy

abdominoplasty

discectomy operations

orthopedic procedures

laparascopic

alfentanyl <sup>60</sup>laminectomy and

remifentanyl 214 brest cancer surgery

isoflurane pr, remifentanil 100 middle ear surgery

**Reference VS Treatment Control No. of** 

Briggs et al.

Doze et al.

Borgeat et al.

Anker-Møller

V Hemelrijck

Hendolin et al.

Jellish et al.

Petersen-Felix

Eriksson et al.

Zacny et al.

Davis et al.

Boccara et al.

Ozkose et al.

Hand et al.

Mukherjee et

Hofer et al.

Coolong et al

Frölich et al.

Cheng et al.

Fassoulaki et

Hasani et al.

Tan et al.

Pieters et al.

Shin et al.

Bandschapp et


NS - no significant difference between treatment groups or no significant difference in favor of the treatment; *P*<0.05 - significant difference between treatment groups in favor of the treatment; NE - not evaluated.

Table 2. Details of study included.

Propofol and Postoperative Pain: Systematic Review and Meta-Analysis 233

The data of 25 randomized controlled studies were included in the present meta-analysis (Table 1,2 &3). A total of 1970 patients (909 with propofol), male and female were included. The patients were 1-85 year old. The 294 patients were children, aged 1-18 year (Borgeat et al.,1990, Pieters et al., 2010, Davis et al., 1997 & Hasani et al., 2009). The participans undergoing brest, ginecologic, orthopedic, ENT, abdominal, urogenital, spine, cosmetic or eye surgery. In 7 studies the participants were volunteer and have no surgery (total 163 volunteers) (Briggs et al., 1982, Anker-Møller et al., 1991, Zacny et al., 1996, Petersen-Felix et al., 1996, Hand et al., 2001, Frolich et al., 2005 & Bandschapp et al.

The participants were randomly assigned to receive propofol and in control group: thiopental (Briggs et al.,1982 & Coolong et al.,2003); thiopental and saline (Anker-Møller et al., 1991); thiopental with halothane (Borgeat et al.,1990); or, thiopenthal with isoflurane (Doze et al., 1988 , Hendolin et al.,1994 & Jellish et al.,1995). In control grup the inhalation anesthetics used were halothane (Hasani et al., 2009), isoflurane (Boccara et al., 1998& Cheng et al.,2008), sevoflurane (Ozkose et al.,2001, Hofer et al., 2003, Tan et al., 2010, Pieters et al., 2010 & Shin et al., 2010) and desflurane (Van Hemelrijck et al.,1991&Fassoulaki et al., 2010). Also, the control groups contained opioids: fentanyl, remifentanil (Davis et al., 1997, Mukherjee et al., 2003 & Shin et al., 2010) and alfentanil (Petersen-Felix et al., 1996& Davis et

Intensity of pain scores was considered adequate (>30 mm VAS) in all trials. VAS (visual analogue score) pain score was not present in 9 studies. The pain scores used in studies was NRS-numeric rating scale (Hand et al., 2001&Bandschapp et al. ,2010), NAS-Numerical analogue score (Cheng et al., 2008), CHEOPS-Children's Hospital of Eastern Ontario Scale (Pieters et al., 2010), tibial pressure algesimetry (Briggs et al., 1982), VNSRverbal numeric rating scale (Coolong et al., 2003), laser power meter (Anker-Møller et al., 1991), FPS- faces pain scale (Hasani et al., 2009) and OPDS-Objective Pain Discomfort

> **Favours interventions**

**Favours control**

**Weight %** 6.2 16.1 6.1 5.7 14.5 5.4 15 7.9 10.8 12.3 100.0

,2010).

al., 1997).

**Pain**

Scale (Davis et al., 1997).

Briggs (1982 1 20 12 20 Doze (1988) 30 60 34 60 Borgeat (1990) 1 20 9 20 Anker-Møller (1991) 1 12 6 7 Van Hemelrijck (1991) 15 46 17 46 Hendolin (1994) 1 21 3 20 Jellish (1995) 14 34 34 68 Eriksson (1996) 2 29 4 58 Davis (1997) 6 20 5 109 Mukherjee (2003) 5 44 17 48

**nNnN**

Fig. 3. Risk of postoperative pain after propofol anesthesia.

**Propofol Control**

I² 64% (95% CI = 10.7% to 80.1%)

Cochran Q = 25.00 (df = 9) P = 0.003


NS - no significant difference between treatment groups or no significant difference in favor of the treatment;

*P*<0.05 - significant difference between treatment groups in favor of the treatment; NE - not evaluated.

Table 3. Details of study included (side effects).

Quantitative analyses of combined data were intended by calculation of the number of patients reporting any pain or no pain (pain response rate) between treatment groups. For studies with multiple intervention groups, we partitioned the count of events and patients in the control group into two or more control groups within any meta-analysis to avoid a unit of analysis error. For the studies participating in the indirect comparisons, we partitioned the comparator group according to how many times it was used for indirect comparisons (across meta-analyses). The summary relative risks and 95% confidence intervals were estimated using a random effects Mantel-Haenszel method in RevMan 5.0 (Cochrane Collaboration). Statistical heterogeneity was assessed by the I2 value.

The weight given to each study in this analysis (*i.e.*, how much influence each study had on the overall results) was determined by the precision of its estimate by taking into account study size and SDs of the pain in the individual trials. For the current use, a mean for each treatment group was calculated in every trial from all available recordings performed after anesthesia with propofol. Verbal rating pain scores and similar scores were converted to VAS pain scores (*e.g.*, a four-point verbal rating score including no, light, moderate, and severe pain was converted to 0, 25, 50, and 75 mm VAS, respectively).

#### **5. Results**

The systematic search in the databases identified 561 relevant articles. After screening, 25 studies potentially met the inclusion criteria. The full-text publications of these studies were examined in more detail. Four study was excluded, because it was reviews or editorial articles. In 90 studies the subject of investigation were animals and also were excluded. (Fig. 1).

**Study Propofol Control** *P* **Propofol Control** *P* **Propofol Control** *P* 

Doze 1988 1/ 60 8 /60 P<0.05 3/ 60 16/60 P<0.05 10 në 60 34/60 P<0.05 Borgeat 1990 0/20 2/20 NS 0/20 2 në 20 NE 16/20 20/20 P<0.05 Vhemelrijck 1991 P<0.05 P<0.05 9/46 46/46 P<0.05 Hendolin 1994 0/20 2/21 NS 0/20 1/21 2 /21 2 /21 NS

Eriksson 1996 NS NS NS Davis 1997 6/20 32/57 P<0.05 0/20 23/57 P<0.05 Boccara 1998 5/ 20 12/ 20 P<0.05 NS

Mukherjee 2003 NS NS NS

Coolong 2003 NS NS NS Cheng 2008 NS NS NS Hasani 2009 NS NS NS Tan 2010 NS NS NS Pieters 2010 1/19 7/19 P<0.05 1/19 7/19 P<0.05 NS Shin 2010 29/96 40/90 P<0.005 29/ 96 40/90 P<0.005 50/96 42/90 NS NS - no significant difference between treatment groups or no significant difference in favor of the

*P*<0.05 - significant difference between treatment groups in favor of the treatment; NE - not evaluated.

Quantitative analyses of combined data were intended by calculation of the number of patients reporting any pain or no pain (pain response rate) between treatment groups. For studies with multiple intervention groups, we partitioned the count of events and patients in the control group into two or more control groups within any meta-analysis to avoid a unit of analysis error. For the studies participating in the indirect comparisons, we partitioned the comparator group according to how many times it was used for indirect comparisons (across meta-analyses). The summary relative risks and 95% confidence intervals were estimated using a random effects Mantel-Haenszel method in RevMan 5.0

The weight given to each study in this analysis (*i.e.*, how much influence each study had on the overall results) was determined by the precision of its estimate by taking into account study size and SDs of the pain in the individual trials. For the current use, a mean for each treatment group was calculated in every trial from all available recordings performed after anesthesia with propofol. Verbal rating pain scores and similar scores were converted to VAS pain scores (*e.g.*, a four-point verbal rating score including no, light, moderate, and

The systematic search in the databases identified 561 relevant articles. After screening, 25 studies potentially met the inclusion criteria. The full-text publications of these studies were examined in more detail. Four study was excluded, because it was reviews or editorial articles.

In 90 studies the subject of investigation were animals and also were excluded. (Fig. 1).

(Cochrane Collaboration). Statistical heterogeneity was assessed by the I2 value.

severe pain was converted to 0, 25, 50, and 75 mm VAS, respectively).

n/N n/N n/N n/N n/N n/N

**Other side effects** 

**Nauzea Vomiting** 

Jellish 1995 3/34 20/68 P<0.05 5/34 15/68 NS

Ozkose 2001 1 /20 22/40 P<0.05

Hofer 2003 50/155 75/146 P<0.001 34/155 50/146 P<0.01

Table 3. Details of study included (side effects).

treatment;

**5. Results** 

The data of 25 randomized controlled studies were included in the present meta-analysis (Table 1,2 &3). A total of 1970 patients (909 with propofol), male and female were included. The patients were 1-85 year old. The 294 patients were children, aged 1-18 year (Borgeat et al.,1990, Pieters et al., 2010, Davis et al., 1997 & Hasani et al., 2009). The participans undergoing brest, ginecologic, orthopedic, ENT, abdominal, urogenital, spine, cosmetic or eye surgery. In 7 studies the participants were volunteer and have no surgery (total 163 volunteers) (Briggs et al., 1982, Anker-Møller et al., 1991, Zacny et al., 1996, Petersen-Felix et al., 1996, Hand et al., 2001, Frolich et al., 2005 & Bandschapp et al. ,2010).

The participants were randomly assigned to receive propofol and in control group: thiopental (Briggs et al.,1982 & Coolong et al.,2003); thiopental and saline (Anker-Møller et al., 1991); thiopental with halothane (Borgeat et al.,1990); or, thiopenthal with isoflurane (Doze et al., 1988 , Hendolin et al.,1994 & Jellish et al.,1995). In control grup the inhalation anesthetics used were halothane (Hasani et al., 2009), isoflurane (Boccara et al., 1998& Cheng et al.,2008), sevoflurane (Ozkose et al.,2001, Hofer et al., 2003, Tan et al., 2010, Pieters et al., 2010 & Shin et al., 2010) and desflurane (Van Hemelrijck et al.,1991&Fassoulaki et al., 2010). Also, the control groups contained opioids: fentanyl, remifentanil (Davis et al., 1997, Mukherjee et al., 2003 & Shin et al., 2010) and alfentanil (Petersen-Felix et al., 1996& Davis et al., 1997).

Intensity of pain scores was considered adequate (>30 mm VAS) in all trials. VAS (visual analogue score) pain score was not present in 9 studies. The pain scores used in studies was NRS-numeric rating scale (Hand et al., 2001&Bandschapp et al. ,2010), NAS-Numerical analogue score (Cheng et al., 2008), CHEOPS-Children's Hospital of Eastern Ontario Scale (Pieters et al., 2010), tibial pressure algesimetry (Briggs et al., 1982), VNSRverbal numeric rating scale (Coolong et al., 2003), laser power meter (Anker-Møller et al., 1991), FPS- faces pain scale (Hasani et al., 2009) and OPDS-Objective Pain Discomfort Scale (Davis et al., 1997).

Fig. 3. Risk of postoperative pain after propofol anesthesia.

Propofol and Postoperative Pain: Systematic Review and Meta-Analysis 235

The presence of vomiting was analyzed in 9 researches. The risk ratio for vomiting was RR=

0.526 (95% CI 0.371-0.746) in intervention group with propofol (Fig. 5).

**nNnN**

0.46 in intervention group (95% CI 0.21 to 1.02) (Fig. 6).

were evaluated with pro *versus* con debates.

requirements in those anesthetized with isoflurane.

*PRO***: Propofol has analgesic effect** 

**Propofol Control**

**Favours interventions**

Fig. 6. Risk of the other side effects after propofol anesthesia during the postoperative period. The other side effects which occurred in patients anesthetized with propofol were analyzed in 9 researches. In the term "the other side effects" was included: pain during propofol injection in induction period, bradycardia, hypotension, and spontaneous movements also described in perioperative period. Apnea, hypersalivation, laryngospasm and bronchospasm are also included in possible complications in postoperative period. The other side effects were also rare in the propofol anesthesia treated patients with the risk ratio

Is propofol analgesic? ; still remain unclear. Experts held very different opinions on the value and clinical utility of an analgesic effect of propofol. The answers for this question

Discussions about analgesic effect of propofol restarted with the study published in *Anesthesia & Analgesia* in January 2008 by Cheng et al. The trial was based in hypothesis that women scheduled for hysterectomy or myomectomy and anesthetized with volatile anesthesia, isoflurane induces a hyperalgesic state, and that patients anesthetized with propofol was neutral in its modulation of pain sensitivity. They found that patients anesthetized with isoflurane reported more postoperative pain than those anesthetized with propofol. The other finding was the difference in postoperative opioid use with more

Two years later, in 2010 issue of *Anesthesia & Analgesia*, Tan et al. report on a trial that tests the hypothesis that patients undergoing day surgery anesthetized with propofol have less pain and a better quality of recovery compared with patients anesthetized with sevoflurane. In this prospective, double-blind, randomized trial, the authors used a study design in

**Favours control**

**Weight %** 20.9 19.6 20.1 9.5 6.1 23.8 100.0

Cochran Q = 19.58562 (df = 5) P = 0.0015 I² 74.5% (95% CI = 20.8% to 86.9%)

**6. Discussion** 

Doze (41) 10 60 34 60 Borgeat (42) 16 20 20 20 Van Hemelrijck (44) 9 46 46 46 Hendolin (45) 2 21 2 21 Davis (50) 0 20 23 57 Shin (64) 50 96 42 90

**Other side effects**

In selected 25 randomized controlled trials the postoperative pain was evaluated in patients treated with propofol. In 15 of them the degree of pain was given as the mean and, in our research to find risk ratio (Mantel Haenszel, random) we included 10 researches in which pain was expressed as present or absent.

Pain was rarely present in the groups treated with propofol 0.615 (95% CI 0.320-1.181) (Fig. 3).

Fig. 4. Risk of postoperative nauzea after propofol anesthesia.

To study the presence of nausea we analyzed eight researches that have investigated this symptom in postoperative period. Nausea was the rare risk ratio 0.552 in intervention group (95% CI 0.407-0.749) (Fig. 4).

Fig. 5. Risk of postoperative vomiting after propofol anesthesia.

The presence of vomiting was analyzed in 9 researches. The risk ratio for vomiting was RR= 0.526 (95% CI 0.371-0.746) in intervention group with propofol (Fig. 5).

Fig. 6. Risk of the other side effects after propofol anesthesia during the postoperative period.

The other side effects which occurred in patients anesthetized with propofol were analyzed in 9 researches. In the term "the other side effects" was included: pain during propofol injection in induction period, bradycardia, hypotension, and spontaneous movements also described in perioperative period. Apnea, hypersalivation, laryngospasm and bronchospasm are also included in possible complications in postoperative period. The other side effects were also rare in the propofol anesthesia treated patients with the risk ratio 0.46 in intervention group (95% CI 0.21 to 1.02) (Fig. 6).

### **6. Discussion**

234 Pain Management – Current Issues and Opinions

In selected 25 randomized controlled trials the postoperative pain was evaluated in patients treated with propofol. In 15 of them the degree of pain was given as the mean and, in our research to find risk ratio (Mantel Haenszel, random) we included 10 researches in which

Pain was rarely present in the groups treated with propofol 0.615 (95% CI 0.320-1.181) (Fig. 3).

To study the presence of nausea we analyzed eight researches that have investigated this symptom in postoperative period. Nausea was the rare risk ratio 0.552 in intervention group

> **Favours interventions**

Fig. 5. Risk of postoperative vomiting after propofol anesthesia.

**Favours interventions**

Fig. 4. Risk of postoperative nauzea after propofol anesthesia.

nNnN

Propofol Control

95% CI

**Favours control**

> **Favours control**

100.0

**Weight %** 7.0 1.2 1.1 9.4 10.9 2.8 35.6 2.5 29.5 100.0

2.1 1.0 1.0 5.6 6.3 52.0 2.0 30.0

**Weight %**

pain was expressed as present or absent.

n Nn N

Propofol Control

(95% CI 0.407-0.749) (Fig. 4).

Doze (41) 3 60 16 60 Borgeat (42) 0 20 2 20 Hendolin (45) 0 20 1 21 Jellish (46) 5 34 15 68 Davis (50) 6 20 32 57 Ozkose (52) 1 20 22 40 Hofer (55) 34 155 50 146 Pieters (63) 1 19 7 19 Shin (64) 29 96 40 90

**Vomitus**

Cochran Q = 8.77 (df = 8) P = 0.3617

I² 8.8% (95% CI = 0% to 58.3%)

Nausea

Is propofol analgesic? ; still remain unclear. Experts held very different opinions on the value and clinical utility of an analgesic effect of propofol. The answers for this question were evaluated with pro *versus* con debates.

#### *PRO***: Propofol has analgesic effect**

Discussions about analgesic effect of propofol restarted with the study published in *Anesthesia & Analgesia* in January 2008 by Cheng et al. The trial was based in hypothesis that women scheduled for hysterectomy or myomectomy and anesthetized with volatile anesthesia, isoflurane induces a hyperalgesic state, and that patients anesthetized with propofol was neutral in its modulation of pain sensitivity. They found that patients anesthetized with isoflurane reported more postoperative pain than those anesthetized with propofol. The other finding was the difference in postoperative opioid use with more requirements in those anesthetized with isoflurane.

Two years later, in 2010 issue of *Anesthesia & Analgesia*, Tan et al. report on a trial that tests the hypothesis that patients undergoing day surgery anesthetized with propofol have less pain and a better quality of recovery compared with patients anesthetized with sevoflurane. In this prospective, double-blind, randomized trial, the authors used a study design in

Propofol and Postoperative Pain: Systematic Review and Meta-Analysis 237

neuronal "windup" in the spinal cord, a factor associated with persistent pain. The study from Goto et al., 1994, reported that propofol, unlike pentobarbital, had no effect on secondphase nocifensive behavioral responses elicited by formalin injection in the hind paws of rats. Wilder-Smith et al. , 1995, also determined that propofol infusions did not affect

The human studies of interest, (Boccara et al., 1998) compared postoperative pain and analgesic requirements in patients receiving propofol or isoflurane for maintenance of anesthesia and reported that patients receiving propofol actually had increased pain and opioid requirements for the first 6 hours after surgery compared with patients receiving

We conduct a more recent clinical study, published in *Anesthesia & Analgesia* in November 2008, by Fassoulaki et al., in patients undergoing abdominal hysterectomy or myomectomy under sevoflurane, desflurane or propofol anesthesia. Anesthesia was induced with propofol, morphine and cisatracrium; and maintained with sevoflurane or desflurane or propofol. Postoperative analgesia was maintained with morphine. They were unable to demonstrate any difference in postoperative pain scores or in the requirement for opioid analgesic medication among patients maintained with propofol, sevoflurane, or desflurane. Presented data explained the inconsistency between the studies regarding the post-

Postoperative nausea and vomiting (PONV) are unpleasant, often underestimated side effects of anesthesia and surgery, not devoid of medical complications. Prevention with antiemetics is only partially effective. Propofol has been shown recently to possess

The limitation of our analysis is mainly related to the methodological heterogeneity of several studies. The dose of propofol varied between the studies and my influenced the postoperative analgesic effect. The methods of postoperative pain assessment my bias the results of our meta-analyses. On the other hand, the number of analyzed clinical trials may

Our meta-analysis indicates that propofol provides a prolonged and improved postoperative analgesia with few adverse effects compared with an other inhalation and intravenous anaesthetics. However, propofol have improved antiemetic effect. The other

Propofol changed the practice of anesthesia, nevertheless postoperative analgesia with

Finally, we accomplished that propofol is not an analgesic, but many studies have certainly

Anker-Møller, E; Spangsberg, N; Arendt-Nielsen, L; Schultz, P; Kristensen, MS & Bjerring, P.

(1991). Subhypnotic doses of thiopentone and propofol cause analgesia to

side effects are minimal, with exception of pain during injection of propofol.

experimentally induced acute pain*. Br J Anaesth* 66:185-8.

isoflurane. These findings were exactly the opposite of the findings of Cheng et al.

thermal pain thresholds.

operative analgesic effect of propofol.

antiemetic properties in several situations.

ordinary analgesics must be sustained.

demonstrated analgesic properties of propofol.

also bias our results.

**7. Conclusions** 

**8. References** 

Our findings support the analgesic effect of propofol.

which one group had an induction with inhalation of sevoflurane followed by sevoflurane maintenance, whereas the other group had an IV induction with propofol followed by propofol maintenance. The subjects were treated during surgery with alfentanil, paracetamol, and diclofenac for pain and dexamethasone and ondansetron for nausea. Pain was treated after surgery using morphine until visual analog scale score was <4 and then oral oxycodone. The authors found that propofol provided a statistically significant (*P* < 0.01) difference, decrease in postoperative pain. Hendolin et al., 1994, found that propofol significantly reduced pain in the second hour compared with patients receiving isoflurane, corroborating the results of the present study.

The other study published in *Anesthesiology* August 2010 by Bandschapp et al., investigated the pain perception or central sensitization effects of propofol and its solvent (10% Intralipid) in healthy volunteers. They experienced decreased pain, hyperalgesia and allodynia elicited by intra-cutaneous electrical stimulation when they received a targetcontrol infusion of propofol (2µg/ml) compared with controls (the solvent 10% Intralipid and saline). However, the results provide no evidence for a modulatory role of the solvent of propofol (10% Intralipid) in the analgesic and antihyperalgesic properties of propofol.

Propofol reduced pain by 40% and nearly abolished hypersensitivity which disappears on discontinuation of the drug. The EC50 for the analgesic effect of propofol was 3.2 µg/ml.

There is animal literature that addresses the modulatory effects of anesthetics in different nociceptive models.

In the 1990s, Ewen et al., found that in rats an IV infusion of propofol resulted in an initial decline followed by a rise in nociceptive threshold as the plasma concentration and degree of sedation increased. They suggest that smaller concentrations of propofol than sedative doses are responsible for hyperalgesia. However, the similar experiments in a postoperative pain models in mice were unable to detect any hyperalgesic phase at lower than sedative doses of propofol or on emergence (Udesky et al., 2005). Other groups have found an analgesic response to propofol, particularly in inflammatory pain models (Daniels&Roberts, 1998). A study in rodents by Guindon et al., 2007, demonstrated that in a test of inflammatory pain, locally injected propofol decreased pain behavior in a dose-dependent manner. The authors hypothesized that this antinociceptive activity was mediated, in part, by cannabinoid receptors 1 and 2 (CB1 and CB2). Gilron et al., 1999, however, showed that propofol suppressed hindpaw formalin-evoked expression of fos-like immunoreactivity (FLI) in spinal neurons, suggesting an important analgesic effect.

Clearly, most of the animal and human data on nociceptive effects mediated by propofol may provide advantages.

#### *CON:* **Propofol has not analgesic effect**

On the other hand, many studies with propofol in both animals and humans have failed to demonstrate any evidence of analgesic-like activity.

In an animal study by Merrill et al., 2006, propofol produced anesthesia but failed to produce the experimental findings typically associated with nociception, suggesting that propofol lacks analgesic properties. Accurately, propofol sufficient to produce immobility did not prevent increased activation (c-fos expression) of spinal neurons by intraplantar formalin injection, a finding consistent with propofol lacking analgesic properties. Mice with a mutation of the gamma-aminobutyric acid type A receptor were resistant to propofol anesthesia, supporting the importance of this receptor for propofol's action. Another rodent study (Ng & Antognini, 2006) found that isoflurane and propofol both had similar effects on neuronal "windup" in the spinal cord, a factor associated with persistent pain. The study from Goto et al., 1994, reported that propofol, unlike pentobarbital, had no effect on secondphase nocifensive behavioral responses elicited by formalin injection in the hind paws of rats. Wilder-Smith et al. , 1995, also determined that propofol infusions did not affect thermal pain thresholds.

The human studies of interest, (Boccara et al., 1998) compared postoperative pain and analgesic requirements in patients receiving propofol or isoflurane for maintenance of anesthesia and reported that patients receiving propofol actually had increased pain and opioid requirements for the first 6 hours after surgery compared with patients receiving isoflurane. These findings were exactly the opposite of the findings of Cheng et al.

We conduct a more recent clinical study, published in *Anesthesia & Analgesia* in November 2008, by Fassoulaki et al., in patients undergoing abdominal hysterectomy or myomectomy under sevoflurane, desflurane or propofol anesthesia. Anesthesia was induced with propofol, morphine and cisatracrium; and maintained with sevoflurane or desflurane or propofol. Postoperative analgesia was maintained with morphine. They were unable to demonstrate any difference in postoperative pain scores or in the requirement for opioid analgesic medication among patients maintained with propofol, sevoflurane, or desflurane.

Presented data explained the inconsistency between the studies regarding the postoperative analgesic effect of propofol.

Our findings support the analgesic effect of propofol.

Postoperative nausea and vomiting (PONV) are unpleasant, often underestimated side effects of anesthesia and surgery, not devoid of medical complications. Prevention with antiemetics is only partially effective. Propofol has been shown recently to possess antiemetic properties in several situations.

The limitation of our analysis is mainly related to the methodological heterogeneity of several studies. The dose of propofol varied between the studies and my influenced the postoperative analgesic effect. The methods of postoperative pain assessment my bias the results of our meta-analyses. On the other hand, the number of analyzed clinical trials may also bias our results.

#### **7. Conclusions**

236 Pain Management – Current Issues and Opinions

which one group had an induction with inhalation of sevoflurane followed by sevoflurane maintenance, whereas the other group had an IV induction with propofol followed by propofol maintenance. The subjects were treated during surgery with alfentanil, paracetamol, and diclofenac for pain and dexamethasone and ondansetron for nausea. Pain was treated after surgery using morphine until visual analog scale score was <4 and then oral oxycodone. The authors found that propofol provided a statistically significant (*P* < 0.01) difference, decrease in postoperative pain. Hendolin et al., 1994, found that propofol significantly reduced pain in the second hour compared with patients receiving isoflurane,

The other study published in *Anesthesiology* August 2010 by Bandschapp et al., investigated the pain perception or central sensitization effects of propofol and its solvent (10% Intralipid) in healthy volunteers. They experienced decreased pain, hyperalgesia and allodynia elicited by intra-cutaneous electrical stimulation when they received a targetcontrol infusion of propofol (2µg/ml) compared with controls (the solvent 10% Intralipid and saline). However, the results provide no evidence for a modulatory role of the solvent of propofol (10% Intralipid) in the analgesic and antihyperalgesic properties of propofol. Propofol reduced pain by 40% and nearly abolished hypersensitivity which disappears on discontinuation of the drug. The EC50 for the analgesic effect of propofol was 3.2 µg/ml. There is animal literature that addresses the modulatory effects of anesthetics in different

In the 1990s, Ewen et al., found that in rats an IV infusion of propofol resulted in an initial decline followed by a rise in nociceptive threshold as the plasma concentration and degree of sedation increased. They suggest that smaller concentrations of propofol than sedative doses are responsible for hyperalgesia. However, the similar experiments in a postoperative pain models in mice were unable to detect any hyperalgesic phase at lower than sedative doses of propofol or on emergence (Udesky et al., 2005). Other groups have found an analgesic response to propofol, particularly in inflammatory pain models (Daniels&Roberts, 1998). A study in rodents by Guindon et al., 2007, demonstrated that in a test of inflammatory pain, locally injected propofol decreased pain behavior in a dose-dependent manner. The authors hypothesized that this antinociceptive activity was mediated, in part, by cannabinoid receptors 1 and 2 (CB1 and CB2). Gilron et al., 1999, however, showed that propofol suppressed hindpaw formalin-evoked expression of fos-like immunoreactivity

Clearly, most of the animal and human data on nociceptive effects mediated by propofol

On the other hand, many studies with propofol in both animals and humans have failed to

In an animal study by Merrill et al., 2006, propofol produced anesthesia but failed to produce the experimental findings typically associated with nociception, suggesting that propofol lacks analgesic properties. Accurately, propofol sufficient to produce immobility did not prevent increased activation (c-fos expression) of spinal neurons by intraplantar formalin injection, a finding consistent with propofol lacking analgesic properties. Mice with a mutation of the gamma-aminobutyric acid type A receptor were resistant to propofol anesthesia, supporting the importance of this receptor for propofol's action. Another rodent study (Ng & Antognini, 2006) found that isoflurane and propofol both had similar effects on

(FLI) in spinal neurons, suggesting an important analgesic effect.

corroborating the results of the present study.

nociceptive models.

may provide advantages.

*CON:* **Propofol has not analgesic effect** 

demonstrate any evidence of analgesic-like activity.

Our meta-analysis indicates that propofol provides a prolonged and improved postoperative analgesia with few adverse effects compared with an other inhalation and intravenous anaesthetics. However, propofol have improved antiemetic effect. The other side effects are minimal, with exception of pain during injection of propofol.

Propofol changed the practice of anesthesia, nevertheless postoperative analgesia with ordinary analgesics must be sustained.

Finally, we accomplished that propofol is not an analgesic, but many studies have certainly demonstrated analgesic properties of propofol.

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**12** 

*Italy* 

**Efficacy of Continuous Femoral** 

**Catheters Versus Nonstimulating** 

Mario Dauri, Ludovica Celidonio, Sarit Nahmias,

**Catheters - A Systematic-Narrative Review** 

*Departement of Anesthesia and Intensive Care Unit, Tor Vergata University, Rome,* 

A femoral nerve block is simple to perform, has a high rate success, carries a low risk of complications, and it is widely used technique for surgical anesthesia and post-operative pain management of the lower extremity. It provides analgesia to the anterior thigh, including the flexor muscles of the hip and extensor muscles of the knee and therefore, it is well suited for surgeries that involve the hip, the knee or the anterior thigh zone. The femoral nerve block is often associated with sciatic nerve block in order to achieve a lower

The anterior approach to the femoral nerve block initially described as a 3-in-1 block by Winnie et al (Winnie et al., 1973), suggested that the femoral, lateral femoral cutaneous, and obturator nerves could be blocked from a single paravascular injection at a point inferior to the inguinal crease. Studies have since showed that the femoral can be reliably blocked by a single injection, the lateral femoral cutaneous nerves is blocked in 95%, but the obturator nerve is almost always spared (Parkinson et al., 1989). Therefore, a 3-in-1 block with the paravascular approach seems difficult to obtain, and, as a consequence, when all three nerves need to be anesthetized a posterior lumbar plexus block or a multitruncular block should be performed. The anterior approach to the femoral nerve is similar for "single shot" or continuous nerve blocks. A femoral nerve block can be obtained with single shot of local anesthetic or by using a continuous catheter technique. The localization of the femoral nerve can be obtained by the use of nerve stimulator or with ultrasound guidance. When using single shot technique, the local anesthetic agent is injected through the needle after location of the nerve with the nerve stimulator. When using continuous catheter techniques, the nerve can be stimulated via the needle through which the catheter is placed, or via both the

This narrative review summarizes the evidence derived from randomized controlled trials (RCTs) and retrospective analysis, in order to determine the efficacy of continuous femoral nerve block comparing the use of stimulating catheters with non-stimulating catheters for lower-extremity surgery. Furthermore, we explore the adjunctive use of ultrasonography for

**1. Introduction** 

extremity analgesia.

needle and the catheter itself**.** 

femoral nerve block.

Eleonora Fabbi, Filadelfo Coniglione and Maria Beatrice Silvi

**Nerve Block with Stimulating** 


### **Efficacy of Continuous Femoral Nerve Block with Stimulating Catheters Versus Nonstimulating Catheters - A Systematic-Narrative Review**

Mario Dauri, Ludovica Celidonio, Sarit Nahmias, Eleonora Fabbi, Filadelfo Coniglione and Maria Beatrice Silvi *Departement of Anesthesia and Intensive Care Unit, Tor Vergata University, Rome, Italy* 

#### **1. Introduction**

242 Pain Management – Current Issues and Opinions

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Maintenance anaesthetics during remifentanil-based anaesthesia might affect postoperative pain control after breast cancer surgery. *Br J Anaesth* 105:661-7. Tan, T, Bhinder, R, Carey, M & Briggs, L. (2010). Day-surgery patients anesthetized with

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A femoral nerve block is simple to perform, has a high rate success, carries a low risk of complications, and it is widely used technique for surgical anesthesia and post-operative pain management of the lower extremity. It provides analgesia to the anterior thigh, including the flexor muscles of the hip and extensor muscles of the knee and therefore, it is well suited for surgeries that involve the hip, the knee or the anterior thigh zone. The femoral nerve block is often associated with sciatic nerve block in order to achieve a lower extremity analgesia.

The anterior approach to the femoral nerve block initially described as a 3-in-1 block by Winnie et al (Winnie et al., 1973), suggested that the femoral, lateral femoral cutaneous, and obturator nerves could be blocked from a single paravascular injection at a point inferior to the inguinal crease. Studies have since showed that the femoral can be reliably blocked by a single injection, the lateral femoral cutaneous nerves is blocked in 95%, but the obturator nerve is almost always spared (Parkinson et al., 1989). Therefore, a 3-in-1 block with the paravascular approach seems difficult to obtain, and, as a consequence, when all three nerves need to be anesthetized a posterior lumbar plexus block or a multitruncular block should be performed. The anterior approach to the femoral nerve is similar for "single shot" or continuous nerve blocks. A femoral nerve block can be obtained with single shot of local anesthetic or by using a continuous catheter technique. The localization of the femoral nerve can be obtained by the use of nerve stimulator or with ultrasound guidance. When using single shot technique, the local anesthetic agent is injected through the needle after location of the nerve with the nerve stimulator. When using continuous catheter techniques, the nerve can be stimulated via the needle through which the catheter is placed, or via both the needle and the catheter itself**.** 

This narrative review summarizes the evidence derived from randomized controlled trials (RCTs) and retrospective analysis, in order to determine the efficacy of continuous femoral nerve block comparing the use of stimulating catheters with non-stimulating catheters for lower-extremity surgery. Furthermore, we explore the adjunctive use of ultrasonography for femoral nerve block.

Efficacy of Continuous Femoral Nerve Block with Stimulating

the Vastus intermedius.

femoris.

Articular branches

**Anterior division** 

**Posterior division** 

muscle

**1.2 Indications** 

the knee join.

**1.3 Contraindications** 

Local anesthetic allergy

provides sensory innervation to the skin of the anterior and medial thigh and motor innervation to the Sartorius and Pectineus muscles.

provides sensory innervation to the medial part of the lower leg and motor

innervation to the quadriceps

Table 1. Anatomy of femoral nerve

Infection or haematoma In the puncture site

Refusal of the procedure by the patient

**2. History of continuous nerve blocks** 

who underwent hand surgery. (Selander, 1977).

Neurological deficit of the leg to be anaesthetised

Lesion of the nerves to be stimulated distal to the puncture site

Catheters Versus Nonstimulating Catheters - A Systematic-Narrative Review 245

**Femoral Branches**

The femoral nerve block is mainly indicated for the pain control associated with unilateral anterior knee surgery (total knee arthroplasty, ACL). It is also ideal for surgery that involves the hip (femoral fracture repair) or anterior thigh. The block is often combined with a sciatic nerve block or with obturator nerve block if surgery is distal or posterior to

The first attempt to practice a continuous peripheral nerve blockade was done by Ansbro in 1946, who described a continuous block of the brachial plexus at a supraclavicular level (Ansbro, 1946). A continuous axillary block was performed in 1977 by Selander in patients

Muscular branches

Saphenous nerve

muscle) Articular branches

Anterior cutaneous branches

thigh and give off filament to the Articularis genu and the knee-joint.

muscle about its middle, and gives off a filament to the knee-joint. The branches to the Vastus intermedius, two or three in number, enter the muscle about the middle of the

o articular branch to the hip-joint is derived from the nerve to the Rectus

o articular branches to the knee-joint are three in number. One is derived from the nerve to the Vastus lateralis, the second derived from the nerve to the Vastus medialis and the third branch is derived from the nerve to

> o intermediate cutaneous nerves o medial cutaneous nerves

o nerve to the Pectineus o nerve to the Sartorius

o to the hip-joint

Muscular branches (individual heads of the quadriceps

o branches to the knee-joint

#### **1.1 Anatomy (Gray & Henry, 1918)**

The Femoral Nerve, the largest branch of the lumbar plexus, arises from the dorsal divisions of the second, third, and fourth lumbar nerves. It descends through the fibers of the Psoas major, emerging from the muscle at the lower part of its lateral border, and passes down between it and the Iliacus, behind the iliac fascia; it then runs beneath the inguinal ligament, into the thigh, and splits into an anterior and a posterior division. At this level it is located lateral and posterior to the femoral artery.

The anterior division of the femoral nerve gives off (Table 1 ):

	- o The intermediate cutaneous nerve pierces the fascia lata (and generally the Sartorius) and divides into two branches which supply the skin as low as the front of the knee. Here they communicate with the medial cutaneous nerve and the infrapatellar branch of the saphenous, to form the patellar plexus.
	- o The medial cutaneous nerve passes obliquely across the upper part of the sheath of the femoral artery, and divides into two branches, an anterior and a posterior. Before dividing it gives off a few filaments, which supply the integument of the medial side of the thigh, accompanying the long saphenous vein. The anterior branch divides into two branches: one supplies the integument as low down as the medial side of the knee; the other crosses to the lateral side of the patella. The posterior branch descends along the medial border of the Sartorius muscle to the knee, where it pierces the fascia lata, communicates with the saphenous nerve, and gives off several cutaneous branches. It then passes down to supply the integument of the medial side of the leg.

The posterior division of the femoral nerve gives off (Table 1):


muscle about its middle, and gives off a filament to the knee-joint. The branches to the Vastus intermedius, two or three in number, enter the muscle about the middle of the thigh and give off filament to the Articularis genu and the knee-joint.

Articular branches

244 Pain Management – Current Issues and Opinions

The Femoral Nerve, the largest branch of the lumbar plexus, arises from the dorsal divisions of the second, third, and fourth lumbar nerves. It descends through the fibers of the Psoas major, emerging from the muscle at the lower part of its lateral border, and passes down between it and the Iliacus, behind the iliac fascia; it then runs beneath the inguinal ligament, into the thigh, and splits into an anterior and a posterior division. At this level it is located

Anterior cutaneous branches. The anterior cutaneous branches comprise the

infrapatellar branch of the saphenous, to form the patellar plexus.

Muscular branches—The nerve to the Pectineus and the nerve to the Sartorius

 The saphenous nerve - the largest cutaneous branch of the femoral nerve. It approaches the femoral artery where this vessel passes beneath the Sartorius, and lies in front of it, behind the aponeurotic covering of the adductor canal, as far as the opening in the lower part of the Adductor magnus. It descends vertically along the medial side of the knee behind the Sartorius, pierces the fascia lata, between the tendons of the Sartorius and Gracilis, and becomes subcutaneous. The nerve then passes along the tibial side of the leg, accompanied by the great saphenous vein, descends behind the medial border of the tibia, and, at the lower third of the leg, divides into two branches: one continues its course along the margin of the tibia, and ends at the ankle; the other passes in front of the ankle, and is distributed to the skin on the medial side of the foot, as far as the ball of the great toe. The saphenous nerve, about the middle of the thigh, gives off a branch which joins the subsartorial plexus. At the medial side of the knee it gives off a large infrapatellar branch, which pierces the Sartorius and fascia lata, and is distributed to the skin in front of the patella. Below the knee, the branches of the saphenous nerve are distributed to the skin of the front and medial side of the leg, communicating with the cutaneous branches of the femoral, or with filaments from

 Muscular branches supply the four parts of the Quadriceps femoris. The branch to the Rectus femoris enters the upper part of the muscle, and supplies a filament to the hipjoint. The branch to the Vastus lateralis enters the lower part of the muscle and gives off an articular filament to the knee-joint. The branch to the Vastus medialis enters the

o The intermediate cutaneous nerve pierces the fascia lata (and generally the Sartorius) and divides into two branches which supply the skin as low as the front of the knee. Here they communicate with the medial cutaneous nerve and the

o The medial cutaneous nerve passes obliquely across the upper part of the sheath of the femoral artery, and divides into two branches, an anterior and a posterior. Before dividing it gives off a few filaments, which supply the integument of the medial side of the thigh, accompanying the long saphenous vein. The anterior branch divides into two branches: one supplies the integument as low down as the medial side of the knee; the other crosses to the lateral side of the patella. The posterior branch descends along the medial border of the Sartorius muscle to the knee, where it pierces the fascia lata, communicates with the saphenous nerve, and gives off several cutaneous branches. It then passes down to supply the integument

**1.1 Anatomy (Gray & Henry, 1918)** 

lateral and posterior to the femoral artery.

The anterior division of the femoral nerve gives off (Table 1 ):

intermediate and medial cutaneous nerves

of the medial side of the leg.

the obturator nerve.

The posterior division of the femoral nerve gives off (Table 1):



Table 1. Anatomy of femoral nerve

#### **1.2 Indications**

The femoral nerve block is mainly indicated for the pain control associated with unilateral anterior knee surgery (total knee arthroplasty, ACL). It is also ideal for surgery that involves the hip (femoral fracture repair) or anterior thigh. The block is often combined with a sciatic nerve block or with obturator nerve block if surgery is distal or posterior to the knee join.

#### **1.3 Contraindications**


#### **2. History of continuous nerve blocks**

The first attempt to practice a continuous peripheral nerve blockade was done by Ansbro in 1946, who described a continuous block of the brachial plexus at a supraclavicular level (Ansbro, 1946). A continuous axillary block was performed in 1977 by Selander in patients who underwent hand surgery. (Selander, 1977).

Efficacy of Continuous Femoral Nerve Block with Stimulating

catheter. (Dauri et al., 2007)

Fig. 2. Catheter placement

infusion of 5-8 ml/h and bolus option.

Neural ischemia and/or neural toxicity

 Catheter breakage, formation of knots or loops Local anesthetic leakage (Gurnaney et al., 2011)

Seizures (from systemic injection and local anesthetic toxicity)

**4. Continuous femoral block versus other techniques** 

o CNS: tinnitus, confusion, metallic taste in the mouth o Cardiac: tachycardia, hypertension, arrhythmia

Many studies were conducted in order to explore the benefits arising from continuous femoral nerve block compared with other analgesic techniques. Some of the studies

**3.1 Local anesthetics** 

**3.2 Complications**  Vascular puncture Local infection

Local anesthetic toxicity:

Dislocation of the catheter

conclusions are reported below:

Catheters Versus Nonstimulating Catheters - A Systematic-Narrative Review 247

When stimulating catheter is being used, the catheter has to be connected to the PNS without changing the current output. The catheter is advanced 5 to 15 cm past the needle tip, and its position is adjusted until quadriceps femoris contractions are still elicited at a current output between 0.4 to 0.5 mA. At this point, the needle is withdrawn and quadriceps contractions are elicited via the catheter again to confirm the final perineural position of the

A number of local anesthetics may be used for femoral nerve blocks. In general, the volume of local anesthetic used to achieve a surgery anesthesia for a femoral nerve block will range from 15-20 ml. For 3-in-1 nerve block, the volume ranges from 25-30 ml. When postoperative analgesia is required, 0.5% of long acting anesthetic agents ropivacaine or levobupivacaine is often used. For postoperative analgesia, 1-2 mg/ml ropivacaine or 0.625-1.25 mg/ml levobupivacaine are used. The drugs are best administered by PCA pump with a basal rate

The first use of an epidural catheter at the level of the lumbar plexus was reported by Brands and Callanan. Their conclusion was that continuous lumbar plexus blockade reduced administration of opioids and resulted in effective pain relief. (Brands E& Callanan VI, 1987 as cited in Navas et al., 2005). A continuous sciatic nerve block to relieve pain from ischaemic gangrene of the foot was described in 1984 by Smith et al. (Smith et al, 1984 as cited by Navas et al., 2005).

In order to provide reliable post-operative analgesia and prevent readmission due to failed catheter placement, it was necessary to develop methods to ensure accurate catheter positioning and to prevent catheter dislodgment.

Improvements in techniques and instruments have led to a painless, longer-lasting postoperative analgesia, with reduction of Opioids consumption, better functional recovery, increased patient satisfaction and reduced side-effects. New techniques and devices are increasingly appearing, and catheters are constantly being developed and improved (Navas et al., 2005)

#### **3. Continuous femoral catheter placement technique (Fig 1- 2)**

The patient should be in the supine position with legs spread slightly apart. After aseptic skin disinfection and sterile draping of the inguinal region, a local anesthetic is injected superficially. The stimulating needle insertion site is immediately below the inguinal crease, 1 to 2 cm lateral to the femoral artery pulsation. A 50-mm 18-gauge insulated stimulating needle is then connected to the peripheral nerve stimulator (PNS) with an initial current output of 1 mA (2 Hz, 0.1 ms). The stimulating needle has to be inserted with a 45° angle and advanced in a cephalad direction until quadriceps femoris muscle contractions were elicited (as evidenced by cephalad patellar movements). The needle position has to be adjusted until quadriceps femoris contractions are still elicited at a current of 0.5 mA or less. At this point, a 20-gauge catheter is introduced through the needle. The catheter is then advanced for 10 to 15 cm beyond the needle tip, needle is withdrawn and the catheter has to be secured in place. The local anesthetic of choice, has to be injected slowly through the catheter.

Fig. 1. Equipement

When stimulating catheter is being used, the catheter has to be connected to the PNS without changing the current output. The catheter is advanced 5 to 15 cm past the needle tip, and its position is adjusted until quadriceps femoris contractions are still elicited at a current output between 0.4 to 0.5 mA. At this point, the needle is withdrawn and quadriceps contractions are elicited via the catheter again to confirm the final perineural position of the catheter. (Dauri et al., 2007)

Fig. 2. Catheter placement

#### **3.1 Local anesthetics**

246 Pain Management – Current Issues and Opinions

The first use of an epidural catheter at the level of the lumbar plexus was reported by Brands and Callanan. Their conclusion was that continuous lumbar plexus blockade reduced administration of opioids and resulted in effective pain relief. (Brands E& Callanan VI, 1987 as cited in Navas et al., 2005). A continuous sciatic nerve block to relieve pain from ischaemic gangrene of the foot was described in 1984 by Smith et al. (Smith et al, 1984 as cited by Navas

In order to provide reliable post-operative analgesia and prevent readmission due to failed catheter placement, it was necessary to develop methods to ensure accurate catheter

Improvements in techniques and instruments have led to a painless, longer-lasting postoperative analgesia, with reduction of Opioids consumption, better functional recovery, increased patient satisfaction and reduced side-effects. New techniques and devices are increasingly appearing, and catheters are constantly being developed and improved (Navas

The patient should be in the supine position with legs spread slightly apart. After aseptic skin disinfection and sterile draping of the inguinal region, a local anesthetic is injected superficially. The stimulating needle insertion site is immediately below the inguinal crease, 1 to 2 cm lateral to the femoral artery pulsation. A 50-mm 18-gauge insulated stimulating needle is then connected to the peripheral nerve stimulator (PNS) with an initial current output of 1 mA (2 Hz, 0.1 ms). The stimulating needle has to be inserted with a 45° angle and advanced in a cephalad direction until quadriceps femoris muscle contractions were elicited (as evidenced by cephalad patellar movements). The needle position has to be adjusted until quadriceps femoris contractions are still elicited at a current of 0.5 mA or less. At this point, a 20-gauge catheter is introduced through the needle. The catheter is then advanced for 10 to 15 cm beyond the needle tip, needle is withdrawn and the catheter has to be secured in place. The

**3. Continuous femoral catheter placement technique (Fig 1- 2)** 

local anesthetic of choice, has to be injected slowly through the catheter.

et al., 2005).

et al., 2005)

Fig. 1. Equipement

positioning and to prevent catheter dislodgment.

A number of local anesthetics may be used for femoral nerve blocks. In general, the volume of local anesthetic used to achieve a surgery anesthesia for a femoral nerve block will range from 15-20 ml. For 3-in-1 nerve block, the volume ranges from 25-30 ml. When postoperative analgesia is required, 0.5% of long acting anesthetic agents ropivacaine or levobupivacaine is often used. For postoperative analgesia, 1-2 mg/ml ropivacaine or 0.625-1.25 mg/ml levobupivacaine are used. The drugs are best administered by PCA pump with a basal rate infusion of 5-8 ml/h and bolus option.

#### **3.2 Complications**

	- o CNS: tinnitus, confusion, metallic taste in the mouth
	- o Cardiac: tachycardia, hypertension, arrhythmia

#### **4. Continuous femoral block versus other techniques**

Many studies were conducted in order to explore the benefits arising from continuous femoral nerve block compared with other analgesic techniques. Some of the studies conclusions are reported below:

Efficacy of Continuous Femoral Nerve Block with Stimulating

**6. Aim of the review** 

**7. Methods of searching literature** 

**8. Study description and results (Table 2 )** 

block.

trials.

nonstimulating catheters .

success between the two techniques.

Catheters Versus Nonstimulating Catheters - A Systematic-Narrative Review 249

This narrative review summarizes the evidence derived from randomized controlled trials (RCTs) and retrospective analysis, in order to determine the benefits and harm comparing continuous femoral nerve block with stimulating catheters versus non-stimulating catheters for lower-extremity surgery; moreover we will explore the association with adjunctive ultrasonography (US) and stimulating perineural catheters for femoral nerve

We searched PubMed, EMBASE, and the Cochrane Database using the following search terms: "ACL or anterior cruciate ligament" OR "knee arthroplasty" OR "knee surgery" AND "femoral nerve block" OR " peripheral nerve block" OR "regional anesthesia" AND "stimulating catheters" OR "non-stimulating catheters" AND "ultrasonography". Study were included in the review if they were randomized clinical trial (RCTs) and non randomized clinical trial comparing femoral nerve block with stimulating catheters versus non-stimulating catheters for elective knee surgery or RCTs comparing the insertion of stimulating catheters with or without ultrasonographic guidance; limits: English language, human adults. In addition to the systematic search of the bibliographic databases, the reference lists of all retrieved articles were screened for additional relevant

An initial search yielded 8 potentially relevant clinical trial that were further examined. Two of these was subsequently excluded because it did not meet the inclusions criteria. A total of 733 patients were investigated: 311 patients with stimulating and 422 with

Salinas et Al. in 2004 (Salinas et al., 2004) published a prospective comparison of continuous femoral nerve block with nonstimulating catheter placement versus stimulating catheterguided perineural placement, randomizing twenty volunteers; a stimulating catheter was placed on one side and an identical non-stimulating catheter on the contralateral side. Success of femoral block was defined as loss of sensation to cold and pinprick stimuli. Quality of successful block was determined by tolerance to transcutaneous electrical stimulation and force dynamometry of quadriceps strength. Despite the trial shown that block success was 100% via the stimulating catheters versus 85% via the nonstimulating catheters, they concluded that there was no statistically significant difference in block

Morin et Al. (Morin et al., 2005) in the following year published the results from the comparison between femoral nerve catheters inserted under continuous stimulation and catheters that were placed using the conventional technique of blind advancement in 81 patients undergoing major knee surgery. The aim of his randomized double blind trial was to determine whether accurate catheter positioning under continuous stimulation accelerates the onset of sensory and motor block, improves the quality of postoperative analgesia, and enhances functional recovery. He concluded that with continuous femoral nerve blocks, blind catheter advancement is as effective as the stimulating catheter


#### **5. Correlation between catheter position and the rate of effective sensory and motor blockades**

Continuous femoral nerve block is commonly obtained with a peripheral nerve stimulator connected to a stimulating needle to localize the femoral nerve. The localization of the nerve is then followed by insertion of the catheter through the needle. Studies using blind advancement of femoral catheters indicate that catheter position in relation to the nerve is unpredictable. (Ganapathy et al., 1999; Capdevila et al., 2002) Therefore, even if the initial injection of local anesthetic through the needle produces adequate intraoperative anesthesia/analgesia, subsequent infusion through the catheter may not provide adequate postoperative analgesia. Furthermore, it is difficult to determine the correct catheter's position in order to obtain an effective postoperative analgesia; on the other side the proximity of the catheter to the femoral nerve could guarantee a better analgesia. Few studies were conducted on the matter:

 Marhofer et al. used MRI scans in order to verify the distribution of local anesthetic. They showed that there is no evidence of cephalad spread of 30 ml of local anaesthetic when a 3-in-1 blockade is performed (Marhofer et al., 2000) .


The reported results may highlight the theoretical advantages of using a stimulating catheter to ensure proper perineural catheter placement. The catheter's position could be fixed at a point where the desired motor response is observed at a stimulation intensity that guarantees its proximity to the femoral nerve.

### **6. Aim of the review**

248 Pain Management – Current Issues and Opinions

 Continuous peripheral nerve blocks improve postoperative analgesia, patient satisfaction, and rehabilitation compared with IV narcotic therapy for lower extremity

 Continuous femoral nerve block technique provides similar or better analgesia with fewer undesirable effects than intravenous PCA and the epidural technique during the first 48 h of postoperative management after total knee arthroplasty and after total hip

 Outcome with continuous femoral nerve block has shown to be better than "single shot" femoral block and continuous epidural anesthesia. For analgesia after proximal lower limb orthopedic surgery, continuous three-in-one nerve blockade is as effective as epidural analgesia, with fewer side effects (urinary retention, nausea, and risk of spinal subarachnoid hemorrhage in anticoagulated patients) (Capdevila et al., 1999; Singelyn

**5. Correlation between catheter position and the rate of effective sensory and** 

Continuous femoral nerve block is commonly obtained with a peripheral nerve stimulator connected to a stimulating needle to localize the femoral nerve. The localization of the nerve is then followed by insertion of the catheter through the needle. Studies using blind advancement of femoral catheters indicate that catheter position in relation to the nerve is unpredictable. (Ganapathy et al., 1999; Capdevila et al., 2002) Therefore, even if the initial injection of local anesthetic through the needle produces adequate intraoperative anesthesia/analgesia, subsequent infusion through the catheter may not provide adequate postoperative analgesia. Furthermore, it is difficult to determine the correct catheter's position in order to obtain an effective postoperative analgesia; on the other side the

 Marhofer et al. used MRI scans in order to verify the distribution of local anesthetic. They showed that there is no evidence of cephalad spread of 30 ml of local anaesthetic

 Ganapathy et al. used CT scans to verify the catheter position. They observed that only 40% of catheters are located in an 'ideal' position, defined as catheter-tip position at 2 cm of the cephalad extremity of the sacroiliac joint or between the sacral promontory and the lateral portion of the vertebral bodies of L4 and L5. (Ganapathy et al., 1999) Capdevila et al. used anteroposterior pelvic radiograph to determine the location of the distal tip of the catheter. They showed catheter location in a continuous 3-in-1 block to be unpredictable. Their conclusion was that during a continuous three-in-one block, the threaded catheter rarely reached the lumbar plexus and that the quality of sensory and motor blockade and initial pain relief depend on the location of the catheter tip under

The reported results may highlight the theoretical advantages of using a stimulating catheter to ensure proper perineural catheter placement. The catheter's position could be fixed at a point where the desired motor response is observed at a stimulation intensity that

proximity of the catheter to the femoral nerve could guarantee a better analgesia.

when a 3-in-1 blockade is performed (Marhofer et al., 2000) .

procedures (Capdevila et al., 1999; Singelyn et al., 1998; Ganapathy et al., 1999) Continuous femoral nerve blocks have been demonstrated to improve the outcome of

total knee arthroplasty (capdevila et al., 1999; Chelly et al, 2001)

arthroplasty (Singelyn et al., 1998; Singelyn et al., 1999).

et al 1998)

**motor blockades** 

Few studies were conducted on the matter:

the fascia iliaca. (Capdevila et al., 2002) .

guarantees its proximity to the femoral nerve.

This narrative review summarizes the evidence derived from randomized controlled trials (RCTs) and retrospective analysis, in order to determine the benefits and harm comparing continuous femoral nerve block with stimulating catheters versus non-stimulating catheters for lower-extremity surgery; moreover we will explore the association with adjunctive ultrasonography (US) and stimulating perineural catheters for femoral nerve block.

#### **7. Methods of searching literature**

We searched PubMed, EMBASE, and the Cochrane Database using the following search terms: "ACL or anterior cruciate ligament" OR "knee arthroplasty" OR "knee surgery" AND "femoral nerve block" OR " peripheral nerve block" OR "regional anesthesia" AND "stimulating catheters" OR "non-stimulating catheters" AND "ultrasonography". Study were included in the review if they were randomized clinical trial (RCTs) and non randomized clinical trial comparing femoral nerve block with stimulating catheters versus non-stimulating catheters for elective knee surgery or RCTs comparing the insertion of stimulating catheters with or without ultrasonographic guidance; limits: English language, human adults. In addition to the systematic search of the bibliographic databases, the reference lists of all retrieved articles were screened for additional relevant trials.

#### **8. Study description and results (Table 2 )**

An initial search yielded 8 potentially relevant clinical trial that were further examined. Two of these was subsequently excluded because it did not meet the inclusions criteria. A total of 733 patients were investigated: 311 patients with stimulating and 422 with nonstimulating catheters .

Salinas et Al. in 2004 (Salinas et al., 2004) published a prospective comparison of continuous femoral nerve block with nonstimulating catheter placement versus stimulating catheterguided perineural placement, randomizing twenty volunteers; a stimulating catheter was placed on one side and an identical non-stimulating catheter on the contralateral side. Success of femoral block was defined as loss of sensation to cold and pinprick stimuli. Quality of successful block was determined by tolerance to transcutaneous electrical stimulation and force dynamometry of quadriceps strength. Despite the trial shown that block success was 100% via the stimulating catheters versus 85% via the nonstimulating catheters, they concluded that there was no statistically significant difference in block success between the two techniques.

Morin et Al. (Morin et al., 2005) in the following year published the results from the comparison between femoral nerve catheters inserted under continuous stimulation and catheters that were placed using the conventional technique of blind advancement in 81 patients undergoing major knee surgery. The aim of his randomized double blind trial was to determine whether accurate catheter positioning under continuous stimulation accelerates the onset of sensory and motor block, improves the quality of postoperative analgesia, and enhances functional recovery. He concluded that with continuous femoral nerve blocks, blind catheter advancement is as effective as the stimulating catheter

Efficacy of Continuous Femoral Nerve Block with Stimulating

prospective study of patients undergoing

randomized

TKA SC=19, NSC=22

 amounts of local anesthetics postoperative pain scores, opioid use side effects acute functional orthopedic outcomes

prospective

Outcomes: pain score adverse effects need for supplemental anesthesia and analgesia other than a

continuous postoperative infusion of ropivacaine 2 mg/mL set at 7 mL/h.

randomized,

(POD 2) Morphine requirements pain scores markers of early recovery

Outcomes:

controlled, doubleblind trial in patient undergoing TKA SC=40, NSC=42

 Sensory blockade at 10 min, 20 min after injection of, lidocaine via femoral catheter and at postoperative days 1 (POD 1) and 2

randomized controlled trial in patients undergoing anterior cruciate ligament reconstruction SC=35, NSC=35

Outcomes:

**Hayek et al., 2006** 

**Dauri et al., 2007** 

**Barrington et al., 2008** 

Catheters Versus Nonstimulating Catheters - A Systematic-Narrative Review 251

**Study design Results Conclusions** 

anesthesia

consumed.

 no statistically significant differences in the amount of ropivacaine administered (MD – 0.6, CI – 2.3 to 0.6. P=0.26) No significant differences between groups for the amount of fentanyl dispensed by the IV patient-controlled

The use of stimulating catheters in continuous femoral nerve blocks for TKA does not offer significant benefits over

Although the use of a stimulating catheter was associated with faster onset time for the femoral nerve block and lower additional

postoperatively, the clinical superiority (analgesia; lateral femoral cutaneous, and obturator nerve block) of stimulating catheters was not evident in this clinical setting.

In this study, blind catheter advancement was as reliable as a SC technique for establishing and maintaining CFNB for postoperative analgesia as a part of multimodal analgesia technique after TKA.

traditional nonstimulating catheters.

analgesics

 No differences in numeric pain rating scale scores No differences in acute functional orthopedic outcomes, side effects, or amounts of oral opioids

 Onset time was faster in the SC group (SC: 6.4± 2.5, NSC: 8.3±2.9 min, *P* 0.006). No differences in Visual analog scale. The number of patient-

> controlled regional analgesia boluses (SC: 14.6 ± 12.6, NSC:23.2±13.6 mg ropivacaine 2 mg/mL, *P*\_.008) as well as intravenous rescue ketorolac (SC: 34.3±35.7, NSC: 54±39.7 mg, *P* 0 .033) administered were higher in the NSC group.

 No differences on sensory blockade in the femoral nerve

 At 24 h, the 95% confidence interval for difference in morphine consumption between groups was -8 to 5

 No difference between groups in visual analog scale scores at rest on POD 1 and POD 2, during active and passive

distribution

physiotherapy No differences in markers of early recovery after surgery.

mg.

Table 2. Study included in analysis (SC= stimulating catheter, NSC= non stimulating catheter, TKA= Total knee arthroplasty, CFNB= continuous femoral nerve block)

technique with respect to onset time of sensory and motor block as well as for postoperative pain reduction and functional outcome.

A retrospective non randomized study of 419 patients was published in 2005 (Jack et al., 2005) comparing stimulating versus nonstimulating femoral catheter; it demonstrated no differences in term of visual analogue scale score and total morphine consumption with 3 days follow up. The conclusion was that the practical advantages of the stimulating catheter, as reported by previous investigators, were not obvious in this clinical situation.

In 2006 (Hayek et al., 2006) a randomized study was performed to evaluate whether a stimulating catheter allowed the use of lesser amounts of local anesthetics than a nonstimulating catheter concluding that the use of stimulating catheters in continuous femoral nerve blocks for TKA does not offer significant benefits over traditional nonstimulating catheters.

The experience from our department (Dauri et al., 2007) is about the evaluation of the efficacy of stimulating catheter to perform continuous femoral nerve block for anterior cruciate ligament reconstruction; data collection from 70 patient regarded pain scores, adverse effects, and need for supplemental anesthesia and analgesia other than a continuous postoperative infusion of ropivacaine 2 mg/mL through the continuous femoral nerve catheter set at 7 mL/h. Data collected shown that although the use of a stimulating catheter was associated with faster onset time for the femoral nerve block and lower additional analgesics postoperatively, the conclusions was that the clinical superiority (analgesia; lateral femoral cutaneous, and obturator nerve block) of stimulating catheters was not evident in this clinical setting.


technique with respect to onset time of sensory and motor block as well as for postoperative

A retrospective non randomized study of 419 patients was published in 2005 (Jack et al., 2005) comparing stimulating versus nonstimulating femoral catheter; it demonstrated no differences in term of visual analogue scale score and total morphine consumption with 3 days follow up. The conclusion was that the practical advantages of the stimulating catheter,

In 2006 (Hayek et al., 2006) a randomized study was performed to evaluate whether a stimulating catheter allowed the use of lesser amounts of local anesthetics than a nonstimulating catheter concluding that the use of stimulating catheters in continuous femoral nerve blocks for TKA does not offer significant benefits over traditional

The experience from our department (Dauri et al., 2007) is about the evaluation of the efficacy of stimulating catheter to perform continuous femoral nerve block for anterior cruciate ligament reconstruction; data collection from 70 patient regarded pain scores, adverse effects, and need for supplemental anesthesia and analgesia other than a continuous postoperative infusion of ropivacaine 2 mg/mL through the continuous femoral nerve catheter set at 7 mL/h. Data collected shown that although the use of a stimulating catheter was associated with faster onset time for the femoral nerve block and lower additional analgesics postoperatively, the conclusions was that the clinical superiority (analgesia; lateral femoral cutaneous, and obturator nerve block) of stimulating catheters was not

**Study design Results Conclusions** 

Block success :

 SC 100% , NSC 85%(p0.07) Overall tolerance to

 onset time of sensory and motor block similar in both

groups no differences in the postoperative IV opioid consumption, and visual analog scale pain scores at rest and movement No differences in maximal bending and stretching of the knee joint during the 5 days

after surgery.

transcutaneous electrical stimulation (p 0.009) and overall depth of motor block(p 0.03) was significantly higher in the stimulating catheter-guided femoral nerve blocks

There was no statistically significant difference in block success between the two techniques. Stimulating catheterguided placement provided an increased overall quality of continuous femoral perineural blockade.

With continuous femoral nerve blocks, blind catheter advancement is as effective as the stimulating catheter technique with respect to onset time of sensory and motor

block, for

postoperative pain reduction and functional outcome.

as reported by previous investigators, were not obvious in this clinical situation.

pain reduction and functional outcome.

nonstimulating catheters.

evident in this clinical setting.

Prospective ,

 Overall depth of motor block

 Randomized,controlle d observer blinded trial in patients after major knee surgery SC=38, NSC=43

 onset of sensory and motor block, quality of postoperative analgesia functional recovery

Outcomes: Block success Overall tolerance to transcutaneous electrical stimulation

Outcomes:

randomized double blind study in volounteers SC= 20, NSC=20

**Salinas et al., 2004** 

**Morin et al., 2005** 


Table 2. Study included in analysis (SC= stimulating catheter, NSC= non stimulating catheter, TKA= Total knee arthroplasty, CFNB= continuous femoral nerve block)

Efficacy of Continuous Femoral Nerve Block with Stimulating

of might be inside the nerve.

2000).

Catheters Versus Nonstimulating Catheters - A Systematic-Narrative Review 253

The rational for using stimulating catheters, introduced in 1999 (Boezaart et al., 1999) is based on the assumption that catheter tips are directed close to nerves; in fact it provide the possibility to verify the position the catheter takes during advancement through the cannula. A study performed by Pham Dang et al (Pham Dang et al., 2003) concluded that the ability to electrostimulate nerves using an in situ catheter increases success rate in catheter placement for continuous peripheral nerve blocks. However, they were surprised to find that the amperage required to elicit motor responses is higher with the stimulating catheter than with the introducer needle. In a study performed by Morin et al (Morin et al., 2005), the authors did not find a relationship between the current that had to be applied via the stimulating catheter to evoke a motor response and any of the variables determined to judge the success of the catheter positioning. Viewing this works, doubts may arise regarding the reliability of stimulating catheter to elucidate motor contruction and to determine correct catheter positioning. Furthermore, A stimulation current 0.5mA or less is considered safe in order to avoid nerve injury and to deliver adequate stimulus to provoke a motor response. A stady performed by Bigeleisen et al (Bigeleisen et al., 2009) suggest that stimulation currents of more than 0.2 and no more than 0.5 mA could not rule out an intraneural position of the needle or catheter tip. Therefore, even with the use of low stimulation (0.2-0.5 mA) the tip of the stimulating catheters are not ascertained to be in the vicinity of the nerve

Placement of the catheter tip should ideally be as close as possible to the nerve to attain the minimal blocking concentration that will block the fibers responsible for transmission of painful stimuli. From a practical point, use of larger volumes may permit more successful blocks when nerves are less than ideally localized. This concept is expressed also by Pham Dang et al. (Pham Dang et al., 2009) affirming that interpretation of their data suggests that the failure of previous studies to show a superiority of stimulating catheters has perhaps been masked by methodological problems in previous investigations on the subject. In fact in their study, stimulating catheters seem to provide early analgesia within the femoral nerve distribution using low-dose initial bolus and subsequent low-volume infusion. Small doses of local anesthetics suffice if a catheter is correctly placed next the femoral nerve and that pain from unblocked obturator and sciatic nerves should be treated specifically (Pham Dang 2009). Moreover, use of larger volumes of local anesthetics may potentially increase the risk of systemic toxicity and potentially increase motor block (Borgeat et al., 2001; Bergman et al.,

More importantly, minimal motor weakness is desired for continuous femoral analgesia after total knee arthroplasty, because excessive quadriceps motor block may impair active knee extension required for rehabilitation protocols and potentially delay achievement of predetermined functional physical therapy goals. To better ascertain the difference between a well placed and a poorly placed catheter, one should use smaller amounts of local anesthetics. Hayek et al. (Hayek et al., 2006), analyzed data regarding the total amount of local anesthetic used in patient treated with stimulating catheter versus nonstimulating group founding no

The question arises whether nerve proximity is really needed for the femoral nerve to be blocked effectively in routine clinical use. Several reasons argue against this necessity, particularly when larger volumes (40 ml) of local anaesthetic are used. Firstly, anatomical review suggests that, once the iliac fascia is penetrated, there are no relevant diffusion barriers for local anaesthetics. Secondly, catheters threaded 16–20 cm from the inguinal level radiographically deviated in 77% of cases but were as effective in motor blockade of the

statistically significant differences in the amount of ropivacaine administered .

Recently, a randomized clinical trial (Barrington et al., 2008) compared a stimulating catheter with a nonstimulating catheter technique for institution of continuous femoral nerve block and its effects on quality of analgesia after total knee arthroplasty performed under general anesthesia in 82 patients. Patients were randomized to have continuous femoral nerve block instituted using either a non-stimulating or a stimulating catheter technique. There were no differences in term of included morphine requirements, pain scores, and markers of early recovery. There was an increase in procedural time required for insertion of a SC compared with a NSC (10 and 6 min, respectively); however, this is of debatable clinical significance.

They concluded that blind catheter advancement was as reliable as a stimulating catheter technique for establishing and maintaining continuous femoral nerve block for postoperative analgesia as a part of multimodal analgesia technique after total knee arthroplasty.

In summary, although advantageous from a theoretical standpoint and in experimental designs (Salinas et al., 2004), randomized controlled trials in the clinical environment have yielded limited evidence to justify use of stimulating catheters for continuous femoral nerve block after knee surgery. The increased cost and need for additional catheter adjustments compared with nonstimulating catheter also make it hard to justify their use in this clinical setting.

#### **9. Discussion: Focus on**

Postoperative pain after major knee surgery is a major concern. It is severe in 60% of patients and moderate in another 30% (Singelyn et al., 1998; 2000). Pain has a major impact on patient satisfaction and postoperative well-being. In addition, pain impairs early intensive physical therapy and rehabilitation, probably the most influential factor for good postoperative knee rehabilitation (Singelyn & Gouverneur, 2000; Capdevila et al., 1999).

Continuous peripheral nerve blocks offer the potential benefits of extended postoperative analgesia, few side effects, improved patient satisfaction, and accelerated functional recovery after major knee surgery (Liu & Salinas, 2003); for this reason continuous femoral nerve block is often used to provide postoperative analgesia in this clinical setting (Singelyn et al.,1998; Capdevila et al., 1999)

#### **9.1 Catheter tip**

When performing a continuous femoral nerve block, efforts are made to place the catheter close to the nerve to achieve effective perioperative analgesia. Traditionally, catheter placement is performed through a stimulating needle, followed by injection of the local anesthetic and then blind advancement of the peripheral catheter beyond the needle tip. Secondary analgesic block failure rate (failure of a catheter to produce postoperative analgesia after having provided sufficient intraoperative analgesia with the bolus administration) with this technique ranges from 10% (Grant et al., 2001; Chelly & Casati, 2003) up to 40% (Salinas, 2003). This may be explained by the fact that the catheter can curl away from the needle during uncontrolled advancement (Salinas 2003). Correct catheter placement is confirmed by testing for a clinical effect of satisfactory analgesia or by sensory modality testing within the desired sensory distribution after injection of the local anesthetic. However, in case of insufficient block, the catheter cannot be further redirected.

Recently, a randomized clinical trial (Barrington et al., 2008) compared a stimulating catheter with a nonstimulating catheter technique for institution of continuous femoral nerve block and its effects on quality of analgesia after total knee arthroplasty performed under general anesthesia in 82 patients. Patients were randomized to have continuous femoral nerve block instituted using either a non-stimulating or a stimulating catheter technique. There were no differences in term of included morphine requirements, pain scores, and markers of early recovery. There was an increase in procedural time required for insertion of a SC compared with a NSC (10 and 6 min, respectively); however, this is of

They concluded that blind catheter advancement was as reliable as a stimulating catheter technique for establishing and maintaining continuous femoral nerve block for postoperative analgesia as a part of multimodal analgesia technique after total knee

In summary, although advantageous from a theoretical standpoint and in experimental designs (Salinas et al., 2004), randomized controlled trials in the clinical environment have yielded limited evidence to justify use of stimulating catheters for continuous femoral nerve block after knee surgery. The increased cost and need for additional catheter adjustments compared with nonstimulating catheter also make it hard to justify their use in this clinical

Postoperative pain after major knee surgery is a major concern. It is severe in 60% of patients and moderate in another 30% (Singelyn et al., 1998; 2000). Pain has a major impact on patient satisfaction and postoperative well-being. In addition, pain impairs early intensive physical therapy and rehabilitation, probably the most influential factor for good postoperative knee rehabilitation (Singelyn & Gouverneur, 2000; Capdevila et al., 1999). Continuous peripheral nerve blocks offer the potential benefits of extended postoperative analgesia, few side effects, improved patient satisfaction, and accelerated functional recovery after major knee surgery (Liu & Salinas, 2003); for this reason continuous femoral nerve block is often used to provide postoperative analgesia in this clinical setting (Singelyn

When performing a continuous femoral nerve block, efforts are made to place the catheter close to the nerve to achieve effective perioperative analgesia. Traditionally, catheter placement is performed through a stimulating needle, followed by injection of the local anesthetic and then blind advancement of the peripheral catheter beyond the needle tip. Secondary analgesic block failure rate (failure of a catheter to produce postoperative analgesia after having provided sufficient intraoperative analgesia with the bolus administration) with this technique ranges from 10% (Grant et al., 2001; Chelly & Casati, 2003) up to 40% (Salinas, 2003). This may be explained by the fact that the catheter can curl away from the needle during uncontrolled advancement (Salinas 2003). Correct catheter placement is confirmed by testing for a clinical effect of satisfactory analgesia or by sensory modality testing within the desired sensory distribution after injection of the local anesthetic. However, in case of insufficient block, the catheter cannot be further

debatable clinical significance.

**9. Discussion: Focus on** 

et al.,1998; Capdevila et al., 1999)

**9.1 Catheter tip** 

redirected.

arthroplasty.

setting.

The rational for using stimulating catheters, introduced in 1999 (Boezaart et al., 1999) is based on the assumption that catheter tips are directed close to nerves; in fact it provide the possibility to verify the position the catheter takes during advancement through the cannula. A study performed by Pham Dang et al (Pham Dang et al., 2003) concluded that the ability to electrostimulate nerves using an in situ catheter increases success rate in catheter placement for continuous peripheral nerve blocks. However, they were surprised to find that the amperage required to elicit motor responses is higher with the stimulating catheter than with the introducer needle. In a study performed by Morin et al (Morin et al., 2005), the authors did not find a relationship between the current that had to be applied via the stimulating catheter to evoke a motor response and any of the variables determined to judge the success of the catheter positioning. Viewing this works, doubts may arise regarding the reliability of stimulating catheter to elucidate motor contruction and to determine correct catheter positioning. Furthermore, A stimulation current 0.5mA or less is considered safe in order to avoid nerve injury and to deliver adequate stimulus to provoke a motor response. A stady performed by Bigeleisen et al (Bigeleisen et al., 2009) suggest that stimulation currents of more than 0.2 and no more than 0.5 mA could not rule out an intraneural position of the needle or catheter tip. Therefore, even with the use of low stimulation (0.2-0.5 mA) the tip of the stimulating catheters are not ascertained to be in the vicinity of the nerve of might be inside the nerve.

Placement of the catheter tip should ideally be as close as possible to the nerve to attain the minimal blocking concentration that will block the fibers responsible for transmission of painful stimuli. From a practical point, use of larger volumes may permit more successful blocks when nerves are less than ideally localized. This concept is expressed also by Pham Dang et al. (Pham Dang et al., 2009) affirming that interpretation of their data suggests that the failure of previous studies to show a superiority of stimulating catheters has perhaps been masked by methodological problems in previous investigations on the subject. In fact in their study, stimulating catheters seem to provide early analgesia within the femoral nerve distribution using low-dose initial bolus and subsequent low-volume infusion. Small doses of local anesthetics suffice if a catheter is correctly placed next the femoral nerve and that pain from unblocked obturator and sciatic nerves should be treated specifically (Pham Dang 2009). Moreover, use of larger volumes of local anesthetics may potentially increase the risk of

systemic toxicity and potentially increase motor block (Borgeat et al., 2001; Bergman et al., 2000).

More importantly, minimal motor weakness is desired for continuous femoral analgesia after total knee arthroplasty, because excessive quadriceps motor block may impair active knee extension required for rehabilitation protocols and potentially delay achievement of predetermined functional physical therapy goals. To better ascertain the difference between a well placed and a poorly placed catheter, one should use smaller amounts of local anesthetics. Hayek et al. (Hayek et al., 2006), analyzed data regarding the total amount of local anesthetic used in patient treated with stimulating catheter versus nonstimulating group founding no statistically significant differences in the amount of ropivacaine administered .

The question arises whether nerve proximity is really needed for the femoral nerve to be blocked effectively in routine clinical use. Several reasons argue against this necessity, particularly when larger volumes (40 ml) of local anaesthetic are used. Firstly, anatomical review suggests that, once the iliac fascia is penetrated, there are no relevant diffusion barriers for local anaesthetics. Secondly, catheters threaded 16–20 cm from the inguinal level radiographically deviated in 77% of cases but were as effective in motor blockade of the

Efficacy of Continuous Femoral Nerve Block with Stimulating

**9.3 An alternative: Ultrasonographic guidance** 

et al., 2005; Salinas et al., 2004; Birnbaum et al., 2007).

Fig. 3. Ultrasound-guided femoral nerve block: in plane approach

(Fig. 3- 4- 5).

Catheters Versus Nonstimulating Catheters - A Systematic-Narrative Review 255

Continuous femoral nerve blocks, have recently evolved towards being the gold standard for acute pain therapy after major reconstructive knee surgery, including total knee arthroplasty and certain techniques for anterior cruciate ligament reconstruction. As shown previously, accurate placement of femoral nerve catheters in close proximity to the femoral nerve, allows for a therapy with low infusion rates and minimal boluses, thus increasing its effectiveness and allowing for prolonged analgesia (48-72hours) with small portable disposable pumps in the outpatient setting. Neuro-stimulation and stimulating catheters, were the basis for perfecting continuous femoral blocks. While usually a simple technique, with minimal risks, occasionally, even in experienced hands, stimulating catheters present several shortcomings: lack of placement time consistency, increased costs, lack of direct visualization of local anesthetic spread, variability in stimulating catheter design and quality, uncertainty about nerve stimulation endpoints ( Hayek, 2006; Jack et al., 2005; Morin

An alternative for assisting with correct catheter placement is ultrasonographic guidance

femoral nerve, and only marginally less effective in sensory blockade of the femoral nerve, compared with radiographically well placed catheters (Capdevila et al., 2002). Thirdly, iliac fascia blocks performed without any nerve stimulation are as effective as femoral nerve blocks, in both children (Dalens et al.,1989) and adults (Capdevila et al., 1998), suggesting no clinically meaningful reason for placing catheter tips in close proximity to the femoral nerve. For these reasons, Birbaum affirmed that well designed studies should to be done to prove the superiority of stimulating catheters, but not for the femoral nerve (Birnbaum & Volk., 2006).

However , without direct visualization, catheter positions corresponding to the various stimulating tip-to-nerve distances could only be inferred on the basis of the neurostimulation recently developed by Johnson et al. (Jonson et al., 2007).

Another common problem to underling is the lack of control of the pain transmitted by the unblocked obturator nerve in all studies (Morin et al., 2005; Barrington et al., 2008) and the unblocked sciatic nerve in 2 studies (Morin et al., 2005; Hayek et al., 2006). These unblocked nerves constitute major confounding factors during assessment of the femoral block based on pain scores, given that the knee is innervated principally by the femoral, obturator, and sciatic nerves. In contrast to these studies, ours used a low dose of ropivacaine (0.2%) for initiation and maintenance of femoral nerve block and eliminated pain from obturator and sciatic nerves by blocking them.(Pham Dang et al., 2009).

It is conceivable that clinicians with less experience might find that the ability to verify accuracy of catheter placement with the stimulating catheter system improves their clinical outcomes. However the introduction of the stimulating catheter requires more expertise than introduction of the non-stimulating catheter. Placing the catheter to give good contractions often involves extra manipulation, reintroduction of the needle, or both. Thus, it would not (necessarily) expect the stimulating catheter to give better results in inexperienced hands.

#### **9.2 Effect on neurostimulation of injectates used for perineural space expansion**

A randomized clinical trial (Pham Dang et al., 2009) clinically assessed the electrophysiologic effect of dextrose 5% in water and of normal saline used for expansion of the perineural space before placing a stimulating catheter. They questioned if higher current was required with normal saline but not with dextrose 5% in water, as has been observed experimentally. This was a prospective randomized double-blind study of ASA I to II patients scheduled for total knee replacement. Patients were randomly assigned to receive unidentified injectate dextrose 5% in water (n = 25) or normal saline (n = 25). The primary outcome was the minimal intensity of stimulation (MIS) recorded before and after 2 and 5 mL of study injectates were flushed through the needle before placing a stimulating catheter for continuous femoral and sciatic nerve blocks. Secondary outcomes included, among other parameters, minimal intensity of stimulation recorded during placement of stimulating catheters.

Analysis of the primary outcome using a between-group comparison showed that minimal intensity of stimulation recorded during electrostimulation via the needle was significantly higher after normal saline than after dextrose 5% in water in all blocks and at each volume of injectate. This presumably reflects the electrophysiologic properties of normal saline versus dextrose 5% in water given the absence of difference between groups with all other parameters assessed in this study. To conclude, the use of normal saline for expanding the perineural space led to increased intensity for nerve electrostimulation, which may lead to potential errors when electrolocating the nerve. Dextrose 5% in water seemed to be a superior medium for perineural space expansion, which is in agreement with the animal and clinical studies of Tsui et al.(Tsui et al., 2005).

#### **9.3 An alternative: Ultrasonographic guidance**

254 Pain Management – Current Issues and Opinions

femoral nerve, and only marginally less effective in sensory blockade of the femoral nerve, compared with radiographically well placed catheters (Capdevila et al., 2002). Thirdly, iliac fascia blocks performed without any nerve stimulation are as effective as femoral nerve blocks, in both children (Dalens et al.,1989) and adults (Capdevila et al., 1998), suggesting no clinically meaningful reason for placing catheter tips in close proximity to the femoral nerve. For these reasons, Birbaum affirmed that well designed studies should to be done to prove the superiority of stimulating catheters, but not for the femoral nerve (Birnbaum & Volk., 2006). However , without direct visualization, catheter positions corresponding to the various stimulating tip-to-nerve distances could only be inferred on the basis of the

Another common problem to underling is the lack of control of the pain transmitted by the unblocked obturator nerve in all studies (Morin et al., 2005; Barrington et al., 2008) and the unblocked sciatic nerve in 2 studies (Morin et al., 2005; Hayek et al., 2006). These unblocked nerves constitute major confounding factors during assessment of the femoral block based on pain scores, given that the knee is innervated principally by the femoral, obturator, and sciatic nerves. In contrast to these studies, ours used a low dose of ropivacaine (0.2%) for initiation and maintenance of femoral nerve block and eliminated pain from obturator and

It is conceivable that clinicians with less experience might find that the ability to verify accuracy of catheter placement with the stimulating catheter system improves their clinical outcomes. However the introduction of the stimulating catheter requires more expertise than introduction of the non-stimulating catheter. Placing the catheter to give good contractions often involves extra manipulation, reintroduction of the needle, or both. Thus, it would not (necessarily) expect the stimulating catheter to give better results in inexperienced hands.

**9.2 Effect on neurostimulation of injectates used for perineural space expansion**  A randomized clinical trial (Pham Dang et al., 2009) clinically assessed the electrophysiologic effect of dextrose 5% in water and of normal saline used for expansion of the perineural space before placing a stimulating catheter. They questioned if higher current was required with normal saline but not with dextrose 5% in water, as has been observed experimentally. This was a prospective randomized double-blind study of ASA I to II patients scheduled for total knee replacement. Patients were randomly assigned to receive unidentified injectate dextrose 5% in water (n = 25) or normal saline (n = 25). The primary outcome was the minimal intensity of stimulation (MIS) recorded before and after 2 and 5 mL of study injectates were flushed through the needle before placing a stimulating catheter for continuous femoral and sciatic nerve blocks. Secondary outcomes included, among other parameters, minimal intensity of

Analysis of the primary outcome using a between-group comparison showed that minimal intensity of stimulation recorded during electrostimulation via the needle was significantly higher after normal saline than after dextrose 5% in water in all blocks and at each volume of injectate. This presumably reflects the electrophysiologic properties of normal saline versus dextrose 5% in water given the absence of difference between groups with all other parameters assessed in this study. To conclude, the use of normal saline for expanding the perineural space led to increased intensity for nerve electrostimulation, which may lead to potential errors when electrolocating the nerve. Dextrose 5% in water seemed to be a superior medium for perineural space expansion, which is in agreement with the animal

neurostimulation recently developed by Johnson et al. (Jonson et al., 2007).

sciatic nerves by blocking them.(Pham Dang et al., 2009).

stimulation recorded during placement of stimulating catheters.

and clinical studies of Tsui et al.(Tsui et al., 2005).

Continuous femoral nerve blocks, have recently evolved towards being the gold standard for acute pain therapy after major reconstructive knee surgery, including total knee arthroplasty and certain techniques for anterior cruciate ligament reconstruction. As shown previously, accurate placement of femoral nerve catheters in close proximity to the femoral nerve, allows for a therapy with low infusion rates and minimal boluses, thus increasing its effectiveness and allowing for prolonged analgesia (48-72hours) with small portable disposable pumps in the outpatient setting. Neuro-stimulation and stimulating catheters, were the basis for perfecting continuous femoral blocks. While usually a simple technique, with minimal risks, occasionally, even in experienced hands, stimulating catheters present several shortcomings: lack of placement time consistency, increased costs, lack of direct visualization of local anesthetic spread, variability in stimulating catheter design and quality, uncertainty about nerve stimulation endpoints ( Hayek, 2006; Jack et al., 2005; Morin et al., 2005; Salinas et al., 2004; Birnbaum et al., 2007).

An alternative for assisting with correct catheter placement is ultrasonographic guidance (Fig. 3- 4- 5).

Fig. 3. Ultrasound-guided femoral nerve block: in plane approach

Efficacy of Continuous Femoral Nerve Block with Stimulating

using nerve stimulators (Marhofer, 1997-1998).

Catheters Versus Nonstimulating Catheters - A Systematic-Narrative Review 257

Ultrasound-guided regional anesthesia is an evolving field and its use has gained enormous popularity in the last 10 years. In one investigation, the onset of sensory blockade with ultrasound guidance was significantly shorter and the quality of sensory block significantly better compared with the nerve stimulator needle-assisted application of local anesthetic (Marhofer et al., 1997). Addition of ultrasound guidance to nerve stimulation could offer the benefits of rapid localization and visualization of local anesthetic spread, at the cost of several disadvantages: need for multiple assistants, increased time and cost; moreover the tip position can suggest proximity even though sufficient nerve stimulation is not achieved,

Other authors have reported both increased block density and lower anesthetic dose requirements with US-guided techniques when compared with conventional techniques

Mariano et al. (Mariano et al., 2009) performed a study were patients receiving a femoral perineural catheter for knee surgery were randomly assigned to either ultrasound guidance with a nonstimulating catheter or electrostimulation guidance with a stimulating catheter. The primary outcome was the catheter placement procedure time (minutes) starting when the ultrasound transducer (ultrasound group) or catheter insertion needle (electrostimulator group) first touched the patient and ending when the catheter insertion needle was removed after catheter insertion. He concluded that for femoral perineural catheter placement, an ultrasound-guided technique decreases the procedure time compared with nerve electrostimulation alone while maintaining a similar success rate. Furthermore, patients in the ultrasound group reported less procedure-related pain during perineural catheter

It is possible that using a combination of both approaches may offer additional benefits over either technique alone for brachial plexus perineural catheters (Mariano et al., 2009;Fredricksonet al., 2008). For continuous femoral nerve block the needle is inserted at the level of the inguinal crease along the long axis of the ultrasound probe. The needle shaft and needle tip are clearly visible with this approach during advancement of the needle toward the femoral nerve. Once the needle pierces the fascia iliaca lateral to the nerve, the needle tip is advanced 2 to 3 mm toward the nerve. This is contrary to the common method of placing the needle tip in close proximity to the nerve. At this point, 5 mL of dextrose 5% solution is injected to expand the perineural space, and electrical stimulation conforms a quadriceps or patellar twitch. The position of the needle in conjunction with the injected dextrose provides a path for catheter advancement toward the nerve and the catheter tip to lie in close approximation to the nerve. Had the needle tip initially been placed next to the

Another method to possibly improve catheter advancement is slight withdrawal of the catheter guide wire by 1 to 2 cm from the tip. This will provide more flexibility to the catheter tip but stiffness to the remainder of the catheter during advancement. This may further decrease the likelihood of catheter advancement away from the tract formed by the injected dextrose solution, thereby improving the ease of catheter insertion (Niazi et al., 2009). To date, however, the need for electro-stimulation in addition to ultrasound guidance remains controversial, especially for lower extremity perineural catheter placement (Chan et al., 2007; Walker & Roberts, 2007; Beach et al., 2006; Gürkan et al., 2008; Dingemans et al.,

Moreover combining ultrasound with electro-stimulation does negate any cost advantages

injection of local anaesthetic usually produces a clinically effective block.

placement and had fewer inadvertent vascular punctures (20% less).

femoral nerve, the catheter would have advanced medially past the nerve.

attributed to ultrasound guidance alone (Sandhu et al., 2004).

2007).

Fig. 4. Ultrasound guided femoral nerve block: needle insertion

Fig. 5. Ultrasound guided femoral nerve block: catheter insertion

Fig. 4. Ultrasound guided femoral nerve block: needle insertion

Fig. 5. Ultrasound guided femoral nerve block: catheter insertion

Ultrasound-guided regional anesthesia is an evolving field and its use has gained enormous popularity in the last 10 years. In one investigation, the onset of sensory blockade with ultrasound guidance was significantly shorter and the quality of sensory block significantly better compared with the nerve stimulator needle-assisted application of local anesthetic (Marhofer et al., 1997). Addition of ultrasound guidance to nerve stimulation could offer the benefits of rapid localization and visualization of local anesthetic spread, at the cost of several disadvantages: need for multiple assistants, increased time and cost; moreover the tip position can suggest proximity even though sufficient nerve stimulation is not achieved, injection of local anaesthetic usually produces a clinically effective block.

Other authors have reported both increased block density and lower anesthetic dose requirements with US-guided techniques when compared with conventional techniques using nerve stimulators (Marhofer, 1997-1998).

Mariano et al. (Mariano et al., 2009) performed a study were patients receiving a femoral perineural catheter for knee surgery were randomly assigned to either ultrasound guidance with a nonstimulating catheter or electrostimulation guidance with a stimulating catheter. The primary outcome was the catheter placement procedure time (minutes) starting when the ultrasound transducer (ultrasound group) or catheter insertion needle (electrostimulator group) first touched the patient and ending when the catheter insertion needle was removed after catheter insertion. He concluded that for femoral perineural catheter placement, an ultrasound-guided technique decreases the procedure time compared with nerve electrostimulation alone while maintaining a similar success rate. Furthermore, patients in the ultrasound group reported less procedure-related pain during perineural catheter placement and had fewer inadvertent vascular punctures (20% less).

It is possible that using a combination of both approaches may offer additional benefits over either technique alone for brachial plexus perineural catheters (Mariano et al., 2009;Fredricksonet al., 2008). For continuous femoral nerve block the needle is inserted at the level of the inguinal crease along the long axis of the ultrasound probe. The needle shaft and needle tip are clearly visible with this approach during advancement of the needle toward the femoral nerve. Once the needle pierces the fascia iliaca lateral to the nerve, the needle tip is advanced 2 to 3 mm toward the nerve. This is contrary to the common method of placing the needle tip in close proximity to the nerve. At this point, 5 mL of dextrose 5% solution is injected to expand the perineural space, and electrical stimulation conforms a quadriceps or patellar twitch. The position of the needle in conjunction with the injected dextrose provides a path for catheter advancement toward the nerve and the catheter tip to lie in close approximation to the nerve. Had the needle tip initially been placed next to the femoral nerve, the catheter would have advanced medially past the nerve.

Another method to possibly improve catheter advancement is slight withdrawal of the catheter guide wire by 1 to 2 cm from the tip. This will provide more flexibility to the catheter tip but stiffness to the remainder of the catheter during advancement. This may further decrease the likelihood of catheter advancement away from the tract formed by the injected dextrose solution, thereby improving the ease of catheter insertion (Niazi et al., 2009). To date, however, the need for electro-stimulation in addition to ultrasound guidance remains controversial, especially for lower extremity perineural catheter placement (Chan et al., 2007; Walker & Roberts, 2007; Beach et al., 2006; Gürkan et al., 2008; Dingemans et al., 2007).

Moreover combining ultrasound with electro-stimulation does negate any cost advantages attributed to ultrasound guidance alone (Sandhu et al., 2004).

Efficacy of Continuous Femoral Nerve Block with Stimulating

94: 1001–6

Jul-Aug;32(4):282-7.

2008; 33:122–128.

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Catheters Versus Nonstimulating Catheters - A Systematic-Narrative Review 259

Capdevila X, Biboulet P, Morau D et al. Continuous three-inone block for postoperative pain

Chan VW, Perlas A, McCartney CJ, Brull R, Xu D, Abbas S. Ultrasound guidance improves success rate of axillary brachial plexus block*. Can J Anaesth* 2007; 54:176–182..9,26–29. Chelly JE, Casati A. Are nonstimulating catheters really inappropriate for continuous nerve

Chelly JE, Greger J, Gebhard R et al. Continuous femoral blocks improve recovery and outcome of patients undergoing total knee arthroplasty*. J Arthroplasty* 2001; 16: 436—45. Dalens B, Vanneuville G, Tanguy A. Comparison of the fascia iliaca compartment block with

Dauri M, Sidiropoulou T, Fabbi E, Giannelli M, Faria S, Mariani P, Sabato AF. Efficacy of

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Fredrickson MJ, Ball CM, Dalgleish AJ. Successful continuous interscalene analgesia for

Ganapathy S, Wasserman RA, Watson JT, et al. Modified continuous femoral three-in-one block for postoperative pain after total knee arthroplasty. *Anesth Analg* 1999;89:1197–202 Grant SA, Nielsen KC, Greengrass RA, et al. Continuous peripheral nerve block for

Gray, Henry. Anatomy of the Human Body*.* Philadelphia: *Lea & Febiger*, 1918; Bartleby.com, 200. Gürkan Y, Acar S, Solak M, Toker K. Comparison of nerve stimulation vs. ultrasound-guided lateral sagittal infraclavicular block. *Acta Anaesthesiol Scand* 2008; 52:851–855. Gurnaney H, Kraemer FW, Ganesh A. Dermabond decreases pericatheter local anesthetic leakage after continuous perineural infusions. *Anesth Analg*. 2011 Jul;113(1):206. Hayek SM, Ritchey RM, Sessler D, Helfand R, Samuel S, Xu M, Beven M, Bourdakos D,

Jack NT, Liem EB, Vonhögen LH. Use of a stimulating catheter for total knee replacement surgery: preliminary results. *Br J Anaesth.*2005 Aug;95(2):250-4. Epub 2005 May 27. Johnson CR, Barr RC, Klein SM. A computer model of electrical stimulation of peripheral

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Marhofer P, Nael C, Sitwohl C et al. Magnetic resonance imaging of the distribution of local anesthetic during the three-in-one block. *Anesth Analg* 2000; 90: 119—24. Marhofer P, Schrogendorfer K, Koinig H, et al. Ultrasonographic guidance improves sensory block and onset time of three-in-one blocks. *Anesth Analg* 1997;85:854–7. Mariano ER, Afra R, Loland VJ, et al. Continuous interscalene brachial plexus block via an

ultrasound-guided posterior approach: a randomized, triple-masked, placebo-

nerves in regional anesthesia*. Anesthesiology*. 2007;106:323Y330.

analgesia. *Anesth Analg* 2003;96:263–72.

controlled study. *Anesth Analg* 2009; 108:1688–1694.

continuous femoral nerve block with stimulating catheters versus nonstimulating catheters for anterior cruciate ligament reconstruction. *Reg Anesth Pain Med*. 2007

infraclavicular block: a prospective randomized trial. *Anesth Analg* 2007; 104:1275–1280.

ambulatory shoulder surgery in a private practice setting. *Reg Anesth Pain Med*

Barsoum W, Brooks P. Continuous femoral nerve analgesia after unilateral total knee arthroplasty: stimulating versus nonstimulating catheters. *Anesth Analg.* 2006

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ambulatory surgery. *Reg Anesth Pain Med* 2001;26:209–14.

after lower limb orthopedic surgery: where do the catheters go? *Anesth Analg* 2002;

#### **10. Conclusions**

Randomized controlled trials in the clinical environment have yielded limited evidence to justify use of stimulating catheters for continuous femoral nerve block after knee surgery. It can be affirmed that failure of previous studies to show a superiority of stimulating catheters has perhaps been masked by methodological problems, above all regarding the dose and volume of local anesthetics used. However ultrasound guidance offer a safe and cost/effective technique for femoral catheter placement.

#### **11. Future directions**

It is important to design future trials in a consistent manner to make studies comparable and to enable a standard quantitative meta-analysis. Future study designs need to account for differences between the primary anesthetic block (bolus or a relatively large mass of concentrated local anesthetic via either the needle or catheter, typically with a long-acting agent) and the secondary analgesic block (infusion of a dilute local anesthetic). Injection of long-acting local anesthetic as the primary block renders interpretation of the secondary analgesic infusion difficult if not impossible for the first 12 to 24 hrs as the residual analgesic effects of the primary block may still be effective.

#### **12. References**


Randomized controlled trials in the clinical environment have yielded limited evidence to justify use of stimulating catheters for continuous femoral nerve block after knee surgery. It can be affirmed that failure of previous studies to show a superiority of stimulating catheters has perhaps been masked by methodological problems, above all regarding the dose and volume of local anesthetics used. However ultrasound guidance offer a safe and

It is important to design future trials in a consistent manner to make studies comparable and to enable a standard quantitative meta-analysis. Future study designs need to account for differences between the primary anesthetic block (bolus or a relatively large mass of concentrated local anesthetic via either the needle or catheter, typically with a long-acting agent) and the secondary analgesic block (infusion of a dilute local anesthetic). Injection of long-acting local anesthetic as the primary block renders interpretation of the secondary analgesic infusion difficult if not impossible for the first 12 to 24 hrs as the residual analgesic

Ansbro P. A method of continuous brachial plexus block. *American Journal of Surgery* 1946;

Barrington MJ, Olive DJ, McCutcheon CA, Scarff C, Said S, Kluger R, et al. Stimulating

Bigeleisen P.E, Moayeri N, Groen G.J. Extraneural versus Intraneural Stimulation

Birnbaum J et al. "Electrical nerve stimualtion for plexus and nerve blocks" *Anaesthesist*.

Birnbaum J., Volk T. Use of a stimulating catheter for femoral nerve block*. British Journal of* 

Boezaart AP, de Beer JF, duToit C, van Rooyen KA. New technique of continuous

Borgeat A, Ekatodramis G, Kalberer F, Benz C. Acute and nonacute complications associated with interscalene block: A prospective study. *Anesthesiology* 2001;95:875-880. Capdevila X, Barthelet Y, Biboulet P, et al. Effects of perioperative analgesic technique on

Capdevila X, Biboulet P, Bouregba M, Barthelet Y, Rubenovitch J, d'Athis F. Comparison of

continuous axillary catheters. *Anesth Analg* 2000;96:247-252.

interscalene nerve block. *Can J Anaesth* 1999;46:275–81.

radiographic analysis. *Anesth Analg* 1998; 86: 1039–44.

catheters for continuous femoral blockade after total knee arthroplasty: a randomized, controlled, double blind trial. *Anesth Analg*. 2008;106:1316Y1321. Beach ML, Sites BD, Gallagher JD. Use of a nerve stimulator does not improve the efficacy of ultrasound-guided supraclavicular nerve blocks*. J Clin Anesth* 2006; 18:580–584. Bergman BD, Hebl JR, Kent J, Horlocker TT. Neurologic complications of 405 consecutive

Thresholds during Ultrasound-guided Supraclavicular Block. *Anesthesiology 2009;* 

the surgical outcome and duration of rehabilitation after major knee surgery.

the three-in-one and fascia iliaca compartment blocks in adults: clinical and

cost/effective technique for femoral catheter placement.

effects of the primary block may still be effective.

**10. Conclusions** 

**11. Future directions** 

**12. References** 

121: 716 – 722

*110:1235–43* 

2007 Nov; 56(11): 1156-62 .

*Anaesthesia* 96 (1): 139–42 (2006)

*Anesthesiology* 1999; 91:8–15.


**13** 

*USA* 

*Department of Anesthesiology,* 

**Regional Anesthesia for the Trauma Patient** 

Trauma is the sixth most common cause of death globally [WHO, 2011]. In the United States, almost 30 million patients receive medical care for trauma every year [CDC, 2011], and trauma results in 30% of intensive care unit (ICU) admissions in the United States [Mackenzie et al., 2007]. In the Emergency Department, 91% of trauma patients are in pain [Berben et al., 2008], and two-thirds of those patients are discharged from the Emergency Department with moderate to severe pain [Berben et al., 2008]. Regional anesthesia (RA) can reduce pain in many of these patients. In this chapter, common problems with managing trauma patients that can be addressed with RA, and data suggesting that regional anesthesia can improve outcomes will be presented, as well as the different challenges to using RA in this patient population. We will also look into new and controversial areas of inquiry in this

**2. Patients with traumatic injuries who can benefit from regional anesthesia** 

Thoracic injury accounts for 25% of deaths among trauma patients. It is second only to head injury as a cause of trauma-related deaths in the United States [Trunkey & Lewis, 1980]. Rib fractures are common, and morbidity and mortality are directly correlated with the number of rib fractures [Flagel et al., 2005].Elderly patients have a particularly high incidence of rib fractures, with a higher rate of morbidity and mortality from these fractures than younger patients [Bulger et al., 2000; Shorr et al., 1989]. Improved analgesia, by various methods, has been shown to improve pulmonary function, including peak expiratory flow, maximum inspiratory force, tidal volume, and oxygen saturation [Luchette et al., 1994; Moon et al.,

Thoracic epidural analgesia (TEA) has been shown to improve outcome after multiple rib fractures [Bulger et al., 2004;Flagel et al., 2005; Moon et al., 1999; Wisner, 1990].As early as 1990, a retrospective regression analysis of a trauma database revealed decreased pulmonary complications and decreased mortality in elderly patients with rib fractures that were treated with TEA as compared to parenteral opiates [Wisner, 1990].Moon et al showed improved pulmonary mechanics and decreased levels of the proinflammatory chemoattractant, interleukin 8, in a prospective, randomized trial that compared TEA with parenteral opioids in patients with thoracic trauma [Moon et al., 1999]. Another

**1. Introduction** 

field.

**2.1 Thoracic trauma and rib fractures** 

1999; Osinowo et al., 2004].

Stephen D. Lucas, Linda Le-Wendling and F. Kayser Enneking

*University of Florida College of Medicine, Gainesville, Florida,* 


### **Regional Anesthesia for the Trauma Patient**

Stephen D. Lucas, Linda Le-Wendling and F. Kayser Enneking

*Department of Anesthesiology, University of Florida College of Medicine, Gainesville, Florida, USA* 

#### **1. Introduction**

260 Pain Management – Current Issues and Opinions

Mariano ER, Loland VJ, Sandhu NS, Bellars RH, Bishop ML, Afra R, Ball ST, Meyer RS,

Navas A.M, Gutieirrez T.V, Moreno M.E. Continuous peripheral nerve blockade in lower

Niazi AU, Prasad A, Ramlogan R, Chan VW. Methods to ease placement of stimulating

Parkinson SK, Mueller JB, Little WL, Bailey SL. Extent of blockade with various approaches

Pham-Dang C., Kick o, Collet T, et al. Continuous peripheral nerve blocks with stimulating

Pham Dang C, Difalco C, Guilley J, Venet G, Hauet P, Lejus C. Various possible positions of

Pham Dang C, Lelong A, Guilley J, Nguyen JM, Volteau C, Venet G, Perrier C, Lejus C,

Salinas FV. Location, location, location: continuous peripheral nerve blocks and stimulating

Sandhu NS, Sidhu DS, Capan LM. The cost comparison of infraclavicular brachial plexus

Singelyn F, Deyaert M, Pendeville E et al. Effects of intravenous patient-controlled analgesia

Singelyn F, Gouverneur JM. Postoperative analgesia after total hip arthroplasty: i.v. PCA

Singelyn FJ, Gouverneur JM. Extended "three-in-one" block after total knee arthroplasty: continuous versus patient-controlled techniques. *Anesth Analg* 2000;91:176–80.). Tsui BC, Kropelin B, Ganapathy S, Finucane B. Dextrose 5% in water: fluid medium

Walker A, Roberts S. Stimulating catheters: a thing of the past? *Anesth Analg* 2007; 104:1001–1002. Winnie AP, Ramamurthy S, Durrani Z. The inguinal paravascular technique of lumbar

plexus anesthesia: The "3 in 1" block. *Anesth Analg* 1973;52:989-996.

Selander D. Catheter technique in axillary block. *Acta Anaesth Scand* 1977;21:324–329.

dextrose 5% in water.*Reg Anesth Pain Med.* 2009 Sep-Oct;34(5):398-403. Salinas FV, Neal JM, Sueda LA, Kopacz DJ, Liu SS. Prospective comparison of continuous

extremity surgery. *Acta Anaesthesiol Scand* 2005; 49: 1048—1055

to the lumbar plexus. *Anesth Analg* 1989;68:243-248.

catheters. *Reg Anesth Pain Med 2003;28:83-88.*

*Anesth Pain Med.* 2009 Jul-Aug;34(4):285-9.

catheters. *Reg Anesth Pain Med* 2003;28:79–82.

arthroplasty. *Anesth Analg* 1998; 87: 88—92.

placement. *Acta Anaesthesiol Scand*. 2005;49:1562Y1565.

*Analg*. 2005 May;100(5):1503-10.

*Med.* 2009 Jul-Aug;34(4):380-1.

May-Jun;29(3):212-20

*Anesth* 1999; 11: 550—4.

Maldonado RC, Ilfeld BM. Ultrasound guidance versus electrical stimulation for femoral perineural catheter insertion*. J Ultrasound Med.* 2009 Nov;28(11):1453-60. Morin AM, Eberhart LH, Behnke HK, Wagner S, Koch T, Wolf U, Nau W, Kill C, Geldner G,

Wulf H. Does femoral nerve catheter placement with stimulating catheters improve effective placement? A randomized, controlled, and observer-blinded trial. *Anesth* 

catheters during in-plane ultrasound-guided femoral nerve block*. Reg Anesth Pain* 

conventional catheters around the femoral nerve revealed by neurostimulation. *Reg* 

Blanloeil Y. Effect on neurostimulation of injectates used for perineural space expansion before placement of a stimulating catheter: normal saline versus

femoral nerve block with nonstimulating catheter placement versus stimulating catheter-guided perineural placement in volunteers. *Reg Anesth Pain Med*. 2004

block by nerve stimulator and ultrasound guidance. *Anesth Analg* 2004; 98:267–268.

with morphine, continuous epidural analgesia and continuous three-in-one block on postoperative pain and knee rehabilitation after unilateraltotal knee

with morphine, patientcontrolled epidural analgesia, or continuous '3-in-1' block?: a prospective evaluation by our acute pain service in more han 1,300 patients. *J Clin* 

maintaining electrical stimulation of peripheral nerve during stimulating catheter

Trauma is the sixth most common cause of death globally [WHO, 2011]. In the United States, almost 30 million patients receive medical care for trauma every year [CDC, 2011], and trauma results in 30% of intensive care unit (ICU) admissions in the United States [Mackenzie et al., 2007]. In the Emergency Department, 91% of trauma patients are in pain [Berben et al., 2008], and two-thirds of those patients are discharged from the Emergency Department with moderate to severe pain [Berben et al., 2008]. Regional anesthesia (RA) can reduce pain in many of these patients. In this chapter, common problems with managing trauma patients that can be addressed with RA, and data suggesting that regional anesthesia can improve outcomes will be presented, as well as the different challenges to using RA in this patient population. We will also look into new and controversial areas of inquiry in this field.

#### **2. Patients with traumatic injuries who can benefit from regional anesthesia**

#### **2.1 Thoracic trauma and rib fractures**

Thoracic injury accounts for 25% of deaths among trauma patients. It is second only to head injury as a cause of trauma-related deaths in the United States [Trunkey & Lewis, 1980]. Rib fractures are common, and morbidity and mortality are directly correlated with the number of rib fractures [Flagel et al., 2005].Elderly patients have a particularly high incidence of rib fractures, with a higher rate of morbidity and mortality from these fractures than younger patients [Bulger et al., 2000; Shorr et al., 1989]. Improved analgesia, by various methods, has been shown to improve pulmonary function, including peak expiratory flow, maximum inspiratory force, tidal volume, and oxygen saturation [Luchette et al., 1994; Moon et al., 1999; Osinowo et al., 2004].

Thoracic epidural analgesia (TEA) has been shown to improve outcome after multiple rib fractures [Bulger et al., 2004;Flagel et al., 2005; Moon et al., 1999; Wisner, 1990].As early as 1990, a retrospective regression analysis of a trauma database revealed decreased pulmonary complications and decreased mortality in elderly patients with rib fractures that were treated with TEA as compared to parenteral opiates [Wisner, 1990].Moon et al showed improved pulmonary mechanics and decreased levels of the proinflammatory chemoattractant, interleukin 8, in a prospective, randomized trial that compared TEA with parenteral opioids in patients with thoracic trauma [Moon et al., 1999]. Another

Regional Anesthesia for the Trauma Patient 263

thoracic paravertebral block [Purcell-Jones et al., 1989]. The authors have also experienced and reported the unintended placement of a catheter in the epidural space during TPVC placement [Lucas et al., 2011, Epub ahead of print]. Considerable controversy exists regarding the relative safety of paravertebral blocks vs. epidurals in the face of anticoagulation and coagulopathy, which will be discussed later in the chapter. Frequently, bilateral rib fractures or other injuries, such as an exploratory laparotomy incision, require bilateral blockade. Although studies on the use of TPVC are still quite undeveloped, findings by Richardson et al, in a literature review on bilateral paravertebral blocks, found a favorable side effect profile. The high local anesthetic load associated with bilateral TPVC is a worthwhile consideration for analgesia in thoracic trauma patients [Richardson et al.,

The clinician is faced with a number of questions about how to proceed with regional analgesia techniques for blunt thoracic trauma. Does the patient need a catheter or not? The literature supports using either TEA or TPVC for more than three rib fractures, and in the elderly. The timing of catheter placement should be as early as *practicable*, although sometimes a short delay may be prudent to allow the anticoagulant effects to dissipate. Patients with very severe injuries may not benefit from early catheter placement, as the improvement in analgesia from RA may not likely alter the length of ventilator management. However, continuous and close monitoring in close consultation with Trauma Surgery and Critical Care Medicine can be used to determine when a patient will benefit from TPVC. Should TEA or bilateral TPVC be used? Extensive bilateral pathology is considered an indication for using thoracic epidural catheters over thoracic paravertebral catheters because of the extensive amount of local anesthetic required for multiple bilateral TPVC; however, there is scant literature to address this question. Another area of practical practice management in question is in regard to the number of catheters to place. Studies have shown loss of pinprick sensation in one to 13 dermatomes after a single-shot paravertebral block [Cheema et al., 1995; Saito et al., 2001]**.** Richardson et al measured somatosensory evoked potentials of the intercostal nerves and reliably ablated one, but only occasionally two or three nerve potentials [Richardson et al., 1998]. Most patients appear to reliably experience analgesia in approximately five dermatomes; therefore we recommend placing a second unilateral catheter for greater than four fractured ribs. This will provide some margin for error. As the process of adequately positioning and sedating these types of patients can be quite challenging, this seems to be a prudent approach. Figure 1 provides a

A number of different techniques have been reported for TPVC. When advancing a predetermined, fixed distance (1.0-1.5 cm) beyond the transverse process, loss of resistance, peripheral nerve stimulation(PNS), and various ultrasound-guided techniques have been described [Ben-Ari et al., 2009; Eason & Wyatt, 1979; Luyet et al., 2009; Naja et al., 2006]. Although any of these techniques can be used in different situations, it should be noted that ultrasound guidance and peripheral nerve stimulation can be technically limited in these patients, as they often have subcutaneous emphysema and hematomas. Measuring the depth of the transverse process and the parietal pleura on CT scan provides definitive information that can be used to guide the depth of needle insertion, thereby improving the safety margin and significantly expediting catheter placement. A CT scan also helps to

simplified algorithm for managing these patients.

determine the most severely injured ribs and flail segments.

2011].

prospective study comparing TEA and parenteral opioid analgesia for patients with rib fractures showed decreased rates of nosocomial pneumonia and a shorter duration of mechanical ventilation in the TEA group [Bulger et al., 2004].However, one frequently cited meta-analysis is noteworthy to illustrate its limitations. Carrier et al reported that there was no significant difference when using epidural analgesia over other methods in terms of mortality, ICU length of stay, and duration of mechanical ventilation [Carrier et al., 2009]. Their analysis is of limited utility, however, because they included two studies using lumbar epidural catheters and three studies using only opiate medications with the epidural infusions; these are significant departures from recommended practices. Flagel et al performed a thorough analysis of a large, sophisticated trauma database [Flagel et al., 2005].They showed that TEA was associated with a reduction in mortality for all patients who sustained rib fractures, particularly those having more than four fractures. These findings have resulted in the recommendation that TEA be included in a widely proliferated pain management guideline for blunt thoracic trauma [Simon et al., 2005].

Despite all of the enthusiasm for epidural analgesia in patients with blunt thoracic trauma, there are considerable limitations to this approach. In the previously mentioned study by Bulger et al [Bulger et al., 2004], 282 patients of 408 admitted to the hospital had to be excluded for a variety of reasons. Thoracic epidural analgesia is contraindicated in patients on anticoagulants or those who have developed a coagulopathy [Horlocker et al., 2010].Brain or spinal injuries represent, at minimum, relative contraindications to the use of TEA, as most practitioners are uncomfortable placing epidurals in the face of elevated intracranial pressure. Possible spinal cord injury, even remote from the proposed insertion site, presents a dilemma, as an epidural may obscure or alter the neurologic examination. Spinal bone injuries may also make epidural placement more technically challenging. The hypotension caused by epidurals can frequently be a significant deterrent in critically ill patients who are already hemodynamically unstable from other causes.

Thoracic paravertebral catheterization (TPVC) has emerged as an enticing answer to some, if not all of the above mentioned concerns. A small pilot study showed comparable outcomes between TEA and TPVC when they were used in patients with unilateral rib fractures [Mohta et al., 2009].These findings are bolstered by similar results in the analogous case of analgesia after thoracotomy [Davies et al., 2006; Pintaric et al., 2011; Powell et al., 2011]. Davies et al presented a systematic review and meta-analysis of 10 randomized clinical trials comparing TPVC and TEA for thoracic surgery. They found no difference in pain scores, but did note a lower incidence of pulmonary complications, urinary retention, nausea and vomiting, and hypotension in the TPVC groups [Davies et al., 2006]. A large, prospective multicenter study of pneumonectomy in the United Kingdom found that TEA was associated with a higher incidence of major complications compared to TPVC [Powell et al., 2011]. A recent prospective randomized study comparing TEA and TPVC, with a primary endpoint of hemodynamic stability, found that TPVC was associated with similar analgesia levels to TEA, but with greater hemodynamic stability [Pintaric et al., 2011].

Should TPVC supplant TEA as the primary modality for providing analgesia for blunt thoracic trauma? A few caveats are in order. Epidural spread has been reported with

prospective study comparing TEA and parenteral opioid analgesia for patients with rib fractures showed decreased rates of nosocomial pneumonia and a shorter duration of mechanical ventilation in the TEA group [Bulger et al., 2004].However, one frequently cited meta-analysis is noteworthy to illustrate its limitations. Carrier et al reported that there was no significant difference when using epidural analgesia over other methods in terms of mortality, ICU length of stay, and duration of mechanical ventilation [Carrier et al., 2009]. Their analysis is of limited utility, however, because they included two studies using lumbar epidural catheters and three studies using only opiate medications with the epidural infusions; these are significant departures from recommended practices. Flagel et al performed a thorough analysis of a large, sophisticated trauma database [Flagel et al., 2005].They showed that TEA was associated with a reduction in mortality for all patients who sustained rib fractures, particularly those having more than four fractures. These findings have resulted in the recommendation that TEA be included in a widely proliferated pain management guideline for blunt thoracic trauma [Simon et al.,

Despite all of the enthusiasm for epidural analgesia in patients with blunt thoracic trauma, there are considerable limitations to this approach. In the previously mentioned study by Bulger et al [Bulger et al., 2004], 282 patients of 408 admitted to the hospital had to be excluded for a variety of reasons. Thoracic epidural analgesia is contraindicated in patients on anticoagulants or those who have developed a coagulopathy [Horlocker et al., 2010].Brain or spinal injuries represent, at minimum, relative contraindications to the use of TEA, as most practitioners are uncomfortable placing epidurals in the face of elevated intracranial pressure. Possible spinal cord injury, even remote from the proposed insertion site, presents a dilemma, as an epidural may obscure or alter the neurologic examination. Spinal bone injuries may also make epidural placement more technically challenging. The hypotension caused by epidurals can frequently be a significant deterrent in critically ill patients who are already hemodynamically unstable from other

Thoracic paravertebral catheterization (TPVC) has emerged as an enticing answer to some, if not all of the above mentioned concerns. A small pilot study showed comparable outcomes between TEA and TPVC when they were used in patients with unilateral rib fractures [Mohta et al., 2009].These findings are bolstered by similar results in the analogous case of analgesia after thoracotomy [Davies et al., 2006; Pintaric et al., 2011; Powell et al., 2011]. Davies et al presented a systematic review and meta-analysis of 10 randomized clinical trials comparing TPVC and TEA for thoracic surgery. They found no difference in pain scores, but did note a lower incidence of pulmonary complications, urinary retention, nausea and vomiting, and hypotension in the TPVC groups [Davies et al., 2006]. A large, prospective multicenter study of pneumonectomy in the United Kingdom found that TEA was associated with a higher incidence of major complications compared to TPVC [Powell et al., 2011]. A recent prospective randomized study comparing TEA and TPVC, with a primary endpoint of hemodynamic stability, found that TPVC was associated with similar analgesia levels to TEA, but with greater hemodynamic

Should TPVC supplant TEA as the primary modality for providing analgesia for blunt thoracic trauma? A few caveats are in order. Epidural spread has been reported with

2005].

causes.

stability [Pintaric et al., 2011].

thoracic paravertebral block [Purcell-Jones et al., 1989]. The authors have also experienced and reported the unintended placement of a catheter in the epidural space during TPVC placement [Lucas et al., 2011, Epub ahead of print]. Considerable controversy exists regarding the relative safety of paravertebral blocks vs. epidurals in the face of anticoagulation and coagulopathy, which will be discussed later in the chapter. Frequently, bilateral rib fractures or other injuries, such as an exploratory laparotomy incision, require bilateral blockade. Although studies on the use of TPVC are still quite undeveloped, findings by Richardson et al, in a literature review on bilateral paravertebral blocks, found a favorable side effect profile. The high local anesthetic load associated with bilateral TPVC is a worthwhile consideration for analgesia in thoracic trauma patients [Richardson et al., 2011].

The clinician is faced with a number of questions about how to proceed with regional analgesia techniques for blunt thoracic trauma. Does the patient need a catheter or not? The literature supports using either TEA or TPVC for more than three rib fractures, and in the elderly. The timing of catheter placement should be as early as *practicable*, although sometimes a short delay may be prudent to allow the anticoagulant effects to dissipate. Patients with very severe injuries may not benefit from early catheter placement, as the improvement in analgesia from RA may not likely alter the length of ventilator management. However, continuous and close monitoring in close consultation with Trauma Surgery and Critical Care Medicine can be used to determine when a patient will benefit from TPVC. Should TEA or bilateral TPVC be used? Extensive bilateral pathology is considered an indication for using thoracic epidural catheters over thoracic paravertebral catheters because of the extensive amount of local anesthetic required for multiple bilateral TPVC; however, there is scant literature to address this question. Another area of practical practice management in question is in regard to the number of catheters to place. Studies have shown loss of pinprick sensation in one to 13 dermatomes after a single-shot paravertebral block [Cheema et al., 1995; Saito et al., 2001]**.** Richardson et al measured somatosensory evoked potentials of the intercostal nerves and reliably ablated one, but only occasionally two or three nerve potentials [Richardson et al., 1998]. Most patients appear to reliably experience analgesia in approximately five dermatomes; therefore we recommend placing a second unilateral catheter for greater than four fractured ribs. This will provide some margin for error. As the process of adequately positioning and sedating these types of patients can be quite challenging, this seems to be a prudent approach. Figure 1 provides a simplified algorithm for managing these patients.

A number of different techniques have been reported for TPVC. When advancing a predetermined, fixed distance (1.0-1.5 cm) beyond the transverse process, loss of resistance, peripheral nerve stimulation(PNS), and various ultrasound-guided techniques have been described [Ben-Ari et al., 2009; Eason & Wyatt, 1979; Luyet et al., 2009; Naja et al., 2006]. Although any of these techniques can be used in different situations, it should be noted that ultrasound guidance and peripheral nerve stimulation can be technically limited in these patients, as they often have subcutaneous emphysema and hematomas. Measuring the depth of the transverse process and the parietal pleura on CT scan provides definitive information that can be used to guide the depth of needle insertion, thereby improving the safety margin and significantly expediting catheter placement. A CT scan also helps to determine the most severely injured ribs and flail segments.

Regional Anesthesia for the Trauma Patient 265




supraclavicular block





paravertebral or deep cervical plexus





extremity below knee

popliteal)

Table 1. Regional Anesthesia Considerations for Common Long Bone Fractures

block, or

continuous

continuous -Interscalene or cervical paravertebral


Greater predominance

of sciatic nerve innervation

fractures

Radial nerve injury may occur with midshaft humeral

Possibility of brachial plexus injury due to surgical fixation

Skin overlying clavicle is innervated by supraclavicular nerves, which may be injured during surgery

Compartment

accidents

syndrome may occur, especially with young males in high-velocity

Femoral nerve Sciatic

predominantly C6-C7-

predominantly C5-C6

predominantly C4, C5, C6 roots

Radius/Ulna Brachial plexus, C5-T1 -Single injection

predominantly Possibly femoral nerve in proximal fractures such as tibial

plateau


nerve

roots

roots

roots

Distal humerus -Brachial plexus,

Clavicle (distal) Brachial plexus,

Clavicle (proximal) Brachial plexus,

Tibia/Fibula Sciatic nerve

Midshaft and distal

Proximal and midhumerus

femur

Fig. 1. Algorithm for managing analgesia in patients with multiple rib fractures.

#### **2.2 Long bone fractures**

Long bones are composed of a diaphysis, or hollow shaft, connected to the physis, or growth plate, at each end via the metaphysis. Long bones in the body include the humerus, radius, ulna, femur, tibia, fibula, and phalanges. Long bone fractures can result in significant pain, especially prior to stabilization, due to the significant number of nerve endings located in the periosteum and mineralized bone [Mach et al., 2002]. While sclerotome maps have been created to assist in the understanding of innervation to the bones, little evidence exists to confirm their accuracy. Classic studies, including those by Inman and Saunders in 1944 [Inman & Saunders, 1944], provide some evidence for the skeletal innervation [Ivanusic, 2007]. We will review anatomical considerations of the most common fractures and suggest strategies for analgesic management (Table 1).


Fig. 1. Algorithm for managing analgesia in patients with multiple rib fractures.

Long bones are composed of a diaphysis, or hollow shaft, connected to the physis, or growth plate, at each end via the metaphysis. Long bones in the body include the humerus, radius, ulna, femur, tibia, fibula, and phalanges. Long bone fractures can result in significant pain, especially prior to stabilization, due to the significant number of nerve endings located in the periosteum and mineralized bone [Mach et al., 2002]. While sclerotome maps have been created to assist in the understanding of innervation to the bones, little evidence exists to confirm their accuracy. Classic studies, including those by Inman and Saunders in 1944 [Inman & Saunders, 1944], provide some evidence for the skeletal innervation [Ivanusic, 2007]. We will review anatomical considerations of the most common fractures and suggest

Block for Analgesia



anesthesia, neuraxial anesthesia may decrease incidence of postoperative confusion

For surgical

**2.2 Long bone fractures** 

strategies for analgesic management (Table 1).

Proximal femur Femoral nerve Sciatic

nerve

Fracture Innervation Recommended Nerve

nerve Obturator


Table 1. Regional Anesthesia Considerations for Common Long Bone Fractures

Regional Anesthesia for the Trauma Patient 267

Sciatic nerve blocksbecome more important in more distal femur fractures and fractures of the leg and ankle. Various approaches to the sciatic nerve are utilized. For femur fractures, more proximal approaches, such as the classic Labat technique or the subgluteal approach [Di Benedetto et al, 2002; Franco et al., 2006], are appropriate. For leg and ankle fractures, a more distal approach, such as a popliteal catheter, may be more suitable, as sparing of the

The subgluteal approach can be achieved with stimulation or ultrasound. Using the stimulation technique, the proceduralist elicits appropriate motor twitches, such as plantar/dorsiflexion and gastrocnemius twitches. When employing ultrasound [Danelli et al., 2009; Karmaker et al., 2007], a low frequency ultrasound probe allows visualization of the proximal femur and ischial tuberosity, as well as the sciatic nerve between these two bones. Confirmation of the nerve location on ultrasound can be done by tracing the nerve distally to the popliteal crease as the nerve divides into its two terminal branches: the

Proximal humerus fractures are the third, most common fracture in the elderly patient (4-5% of all fractures) after femur fractures and radial fractures [Court-Brown et al., 2001]. The most common mechanism of proximal humeral fractures in the elderly are falls [Chu et al., 2004]. Midhumeral fractures occur in 1-2% of patients, with the mechanism of this injury usually resulting from a direct blow to the arm or application of a bending force to the humeral shaft. This type of fracture typically occurs in the young, physically active patient [Ogawa et al., 1998]. Documentation of any radial nerve injury is important prior to proceeding with a regional anesthetic technique, especially with midhumeral shaft fractures in which the radial nerve may be injured from the trauma as it courses posteriorly alongside the humerus in the spiral groove [Ekholm et al., 2006]. Clavicle fractures also occur in the younger population and are usually related to direct or indirect trauma to the clavicle, commonly due to traffic accidents or a sports-related injury [Pecci et al., 2008; Postacchini et

The humerus receives its innervation from the brachial plexus. Like the femur, multiple nerves are involved in providing sensation to the bone. Derivations of the C5 and C6 nerve root predominantly innervate the humerus. As the fracture becomes more distal, the innervation emanates from derivations of the C7 nerve root, and a regional anesthetic

Single injections may be performed using a cervical paravertebral, interscalene, or supraclavicular block. However, fractures of the humerus are painful, even after surgical stabilization, and a continuous approach is recommended for prolonged analgesia. Both stimulation and ultrasound-guided approaches have been utilized successfully. If using stimulation, biceps and deltoids are elicited as endpoints for a proximal humerus fracture and triceps stimulation for distal humeral fractures. As with femur fractures, use of stimulation may result in severe pain, and short but intense systemic analgesia may be needed for patient comfort. Ultrasound allows visualization of the brachial plexus from the root all the way to the terminal nerve, and can assist in minimizing needle attempts. By using ultrasound, nerves can be traced to their origin where they exit the intervertebral foramen as they convene in the interscalene groove, and

hamstring musculature is important for ambulation.

**2.2.2 Humerus and clavicle fractures** 

al., 2002; Robinson et al., 1998].

technique should be targeted accordingly.

common perineal and posterior tibial nerve [Bruhn et al., 2008].

#### **2.2.1 Femur fractures**

Femur fractures represent a majority of the patients who suffer from long bone fractures, with one-third of these eventually undergoing surgical stabilization. Regional anesthesia for lower extremity fractures, including femur and hip fractures, has been extensively studied in the literature. Meta-analyses suggest that regional anesthesia, specifically neuraxial anesthesia, decreases the incidence of DVT and pulmonary embolism as well as the incidence of postoperative confusion, in addition to reducing the risk of postoperative pneumonia in patients who require surgical stabilization. Whether regional anesthesia affects mortality in the patient with a femur fracture has yet to be determined [Luger et al., 2010; Parker et al., 2004]. Evidence does suggest that analgesia is improved, and systemic analgesics are spared, when regional anesthesia techniques, such as perineural nerve blocks, are used to help manage pain in patients with hip fractures [Parker, 2002]. Femoral nerve blocks have also been shown to optimize patient positioning for performance of a neuraxial block [Sia et al., 2004; Yun, 2009]**.**

Analgesia for proximal femur fractures may be obtained by blocking the femoral nerve, whether via a single injection or continuous block technique. Although the femur has innervations from multiple nerves, proximally, the femur is predominantly innervated by the femoral nerve, with contributions from the sciatic nerve and an articular branch of the obturator nerve [Locher et al., 2008].

There are a variety of methods available for performance of femoral nerve blocks. The femoral nerve can be anesthetized using stimulation, ultrasound [Beaudoin et al., 2010; Marhofer et al., 1998]**,** or a fascial-pop technique [Candal-Couto et al., 2005; Dalens et al., 1989; Haddad et al., 1995]

Nerve stimulation approaches to the femoral nerve block are common but may cause significant discomfort in a patient with a fracture. The use of ultrasound has been popularized in the past decade for its various benefits. The femoral nerve can be easily visualized at the inguinal crease lateral to the femoral artery, below the fascia lata and iliaca, on the anteromedial aspect of the iliopsoas muscle as it attaches to the proximal femur. The needle can be readily identified since the femoral nerve is typically superficial in nature, and local anesthetic spread is obvious on ultrasound as it encircles the nerve.

In the absence of available ultrasound machines or nerve stimulators, the fascia iliaca compartment block can be easily performed using a simple blunt needle and local anesthetic. This technique has been successfully used in the emergency department setting [Foss et al., 2007; Monzon et al., 2007; Wathen et al., 2007]. The proceduralist draws a line connecting the pubic bone to the anterior superior iliac spine, and divides this line into thirds. At the marking between the distal third (near the anterior superior iliac spine) and middle third, a blunt needle is advanced one centimeter below this point until two pops are felt, the first as the needle punctures the fascia lata and the second as the needle punctures the fascia iliaca. Local anesthetic volumes similar to those used for stimulation-based approaches (20 mL) have been used successfully with the fascia iliaca block with good efficacy [Lopez et al., 2003]; however**,** weight-based dosing (0.3 mL/kg) [Monzon et al., 2007; Mouzopoulos et al., 2009] and higher doses may be considered to improve local anesthetic delivery [Candal-Couto et al., 2005]. As with any block performed with high volume, confirmation that no intravascular injection has occurred is necessary.

Femur fractures represent a majority of the patients who suffer from long bone fractures, with one-third of these eventually undergoing surgical stabilization. Regional anesthesia for lower extremity fractures, including femur and hip fractures, has been extensively studied in the literature. Meta-analyses suggest that regional anesthesia, specifically neuraxial anesthesia, decreases the incidence of DVT and pulmonary embolism as well as the incidence of postoperative confusion, in addition to reducing the risk of postoperative pneumonia in patients who require surgical stabilization. Whether regional anesthesia affects mortality in the patient with a femur fracture has yet to be determined [Luger et al., 2010; Parker et al., 2004]. Evidence does suggest that analgesia is improved, and systemic analgesics are spared, when regional anesthesia techniques, such as perineural nerve blocks, are used to help manage pain in patients with hip fractures [Parker, 2002]. Femoral nerve blocks have also been shown to optimize patient positioning for performance of a neuraxial

Analgesia for proximal femur fractures may be obtained by blocking the femoral nerve, whether via a single injection or continuous block technique. Although the femur has innervations from multiple nerves, proximally, the femur is predominantly innervated by the femoral nerve, with contributions from the sciatic nerve and an articular branch of the

There are a variety of methods available for performance of femoral nerve blocks. The femoral nerve can be anesthetized using stimulation, ultrasound [Beaudoin et al., 2010; Marhofer et al., 1998]**,** or a fascial-pop technique [Candal-Couto et al., 2005; Dalens et al.,

Nerve stimulation approaches to the femoral nerve block are common but may cause significant discomfort in a patient with a fracture. The use of ultrasound has been popularized in the past decade for its various benefits. The femoral nerve can be easily visualized at the inguinal crease lateral to the femoral artery, below the fascia lata and iliaca, on the anteromedial aspect of the iliopsoas muscle as it attaches to the proximal femur. The needle can be readily identified since the femoral nerve is typically superficial in nature, and

In the absence of available ultrasound machines or nerve stimulators, the fascia iliaca compartment block can be easily performed using a simple blunt needle and local anesthetic. This technique has been successfully used in the emergency department setting [Foss et al., 2007; Monzon et al., 2007; Wathen et al., 2007]. The proceduralist draws a line connecting the pubic bone to the anterior superior iliac spine, and divides this line into thirds. At the marking between the distal third (near the anterior superior iliac spine) and middle third, a blunt needle is advanced one centimeter below this point until two pops are felt, the first as the needle punctures the fascia lata and the second as the needle punctures the fascia iliaca. Local anesthetic volumes similar to those used for stimulation-based approaches (20 mL) have been used successfully with the fascia iliaca block with good efficacy [Lopez et al., 2003]; however**,** weight-based dosing (0.3 mL/kg) [Monzon et al., 2007; Mouzopoulos et al., 2009] and higher doses may be considered to improve local anesthetic delivery [Candal-Couto et al., 2005]. As with any block performed with high volume, confirmation that no intravascular injection has occurred is

local anesthetic spread is obvious on ultrasound as it encircles the nerve.

**2.2.1 Femur fractures** 

block [Sia et al., 2004; Yun, 2009]**.**

obturator nerve [Locher et al., 2008].

1989; Haddad et al., 1995]

necessary.

Sciatic nerve blocksbecome more important in more distal femur fractures and fractures of the leg and ankle. Various approaches to the sciatic nerve are utilized. For femur fractures, more proximal approaches, such as the classic Labat technique or the subgluteal approach [Di Benedetto et al, 2002; Franco et al., 2006], are appropriate. For leg and ankle fractures, a more distal approach, such as a popliteal catheter, may be more suitable, as sparing of the hamstring musculature is important for ambulation.

The subgluteal approach can be achieved with stimulation or ultrasound. Using the stimulation technique, the proceduralist elicits appropriate motor twitches, such as plantar/dorsiflexion and gastrocnemius twitches. When employing ultrasound [Danelli et al., 2009; Karmaker et al., 2007], a low frequency ultrasound probe allows visualization of the proximal femur and ischial tuberosity, as well as the sciatic nerve between these two bones. Confirmation of the nerve location on ultrasound can be done by tracing the nerve distally to the popliteal crease as the nerve divides into its two terminal branches: the common perineal and posterior tibial nerve [Bruhn et al., 2008].

#### **2.2.2 Humerus and clavicle fractures**

Proximal humerus fractures are the third, most common fracture in the elderly patient (4-5% of all fractures) after femur fractures and radial fractures [Court-Brown et al., 2001]. The most common mechanism of proximal humeral fractures in the elderly are falls [Chu et al., 2004]. Midhumeral fractures occur in 1-2% of patients, with the mechanism of this injury usually resulting from a direct blow to the arm or application of a bending force to the humeral shaft. This type of fracture typically occurs in the young, physically active patient [Ogawa et al., 1998]. Documentation of any radial nerve injury is important prior to proceeding with a regional anesthetic technique, especially with midhumeral shaft fractures in which the radial nerve may be injured from the trauma as it courses posteriorly alongside the humerus in the spiral groove [Ekholm et al., 2006]. Clavicle fractures also occur in the younger population and are usually related to direct or indirect trauma to the clavicle, commonly due to traffic accidents or a sports-related injury [Pecci et al., 2008; Postacchini et al., 2002; Robinson et al., 1998].

The humerus receives its innervation from the brachial plexus. Like the femur, multiple nerves are involved in providing sensation to the bone. Derivations of the C5 and C6 nerve root predominantly innervate the humerus. As the fracture becomes more distal, the innervation emanates from derivations of the C7 nerve root, and a regional anesthetic technique should be targeted accordingly.

Single injections may be performed using a cervical paravertebral, interscalene, or supraclavicular block. However, fractures of the humerus are painful, even after surgical stabilization, and a continuous approach is recommended for prolonged analgesia. Both stimulation and ultrasound-guided approaches have been utilized successfully. If using stimulation, biceps and deltoids are elicited as endpoints for a proximal humerus fracture and triceps stimulation for distal humeral fractures. As with femur fractures, use of stimulation may result in severe pain, and short but intense systemic analgesia may be needed for patient comfort. Ultrasound allows visualization of the brachial plexus from the root all the way to the terminal nerve, and can assist in minimizing needle attempts. By using ultrasound, nerves can be traced to their origin where they exit the intervertebral foramen as they convene in the interscalene groove, and

Regional Anesthesia for the Trauma Patient 269

fibula fractures, if uncomplicated, normally do not require more than a single-injection sciatic nerve block, with or without a saphenous nerve block depending on the medial

The anesthesiologist who performs RA for trauma patients has several challenges that must be addressed, and, thus, it is imperative to have a solid understanding of the complexities of compartment syndrome and coagulation issues in the trauma patient. Included in this chapter is a discussion on a number of technical challenges that frequently arise in trauma patients will be discussed, along with various solutions to these challenges. There are presently exciting opportunities in the field of RA for the trauma patient, one of which will

Compartment syndrome has been defined as a condition in which increased pressure within a closed compartment is compromising the circulation and function of the tissues within

In the setting of patients who have experienced trauma, we are primarily concerned with acute compartment syndrome (ACS). The most common sites of ACS are the forearm or leg, although it can occur in any closed compartment. Over 200,000 patients are diagnosed with ACS in the United States every year [Konstanantakos et al., 2007];fractures and various soft tissue injuries are the most common causes (Table 2) [McQueen et al., 2000] .Men are at a substantially greater risk than women, as are patients <35 years old [McQueen et al., 2000].

The sine qua non of ACS management is early diagnosis and treatment, with extensive fasciotomy [Kashuk et al., 2009].Classically, the diagnosis of ACS is made by recognition of the 6 P's (Table 3) [Elliott & Johnstone, 2003].Of these, pulselessness and paralysis occur too late to effectively provide an intervention, and palpation abnormalities are difficult to discern in the traumatized patient. The other signs and symptoms all involve the need for the patient to sense the pain or parasthesia. For this reason, the use of RA in patients at risk for developing

cutaneous involvement of the injury or location of the surgical incision.

be elucidated: the provision of RA in the prehospital or early hospital period.

**3. Challenges and opportunities** 

**3.1 Compartment syndrome** 

that space [Matsen, 1975].

Tibial diaphyseal fracture

Pain out of proportion to injury

Pain with forced dorsiflexion

Parasthesia

Paralysis Pulselessness

Palpation (tense)

Diaphyseal fracture of the radius or ulna

Table 2. Most Common Causes of Acute Compartment Syndrome

compartment syndrome is controversial [Davis et al., 2005; Thonse et al., 2004].

Table 3. The 6 P's: Signs and Symptoms of Acute Compartment Syndrome

Soft tissue injury Distal radius fracture Crush syndrome

further down as they become situated posterolateral to the subclavian artery in the supraclavicular approach.

The clavicle is innervated from nerve roots that are more cephalad in origin [Choi et al., 2005]. While distal clavicle fractures can be anesthetized with a C5/C6 block, more medial fractures, which are more common, may be anesthetized as well by depositing local anesthetic near the C4 nerve root, which can be blocked and confirmed by ultrasound. The physician should be aware that numbness across the shoulder and upper chest wall may occur from surgical fixation due to injury to the supraclavicular nerve [Wang et al., 2010]. Furthermore, the brachial plexus lies between the first rib and clavicle as it courses to the upper extremity, and may be at risk for injury due to its proximity to a clavicle fracture.

#### **2.2.3 Radial/ulnar fractures**

Repair of radial and ulnar fractures are typically carried out in an outpatient setting, and analgesia prior to surgery is usually provided using oral systemic analgesics. Reduction of a dislocated fracture, however, is extremely painful and may be alleviated by either potent and short-acting anesthetics or a regional anesthetic technique [McManus et al., 2008]. Pain from the surgery itself is typically not severe beyond the initial perioperative phase [Chung et al., 2010], and single-injection brachial plexus blocks using a supraclavicular, infraclavicular [Chin et al., 2010], or axillary approach usually results in adequate intraoperative anesthesia and postoperative analgesia. Ultrasound guidance allows for minimal needle passes, sparing of volumes of local anesthetics, and faster onset [Liu et al., 2010; McCartney et al., 2010; Neal et al., 2010]. Because the radius and ulna are innervated by the entire brachial plexus, all branches of the brachial plexus should be considered when providing surgical anesthesia in the operating room; at the trunk level (supraclavicular), this includes the superior, middle and lower trunk, and at the cord level (infraclavicular), the lateral, posterior and medical cord should be covered. At the axillary level, all terminal nerves should be blocked, which includes the median, ulnar, radial, musculocutaneous, and medial cutaneous nerve of the forearm.

#### **2.2.4 Tibia/fibula fractures**

Fractures of the tibia and fibula may occur due to indirect (torsional injuries) or direct impact [Johner et al., 2000]. Open tibia and fibula fracture injuries occur due to high-velocity trauma, such as motor vehicle accidents [Ivarsson et al., 2008], while closed injuries occur due to falls or a sports-related injury. Isolated fibula fractures without concurrent tibial fractures are rare and usually require nonoperative treatment.

The tibia and fibula are predominantly innervated by the sciatic nerve. More proximally, the bones may receive innervation from the femoral nerve. For proximal tibia and fibula fractures, a combined femoral and sciatic nerve block is needed for more complete analgesia, especially if regional anesthesia is utilized for surgical repair Continuous blockade is the technique typically employed for proximal fractures, as many of these patients continue to have severe pain after surgical stabilization. Continuous blockade will also allow monitoring for severe pain out of proportion to what is deemed an appropriate analgesic regimen, as this may signify a developing compartment syndrome. It is important to be aware that patients with tibial fractures are at a particularly high risk of developing compartment syndrome [Park et al., 2009] (discussed in more detail below). Distal tibia and

further down as they become situated posterolateral to the subclavian artery in the

The clavicle is innervated from nerve roots that are more cephalad in origin [Choi et al., 2005]. While distal clavicle fractures can be anesthetized with a C5/C6 block, more medial fractures, which are more common, may be anesthetized as well by depositing local anesthetic near the C4 nerve root, which can be blocked and confirmed by ultrasound. The physician should be aware that numbness across the shoulder and upper chest wall may occur from surgical fixation due to injury to the supraclavicular nerve [Wang et al., 2010]. Furthermore, the brachial plexus lies between the first rib and clavicle as it courses to the upper extremity, and may be at risk for injury due to its proximity to a clavicle

Repair of radial and ulnar fractures are typically carried out in an outpatient setting, and analgesia prior to surgery is usually provided using oral systemic analgesics. Reduction of a dislocated fracture, however, is extremely painful and may be alleviated by either potent and short-acting anesthetics or a regional anesthetic technique [McManus et al., 2008]. Pain from the surgery itself is typically not severe beyond the initial perioperative phase [Chung et al., 2010], and single-injection brachial plexus blocks using a supraclavicular, infraclavicular [Chin et al., 2010], or axillary approach usually results in adequate intraoperative anesthesia and postoperative analgesia. Ultrasound guidance allows for minimal needle passes, sparing of volumes of local anesthetics, and faster onset [Liu et al., 2010; McCartney et al., 2010; Neal et al., 2010]. Because the radius and ulna are innervated by the entire brachial plexus, all branches of the brachial plexus should be considered when providing surgical anesthesia in the operating room; at the trunk level (supraclavicular), this includes the superior, middle and lower trunk, and at the cord level (infraclavicular), the lateral, posterior and medical cord should be covered. At the axillary level, all terminal nerves should be blocked, which includes the median, ulnar, radial, musculocutaneous, and

Fractures of the tibia and fibula may occur due to indirect (torsional injuries) or direct impact [Johner et al., 2000]. Open tibia and fibula fracture injuries occur due to high-velocity trauma, such as motor vehicle accidents [Ivarsson et al., 2008], while closed injuries occur due to falls or a sports-related injury. Isolated fibula fractures without concurrent tibial

The tibia and fibula are predominantly innervated by the sciatic nerve. More proximally, the bones may receive innervation from the femoral nerve. For proximal tibia and fibula fractures, a combined femoral and sciatic nerve block is needed for more complete analgesia, especially if regional anesthesia is utilized for surgical repair Continuous blockade is the technique typically employed for proximal fractures, as many of these patients continue to have severe pain after surgical stabilization. Continuous blockade will also allow monitoring for severe pain out of proportion to what is deemed an appropriate analgesic regimen, as this may signify a developing compartment syndrome. It is important to be aware that patients with tibial fractures are at a particularly high risk of developing compartment syndrome [Park et al., 2009] (discussed in more detail below). Distal tibia and

supraclavicular approach.

**2.2.3 Radial/ulnar fractures** 

medial cutaneous nerve of the forearm.

fractures are rare and usually require nonoperative treatment.

**2.2.4 Tibia/fibula fractures** 

fracture.

fibula fractures, if uncomplicated, normally do not require more than a single-injection sciatic nerve block, with or without a saphenous nerve block depending on the medial cutaneous involvement of the injury or location of the surgical incision.

#### **3. Challenges and opportunities**

The anesthesiologist who performs RA for trauma patients has several challenges that must be addressed, and, thus, it is imperative to have a solid understanding of the complexities of compartment syndrome and coagulation issues in the trauma patient. Included in this chapter is a discussion on a number of technical challenges that frequently arise in trauma patients will be discussed, along with various solutions to these challenges. There are presently exciting opportunities in the field of RA for the trauma patient, one of which will be elucidated: the provision of RA in the prehospital or early hospital period.

#### **3.1 Compartment syndrome**

Compartment syndrome has been defined as a condition in which increased pressure within a closed compartment is compromising the circulation and function of the tissues within that space [Matsen, 1975].

In the setting of patients who have experienced trauma, we are primarily concerned with acute compartment syndrome (ACS). The most common sites of ACS are the forearm or leg, although it can occur in any closed compartment. Over 200,000 patients are diagnosed with ACS in the United States every year [Konstanantakos et al., 2007];fractures and various soft tissue injuries are the most common causes (Table 2) [McQueen et al., 2000] .Men are at a substantially greater risk than women, as are patients <35 years old [McQueen et al., 2000].

Tibial diaphyseal fracture Soft tissue injury Distal radius fracture Crush syndrome Diaphyseal fracture of the radius or ulna

Table 2. Most Common Causes of Acute Compartment Syndrome

The sine qua non of ACS management is early diagnosis and treatment, with extensive fasciotomy [Kashuk et al., 2009].Classically, the diagnosis of ACS is made by recognition of the 6 P's (Table 3) [Elliott & Johnstone, 2003].Of these, pulselessness and paralysis occur too late to effectively provide an intervention, and palpation abnormalities are difficult to discern in the traumatized patient. The other signs and symptoms all involve the need for the patient to sense the pain or parasthesia. For this reason, the use of RA in patients at risk for developing compartment syndrome is controversial [Davis et al., 2005; Thonse et al., 2004].

Pain out of proportion to injury Parasthesia Pain with forced dorsiflexion Palpation (tense) Paralysis Pulselessness

Table 3. The 6 P's: Signs and Symptoms of Acute Compartment Syndrome

Regional Anesthesia for the Trauma Patient 271

There are no reported cases of delayed ACS diagnosis attributed to continuous perineural infusions. The absence of reports certainly does not imply that RA poses no risk to these patients, but may represent a number of factors, such as failure to report complications or avoidance of RA in these patients. Conversely, the literature certainly does not support a wholesale abandonment of RA in patients at risk. We would recommend avoiding longlasting dense blockade, using minimally effective infusions, and promptly addressing insensate limbs by withholding infusions until pinprick sensation returns. Perhaps even more importantly is a high level of vigilance as was exhibited by Cometa et al [Cometa et al., 2011] and close cooperation between the orthopedic surgeons and anesthesiologists involved. Using RA in these patients should only be considered in centers with a willingness to dedicate resources to the close monitoring of these patients and with

Despite all the attention to the subjective symptoms of ACS, they have actually been found to be quite unreliable [Ulmer, 2002 ]. A reliable objective measure to diagnose ACS would drastically improve care. Most of the attention in the past has been centered on direct, invasive measurement of intracompartmental pressures [Al-Dadah et al., 2008; Harris, et al., 2006].These techniques have, to date, been somewhat limited by technical problems. The most promising use of this approach would appear to be the series reported by McQueen and Court-Brown, who suggest that maintaining a differential pressure between the diastolic blood pressure and an intracompartmental pressure greater than 30 mm Hg is protective [McQueen et al., 1996].Much more exciting is the prospect of a noninvasive modality, such as near-infrared spectroscopy or laser Doppler flowmetry capable of diagnosing ACS [Elliott & Johnstone, 2003]. Evidently, further research is needed in this

The trauma patient, depending on the injury, may be at risk for bleeding or clotting. Patients with a high volume blood loss and massive resuscitation can end up with a dilutional coagulopathy, while patients with lower extremity fractures, intracranial injuries, and immobility may be at risk for thromboembolic complications necessitating aggressive anticoagulation strategies. An increasing number of patients present with anticoagulants as part of their home medicine regimen (e.g. Plavix for patients with coronary stents). Close vigilance of the patient's coagulation status, whether hyper- or hypocoagulable, is important

Venous thromboembolism can lead to pulmonary embolism, the most common preventable cause of hospital death. In patients with major trauma who are not receiving thromboprophylaxis, rates of DVT can range anywhere between 40 and 80% [Geerts et al., 2008], with rates of pulmonary embolism between 1 and 2% depending on severity of the injury [Schuerer et al., 2005]. Pulmonary embolism is the 3rd leading cause of death for patients who survive beyond the first day [Geerts et al., 2008]. Independent predictors of DVT include spinal cord injury, lower extremity or pelvic fracture, surgery, increasing age, prolonged immobility, and delay in institution of thromboprophylaxis [Geerts et al.,

caregivers who are acutely aware of the risks involved.

**3.2 Regional anesthesia and anticoagulation** 

prior to initiation of a regional technique.

**3.2.1 Venous thromboembolism risk in the trauma patient** 

area.

2008].

There are no randomized controlled trials comparing outcomes in patients at risk for ACS who had local anesthetic-based analgesia versus opioid-based analgesia. Clinical practice and recommendations have been founded on case reports and retrospective case series [Mar et al., 2009]; Clark's recent excellent editorial pointed out the usefulness of these case reports [Clark, 2011]. However, it is imperative that we carefully review these reports and not overinterpret their significance. It would seem an archaic practice to simply allow all patients at risk for ACS to suffer. Alternatives to RA, such as patient-controlled analgesia, have also been implicated as obscuring an ACS diagnosis [Richards et al., 2004].The literature on these topics will be briefly reviewed, and several recommendations for reasonable practices will be offered.

Recommendations against RA in patients at risk for ACS are based on the premise that any degree of sensory blockade will block the ischemic pain the patient is experiencing in a compromised compartment. Little distinction is made between a limb in which a patient has analgesia but still can sense a pinprick exam, and one that is completely insensate. A recent case report by Cometa illustrated a scenario of a patient with an initially good analgesic block who experienced increasing pain as he developed ACS [Cometa et al., 2011].Because of the prompt recognition of this increasing pain by the anesthesiologists involved, the patient underwent a timely and limb-saving fasciotomy. Although no clear-cut evidence exists to support it, most experts suspect that somewhere on a continuum of density of nerve blockade lies the "danger zone" of sensory blockade in which we are at risk of masking the symptoms of ACS. For this reason, prolonged duration of a dense blockade, such as with a long-acting, potent neuraxial block, are to be discouraged. Intraoperatively and immediately postoperatively, these patients will not be able to report the pain of ACS, so RA and general anesthesia (GA) represent a similar risk. If, however, a dense sensory block persists long after the operative period, then the choice of RA may place the patient at increased risk. For that reason, intraoperative RA - whether neuraxial, single shot peripheral nerve block, or dosing of a continuous perineural catheter - should be limited to short-acting local anesthetic regimens. A much more controversial question is whether a continuous regional anesthetic technique, aimed at providing analgesia but avoiding the "danger zone", should be offered to these patients. Epidural infusions have been implicated in delayed diagnosis of lower extremity ACS [Mar et al., 2009].Unfortunately, in this review of 35 cases, the infusion drugs and concentrations were not reported in the majority of the patients. Of those that were reported, some involved infusates that are much more concentrated than current practices. Eighteen of the 35 patients had symptoms of ACS while the epidural infusions were running. Interestingly, there is a paucity of reports of ACS diagnosis delay in peripheral nerve blockade (PNB), in either single-shot or continuous infusions. Upper limb nerve block has not been associated with delayed ACS diagnosis, but lower limb PNB has been reported in two cases, but the validity of that attribution is extremely doubtful [Mar et al., 2009].In one report, a femoral nerve block was cited for masking a lower leg ACS; as discussed previously, it is obvious that the femoral nerve supplies only cutaneous innervation of the medial lower leg via the saphenous nerve and a small portion of the proximal tibia anteriorly. It cannot block ischemic pain coming from lower leg muscles, all of which are innervated by the sciatic nerve. In the other case, an ankle block was presumed to mask an ACS in the foot, but although severe pain was reported, it was ignored.

There are no randomized controlled trials comparing outcomes in patients at risk for ACS who had local anesthetic-based analgesia versus opioid-based analgesia. Clinical practice and recommendations have been founded on case reports and retrospective case series [Mar et al., 2009]; Clark's recent excellent editorial pointed out the usefulness of these case reports [Clark, 2011]. However, it is imperative that we carefully review these reports and not overinterpret their significance. It would seem an archaic practice to simply allow all patients at risk for ACS to suffer. Alternatives to RA, such as patient-controlled analgesia, have also been implicated as obscuring an ACS diagnosis [Richards et al., 2004].The literature on these topics will be briefly reviewed, and several recommendations for reasonable practices will

Recommendations against RA in patients at risk for ACS are based on the premise that any degree of sensory blockade will block the ischemic pain the patient is experiencing in a compromised compartment. Little distinction is made between a limb in which a patient has analgesia but still can sense a pinprick exam, and one that is completely insensate. A recent case report by Cometa illustrated a scenario of a patient with an initially good analgesic block who experienced increasing pain as he developed ACS [Cometa et al., 2011].Because of the prompt recognition of this increasing pain by the anesthesiologists involved, the patient underwent a timely and limb-saving fasciotomy. Although no clear-cut evidence exists to support it, most experts suspect that somewhere on a continuum of density of nerve blockade lies the "danger zone" of sensory blockade in which we are at risk of masking the symptoms of ACS. For this reason, prolonged duration of a dense blockade, such as with a long-acting, potent neuraxial block, are to be discouraged. Intraoperatively and immediately postoperatively, these patients will not be able to report the pain of ACS, so RA and general anesthesia (GA) represent a similar risk. If, however, a dense sensory block persists long after the operative period, then the choice of RA may place the patient at increased risk. For that reason, intraoperative RA - whether neuraxial, single shot peripheral nerve block, or dosing of a continuous perineural catheter - should be limited to short-acting local anesthetic regimens. A much more controversial question is whether a continuous regional anesthetic technique, aimed at providing analgesia but avoiding the "danger zone", should be offered to these patients. Epidural infusions have been implicated in delayed diagnosis of lower extremity ACS [Mar et al., 2009].Unfortunately, in this review of 35 cases, the infusion drugs and concentrations were not reported in the majority of the patients. Of those that were reported, some involved infusates that are much more concentrated than current practices. Eighteen of the 35 patients had symptoms of ACS while the epidural infusions were running. Interestingly, there is a paucity of reports of ACS diagnosis delay in peripheral nerve blockade (PNB), in either single-shot or continuous infusions. Upper limb nerve block has not been associated with delayed ACS diagnosis, but lower limb PNB has been reported in two cases, but the validity of that attribution is extremely doubtful [Mar et al., 2009].In one report, a femoral nerve block was cited for masking a lower leg ACS; as discussed previously, it is obvious that the femoral nerve supplies only cutaneous innervation of the medial lower leg via the saphenous nerve and a small portion of the proximal tibia anteriorly. It cannot block ischemic pain coming from lower leg muscles, all of which are innervated by the sciatic nerve. In the other case, an ankle block was presumed to mask an ACS in the foot, but

although severe pain was reported, it was ignored.

be offered.

There are no reported cases of delayed ACS diagnosis attributed to continuous perineural infusions. The absence of reports certainly does not imply that RA poses no risk to these patients, but may represent a number of factors, such as failure to report complications or avoidance of RA in these patients. Conversely, the literature certainly does not support a wholesale abandonment of RA in patients at risk. We would recommend avoiding longlasting dense blockade, using minimally effective infusions, and promptly addressing insensate limbs by withholding infusions until pinprick sensation returns. Perhaps even more importantly is a high level of vigilance as was exhibited by Cometa et al [Cometa et al., 2011] and close cooperation between the orthopedic surgeons and anesthesiologists involved. Using RA in these patients should only be considered in centers with a willingness to dedicate resources to the close monitoring of these patients and with caregivers who are acutely aware of the risks involved.

Despite all the attention to the subjective symptoms of ACS, they have actually been found to be quite unreliable [Ulmer, 2002 ]. A reliable objective measure to diagnose ACS would drastically improve care. Most of the attention in the past has been centered on direct, invasive measurement of intracompartmental pressures [Al-Dadah et al., 2008; Harris, et al., 2006].These techniques have, to date, been somewhat limited by technical problems. The most promising use of this approach would appear to be the series reported by McQueen and Court-Brown, who suggest that maintaining a differential pressure between the diastolic blood pressure and an intracompartmental pressure greater than 30 mm Hg is protective [McQueen et al., 1996].Much more exciting is the prospect of a noninvasive modality, such as near-infrared spectroscopy or laser Doppler flowmetry capable of diagnosing ACS [Elliott & Johnstone, 2003]. Evidently, further research is needed in this area.

#### **3.2 Regional anesthesia and anticoagulation**

The trauma patient, depending on the injury, may be at risk for bleeding or clotting. Patients with a high volume blood loss and massive resuscitation can end up with a dilutional coagulopathy, while patients with lower extremity fractures, intracranial injuries, and immobility may be at risk for thromboembolic complications necessitating aggressive anticoagulation strategies. An increasing number of patients present with anticoagulants as part of their home medicine regimen (e.g. Plavix for patients with coronary stents). Close vigilance of the patient's coagulation status, whether hyper- or hypocoagulable, is important prior to initiation of a regional technique.

#### **3.2.1 Venous thromboembolism risk in the trauma patient**

Venous thromboembolism can lead to pulmonary embolism, the most common preventable cause of hospital death. In patients with major trauma who are not receiving thromboprophylaxis, rates of DVT can range anywhere between 40 and 80% [Geerts et al., 2008], with rates of pulmonary embolism between 1 and 2% depending on severity of the injury [Schuerer et al., 2005]. Pulmonary embolism is the 3rd leading cause of death for patients who survive beyond the first day [Geerts et al., 2008]. Independent predictors of DVT include spinal cord injury, lower extremity or pelvic fracture, surgery, increasing age, prolonged immobility, and delay in institution of thromboprophylaxis [Geerts et al., 2008].

Regional Anesthesia for the Trauma Patient 273

administration of thromboprophylaxis. The catheters were maintained during routine use of prophylactic dosing and withdrawn regardless of timing of the anticoagulant. The authors noted no significant hematomas.In another study, Buckenmeier described no bleeding complications in a series of 187 patients receiving continuous nerve blocks and LMWH [Buckenmaier et al., 2006]. These series might suggest that, with a high amount of vigilance and a great deal of technical skill, the ASRA guidelines (Table 4) [Horlocker et al., 2010] may represent too conservative an approach to the use of peripheral nerve blocks. However, neither series was powered to detect serious bleeding complications, and, thus, judgment

> Time from block placement to resuming anticoagulant




for 24 hours -If not difficult placement, 6-8 hours

technique, postponement of LMWH for 24 hours -Contraindicated while catheter in situ

or

Time from catheter removal to resume anticoagulant

No contraindication No contraindication



about safety is not warranted.

Subcutaneous unfractionated heparin (5000 U twice

Subcutaneous unfractionated heparin (>5000 U twice daily)

Prophylactic LMWH -12 hours

daily)

Anticoagulant Recommendations

prior to block

removal

after block

placement or catheter




Therapeutic LMWH -24 hours Regardless of

The American College of Chest Physicians published their updated guidelines on antithrombotic and thrombolytic therapy in 2008 [Geerts et al., 2008]. Low-dose unfractionated heparin alone appears to be insufficient as thromboprophylaxis in trauma patients. The recommendation for patients with major trauma is the use of low molecular weight heparin (LMWH) thromboprophylaxis in the absence of major contraindications. If active bleeding or high risk for clinically significant bleeding is a contraindication for LMWH, mechanical thromboprophylaxis is appropriate. In the patient with hip fracture awaiting surgery, the recommendations include routine use of thromboprophylaxis with fondaparinux, LMWH, adjusted dose of a vitamin K antagonist, or low-dose unfractionated heparin if not at high risk for bleeding. Based on evidence and expert opinion, all these recommendations were grade 1 recommendations, indicating that the benefits of thromboprophylaxis outweigh the risks, burden, and costs of implementation. The panel did recognize that, for patients undergoing neuraxial procedures and deep peripheral blocks, the physician should exercise caution when selecting anticoagulant thromboprophylaxis [Geerts et al., 2008].

The EAST Practice Parameter Workgroup for DVT Prophylaxis also published guidelines on anticoagulation focusing on the trauma patient [Simon et al., EAST Practice Management Guidelines Work Group, 2005]. This group states that, while there is inadequate class I evidence for the general use of LMWH in venous thromboembolism prophylaxis, they do recommend that LMWH be standard for thromboprophylaxis in patients with complex pelvic, lower extremity, and spinal cord injuries who are not at risk for significant bleeding. These authors acknowledge that appropriate selection of the subset of patients to administer LMWH without increasing the risk of significant bleeding may be challenging.

#### **3.2.2 American Society of Regional Anesthesia and Pain Medicine (ASRA) guidelines**

The American Society of Regional Anesthesia and Pain Medicine (ASRA) convened a 3rd Consensus Conference on anticoagulation and published the guidelines in 2010 [Horlocker et al., 2010] .Recommendations were made with regard to optimal timing and placement of regional anesthetic techniques when patients have received anticoagulants. The guidelines focus on the appropriate timing of needle placement and catheter manipulation until the patient achieves a reasonable state of coagulation in order to avoid significant bleeding complications associated with needle and catheter placement (spinal hematomas, retroperitoneal hemorrhage). These recommendations were made for patients in the inpatient and outpatient setting, including patients in the intensive care unit who are to receive neuraxial, plexus, or deep peripheral blockade. Little mention is made of the trauma or ICU patient, and much of the literature presented was focused on the patient receiving a regional anesthetic technique in the perioperative setting.

The authors of the ASRA guidelines did acknowledge that fewer recommendations were being presented to allow for "flexibility and individuality in patient management", but stressed proper vigilance when managing a patient with a regional anesthetic and anticoagulation [Horlocker et al., 2010]. The guidelines represent a conservative but safe way to practice regional anesthesia in the anticoagulated patient, and are based on the pharmacologic activity of anticoagulants and large case series reported over a 20-year period. Recently, Chelly et al [Chelly & Schilling, 2008] described a series of orthopedic patients undergoing lumbar paravertebral and perineural blocks placed prior to the

The American College of Chest Physicians published their updated guidelines on antithrombotic and thrombolytic therapy in 2008 [Geerts et al., 2008]. Low-dose unfractionated heparin alone appears to be insufficient as thromboprophylaxis in trauma patients. The recommendation for patients with major trauma is the use of low molecular weight heparin (LMWH) thromboprophylaxis in the absence of major contraindications. If active bleeding or high risk for clinically significant bleeding is a contraindication for LMWH, mechanical thromboprophylaxis is appropriate. In the patient with hip fracture awaiting surgery, the recommendations include routine use of thromboprophylaxis with fondaparinux, LMWH, adjusted dose of a vitamin K antagonist, or low-dose unfractionated heparin if not at high risk for bleeding. Based on evidence and expert opinion, all these recommendations were grade 1 recommendations, indicating that the benefits of thromboprophylaxis outweigh the risks, burden, and costs of implementation. The panel did recognize that, for patients undergoing neuraxial procedures and deep peripheral blocks, the physician should exercise caution when selecting anticoagulant

The EAST Practice Parameter Workgroup for DVT Prophylaxis also published guidelines on anticoagulation focusing on the trauma patient [Simon et al., EAST Practice Management Guidelines Work Group, 2005]. This group states that, while there is inadequate class I evidence for the general use of LMWH in venous thromboembolism prophylaxis, they do recommend that LMWH be standard for thromboprophylaxis in patients with complex pelvic, lower extremity, and spinal cord injuries who are not at risk for significant bleeding. These authors acknowledge that appropriate selection of the subset of patients to administer

**3.2.2 American Society of Regional Anesthesia and Pain Medicine (ASRA) guidelines**  The American Society of Regional Anesthesia and Pain Medicine (ASRA) convened a 3rd Consensus Conference on anticoagulation and published the guidelines in 2010 [Horlocker et al., 2010] .Recommendations were made with regard to optimal timing and placement of regional anesthetic techniques when patients have received anticoagulants. The guidelines focus on the appropriate timing of needle placement and catheter manipulation until the patient achieves a reasonable state of coagulation in order to avoid significant bleeding complications associated with needle and catheter placement (spinal hematomas, retroperitoneal hemorrhage). These recommendations were made for patients in the inpatient and outpatient setting, including patients in the intensive care unit who are to receive neuraxial, plexus, or deep peripheral blockade. Little mention is made of the trauma or ICU patient, and much of the literature presented was focused on the patient receiving a

The authors of the ASRA guidelines did acknowledge that fewer recommendations were being presented to allow for "flexibility and individuality in patient management", but stressed proper vigilance when managing a patient with a regional anesthetic and anticoagulation [Horlocker et al., 2010]. The guidelines represent a conservative but safe way to practice regional anesthesia in the anticoagulated patient, and are based on the pharmacologic activity of anticoagulants and large case series reported over a 20-year period. Recently, Chelly et al [Chelly & Schilling, 2008] described a series of orthopedic patients undergoing lumbar paravertebral and perineural blocks placed prior to the

LMWH without increasing the risk of significant bleeding may be challenging.

regional anesthetic technique in the perioperative setting.

thromboprophylaxis [Geerts et al., 2008].

administration of thromboprophylaxis. The catheters were maintained during routine use of prophylactic dosing and withdrawn regardless of timing of the anticoagulant. The authors noted no significant hematomas.In another study, Buckenmeier described no bleeding complications in a series of 187 patients receiving continuous nerve blocks and LMWH [Buckenmaier et al., 2006]. These series might suggest that, with a high amount of vigilance and a great deal of technical skill, the ASRA guidelines (Table 4) [Horlocker et al., 2010] may represent too conservative an approach to the use of peripheral nerve blocks. However, neither series was powered to detect serious bleeding complications, and, thus, judgment about safety is not warranted.


Regional Anesthesia for the Trauma Patient 275

In the trauma patient, the risks of bleeding must be weighed against the benefits of regional anesthesia - for instance, the risk of bleeding from TPVC or thoracic epidural catheterization in a patient on LMWH versus the benefit of improved pulmonary function due to improved analgesia with minimal sedative effects, resulting in decreased incidence of hospital-

When comparing a central neuraxial technique to a more peripheral technique (TEA versus TPVC or lumbar plexus block versus a lumbar epidural), one must always consider the closed nature of the spinal column. With a central neuraxial technique, compression of the epidural space may lead to devastating neurologic injury, including paraplegia, compared to a more peripheral technique in which bleeding into the paravertebral space may lead to extensive blood loss or compression neuropraxia but not paraplegia. The choice of a paravertebral block may be more appropriate in a patient on thromboprophylaxis therapy. Perineural blocks are usually performed at the terminal branches of the nerve (e.g. sciatic nerve block, popliteal nerve block, femoral nerve block, saphenous nerve block, axillary nerve block), and, while bleeding may result in neuropraxia and hematoma formation, the severity of the complications is less than that involving neuraxial or deep plexus blocks. The decision to proceed should be based on a careful review of the patient's medical record. Informed consent for the patient and/or their family should include a review of the risks and benefits of the procedure, and their input into medical decision-making should be sought. While normal coagulation status would be preferable prior to the placement of a continuous catheter, this may not be possible or desirable. This decision requires astute clinical judgment on the part of the physician and a careful consideration of the risks versus

Even if the physician and patient both agree to maintain continuous epidural or paravertebral block with thromboprophylactic doses of anticoagulants, waiting until after the peak effect of a potent anticoagulant is prudent in order to avoid further bleeding complications in the already injured patient. Once a neuraxial technique or deep paraneuraxial or perineural technique is performed, maintenance on a prophylactic dose of a potent anticoagulant is reasonable to allow the patient to not only have improved analgesic but effective deep vein thrombosis prophylaxis as well. However, extreme vigilance is required, particularly during the high risk period that occurs when the catheter

Anatomy can be distorted due to the patient's injuries. Swelling and subcutaneous emphysema may result in a difference in the standard sensations felt as the needle is advanced. If a loss of resistance approach is utilized, this may result in an indistinct or false sensation of loss. Even the use of ultrasound may not be helpful in the patient with subcutaneous emphysema, as the image is altered by the air underneath the skin. The use of CT scans to gauge the depth of the epidural space and paravertebral space is very important in allowing the physician to have an intelligent "guesstimate" of the depth of the targeted

Stimulating catheters may be utilized to guide catheters based on the motor response elicited via the catheter. While this provides an extra endpoint for confirmation of catheter

acquired pneumonia [Bulger et al., 2004; Flagel et al., 2005; Karmakor et al, 2003].

**3.2.3 Risks versus benefits** 

benefits.

is removed.

space.

**4. Technical considerations** 


\*Note these recommendations are for single drug therapy and may not apply if patient receives concomitant anticoagulation with other agents

Table 4. ASRA guidelines for common anticoagulant management in the patient receiving a neuraxial, plexus or deep peripheral nerve block[Horlocker et al., 2010].\*

#### **3.2.3 Risks versus benefits**

274 Pain Management – Current Issues and Opinions

>3


situ


No contraindication No contraindication No contraindication

Contraindicated while continuous catheter in

Contraindicated while continuous catheter in

situ

Thrombin inhibitors Contraindication Contraindication Contraindication

Herbals No contraindication No contraindication No contraindication

\*Note these recommendations are for single drug therapy and may not apply if patient receives

Table 4. ASRA guidelines for common anticoagulant management in the patient receiving a

Contraindicated Avoidance for 10days

Contraindicated No recommendation

vessels


No recommendation

after puncture of noncompressible



conditions in 2 studies


Warfarin -Discontinue 4-5 d

Nonsteroidal antiinflammatory

Antiplatelet agents

Platelet GPIIb/IIIa

inhibitors

Fondiparinux (Arixtra)

agents

Plavix

Ticlpidine

prior to procedure

Consider reversal agent to normalize


on length of time -Neuraxial techniques should be avoided if



Recommendations are

neuraxial, plexus or deep peripheral nerve block[Horlocker et al., 2010].\*

to follow strict conditions in 2 studies

possible

hours

concomitant anticoagulation with other agents


INR


Thrombolytic therapy -No recommendation

In the trauma patient, the risks of bleeding must be weighed against the benefits of regional anesthesia - for instance, the risk of bleeding from TPVC or thoracic epidural catheterization in a patient on LMWH versus the benefit of improved pulmonary function due to improved analgesia with minimal sedative effects, resulting in decreased incidence of hospitalacquired pneumonia [Bulger et al., 2004; Flagel et al., 2005; Karmakor et al, 2003].

When comparing a central neuraxial technique to a more peripheral technique (TEA versus TPVC or lumbar plexus block versus a lumbar epidural), one must always consider the closed nature of the spinal column. With a central neuraxial technique, compression of the epidural space may lead to devastating neurologic injury, including paraplegia, compared to a more peripheral technique in which bleeding into the paravertebral space may lead to extensive blood loss or compression neuropraxia but not paraplegia. The choice of a paravertebral block may be more appropriate in a patient on thromboprophylaxis therapy. Perineural blocks are usually performed at the terminal branches of the nerve (e.g. sciatic nerve block, popliteal nerve block, femoral nerve block, saphenous nerve block, axillary nerve block), and, while bleeding may result in neuropraxia and hematoma formation, the severity of the complications is less than that involving neuraxial or deep plexus blocks.

The decision to proceed should be based on a careful review of the patient's medical record. Informed consent for the patient and/or their family should include a review of the risks and benefits of the procedure, and their input into medical decision-making should be sought. While normal coagulation status would be preferable prior to the placement of a continuous catheter, this may not be possible or desirable. This decision requires astute clinical judgment on the part of the physician and a careful consideration of the risks versus benefits.

Even if the physician and patient both agree to maintain continuous epidural or paravertebral block with thromboprophylactic doses of anticoagulants, waiting until after the peak effect of a potent anticoagulant is prudent in order to avoid further bleeding complications in the already injured patient. Once a neuraxial technique or deep paraneuraxial or perineural technique is performed, maintenance on a prophylactic dose of a potent anticoagulant is reasonable to allow the patient to not only have improved analgesic but effective deep vein thrombosis prophylaxis as well. However, extreme vigilance is required, particularly during the high risk period that occurs when the catheter is removed.

#### **4. Technical considerations**

Anatomy can be distorted due to the patient's injuries. Swelling and subcutaneous emphysema may result in a difference in the standard sensations felt as the needle is advanced. If a loss of resistance approach is utilized, this may result in an indistinct or false sensation of loss. Even the use of ultrasound may not be helpful in the patient with subcutaneous emphysema, as the image is altered by the air underneath the skin. The use of CT scans to gauge the depth of the epidural space and paravertebral space is very important in allowing the physician to have an intelligent "guesstimate" of the depth of the targeted space.

Stimulating catheters may be utilized to guide catheters based on the motor response elicited via the catheter. While this provides an extra endpoint for confirmation of catheter

Regional Anesthesia for the Trauma Patient 277

In the patient with perineural catheters, spread of local anesthetic, while not resulting in hemodynamic effects, can be visualized using ultrasound guidance, as these structures are superficial and can be visualized readily with this mode. In patients with paravertebral continuous blocks, the spread of local anesthetic is difficult to assess and may be inconsistent in its distribution. Therefore, dye injection through the catheter and visualization under fluoroscopy can be used as an alternative gauge of local anesthetic

Nursing staff spend the most amount of time with these patients, and can provide important information concerning their perception of whether the patient demonstrates signs of

As previously noted, trauma patients often suffer moderate to severe pain in the Emergency Department [Berben et al., 2008]. In Europe, emergency response teams are frequently physician-based. Regional anesthesia performed in the field, prior to hospital admission, has been described for patients with femoral fractures [Lopez et al., 2003; Schiferer et al., 2007]. A simple fascia iliaca block and a nerve stimulator-guided femoral nerve block have been described. Both studies showed reasonably high success rates, with Schiferer reporting a 90% success rate in the RA group [Schiferer et al., 2007].Pain and anxiety scores were much lower in the RA group, as was heart rate. A mean treatment time of seven minutes in the RA group did delay transport time, which is of concern in this setting. While this paradigm will probably not take hold in the rest of the world, including the United States, it surely represents a call to action, to set up processes to provide earlier RA in the hospital setting.

Trauma patients represent a significant proportion of current surgical volume and of patients being cared for ICUs. Estimates suggest that this proportion will increase [Lopez et al., 2006]. These patients present many challenges and require extreme vigilance on the part of the health care team. An in-depth understanding of anatomy, physiology, and pharmacology is important when dealing with the trauma patient. Flexibility on the part of the physician to respond to the myriad challenges by adapting to different approaches and modalities is key. Clearly, RA can safely decrease suffering and improve outcomes in these

Al-Dadah, O.Q., Darrah, C., Cooper, A., Donell, S.T. & Patel, A.D. (2008). Continuous

Beaudoin, F.L., Nagdev, A., Merchant, R.C. & Becker, B.M. (2010). Ultrasound-guided

Ben-Ari, A., Moreno, M., Chelly, J.E. & Bigeleisen, P.E. (2009). Ultrasound-guided

fractures. *Injury* Oct; Vol. 39(No. 10): 1204-1209.

*Emergency Medicine* Jan; Vol. 28(No. 1): 76-81.

compartment pressure monitoring vs. clinical monitoring in tibial diaphysial

femoral nerve block in elderly patients with hip fractures. *American Journal of* 

paravertebral block using an intercostal approach. *Anesthesia & Analgesia* Nov; Vol.

spread, assuming that the patient has no contraindications to contrast dye (Figure 2).

improved or adequate comfort.

**5. Conclusion** 

**6. References** 

patients when applied judiciously.

109(No. 5): 1691-1694.

**4.2 Early management with regional anesthesia** 

pla stim inc thr acement, motor mulating muscle creased analgesic read a stimulating stimulation may e movement aro c requirements fo g catheter. y result in furthe ound a fracture or block placeme er worsening of ed bone. This, i ent and an incre the patient's pa in turn, may pr ease in time need ain by roduce ded to

In ma Ro of the patient plac attress, the spinal otation of the spin continuous block ced in the lateral l curvature may b ne or lateral disp ks and difficulties l decubitus posit be altered and de placement of the s s in determining m tion on an ICU ependent on the spine may lead to midline. bed with an infl patient's body ha o inaccurate plac latable abitus. cement

#### **4.1 1 Confirmation o of analgesic effe ects of the contin nuous block**

In an pa agi the nonobtund algesic technique tient receiving s itation in the inte ed and nonintu e is simple to ass sedatives. While ensive care unit, i ubated patient, t sess. Unfortunate there are many t is important to r the efficacy of a ely, this is not th reasons for alte rule out severe p a continuous re he case in the intu ered mental statu ain as the cause. egional ubated us and

In sym pre con be the patient who r mpathectomy, wh essors. While the nfirm which nerv inadequate if the received an epidu hich can be prono e sympathectomy ve roots are affecte nerve roots to the ural catheter, accu ounced, and routin y confirms placem ed by the local an e fractured or inju urate placement m nely requires man ment in the epid nesthetic spreads, ured site are spare may be confirmed nagement with flu dural space, it do and analgesia m ed. with a uids or oes not may still

Fig g. 2. Dye injection n through parave rtebral catheter a and confirmation of spread of solu ution.

27

6

acement, motor mulating muscle creased analgesic read a stimulating the patient plac attress, the spinal otation of the spin continuous block

stimulation may e movement aro c requirements fo g catheter. ced in the lateral l curvature may b ne or lateral disp ks and difficulties

Pain

n Management – Cu

urrent Issues and O

Opinions

ain by roduce ded to

latable abitus. cement

egional ubated us and

with a uids or oes not may still

the patient's pa in turn, may pr ease in time need

bed with an infl patient's body ha o inaccurate plac

a continuous re he case in the intu ered mental statu ain as the cause. may be confirmed nagement with flu dural space, it do and analgesia m

ed.

er worsening of ed bone. This, i ent and an incre

tion on an ICU ependent on the spine may lead to

midline.

**nuous block**  the efficacy of a ely, this is not th reasons for alte rule out severe p urate placement m nely requires man ment in the epid nesthetic spreads, ured site are spare

y result in furthe ound a fracture or block placeme

l decubitus posit be altered and de placement of the s s in determining m

**ects of the contin** ubated patient, t sess. Unfortunate there are many t is important to r ural catheter, accu ounced, and routin y confirms placem ed by the local an e fractured or inju

**of analgesic effe** ed and nonintu e is simple to ass sedatives. While ensive care unit, i received an epidu hich can be prono e sympathectomy ve roots are affecte nerve roots to the

**1 Confirmation o** the nonobtund algesic technique tient receiving s itation in the inte the patient who r mpathectomy, wh essors. While the nfirm which nerv inadequate if the

pla stim inc thr In ma Ro of

**4.1** In an pa agi In sym pre con be

Fig

g. 2. Dye injection

n through parave

rtebral catheter a

and confirmation

of spread of solu

ution.

In the patient with perineural catheters, spread of local anesthetic, while not resulting in hemodynamic effects, can be visualized using ultrasound guidance, as these structures are superficial and can be visualized readily with this mode. In patients with paravertebral continuous blocks, the spread of local anesthetic is difficult to assess and may be inconsistent in its distribution. Therefore, dye injection through the catheter and visualization under fluoroscopy can be used as an alternative gauge of local anesthetic spread, assuming that the patient has no contraindications to contrast dye (Figure 2).

Nursing staff spend the most amount of time with these patients, and can provide important information concerning their perception of whether the patient demonstrates signs of improved or adequate comfort.

#### **4.2 Early management with regional anesthesia**

As previously noted, trauma patients often suffer moderate to severe pain in the Emergency Department [Berben et al., 2008]. In Europe, emergency response teams are frequently physician-based. Regional anesthesia performed in the field, prior to hospital admission, has been described for patients with femoral fractures [Lopez et al., 2003; Schiferer et al., 2007]. A simple fascia iliaca block and a nerve stimulator-guided femoral nerve block have been described. Both studies showed reasonably high success rates, with Schiferer reporting a 90% success rate in the RA group [Schiferer et al., 2007].Pain and anxiety scores were much lower in the RA group, as was heart rate. A mean treatment time of seven minutes in the RA group did delay transport time, which is of concern in this setting. While this paradigm will probably not take hold in the rest of the world, including the United States, it surely represents a call to action, to set up processes to provide earlier RA in the hospital setting.

#### **5. Conclusion**

Trauma patients represent a significant proportion of current surgical volume and of patients being cared for ICUs. Estimates suggest that this proportion will increase [Lopez et al., 2006]. These patients present many challenges and require extreme vigilance on the part of the health care team. An in-depth understanding of anatomy, physiology, and pharmacology is important when dealing with the trauma patient. Flexibility on the part of the physician to respond to the myriad challenges by adapting to different approaches and modalities is key. Clearly, RA can safely decrease suffering and improve outcomes in these patients when applied judiciously.

#### **6. References**


Regional Anesthesia for the Trauma Patient 279

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**Part 3** 

**Opioids** 


**Part 3** 

284 Pain Management – Current Issues and Opinions

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**Opioids** 

**14** 

*Australia* 

**Opioid Analgesics** 

Maree T. Smith1,2 and Wei H. Goh1

*St Lucia Campus, Brisbane, Queensland* 

*1Centre for Integrated Preclinical Drug Development,* 

*2School of Pharmacy, The University of Queensland,* 

*The University of Queensland, St Lucia Campus, Brisbane, Queensland* 

Intensive research on the neurobiology of pain over the past two decades has revealed many receptors, ion channels and enzymes with potential as novel targets for development of a new generation of analgesic agents. However, despite large investment in preclinical and clinical development of small molecules and biologics as potential novel pain therapeutics, very few have reached the clinic. Hence, drugs used in the clinical setting for the pharmacological management of pain continue to be those that were first recommended in 1986 by the World Health Organisation (WHO) for the management of chronic cancer pain (WHO, 1986). Twenty-five years on, the WHO 3-step Analgesic Ladder (Figure 1) is still used widely to guide the pharmacological management of pain and opioid analgesics are

the mainstay for alleviation of moderate to severe nociceptive pain.

Fig. 1. World Health Organisation 3-Step Analgesic Ladder (WHO, 1986)

**1. Introduction** 

## **Opioid Analgesics**

#### Maree T. Smith1,2 and Wei H. Goh1

*1Centre for Integrated Preclinical Drug Development, The University of Queensland, St Lucia Campus, Brisbane, Queensland 2School of Pharmacy, The University of Queensland, St Lucia Campus, Brisbane, Queensland Australia* 

#### **1. Introduction**

Intensive research on the neurobiology of pain over the past two decades has revealed many receptors, ion channels and enzymes with potential as novel targets for development of a new generation of analgesic agents. However, despite large investment in preclinical and clinical development of small molecules and biologics as potential novel pain therapeutics, very few have reached the clinic. Hence, drugs used in the clinical setting for the pharmacological management of pain continue to be those that were first recommended in 1986 by the World Health Organisation (WHO) for the management of chronic cancer pain (WHO, 1986). Twenty-five years on, the WHO 3-step Analgesic Ladder (Figure 1) is still used widely to guide the pharmacological management of pain and opioid analgesics are the mainstay for alleviation of moderate to severe nociceptive pain.

Fig. 1. World Health Organisation 3-Step Analgesic Ladder (WHO, 1986)

Opioid Analgesics 289

Codeine Meperidine Fentanyl Hydromorphone Methadone Morphine Oxycodone Tramadol Buprenorphine

Argoff & Silvershein, 2009)

IV = intravenous

**Opioid Analgesic** 

Codeine Fentanyl Hydromorphone Methadone Morphine Oxycodone Tramadol

Smith; Argoff & Silvershein, 2009)

al., 2011)

#large inter-individual variability in range 12-150 h IV = intravenous; TD = transdermal; TM = transmucosal

IR = immediate release; ER = extended release; CR = controlled release

Codeine Meperidine (IV) Methadone Oxycodone Buprenorphine Morphine (IV) Morphine (oral)

Table 1. Typical Mean Elimination Half-lives and Durations of Action for Commonly Prescribed Opioid Analgesics (adapted from Mather & Smith 1998; Trescot et al., 2008;

**Opioid Analgesic Dose × Conversion Factor** 

Table 2. Opioid Analgesic Dose Conversion Table to Oral Morphine (adapted from Nissen et

15-60 mg 100-200 μg (IV) 2-4 mg 5-10 mg 15-30 mg (IR) 10 mg (CR), 5-10 mg (IR) 50-100 mg (IR), 100 mg (ER)

CR = controlled-release; ER = extended-release; IR = immediate-release; IV = intravenous; aNot more than 4 doses per day.

Table 3. Common Starting Doses for Selected Opioid Analgesics (adapted from Mather &

x 0.16 × 0.4 × 1.5 × 1.5 × 50 × 3 × 1

**Oral Administration** 

**Dose Inter-dosing Interval** 

**(h)** 

3-6 6a 3-4 24 4 (IR) 12 (CR), 4-6 (IR) 4-6 (IR), 24 (ER)

**Opioid Analgesic Elimination Half-life (h) Duration of Action (h)** 

3 3.5 3.7 2-3 24# 2.5 3 5-7 3

4-6 4-6 0.5-1 (IV); 72 (TD); 2-4 (TM) 4-5 4-6 3-4 8-12 (CR), 3-4 (IR) 4-6 (IR), 24 (ER) 6

#### **2. WHO Analgesic Ladder**

The WHO Analgesic Ladder provides a succinct encapsulation of the guidelines for the management of chronic pain according to intensity (WHO, 1986). Specifically, for mild pain, non-opioid analgesics on Step 1 of the Analgesic Ladder including acetaminophen, aspirin and nonsteroidal anti-inflammatory drugs such as ibuprofen, are recommended. When the pain has a neuropathic component, addition of an adjuvant agent such as a tricyclic antidepressant, anticonvulsant or anti-arrhythmic agent, is recommended. Weak opioid analgesics such as codeine, tramadol and dextropropoxyphene are added to non-opioid analgesics when mild pain progresses to moderate pain (Step 2); adjuvants are again co-administered when the pain has a neuropathic component. Strong opioid analgesics are recommended for the management of moderate to severe nociceptive pain (Step 3) with morphine the strong opioid analgesic of choice due to its ready availability world-wide at low cost. Strong opioid analgesics are often co-administered with non-opioids, and adjuvants are added when pain has a neuropathic component (WHO, 1986).

According to the WHO guidelines, each patient should receive a period of individualized dose titration on a 'round the clock' rather than an 'as required' basis as this facilitates dosage optimization for the selected analgesic and/or adjuvant (WHO, 1986). Although many opioid analgesics have relatively short elimination half-lives (Table 1), most are available as sustained-release formulations that are administered once or twice-daily to optimize patient compliance as well as pain relief. For patients who experience breakthrough pain during ambulation or activities of daily living, additional bolus doses of immediate-release formulations are given on an "as required" basis. For most patients, the oral dosing route is preferred except where impaired gastrointestinal transit makes this impractical as in the immediate post-operative period or during labor.

#### **3. Opioid analgesics**

Opioid analgesics commonly used for the control of clinical pain include morphine, codeine, oxycodone, hydromorphone, buprenorphine, tramadol, fentanyl, remifentanil, pethidine and methadone. The potencies of these opioid analgesics differ markedly. Equi-analgesic doses and usual starting doses for the oral route derived from the acute pain setting are shown in Tables 2 and 3 respectively.

#### **3.1 Opioid-related adverse effects**

Apart from their desired analgesic action, clinically prescribed opioids also produce many undesired effects including respiratory depression, sedation, nausea, vomiting, constipation, pruritus, tolerance and dependence, to name but a few (Zollner & Stein, 2007). Although studies using -opioid (MOP) receptor knockout mice suggest that the analgesic and adverse effects of opioid analgesics are all produced by activation of the MOP receptor, clinical experience shows that there are marked between-opioid differences with respect to analgesic and tolerability profiles within the same patient (Smith, 2008). However, the precise mechanistic basis underpinning these observations is not well understood.

The WHO Analgesic Ladder provides a succinct encapsulation of the guidelines for the management of chronic pain according to intensity (WHO, 1986). Specifically, for mild pain, non-opioid analgesics on Step 1 of the Analgesic Ladder including acetaminophen, aspirin and nonsteroidal anti-inflammatory drugs such as ibuprofen, are recommended. When the pain has a neuropathic component, addition of an adjuvant agent such as a tricyclic antidepressant, anticonvulsant or anti-arrhythmic agent, is recommended. Weak opioid analgesics such as codeine, tramadol and dextropropoxyphene are added to non-opioid analgesics when mild pain progresses to moderate pain (Step 2); adjuvants are again co-administered when the pain has a neuropathic component. Strong opioid analgesics are recommended for the management of moderate to severe nociceptive pain (Step 3) with morphine the strong opioid analgesic of choice due to its ready availability world-wide at low cost. Strong opioid analgesics are often co-administered with non-opioids, and adjuvants are added when pain has a neuropathic component

According to the WHO guidelines, each patient should receive a period of individualized dose titration on a 'round the clock' rather than an 'as required' basis as this facilitates dosage optimization for the selected analgesic and/or adjuvant (WHO, 1986). Although many opioid analgesics have relatively short elimination half-lives (Table 1), most are available as sustained-release formulations that are administered once or twice-daily to optimize patient compliance as well as pain relief. For patients who experience breakthrough pain during ambulation or activities of daily living, additional bolus doses of immediate-release formulations are given on an "as required" basis. For most patients, the oral dosing route is preferred except where impaired gastrointestinal transit makes this

Opioid analgesics commonly used for the control of clinical pain include morphine, codeine, oxycodone, hydromorphone, buprenorphine, tramadol, fentanyl, remifentanil, pethidine and methadone. The potencies of these opioid analgesics differ markedly. Equi-analgesic doses and usual starting doses for the oral route derived from the acute pain setting are

Apart from their desired analgesic action, clinically prescribed opioids also produce many undesired effects including respiratory depression, sedation, nausea, vomiting, constipation, pruritus, tolerance and dependence, to name but a few (Zollner & Stein, 2007). Although studies using -opioid (MOP) receptor knockout mice suggest that the analgesic and adverse effects of opioid analgesics are all produced by activation of the MOP receptor, clinical experience shows that there are marked between-opioid differences with respect to analgesic and tolerability profiles within the same patient (Smith, 2008). However, the precise mechanistic basis underpinning these observations is

impractical as in the immediate post-operative period or during labor.

**2. WHO Analgesic Ladder** 

(WHO, 1986).

**3. Opioid analgesics** 

not well understood.

shown in Tables 2 and 3 respectively.

**3.1 Opioid-related adverse effects** 


#large inter-individual variability in range 12-150 h

IV = intravenous; TD = transdermal; TM = transmucosal

IR = immediate release; ER = extended release; CR = controlled release

Table 1. Typical Mean Elimination Half-lives and Durations of Action for Commonly Prescribed Opioid Analgesics (adapted from Mather & Smith 1998; Trescot et al., 2008; Argoff & Silvershein, 2009)


IV = intravenous

Table 2. Opioid Analgesic Dose Conversion Table to Oral Morphine (adapted from Nissen et al., 2011)


CR = controlled-release; ER = extended-release; IR = immediate-release; IV = intravenous; aNot more than 4 doses per day.

Table 3. Common Starting Doses for Selected Opioid Analgesics (adapted from Mather & Smith; Argoff & Silvershein, 2009)

Opioid Analgesics 291

nausea, vomiting, miosis, pruritus, constipation, and euphoria/dysphoria. With chronic dosing, tolerance often develops to sedation, nausea and respiratory depression whereas

Several opioid analgesics including morphine, hydromorphone and meperidine are metabolized in the liver to pharmacologically active metabolites that may accumulate in patients with renal impairment. Hence, for patients with renal impairment, opioid analgesics including oxycodone and fentanyl that are devoid of active metabolites, are

Codeine (7,8-didehydro-4,5-epoxy-3-methoxy-17-methylmorphinan-6-ol) is an opioid alkaloid found in opium, the dried exudate of the unripe seed capsule of the opium poppy, *Papaver somniferum,* at 0.7 to 2.5% (Boerner, 1975). Due to its high consumption rates globally, codeine is generally synthesized by O-methylation of morphine, an abundant

Codeine is a weak opioid analgesic that binds to the -opioid (MOP) receptor with low affinity (Ki = 0.7 M) (Volpe et al., 2011). Its analgesic properties are generally thought to be derived from the fact that it is a prodrug for morphine as up to 10% of oral doses are Odemethylated to morphine by cytochrome P450 2D6 (CYP2D6), an enzyme subject to genetic polymorphism (Kadiev et al., 2008, Somogyi et al., 2007, Zollner & Stein, 2007). Supporting this notion, plasma morphine concentrations are virtually undetectable and codeine lacks efficacy in individuals with the poor metabolizer (PM) CYP2D6 phenotype (Poulsen et al., 1996). By contrast, codeine is extensively metabolized to morphine in those with the ultrametabolizer (UM) phenotype who also have an increased risk of respiratory depression after

Doses of codeine generally do not exceed 60 mg (Trescot et al., 2008). Codeine is available in a range of prescription and over-the-counter medicines, often in combination with paracetamol, aspirin or ibuprofen for pain relief (Moore et al., 1997; Moore et al., 2011). It is also the active ingredient in many cough suppressant mixtures and anti-diarrhoeal products (Schiller, 1995; Wee, 2008). Codeine is susceptible to metabolic drug-drug interactions with other commonly prescribed medications that are also metabolized by CYP2D6 including both CYP2D6 inhibitors (e.g. cimetidine) and CYP2D6 inducers (e.g. rifampicin) (Caraco et

Meperidine (pethidine; ethyl-1-methyl-4-phenylpiperidine-4-carboxylate), is a synthetic MOP receptor agonist that binds with low affinity (Ki = 450 nM) at the MOP receptor (Volpe et al., 2011). Meperidine is a weak opioid analgesic with potency at 10% that of morphine for the relief of acute post-operative pain (Latta et al., 2002). Meperidine is metabolized by hepatic esterases to pethidinic acid, an inactive metabolite, and by N-demethylation to a neurotoxic metabolite, normeperidine (Gilman et al., 1980, Armstrong et al., 2009). After multiple doses, normeperidine may accumulate in plasma and cerebrospinal fluid causing tremors, twitches, myoclonus and seizures as it has a longer plasma half-life than

tolerance to constipation and miosis is minimal (Chang et al., 2007).

**3.6 Opioid analgesics and renal impairment** 

opium constituent at 10-15% (Lenz et al., 1986).

regular doses of codeine (Kirchheiner et al., 2007).

preferred (King et al., 2011).

**4.1 Codeine** 

al., 1997; Zhou, 2009).

**4.2 Meperidine (pethidine)** 

**4. Weak opioid analgesics** 

#### **3.1.1 Respiratory depression**

Opioid-related deaths continue to be reported in the acute pain setting underpinned by opioid-induced ventilatory impairment that often develops due to a combination of factors including opioid-induced central respiratory depression, sedation and/or upper airway obstruction (Macintyre et al., 2011). It is recommended that all patients be monitored for opioid-induced ventilatory impairment using sedation scores as a '6th vital sign' so that it can be detected early and appropriate intervention initiated (Macintyre et al., 2011).

#### **3.2 Strategies for minimizing opioid-related adverse effects**

It is essential to assess patients to ensure that adverse effects are genuinely opioid-related rather than being due to another medical problem. Strategies recommended (Swegle & Logemann, 2006) for minimizing opioid-related adverse effects are as follows:


#### **3.3 Strategies for managing intolerable opioid-related adverse effects**

For patients experiencing poor pain relief together with intolerable opioid-related side-effects such as severe vomiting, severe dysphagia or bowel obstruction, changing from the oral to the parenteral (e.g. intravenous, subcutaneous, intramuscular), rectal, buccal, sublingual, transdermal or spinal (epidural, intrathecal) route of administration, may reduce adverse effects to a tolerable level and restore satisfactory analgesia (Walsh, 2005). Another strategy for restoring satisfactory analgesia with tolerable side-effects in such patients is 'opioid rotation' that involves switching from one strong opioid analgesic to another (Smith, 2008; Knotkova et al., 2009; Vissers et al., 2010). Additional clinical strategies for restoring analgesia in patients experiencing inadequate pain relief and intolerable opioid-related side-effects include use of neurolytic blocks as an adjunct or alternative to pharmacotherapy (Eisenberg et al., 2005) or progression to use of anaesthetic intervention if 'opioid rotation' fails (Riley et al., 2007).

#### **3.4 Tolerance to the analgesic effects of opioids**

In the absence of disease progression, tolerance to the analgesic effects of an opioid manifests in patients with clinical pain as the need for progressively higher opioid doses in order to maintain the same level of pain relief (South & Smith, 2001). In rodent studies, analgesic tolerance is demonstrated by a rightward shift in the analgesia dose-response curve for a particular opioid administered after a period of chronic dosing relative to the dose-response curve determined for the same opioid in opioid-naïve animals (South & Smith, 2001).

#### **3.5 Tolerance to opioid-related side-effects**

As already noted, opioid-related adverse effects that may occur after the initation of opioid analgesic treatment in opioid-naïve patients include respiratory depression, somnolence,

Opioid-related deaths continue to be reported in the acute pain setting underpinned by opioid-induced ventilatory impairment that often develops due to a combination of factors including opioid-induced central respiratory depression, sedation and/or upper airway obstruction (Macintyre et al., 2011). It is recommended that all patients be monitored for opioid-induced ventilatory impairment using sedation scores as a '6th vital sign' so that it

It is essential to assess patients to ensure that adverse effects are genuinely opioid-related rather than being due to another medical problem. Strategies recommended (Swegle &

2. Dose reduction to assess if satisfactory analgesia can be obtained with tolerable side-

3. Symptom management including pro-active preventative treatment of nausea and

4. Addition of, or increasing non-opioid or adjuvant analgesic doses for an opioid sparing

For patients experiencing poor pain relief together with intolerable opioid-related side-effects such as severe vomiting, severe dysphagia or bowel obstruction, changing from the oral to the parenteral (e.g. intravenous, subcutaneous, intramuscular), rectal, buccal, sublingual, transdermal or spinal (epidural, intrathecal) route of administration, may reduce adverse effects to a tolerable level and restore satisfactory analgesia (Walsh, 2005). Another strategy for restoring satisfactory analgesia with tolerable side-effects in such patients is 'opioid rotation' that involves switching from one strong opioid analgesic to another (Smith, 2008; Knotkova et al., 2009; Vissers et al., 2010). Additional clinical strategies for restoring analgesia in patients experiencing inadequate pain relief and intolerable opioid-related side-effects include use of neurolytic blocks as an adjunct or alternative to pharmacotherapy (Eisenberg et al., 2005) or progression to use of anaesthetic intervention if 'opioid rotation' fails (Riley et al., 2007).

In the absence of disease progression, tolerance to the analgesic effects of an opioid manifests in patients with clinical pain as the need for progressively higher opioid doses in order to maintain the same level of pain relief (South & Smith, 2001). In rodent studies, analgesic tolerance is demonstrated by a rightward shift in the analgesia dose-response curve for a particular opioid administered after a period of chronic dosing relative to the dose-response

As already noted, opioid-related adverse effects that may occur after the initation of opioid analgesic treatment in opioid-naïve patients include respiratory depression, somnolence,

curve determined for the same opioid in opioid-naïve animals (South & Smith, 2001).

can be detected early and appropriate intervention initiated (Macintyre et al., 2011).

Logemann, 2006) for minimizing opioid-related adverse effects are as follows:

**3.3 Strategies for managing intolerable opioid-related adverse effects** 

**3.2 Strategies for minimizing opioid-related adverse effects** 

**3.1.1 Respiratory depression** 

1. Titrating opioid doses slowly

6. Changing the route of administration

**3.4 Tolerance to the analgesic effects of opioids** 

**3.5 Tolerance to opioid-related side-effects** 

effects

effect 5. Opioid rotation

constipation

7. Frequent re-assessment

nausea, vomiting, miosis, pruritus, constipation, and euphoria/dysphoria. With chronic dosing, tolerance often develops to sedation, nausea and respiratory depression whereas tolerance to constipation and miosis is minimal (Chang et al., 2007).

#### **3.6 Opioid analgesics and renal impairment**

Several opioid analgesics including morphine, hydromorphone and meperidine are metabolized in the liver to pharmacologically active metabolites that may accumulate in patients with renal impairment. Hence, for patients with renal impairment, opioid analgesics including oxycodone and fentanyl that are devoid of active metabolites, are preferred (King et al., 2011).

#### **4. Weak opioid analgesics**

#### **4.1 Codeine**

Codeine (7,8-didehydro-4,5-epoxy-3-methoxy-17-methylmorphinan-6-ol) is an opioid alkaloid found in opium, the dried exudate of the unripe seed capsule of the opium poppy, *Papaver somniferum,* at 0.7 to 2.5% (Boerner, 1975). Due to its high consumption rates globally, codeine is generally synthesized by O-methylation of morphine, an abundant opium constituent at 10-15% (Lenz et al., 1986).

Codeine is a weak opioid analgesic that binds to the -opioid (MOP) receptor with low affinity (Ki = 0.7 M) (Volpe et al., 2011). Its analgesic properties are generally thought to be derived from the fact that it is a prodrug for morphine as up to 10% of oral doses are Odemethylated to morphine by cytochrome P450 2D6 (CYP2D6), an enzyme subject to genetic polymorphism (Kadiev et al., 2008, Somogyi et al., 2007, Zollner & Stein, 2007). Supporting this notion, plasma morphine concentrations are virtually undetectable and codeine lacks efficacy in individuals with the poor metabolizer (PM) CYP2D6 phenotype (Poulsen et al., 1996). By contrast, codeine is extensively metabolized to morphine in those with the ultrametabolizer (UM) phenotype who also have an increased risk of respiratory depression after regular doses of codeine (Kirchheiner et al., 2007).

Doses of codeine generally do not exceed 60 mg (Trescot et al., 2008). Codeine is available in a range of prescription and over-the-counter medicines, often in combination with paracetamol, aspirin or ibuprofen for pain relief (Moore et al., 1997; Moore et al., 2011). It is also the active ingredient in many cough suppressant mixtures and anti-diarrhoeal products (Schiller, 1995; Wee, 2008). Codeine is susceptible to metabolic drug-drug interactions with other commonly prescribed medications that are also metabolized by CYP2D6 including both CYP2D6 inhibitors (e.g. cimetidine) and CYP2D6 inducers (e.g. rifampicin) (Caraco et al., 1997; Zhou, 2009).

#### **4.2 Meperidine (pethidine)**

Meperidine (pethidine; ethyl-1-methyl-4-phenylpiperidine-4-carboxylate), is a synthetic MOP receptor agonist that binds with low affinity (Ki = 450 nM) at the MOP receptor (Volpe et al., 2011). Meperidine is a weak opioid analgesic with potency at 10% that of morphine for the relief of acute post-operative pain (Latta et al., 2002). Meperidine is metabolized by hepatic esterases to pethidinic acid, an inactive metabolite, and by N-demethylation to a neurotoxic metabolite, normeperidine (Gilman et al., 1980, Armstrong et al., 2009). After multiple doses, normeperidine may accumulate in plasma and cerebrospinal fluid causing tremors, twitches, myoclonus and seizures as it has a longer plasma half-life than

Opioid Analgesics 293

actions generally oppose those of morphine in animal studies (Smith, 2000). The elimination

After administration of single doses of morphine to patients with clinical pain, the plasma and CSF concentrations of M3G exceed those of morphine by several-fold (Hasselström & Säwe, 1993) and after chronic dosing, the plasma M3G concentrations exceed the corresponding morphine levels by as much as 10-20 fold (Smith et al., 1999). In patients with renal impairment, M6G and M3G may accumulate in the plasma and CSF, thereby increasing the risk of M6G-induced respiratory depression (Smith & South, 2001) and/or

Morphine is available in immediate-release and sustained-release oral tablet and capsule formulations as well as oral mixtures, rectal suppositories and sterile ampoules for parenteral administration by the intramuscular, intravenous, subcutaneous, epidural and intrathecal routes (Argoff & Silvershein, 2009). The duration of action for immediate-release oral morphine preparations is approximately 3-4 h whereas for oral sustained-released morphine tablets and capsules, the duration of action is 12-24 h (Mather & Smith, 1998). The convenience of once or twice daily dosing provided by sustained-release formulations

Oxycodone ((5-4,5-epoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6-one) is a strong opioid analgesic that is a semi-synthetic derivative of the abundant opium alkaloid, thebaine (Lenz et al., 1986). After oral administration, the bioavailability of oxycodone is high at 60- 87% (Leow et al., 1992; Lalovic et al., 2006). Oxycodone is extensively N-demethylated by the enzyme, CYP3A4, to the analgesically inactive metabolite, noroxycodone (Poyhia et al., 1992; Davis et al., 2003; Lalovic et al., 2004, 2006) with up to another 10% of each dose undergoing CYP2D6-catalyzed O-demethylation to the high affinity MOP receptor agonist oxymorphone (Lalovic et al., 2006). However, metabolically-derived oxymorphone does not contribute significantly to the analgesic actions of oxycodone for the relief of clinical pain because its circulating plasma concentrations are very low (1 ng/mL) in both extensive metabolisers (EMs) and PMs (0.3 ng/mL) as it is rapidly further metabolized to its analgesically-inactive glucuronide conjugate (Lalovic et al., 2006; Zwisler et al., 2010). For patients with post-operative pain, there is no difference in analgesic outcomes between PMs and EMs (Zwisler et al., 2010), affirming earlier work by others showing that the analgesic effects of oxycodone are attributable to the parent opioid alone (Heiskanen et al., 1998;

Radioligand binding studies show that oxycodone has relatively low affinity (Ki = 26 nM) at the cloned MOP receptor (Volpe et al., 2011) and that it has a distinctly different binding profile from morphine in rat brain homogenate (Nielsen et al., 2007). This likely underpins the low extent of cross-tolerance between oxycodone and morphine in rodents (Nielsen et al., 2000) and the success of opioid rotation from morphine to oxycodone for the restoration of analgesia with tolerable opioid-related side-effects in humans (Narabayashi et al., 2008). The potency of intravenous and oral oxycodone for the relief of both post-operative and chronic cancer pain is 1.5 times that of morphine (Kalso et al., 1991; Heiskanen & Kalso, 1997; Bruera et al., 1998). However, when given by the epidural route for the relief of postoperative pain, the potency of oxycodone is much lower than that of morphine at 11%

improves patient compliance and pain relief outcomes (Argoff & Silvershein, 2009).

half-lives of M3G and M6G are in the range 3-4 h (Mather & Smith, 1998).

M3G-induced neuro-excitation (Smith, 2000).

**5.2 Oxycodone** 

Lalovic et al., 1996).

(Backlund et al., 1997).

meperidine itself (Plummer et al., 1995; Simopoulos et al., 2002). Meperidine is contraindicated in patients with impaired renal function as they are at increased risk of normeperidine neurotoxicity due to its faster accumulation (Marinella, 1997; Reutens & Stewart-Wynne, 1989). Generally, meperidine use is discouraged in favour of more efficacious and less toxic opioid analgesics (Latta et al., 2002).

#### **4.3 Tramadol**

Tramadol ((1RS,2RS)-2-[(dimethylamino)methyl]- 1 -(3-methoxyphenyl)-cyclo-hexanol hydrochloride) is a synthetic analgesic that is a racaemic mixture of two enantiomers that bind to the MOP receptor with low (10 M) affinity (Volpe et al., 2011). After systemic administration, tramadol is metabolized in the liver by the enzyme CYP2D6, to its Odemethylated M1 metabolite, a potent -opioid agonist that contributes to its analgesic actions (Subrahmanyam et al., 2001). The (-)-enantiomer of tramadol mainly inhibits noradrenaline reuptake in the central nervous system (CNS) to augment descending inhibition of pain transmission in the spinal cord whereas the (+)-enantiomer preferentially inhibits serotonin reuptake (Reimann & Hennies, 1994). Thus, the pharmacology of tramadol is complex with its analgesic action being due to the combined effects of its two enantiomers and the M1 metabolite. For this reason, the US Food and Drug Administration (FDA) has classified tramadol as a nontraditional, centrally acting analgesic (Grond & Sablotzki, 2004).

For the relief of post-operative pain relief, tramadol is regarded as a "weak" opioid analgesic with potency at 10% that of morphine but it does not produce significant constipation or respiratory depression and it has low abuse potential (Grond & Sablotzki, 2004). When tramadol is given in doses larger than the recommended doses, or if it is coadministered with medications that lower the seizure threshold such as selective serotonin reuptake inhibitors, tricyclic antidepressants and antipsychotic drugs, seizures may be induced (Gardner et al., 2000).

#### **5. Strong opioid analgesics**

#### **5.1 Morphine**

Morphine (7,8-didehydro-4,5,-epoxy-17-methyl-(5,6)-morphinan-3,6-diol) is extracted from opium due to its relatively high abundance at 10-15% by weight (Boerner, 1975). Morphine was first isolated from opium in 1805 by Freidrich Sertűrner, a German pharmacist who named it "morphium" after Morpheus the Greek God of Dreams (Milne et al., 1996).

Morphine is the prototypic strong opioid analgesic that binds with high affinity (Ki = 1.2 nM) at the MOP receptor (Volpe et al., 2011). After oral administration in humans, morphine has low oral bioavailability at 20% due to extensive first-pass metabolism in the liver to two major metabolites, viz morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G) that account for 10% and >50% of each dose, respectively (Milne et al., 1996). Morphine has a short elimination half-life at 2 h consistent with its short duration of action at 4 h (Mather & Smith, 1998).

M6G, like morphine, binds with high affinity at the MOP receptor and it is a more potent analgesic than morphine when given by central routes (Smith & South, 2001). By contrast, supraspinally administered M3G evokes dose-dependent neuro-excitatory effects and its

meperidine itself (Plummer et al., 1995; Simopoulos et al., 2002). Meperidine is contraindicated in patients with impaired renal function as they are at increased risk of normeperidine neurotoxicity due to its faster accumulation (Marinella, 1997; Reutens & Stewart-Wynne, 1989). Generally, meperidine use is discouraged in favour of more

Tramadol ((1RS,2RS)-2-[(dimethylamino)methyl]- 1 -(3-methoxyphenyl)-cyclo-hexanol hydrochloride) is a synthetic analgesic that is a racaemic mixture of two enantiomers that bind to the MOP receptor with low (10 M) affinity (Volpe et al., 2011). After systemic administration, tramadol is metabolized in the liver by the enzyme CYP2D6, to its Odemethylated M1 metabolite, a potent -opioid agonist that contributes to its analgesic actions (Subrahmanyam et al., 2001). The (-)-enantiomer of tramadol mainly inhibits noradrenaline reuptake in the central nervous system (CNS) to augment descending inhibition of pain transmission in the spinal cord whereas the (+)-enantiomer preferentially inhibits serotonin reuptake (Reimann & Hennies, 1994). Thus, the pharmacology of tramadol is complex with its analgesic action being due to the combined effects of its two enantiomers and the M1 metabolite. For this reason, the US Food and Drug Administration (FDA) has classified tramadol as a nontraditional, centrally acting analgesic (Grond &

For the relief of post-operative pain relief, tramadol is regarded as a "weak" opioid analgesic with potency at 10% that of morphine but it does not produce significant constipation or respiratory depression and it has low abuse potential (Grond & Sablotzki, 2004). When tramadol is given in doses larger than the recommended doses, or if it is coadministered with medications that lower the seizure threshold such as selective serotonin reuptake inhibitors, tricyclic antidepressants and antipsychotic drugs, seizures may be

Morphine (7,8-didehydro-4,5,-epoxy-17-methyl-(5,6)-morphinan-3,6-diol) is extracted from opium due to its relatively high abundance at 10-15% by weight (Boerner, 1975). Morphine was first isolated from opium in 1805 by Freidrich Sertűrner, a German pharmacist who named it "morphium" after Morpheus the Greek God of Dreams (Milne et

Morphine is the prototypic strong opioid analgesic that binds with high affinity (Ki = 1.2 nM) at the MOP receptor (Volpe et al., 2011). After oral administration in humans, morphine has low oral bioavailability at 20% due to extensive first-pass metabolism in the liver to two major metabolites, viz morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G) that account for 10% and >50% of each dose, respectively (Milne et al., 1996). Morphine has a short elimination half-life at 2 h consistent with its short duration of action

M6G, like morphine, binds with high affinity at the MOP receptor and it is a more potent analgesic than morphine when given by central routes (Smith & South, 2001). By contrast, supraspinally administered M3G evokes dose-dependent neuro-excitatory effects and its

efficacious and less toxic opioid analgesics (Latta et al., 2002).

**4.3 Tramadol** 

Sablotzki, 2004).

**5.1 Morphine** 

al., 1996).

induced (Gardner et al., 2000).

**5. Strong opioid analgesics** 

at 4 h (Mather & Smith, 1998).

actions generally oppose those of morphine in animal studies (Smith, 2000). The elimination half-lives of M3G and M6G are in the range 3-4 h (Mather & Smith, 1998).

After administration of single doses of morphine to patients with clinical pain, the plasma and CSF concentrations of M3G exceed those of morphine by several-fold (Hasselström & Säwe, 1993) and after chronic dosing, the plasma M3G concentrations exceed the corresponding morphine levels by as much as 10-20 fold (Smith et al., 1999). In patients with renal impairment, M6G and M3G may accumulate in the plasma and CSF, thereby increasing the risk of M6G-induced respiratory depression (Smith & South, 2001) and/or M3G-induced neuro-excitation (Smith, 2000).

Morphine is available in immediate-release and sustained-release oral tablet and capsule formulations as well as oral mixtures, rectal suppositories and sterile ampoules for parenteral administration by the intramuscular, intravenous, subcutaneous, epidural and intrathecal routes (Argoff & Silvershein, 2009). The duration of action for immediate-release oral morphine preparations is approximately 3-4 h whereas for oral sustained-released morphine tablets and capsules, the duration of action is 12-24 h (Mather & Smith, 1998). The convenience of once or twice daily dosing provided by sustained-release formulations improves patient compliance and pain relief outcomes (Argoff & Silvershein, 2009).

#### **5.2 Oxycodone**

Oxycodone ((5-4,5-epoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6-one) is a strong opioid analgesic that is a semi-synthetic derivative of the abundant opium alkaloid, thebaine (Lenz et al., 1986). After oral administration, the bioavailability of oxycodone is high at 60- 87% (Leow et al., 1992; Lalovic et al., 2006). Oxycodone is extensively N-demethylated by the enzyme, CYP3A4, to the analgesically inactive metabolite, noroxycodone (Poyhia et al., 1992; Davis et al., 2003; Lalovic et al., 2004, 2006) with up to another 10% of each dose undergoing CYP2D6-catalyzed O-demethylation to the high affinity MOP receptor agonist oxymorphone (Lalovic et al., 2006). However, metabolically-derived oxymorphone does not contribute significantly to the analgesic actions of oxycodone for the relief of clinical pain because its circulating plasma concentrations are very low (1 ng/mL) in both extensive metabolisers (EMs) and PMs (0.3 ng/mL) as it is rapidly further metabolized to its analgesically-inactive glucuronide conjugate (Lalovic et al., 2006; Zwisler et al., 2010). For patients with post-operative pain, there is no difference in analgesic outcomes between PMs and EMs (Zwisler et al., 2010), affirming earlier work by others showing that the analgesic effects of oxycodone are attributable to the parent opioid alone (Heiskanen et al., 1998; Lalovic et al., 1996).

Radioligand binding studies show that oxycodone has relatively low affinity (Ki = 26 nM) at the cloned MOP receptor (Volpe et al., 2011) and that it has a distinctly different binding profile from morphine in rat brain homogenate (Nielsen et al., 2007). This likely underpins the low extent of cross-tolerance between oxycodone and morphine in rodents (Nielsen et al., 2000) and the success of opioid rotation from morphine to oxycodone for the restoration of analgesia with tolerable opioid-related side-effects in humans (Narabayashi et al., 2008).

The potency of intravenous and oral oxycodone for the relief of both post-operative and chronic cancer pain is 1.5 times that of morphine (Kalso et al., 1991; Heiskanen & Kalso, 1997; Bruera et al., 1998). However, when given by the epidural route for the relief of postoperative pain, the potency of oxycodone is much lower than that of morphine at 11% (Backlund et al., 1997).

Opioid Analgesics 295

administered hydromorphone undergoes extensive first-pass metabolism in the liver to hydromorphone-3-glucuronide (H3G) that accounts for more than 50% of each dose. Although H3G, like M3G, is analgesically inactive, it produces dose-dependent neuroexcitatory effects after supraspinal administration in rodents with a potency 2.5-fold higher than M3G (Wright et al., 2001). Chronic administration of hydromorphone in patients with renal impairment will result in H3G accumulation, raising the risk that neuro-excitatory

The analgesic potency of parenteral hydromorphone is 5-fold higher than that of morphine for the alleviation of moderate to severe acute pain (Bruera et al., 1996; Dunbar et al., 1996; Quigley, 2002; Horn & Nesbit, 2004) whereas for chronic cancer pain, the analgesic

Hydromorphone is available as immediate-release and controlled-release oral formulations (Guay, 2010) as well as ampoules for parenteral administration by either the epidural or

Buprenorphine, ((2S)-2-[(-)-(5R,6R,7R,14S)-9α-cyclopropylmethyl-4,5-epoxy-6,14-ethano-3 hydroxy-6-methoxymorphinan-7-yl]-3,3-dimethylbutan-2-ol), is also a semi-synthetic derivative of thebaine. Buprenorphine binds with high affinity (Ki = 0.2nM) at the MOP receptor (Volpe et al., 2011) and functionally it is a partial agonist (Pick et al., 1997). Buprenorphine also has antagonist actions at the -opioid (KOP) receptor and it interacts with the nociceptin (ORL-1) receptor (Pick et al., 1997). Buprenorphine produces dosedependent analgesia with potency at 25-50 times higher than morphine (Evans & Easthope, 2003). The slow onset and long duration of buprenorphine's pharmacodynamic actions are thought to be due to its slow binding to and dissociation from the MOP receptor (Evans &

Consistent with its partial agonist activity at the MOP receptor, sublingual buprenorphine administered to healthy male volunteers in doses up to 70-fold higher than the recommended analgesic dose (0.3 mg) and 4-8 fold higher than doses (4-8 mg) used to treat opioid addiction, produced ceiling responses for subjective measures of drug liking in doses at 8 to 16 mg (Walsh et al., 1994). In the same subjects a ceiling effect for respiratory depression was observed at 16mg (Walsh et al., 1994). Because buprenorphine exhibited linear pharmacokinetics across the dose range tested, dose-limited sublingual absorption is not responsible for the ceiling effects (Walsh et al., 1994). The KOP antagonist activity of buprenorphine is thought to contribute to its good tolerability characterized by limited

After oral administration, buprenorphine undergoes extensive first-pass metabolism in the liver catalyzed by the enzymes, CYP3A4 and CYP2C8 to produce the active N-dealkylated metabolite, norbuprenorphine (Picard et al., 2005). Consequently the oral bioavailability is low at 14% and so buccal, sublingual, intranasal and transdermal formulations of buprenorphine have been developed that effectively by-pass first-pass metabolism and increase bioavailability to 30-60% (Evans & Easthope, 2003; Johnson et al., 2005; Davis, 2005). Due to its long half-life (26 h) and ceiling pharmacodynamic effects, buprenorphine is used as an alternative to methadone for opioid maintenance therapy in opioid-dependent individuals (Robinson, 2002; Johnson et al., 2005). A combination product containing buprenorphine and naloxone in a 4:1 ratio respectively is available in some countries as a deterrent to illicit use of buprenorphine tablets for parenteral injection (Harris et al., 2004).

potency of hydromorphone is similar to that of morphine (Murray & Hagen, 2005).

side-effects will be produced (Smith, 2000; Mercadante & Arcuri, 2004).

intrathecal routes (Lee et al., 2011; Liu et al., 2011).

dysphoria or psychotomimetic effects (Johnson et al., 2005).

**5.5 Buprenorphine** 

Easthope, 2003).

Oxycodone, like morphine, is available in immediate-release and sustained-release tablet formulations as well as in oral mixtures, rectal suppositories and ampoules for parenteral administration (Argoff & Silvershein, 2009).

#### **5.3 Methadone**

Methadone, 6-dimethylamino-4,4-diphenyl-heptan-3-one, is a synthetic, strong opioid analgesic that is a racaemic mixture of two enantiomers. The analgesic efficacy of methadone is multi-faceted as the R-enantiomer is a high affinity MOP receptor agonist (Ki = 3.4nM) whereas the S-enantiomer augments descending noradrenergic inhibition to block nociceptive signaling in the spinal cord, and both enantiomers have NMDA receptor antagonist activity (Davis and Walsh, 2001).

In humans, methadone has high but unpredictable oral bioavailability at 80% (range 41-99%) with peak plasma concentrations observed at 2-4 h post-dosing (Trescot et al., 2008; Modesto-Lowe et al., 2010). There is a large degree of inter-individual variability in its long elimination half-life (12-150 h) (Trescot et al., 2008). These properties make it difficult to use for the relief of acute pain or for pain that is poorly controlled where rapid dose adjustments are needed (Davis & Walsh, 2001). Further adding to these difficulties, methadone is metabolized by CYP3A4-catalyzed N-demethylation to the analgesically inactive metabolite, normethadone, such that methadone is potentially subject to a large number of metabolic drug-drug interactions as many clinically used drugs are either CYP3A4 inhibitors or inducers (Fishman et al., 2002).

Apart from its use as a strong opioid analgesic for relief of moderate to severe pain, methadone is also widely used for opioid maintenance therapy in patients with heroin addiction (Fishman et al., 2002). Commercially available methadone formulations include oral tablets and mixtures, rectal suppositories and ampoules for parenteral administration (Manfredi et al., 2003). When converting patients from a strong opioid analgesic such as morphine to methadone, caution needs to be exercised. This is because morphinemethadone analgesic ratios vary significantly according to the previous morphine dosing regimen (Mancini et al., 2000).

For individuals receiving chronic methadone treatment for opioid dependence, cardiotoxicity characterized by prolonged QTc intervals are associated with methadone dose and concurrent stimulant use (Modesto-Lowe et al., 2010; Mayet et al., 2011). For individuals receiving methadone at doses exceeding 60 mg/day together with tricyclic antidepressants or other drugs that inhibit methadone metabolism, the QTc interval is lengthened thereby initiating Torsades de Pointes (Krantz et al., 2002, Ehret et al., 2007). QT prolongation with methadone is also influenced by other factors including hypokalaemia, hepatic failure and pre-existing heart disease (Ehret et al., 2007). Unfortunately, the general lack of awareness of the long and highly variable elimination half-life of methadone together with its many metabolic drug-drug interactions, has led to a dramatic increase in methadone-associated deaths (Trescot et al., 2008).

#### **5.4 Hydromorphone**

Hydromorphone, 4,5 alpha-epoxy-3-hydroxy-17-methyl morphinan-6-one, is a semisynthetic opioid analgesic (Murray & Hagen, 2005) that binds with high affinity (Ki = 0.37 nM) at the MOP receptor (Volpe et al., 2011) and to a lesser extent at the -opioid (DOP) receptor but not at the -opioid (KOP) receptor (Murray & Hagen, 2005). Orally

Oxycodone, like morphine, is available in immediate-release and sustained-release tablet formulations as well as in oral mixtures, rectal suppositories and ampoules for parenteral

Methadone, 6-dimethylamino-4,4-diphenyl-heptan-3-one, is a synthetic, strong opioid analgesic that is a racaemic mixture of two enantiomers. The analgesic efficacy of methadone is multi-faceted as the R-enantiomer is a high affinity MOP receptor agonist (Ki = 3.4nM) whereas the S-enantiomer augments descending noradrenergic inhibition to block nociceptive signaling in the spinal cord, and both enantiomers have NMDA receptor

In humans, methadone has high but unpredictable oral bioavailability at 80% (range 41-99%) with peak plasma concentrations observed at 2-4 h post-dosing (Trescot et al., 2008; Modesto-Lowe et al., 2010). There is a large degree of inter-individual variability in its long elimination half-life (12-150 h) (Trescot et al., 2008). These properties make it difficult to use for the relief of acute pain or for pain that is poorly controlled where rapid dose adjustments are needed (Davis & Walsh, 2001). Further adding to these difficulties, methadone is metabolized by CYP3A4-catalyzed N-demethylation to the analgesically inactive metabolite, normethadone, such that methadone is potentially subject to a large number of metabolic drug-drug interactions as many clinically used drugs are either CYP3A4 inhibitors or

Apart from its use as a strong opioid analgesic for relief of moderate to severe pain, methadone is also widely used for opioid maintenance therapy in patients with heroin addiction (Fishman et al., 2002). Commercially available methadone formulations include oral tablets and mixtures, rectal suppositories and ampoules for parenteral administration (Manfredi et al., 2003). When converting patients from a strong opioid analgesic such as morphine to methadone, caution needs to be exercised. This is because morphinemethadone analgesic ratios vary significantly according to the previous morphine dosing

For individuals receiving chronic methadone treatment for opioid dependence, cardiotoxicity characterized by prolonged QTc intervals are associated with methadone dose and concurrent stimulant use (Modesto-Lowe et al., 2010; Mayet et al., 2011). For individuals receiving methadone at doses exceeding 60 mg/day together with tricyclic antidepressants or other drugs that inhibit methadone metabolism, the QTc interval is lengthened thereby initiating Torsades de Pointes (Krantz et al., 2002, Ehret et al., 2007). QT prolongation with methadone is also influenced by other factors including hypokalaemia, hepatic failure and pre-existing heart disease (Ehret et al., 2007). Unfortunately, the general lack of awareness of the long and highly variable elimination half-life of methadone together with its many metabolic drug-drug interactions, has led to a dramatic increase in methadone-associated

Hydromorphone, 4,5 alpha-epoxy-3-hydroxy-17-methyl morphinan-6-one, is a semisynthetic opioid analgesic (Murray & Hagen, 2005) that binds with high affinity (Ki = 0.37 nM) at the MOP receptor (Volpe et al., 2011) and to a lesser extent at the -opioid (DOP) receptor but not at the -opioid (KOP) receptor (Murray & Hagen, 2005). Orally

administration (Argoff & Silvershein, 2009).

antagonist activity (Davis and Walsh, 2001).

inducers (Fishman et al., 2002).

regimen (Mancini et al., 2000).

deaths (Trescot et al., 2008).

**5.4 Hydromorphone** 

**5.3 Methadone** 

administered hydromorphone undergoes extensive first-pass metabolism in the liver to hydromorphone-3-glucuronide (H3G) that accounts for more than 50% of each dose. Although H3G, like M3G, is analgesically inactive, it produces dose-dependent neuroexcitatory effects after supraspinal administration in rodents with a potency 2.5-fold higher than M3G (Wright et al., 2001). Chronic administration of hydromorphone in patients with renal impairment will result in H3G accumulation, raising the risk that neuro-excitatory side-effects will be produced (Smith, 2000; Mercadante & Arcuri, 2004).

The analgesic potency of parenteral hydromorphone is 5-fold higher than that of morphine for the alleviation of moderate to severe acute pain (Bruera et al., 1996; Dunbar et al., 1996; Quigley, 2002; Horn & Nesbit, 2004) whereas for chronic cancer pain, the analgesic potency of hydromorphone is similar to that of morphine (Murray & Hagen, 2005).

Hydromorphone is available as immediate-release and controlled-release oral formulations (Guay, 2010) as well as ampoules for parenteral administration by either the epidural or intrathecal routes (Lee et al., 2011; Liu et al., 2011).

#### **5.5 Buprenorphine**

Buprenorphine, ((2S)-2-[(-)-(5R,6R,7R,14S)-9α-cyclopropylmethyl-4,5-epoxy-6,14-ethano-3 hydroxy-6-methoxymorphinan-7-yl]-3,3-dimethylbutan-2-ol), is also a semi-synthetic derivative of thebaine. Buprenorphine binds with high affinity (Ki = 0.2nM) at the MOP receptor (Volpe et al., 2011) and functionally it is a partial agonist (Pick et al., 1997). Buprenorphine also has antagonist actions at the -opioid (KOP) receptor and it interacts with the nociceptin (ORL-1) receptor (Pick et al., 1997). Buprenorphine produces dosedependent analgesia with potency at 25-50 times higher than morphine (Evans & Easthope, 2003). The slow onset and long duration of buprenorphine's pharmacodynamic actions are thought to be due to its slow binding to and dissociation from the MOP receptor (Evans & Easthope, 2003).

Consistent with its partial agonist activity at the MOP receptor, sublingual buprenorphine administered to healthy male volunteers in doses up to 70-fold higher than the recommended analgesic dose (0.3 mg) and 4-8 fold higher than doses (4-8 mg) used to treat opioid addiction, produced ceiling responses for subjective measures of drug liking in doses at 8 to 16 mg (Walsh et al., 1994). In the same subjects a ceiling effect for respiratory depression was observed at 16mg (Walsh et al., 1994). Because buprenorphine exhibited linear pharmacokinetics across the dose range tested, dose-limited sublingual absorption is not responsible for the ceiling effects (Walsh et al., 1994). The KOP antagonist activity of buprenorphine is thought to contribute to its good tolerability characterized by limited dysphoria or psychotomimetic effects (Johnson et al., 2005).

After oral administration, buprenorphine undergoes extensive first-pass metabolism in the liver catalyzed by the enzymes, CYP3A4 and CYP2C8 to produce the active N-dealkylated metabolite, norbuprenorphine (Picard et al., 2005). Consequently the oral bioavailability is low at 14% and so buccal, sublingual, intranasal and transdermal formulations of buprenorphine have been developed that effectively by-pass first-pass metabolism and increase bioavailability to 30-60% (Evans & Easthope, 2003; Johnson et al., 2005; Davis, 2005). Due to its long half-life (26 h) and ceiling pharmacodynamic effects, buprenorphine is used as an alternative to methadone for opioid maintenance therapy in opioid-dependent individuals (Robinson, 2002; Johnson et al., 2005). A combination product containing buprenorphine and naloxone in a 4:1 ratio respectively is available in some countries as a deterrent to illicit use of buprenorphine tablets for parenteral injection (Harris et al., 2004).

Opioid Analgesics 297

Remifentanil, 3-[4-methoxycarbonyl-4-[1-oxopropyl)phenylamino]-1-piperidine]propanoic acid, methyl ester) is a synthetic derivative of fentanyl with an ester function in its structure that makes it susceptible to hydrolysis by non-specific blood and tissue esterases (Egan et al., 1993). The very rapid metabolism of remifentanil to the inactive remifentanil acid metabolite by non-specific esterases underpins its activity as an ultra-short acting MOP

Parenteral remifentanil has a rapid onset of action (~1 min) and a rapid offset of action following discontinuation (~3–10 min) (Stroumpos et al., 2010) and it is indicated for the relief of pain associated with surgical procedures (Mesolella et al., 2004, Kucukemre et al., 2005). Remifentanil's pharmacokinetics favour its use as an analgesic during labour (Leong et al., 2011), a notion supported by the findings of two recent clinical studies (Buehner et al., 2011; Ng et al., 2011). In the first study, 94% of 244 consecutive women in a small maternity unit who received remifentanil by patient-controlled analgesia (PCA) for relief of labour pain rated their analgesic outcomes as excellent, very good or good (Buehner et al., 2011). The safety profile of remifentanil was also good as the Apgar scores of neonates born to these women did not differ significantly from those for neonates born by normal vaginal delivery to women who received no analgesia (Buehner et al., 2011). In the second study, maternal satisfaction was higher in laboring women who received PCA remifentanil for analgesia compared with intramuscular pethidine (Ng et al., 2011) with no difference in the safety

profile between these two opioid analgesics in the newborn infants (Ng et al., 2011).

For patients experiencing poor pain relief and intolerable opioid-related side-effects on one strong opioid analgesic, switching to a second strong opioid analgesic often results in restoration of satisfactory pain relief with tolerable opioid-related adverse effects (Knotkova et al., 2009; Vissers et al., 2010). The starting dose of the second opioid is selected to minimize potential risks whilst ideally restoring analgesic efficacy and must be informed by an estimate of its potency relative to the first opioid (Fine et al., 2009; Mercadante &

Both pharmacokinetic and pharmacodynamic factors may contribute to the clinical success of opioid rotation. For opioid analgesics such as morphine and hydromorphone that are avidly metabolized to the neuro-excitatory 'anti-analgesic' glucuronide metabolites, M3G and H3G respectively, opioid rotation facilitates clearance of these metabolites from the body enabling restoration of analgesia with the second opioid and resolution of neuroexcitatory side-effects (Smith, 2000). Additionally, opioid rotation exploits incomplete crosstolerance between opioids possibly underpinned by subtle differences in their modulation

**7. Peripherally selective opioid antagonists for improving opioid-induced** 

In patients receiving opioid analgesics for treatment of chronic pain, constipation is a very common side-effect that impairs quality of life and has a prevalence of >80% despite proactive laxative use (Clemens & Mikus, 2010; Diego et al., 2011). A recent approach to the treatment of opioid-induced constipation involves the recent development of quarternary

**5.8.1 Remifentanil** 

agonist (Egan et al., 1993).

**6. Opioid rotation** 

Caraceni, 2011).

**constipation** 

of MOP receptor function (Smith, 2008; Slatkin, 2009).

#### **5.6 Fentanyl**

Fentanyl, *N*-(1-(2-phenylethyl)-4-piperidinyl)-*N*-phenyl-propanamide, is a synthetic opioid analgesic (Horn & Nesbit, 2004) that binds with high affinity (Ki = 1.3 nM) at the MOP receptor (Volpe et al., 2011). Fentanyl is metabolized by CYP3A4 to its N-dealkylated metabolite, norfentanyl that is pharmacologically inactive (Horn & Nesbit, 2004).

After parenteral dosing, fentanyl is ~80-100 fold more potent than morphine with a rapid onset of action but only a short duration at < 60 min (Horn & Nesbit, 2004; Pasero, 2005; Stanley, 2005). For post-operative pain relief, fentanyl may be given by spinal routes whereas for breakthrough or procedural pain, the sublingual, transmucosal, intra-nasal, inhaled or parenteral routes are preferred (Lennernas et al., 2005; Hair et al., 2008; Peng & Sandler, 1999).

Fentanyl has high lipophilicity making it suitable for transdermal delivery. To this end, there are several transdermal patch formulations of fentanyl available for clinical use that effectively overcome fentanyl's short duration of action (Cachia & Ahmedzai, 2011). There is now a large body of evidence to support the use of fentanyl patches for the management of moderate to severe chronic cancer pain, with data suggesting improved pain relief and reduced opioid-related side-effects compared with sustained release oral morphine (Cachia & Ahmedzai, 2011).

#### **5.7 Tapentadol**

Tapentadol, [(-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol], is a recently approved centrally acting analgesic with two complementary modes of action, viz moderate affinity activity at the MOP receptor (Ki = 0.1 M) together with inhibitory effects on the NET transporter (Ki = 0.5 M) to block the re-uptake of norepinephrine in the CNS and so augment descending inhibition to attenuate pain at the level of the spinal cord (Tzschentke et al., 2007; Hartrick, 2009; Wade & Spruill, 2009). After oral dosing, the oral bioavailability of tapentadol is relatively low at 32% (Tzschentke et al., 2006) due to significant first-pass metabolism in the liver to the inactive glucuronide metabolite, tapentadol-O-glucuronide (Terlinden et al., 2010).

The immediate-release (IR) formulation of tapentadol was approved by the FDA in 2008 for the management of moderate-to-severe acute pain as the first new analgesic developed in over 25 years (Vadivelu et al., 2011). When compared with oxycodone in a head-to-head clinical trial for the relief of post-operative pain in patients following bunionectomy, tapentadol provided non-inferior analgesia to oxycodone with a superior gastrointestinal adverse effect profile characterized by significantly less nausea, vomiting, and constipation when compared with oxycodone (Hartrick, 2009; Vadivelu et al., 2011).

More recently, the FDA has approved an extended-release (ER) formulation of tapentadol for twice-daily oral administration for the management of moderate to severe chronic pain in adult patients (Vadivelu et al., 2011). In patients with end-stage joint disease administered IR tapentadol for two weeks followed by the ER formulation for a further 4-weeks, the superior gastrointestinal tolerability of tapentadol relative to oxycodone, was affirmed (Etropolski et al., 2011). Mechanistically, this may be due to an 'opioid-sparing' effect of the inhibitory actions of tapentadol at the NET transporter (Tzschentke et al., 2006).

#### **5.8 Ultra-short acting opioid analgesics**

For patients with cardiovascular instability, ultra-short acting structural analogues of fentanyl such as remifentanil, alfentanil and sufentanil are preferred for use as part of balanced analgesic regimens during anaesthesia (Horn & Nesbit, 2004).

Fentanyl, *N*-(1-(2-phenylethyl)-4-piperidinyl)-*N*-phenyl-propanamide, is a synthetic opioid analgesic (Horn & Nesbit, 2004) that binds with high affinity (Ki = 1.3 nM) at the MOP receptor (Volpe et al., 2011). Fentanyl is metabolized by CYP3A4 to its N-dealkylated

After parenteral dosing, fentanyl is ~80-100 fold more potent than morphine with a rapid onset of action but only a short duration at < 60 min (Horn & Nesbit, 2004; Pasero, 2005; Stanley, 2005). For post-operative pain relief, fentanyl may be given by spinal routes whereas for breakthrough or procedural pain, the sublingual, transmucosal, intra-nasal, inhaled or parenteral routes are preferred (Lennernas et al., 2005; Hair et al., 2008; Peng & Sandler, 1999). Fentanyl has high lipophilicity making it suitable for transdermal delivery. To this end, there are several transdermal patch formulations of fentanyl available for clinical use that effectively overcome fentanyl's short duration of action (Cachia & Ahmedzai, 2011). There is now a large body of evidence to support the use of fentanyl patches for the management of moderate to severe chronic cancer pain, with data suggesting improved pain relief and reduced opioid-related side-effects compared with sustained release oral morphine (Cachia

Tapentadol, [(-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol], is a recently approved centrally acting analgesic with two complementary modes of action, viz moderate affinity activity at the MOP receptor (Ki = 0.1 M) together with inhibitory effects on the NET transporter (Ki = 0.5 M) to block the re-uptake of norepinephrine in the CNS and so augment descending inhibition to attenuate pain at the level of the spinal cord (Tzschentke et al., 2007; Hartrick, 2009; Wade & Spruill, 2009). After oral dosing, the oral bioavailability of tapentadol is relatively low at 32% (Tzschentke et al., 2006) due to significant first-pass metabolism in the liver to the inactive glucuronide metabolite, tapentadol-O-glucuronide

The immediate-release (IR) formulation of tapentadol was approved by the FDA in 2008 for the management of moderate-to-severe acute pain as the first new analgesic developed in over 25 years (Vadivelu et al., 2011). When compared with oxycodone in a head-to-head clinical trial for the relief of post-operative pain in patients following bunionectomy, tapentadol provided non-inferior analgesia to oxycodone with a superior gastrointestinal adverse effect profile characterized by significantly less nausea, vomiting, and constipation

More recently, the FDA has approved an extended-release (ER) formulation of tapentadol for twice-daily oral administration for the management of moderate to severe chronic pain in adult patients (Vadivelu et al., 2011). In patients with end-stage joint disease administered IR tapentadol for two weeks followed by the ER formulation for a further 4-weeks, the superior gastrointestinal tolerability of tapentadol relative to oxycodone, was affirmed (Etropolski et al., 2011). Mechanistically, this may be due to an 'opioid-sparing' effect of the

For patients with cardiovascular instability, ultra-short acting structural analogues of fentanyl such as remifentanil, alfentanil and sufentanil are preferred for use as part of

when compared with oxycodone (Hartrick, 2009; Vadivelu et al., 2011).

balanced analgesic regimens during anaesthesia (Horn & Nesbit, 2004).

inhibitory actions of tapentadol at the NET transporter (Tzschentke et al., 2006).

metabolite, norfentanyl that is pharmacologically inactive (Horn & Nesbit, 2004).

**5.6 Fentanyl** 

& Ahmedzai, 2011).

(Terlinden et al., 2010).

**5.8 Ultra-short acting opioid analgesics** 

**5.7 Tapentadol** 

#### **5.8.1 Remifentanil**

Remifentanil, 3-[4-methoxycarbonyl-4-[1-oxopropyl)phenylamino]-1-piperidine]propanoic acid, methyl ester) is a synthetic derivative of fentanyl with an ester function in its structure that makes it susceptible to hydrolysis by non-specific blood and tissue esterases (Egan et al., 1993). The very rapid metabolism of remifentanil to the inactive remifentanil acid metabolite by non-specific esterases underpins its activity as an ultra-short acting MOP agonist (Egan et al., 1993).

Parenteral remifentanil has a rapid onset of action (~1 min) and a rapid offset of action following discontinuation (~3–10 min) (Stroumpos et al., 2010) and it is indicated for the relief of pain associated with surgical procedures (Mesolella et al., 2004, Kucukemre et al., 2005).

Remifentanil's pharmacokinetics favour its use as an analgesic during labour (Leong et al., 2011), a notion supported by the findings of two recent clinical studies (Buehner et al., 2011; Ng et al., 2011). In the first study, 94% of 244 consecutive women in a small maternity unit who received remifentanil by patient-controlled analgesia (PCA) for relief of labour pain rated their analgesic outcomes as excellent, very good or good (Buehner et al., 2011). The safety profile of remifentanil was also good as the Apgar scores of neonates born to these women did not differ significantly from those for neonates born by normal vaginal delivery to women who received no analgesia (Buehner et al., 2011). In the second study, maternal satisfaction was higher in laboring women who received PCA remifentanil for analgesia compared with intramuscular pethidine (Ng et al., 2011) with no difference in the safety profile between these two opioid analgesics in the newborn infants (Ng et al., 2011).

#### **6. Opioid rotation**

For patients experiencing poor pain relief and intolerable opioid-related side-effects on one strong opioid analgesic, switching to a second strong opioid analgesic often results in restoration of satisfactory pain relief with tolerable opioid-related adverse effects (Knotkova et al., 2009; Vissers et al., 2010). The starting dose of the second opioid is selected to minimize potential risks whilst ideally restoring analgesic efficacy and must be informed by an estimate of its potency relative to the first opioid (Fine et al., 2009; Mercadante & Caraceni, 2011).

Both pharmacokinetic and pharmacodynamic factors may contribute to the clinical success of opioid rotation. For opioid analgesics such as morphine and hydromorphone that are avidly metabolized to the neuro-excitatory 'anti-analgesic' glucuronide metabolites, M3G and H3G respectively, opioid rotation facilitates clearance of these metabolites from the body enabling restoration of analgesia with the second opioid and resolution of neuroexcitatory side-effects (Smith, 2000). Additionally, opioid rotation exploits incomplete crosstolerance between opioids possibly underpinned by subtle differences in their modulation of MOP receptor function (Smith, 2008; Slatkin, 2009).

#### **7. Peripherally selective opioid antagonists for improving opioid-induced constipation**

In patients receiving opioid analgesics for treatment of chronic pain, constipation is a very common side-effect that impairs quality of life and has a prevalence of >80% despite proactive laxative use (Clemens & Mikus, 2010; Diego et al., 2011). A recent approach to the treatment of opioid-induced constipation involves the recent development of quarternary

Opioid Analgesics 299

Naloxone, (1*S*,5*R*,13*R*,17*S*)-10,17-dihydroxy- 4-(prop-2-en-1-yl)-12-oxa-4-azapentacyclo [9.6.1.01,13.05,17.07,18]octadeca-7(18),8,10-trien-14-one, is a non-selective opioid receptor antagonist (Lenz et al., 1986). In the clinical setting, parenteral naloxone is used to reverse life-threatening opioid agonist-induced respiratory depression (Diego et al., 2011). However, as naloxone crosses the blood-brain-barrier, it also reverses centrally mediated analgesia

After oral administration, the bioavailability of naloxone is very low at 2% due to extensive first-pass metabolism which makes it possible to obtain a highly localized opioid antagonist action in the gastrointestinal tract whilst sparing the centrally mediated opioid analgesic effects of oral oxycodone (Leppert, 2010; Diego et al., 2011). The negligible oral bioavailability of naloxone is exploited in an oral prolonged-release tablet that contains oxycodone in combination with naloxone in a fixed 2:1 ratio resulting in less constipation and less laxative consumption relative treatment with oxycodone alone (Leppert, 2010). The oxycodone plus naloxone oxycodone tablet is available in four tablet strengths; 5/2.5 mg, 10/5 mg, 20/10 mg and 40/20 mg oxycodone/naloxone respectively (Leppert, 2010).

Moderate to severe acute and chronic pain continues to be managed with opioid analgesics according to the principles succinctly summarized by Steps 2 and 3 of the WHO 3-step Analgesic Ladder. Weak opioid analgesics are added to non-opioid analgesics for the management of moderate pain with adjuvants added if pain has a neuropathic component. For moderate to severe pain, strong opioid analgesics are recommended with the addition of

Argoff, C.E., Silvershein, D.I. (2009) A comparison of long- and short-acting opioids for the

Armstrong, S.C., Wynn, G.H., Sandson, N.B. (2009) Pharmacokinetic drug interactions of

Bader, S., Jaroslawski, K., Blum, H.E., Becker, G. (2011) Opioid-induced constipation in

Backlund, M., Lindgren, L., Kajimoto, Y., Rosenberg, P.H. (1997) Comparison of epidural morphine and oxycodone for pain after abdominal surgery. *J Clin Anesth* 9: 30-35. Boerner, U. (1975) The metabolism of morphine and heroin and man. *Drug Metab Rev* 4: 39-

Bruera, E., Sloan, P., Mount, B., Scott, J., Suarez-Almazor, M. (1996) A randomized, double-

Bruera, E., Belzile, M., Pituskin, E., Fainsinger, R., Darke, A., Harsanyi, Z., Babul, N., Ford, I.

synthetic opiate analgesics. *Psychosomatics* 50: 169-76.

treatment of chronic noncancer pain: tailoring therapy to meet patient needs. *Mayo* 

advanced illness: safety and efficacy of methylnaltrexone bromide. *Clin Med* 

blind, double-dummy, crossover trial comparing the safety and efficacy of oral sustained-release hydromorphone with immediate-release hydromorphone in patients with cancer pain. Canadian Palliative Care Clinical Trials Group. *J Clin* 

(1998) Randomized, double-blind, cross-over trial comparing safety and efficacy of

**7.3 Oral naloxone** 

(Diego et al., 2011).

**8. Conclusion** 

**9. References** 

73.

non-opioids and adjuvants, as required.

*Clin Proc* 84: 602-12.

*Insights Oncol* 5: 201-11.

*Oncol* 14: 1713-1717.

ammonium opioid antagonists such as alvimopan and methylnaltrexone that have limited absorption across the gastrointestinal mucosa and do not cross the blood-brain-barrier, as well as products that incorporate low-dose oral naloxone that has very low oral bioavailability at 2% (Diego et al., 2011). These products selectively target opioid receptors in the gastrointestinal tract without affecting centrally-mediated analgesic mechanisms (Diego et al., 2011).

#### **7.1 Alvimopan**

Alvimopan, 2-([(2S)-2-([(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl) -3 phenylpropanoyl]amino)acetic acid, is an orally active synthetic MOP receptor antagonist that is unable to cross the blood-brain-barrier due to the presence of a quaternary ammonium group in its chemical structure that is fully ionized at physiological pH (Foss et al., 2008; Diego et al., 2011). Thus after oral administration, its actions are confined to peripheral sites such as the gastrointestinal tract and it does not reverse centrally mediated analgesia (Foss et al., 2008; Karuppiah & Farrah, 2011). Alvimopan has been approved by the FDA for short-term use (maximum of 15 doses at twice-daily intervals) in hospitals to treat post-operative ileus that may be caused or exacerbated by opioid analgesics (Diego et al., 2011). Alvimopan accelerates the time to upper and lower gastrointestinal recovery following partial large or small bowel resection with primary anastomosis and decreases the time to hospital discharge by approximately one day (Diego et al., 2011; Karuppiah & Farrah, 2011).

The recommended dosing regimen for alvimopan is 12 mg at 0.5-5 h pre-surgery followed by 12 mg twice daily for a maximum of 15 doses (Karuppiah & Farrah, 2011). Alvimopan is generally well-tolerated when administered for seven days or less (Karuppiah & Farrah, 2011). However, with long-term use (e.g. 12 months) there is an increased risk of myocardial events (Bader et al., 2011; Karuppiah & Farrah, 2011).

#### **7.2 Methylnaltrexone**

Methylnaltrexone, (5α)-17-(cyclopropylmethyl)-3,14-dihydroxy-17-methyl-4,5 epoxymorphinanium-17-ium-6-one, is a quaternary ammonium derivative of the opioid receptor antagonist, naltrexone (Bader et al., 2011; Diego et al., 2011). Due to the quaternary ammonium group in its chemical structure that is ionized at physiological pH, methylnaltrexone does not cross the blood-brain-barrier and so centrally mediated analgesia is not reversed (Bader et al., Diego et al., 2011).

Methylnaltrexone has 8-fold and 120-fold higher binding affinity at the MOP receptor relative to the KOP and DOP receptors respectively (Bader et al., 2011). Following administration by the subcutaneous route at 0.15-5 mg/kg in humans, mean peak plasma concentrations of methylnaltrexone are observed at 0.5 h post-dosing and the elimination half-life is in the range 8-9 h (Rotshteyn et al., 2011). The mean bioavailability is high at 82% with minimal metabolism and so it has low potential for drug-drug interactions (Rotshteyn et al., 2011).

Methylnaltrexone is approved by the FDA and the European Medicines Agency (EMA) to treat opioid induced constipation in patients with advanced disease where other laxative regimens have failed (Iskedjian et al., 2010; Bader et al., 2011). Methylnaltrexone causes laxation in at least 50% of patients in less than 24 h over the first two weeks of treatment without impairing analgesia or causing serious adverse events (Bader et al., 2011).

ammonium opioid antagonists such as alvimopan and methylnaltrexone that have limited absorption across the gastrointestinal mucosa and do not cross the blood-brain-barrier, as well as products that incorporate low-dose oral naloxone that has very low oral bioavailability at 2% (Diego et al., 2011). These products selectively target opioid receptors in the gastrointestinal tract without affecting centrally-mediated analgesic mechanisms

Alvimopan, 2-([(2S)-2-([(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl) -3 phenylpropanoyl]amino)acetic acid, is an orally active synthetic MOP receptor antagonist that is unable to cross the blood-brain-barrier due to the presence of a quaternary ammonium group in its chemical structure that is fully ionized at physiological pH (Foss et al., 2008; Diego et al., 2011). Thus after oral administration, its actions are confined to peripheral sites such as the gastrointestinal tract and it does not reverse centrally mediated analgesia (Foss et al., 2008; Karuppiah & Farrah, 2011). Alvimopan has been approved by the FDA for short-term use (maximum of 15 doses at twice-daily intervals) in hospitals to treat post-operative ileus that may be caused or exacerbated by opioid analgesics (Diego et al., 2011). Alvimopan accelerates the time to upper and lower gastrointestinal recovery following partial large or small bowel resection with primary anastomosis and decreases the time to hospital discharge by approximately one day (Diego et al., 2011; Karuppiah &

The recommended dosing regimen for alvimopan is 12 mg at 0.5-5 h pre-surgery followed by 12 mg twice daily for a maximum of 15 doses (Karuppiah & Farrah, 2011). Alvimopan is generally well-tolerated when administered for seven days or less (Karuppiah & Farrah, 2011). However, with long-term use (e.g. 12 months) there is an increased risk of myocardial

Methylnaltrexone, (5α)-17-(cyclopropylmethyl)-3,14-dihydroxy-17-methyl-4,5 epoxymorphinanium-17-ium-6-one, is a quaternary ammonium derivative of the opioid receptor antagonist, naltrexone (Bader et al., 2011; Diego et al., 2011). Due to the quaternary ammonium group in its chemical structure that is ionized at physiological pH, methylnaltrexone does not cross the blood-brain-barrier and so centrally mediated analgesia

Methylnaltrexone has 8-fold and 120-fold higher binding affinity at the MOP receptor relative to the KOP and DOP receptors respectively (Bader et al., 2011). Following administration by the subcutaneous route at 0.15-5 mg/kg in humans, mean peak plasma concentrations of methylnaltrexone are observed at 0.5 h post-dosing and the elimination half-life is in the range 8-9 h (Rotshteyn et al., 2011). The mean bioavailability is high at 82% with minimal metabolism and so it has low potential for drug-drug interactions (Rotshteyn

Methylnaltrexone is approved by the FDA and the European Medicines Agency (EMA) to treat opioid induced constipation in patients with advanced disease where other laxative regimens have failed (Iskedjian et al., 2010; Bader et al., 2011). Methylnaltrexone causes laxation in at least 50% of patients in less than 24 h over the first two weeks of treatment

without impairing analgesia or causing serious adverse events (Bader et al., 2011).

events (Bader et al., 2011; Karuppiah & Farrah, 2011).

is not reversed (Bader et al., Diego et al., 2011).

(Diego et al., 2011).

**7.1 Alvimopan** 

Farrah, 2011).

et al., 2011).

**7.2 Methylnaltrexone** 

#### **7.3 Oral naloxone**

Naloxone, (1*S*,5*R*,13*R*,17*S*)-10,17-dihydroxy- 4-(prop-2-en-1-yl)-12-oxa-4-azapentacyclo [9.6.1.01,13.05,17.07,18]octadeca-7(18),8,10-trien-14-one, is a non-selective opioid receptor antagonist (Lenz et al., 1986). In the clinical setting, parenteral naloxone is used to reverse life-threatening opioid agonist-induced respiratory depression (Diego et al., 2011). However, as naloxone crosses the blood-brain-barrier, it also reverses centrally mediated analgesia (Diego et al., 2011).

After oral administration, the bioavailability of naloxone is very low at 2% due to extensive first-pass metabolism which makes it possible to obtain a highly localized opioid antagonist action in the gastrointestinal tract whilst sparing the centrally mediated opioid analgesic effects of oral oxycodone (Leppert, 2010; Diego et al., 2011). The negligible oral bioavailability of naloxone is exploited in an oral prolonged-release tablet that contains oxycodone in combination with naloxone in a fixed 2:1 ratio resulting in less constipation and less laxative consumption relative treatment with oxycodone alone (Leppert, 2010).

The oxycodone plus naloxone oxycodone tablet is available in four tablet strengths; 5/2.5 mg, 10/5 mg, 20/10 mg and 40/20 mg oxycodone/naloxone respectively (Leppert, 2010).

#### **8. Conclusion**

Moderate to severe acute and chronic pain continues to be managed with opioid analgesics according to the principles succinctly summarized by Steps 2 and 3 of the WHO 3-step Analgesic Ladder. Weak opioid analgesics are added to non-opioid analgesics for the management of moderate pain with adjuvants added if pain has a neuropathic component. For moderate to severe pain, strong opioid analgesics are recommended with the addition of non-opioids and adjuvants, as required.

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buprenorphine: evidence for new metabolic pathways. *Drug Metab Dispos* 33: 689-

buprenorphine, a mixed agonist-antagonist with kappa 3 analgesia. *Brain Res* 744:

Codeine and morphine in extensive and poor metabolizers of sparteine: pharmacokinetics, analgesic effect and side effects. *Eur J Clin Pharmacol* 51: 289-95. Poyhia, R., Seppala, T., Olkkola, K.T., Kalso, E. (1992) The pharmacokinetics and metabolism

of oxycodone after intramuscular and oral administration to healthy subjects. *Br J* 


Stanley, T.H. (2005) Fentanyl. *J Pain Symptom Manage* 29: S67-71.


**15** 

 *Germany* 

**Pain Management and Costs of a** 

**in Low Back Pain Patients** 

*Institute of Empirical Health Economics, Burscheid,* 

**Combination of Oxycodone + Naloxone** 

R. Rychlik, K. Viehmann, D. Daniel, P. Kiencke and J. Kresimon

In industrial nations, low back pain (lbp) is one of the leading causes of physical limitation. It is also a main source of incapacitation, suffering and expense. According to the national institute of neurological disorders and stroke in the US, LBP accounts for more sick leave and disability than any other medical condition. In Germany, life time prevalence of LBP reaches up to 84 %, with the highest rate for people aged between 35 and 55. According to the German Health Report of the year 2002, the costs of rehabilitation and early retirement amounted to more than 15 billion € , and direct and indirect cost of illness up to 26 billion EURO. Thus the effective management of low back pain is a major health and economic

In a minority of patients presenting for evaluation in a primary care setting, lbp can be reliably attributed to a specific underlying pathology, such as malignancy, vertebral compression fracture or inflammatory/infectious processes. The majority, 80-90%, of patients present primary or non-specific lbp. There is little documented knowledge of possible causes of non-specific lbp. Risk factors are probably related to genetic predisposition, lifestyle (e.g., overweight, lack of physical activity), physical strain and

Opioid analgesics are well established in the treatment of severe pain conditions and have internationally gained a strong position as a potent daily pain treatment option. Many physicians are still apprehensive about the administration of opioids within a continuous therapy, due to potential drug abuse and possible adverse effects, such as impaired

To achieve a satisfactory balance between analgesia and side effects, the assessment and treatment of opioid side effects are fundamental aspects of the therapy. This may increase the likelihood of a favourable treatment outcome, potentially allow higher and more efficacious opioid doses, and improve quality of life by reducing other discomforting symptoms. Economic consequences of insufficiently treated chronic lbp and treatment of potential adverse drug effects also play a significant role from the society's point of view. Additional expenses may include costs that emerge from additional obligatory treatments,

**1. Introduction** 

concern.

psychological distress.

gastrointestinal functioning.

hospitalization and work incapacity.


## **Pain Management and Costs of a Combination of Oxycodone + Naloxone in Low Back Pain Patients**

R. Rychlik, K. Viehmann, D. Daniel, P. Kiencke and J. Kresimon *Institute of Empirical Health Economics, Burscheid, Germany* 

#### **1. Introduction**

306 Pain Management – Current Issues and Opinions

Wright, A.W., Mather, L.E., Smith, M.T. (2001) Hydromorphone-3-glucuronide: a more

Zhou, S.F. (2009) Polymorphism of human cytochrome P450 2D6 and its clinical significance:

Zwisler, S.T., Enggaard, T.P., Mikkelsen, S., Brosen, K., Sindrup, S.H. (2010) Impact of the

69: 409-420.

part I. *Clin Pharmacokinet* 48: 689-723.

Anaesthesiol Scand 54: 232-40.

Zollner, C., Stein, C. (2007) Opioids. *Handb Exp Pharmacol* 177: 31-63.

potent neuro-excitant than its structural analogue, morphine-3-glucuronide. *Life Sci*

CYP2D6 genotype on post-operative intravenous oxycodone analgesia. Acta

In industrial nations, low back pain (lbp) is one of the leading causes of physical limitation. It is also a main source of incapacitation, suffering and expense. According to the national institute of neurological disorders and stroke in the US, LBP accounts for more sick leave and disability than any other medical condition. In Germany, life time prevalence of LBP reaches up to 84 %, with the highest rate for people aged between 35 and 55. According to the German Health Report of the year 2002, the costs of rehabilitation and early retirement amounted to more than 15 billion € , and direct and indirect cost of illness up to 26 billion EURO. Thus the effective management of low back pain is a major health and economic concern.

In a minority of patients presenting for evaluation in a primary care setting, lbp can be reliably attributed to a specific underlying pathology, such as malignancy, vertebral compression fracture or inflammatory/infectious processes. The majority, 80-90%, of patients present primary or non-specific lbp. There is little documented knowledge of possible causes of non-specific lbp. Risk factors are probably related to genetic predisposition, lifestyle (e.g., overweight, lack of physical activity), physical strain and psychological distress.

Opioid analgesics are well established in the treatment of severe pain conditions and have internationally gained a strong position as a potent daily pain treatment option. Many physicians are still apprehensive about the administration of opioids within a continuous therapy, due to potential drug abuse and possible adverse effects, such as impaired gastrointestinal functioning.

To achieve a satisfactory balance between analgesia and side effects, the assessment and treatment of opioid side effects are fundamental aspects of the therapy. This may increase the likelihood of a favourable treatment outcome, potentially allow higher and more efficacious opioid doses, and improve quality of life by reducing other discomforting symptoms. Economic consequences of insufficiently treated chronic lbp and treatment of potential adverse drug effects also play a significant role from the society's point of view. Additional expenses may include costs that emerge from additional obligatory treatments, hospitalization and work incapacity.

Pain Management and Costs of a

patient's safety and need to perform daily activities.

**4.2 Inclusion and exclusion criteria** 

the informed consent form.

Patients were more than 18 years old.

Newly diagnosed pregnancy.

**4.3 Duration and conduct of the study 4.3.1 Study sites and number of patients** 

Female patients were neither pregnant nor breastfeeding.

accordance with the specifications of the SPC.

Patients were excluded from the study if any of the following applied: A contraindication to the planned treatment regime occurred. The patient withdrew his/her consent to participate in the study.

of administration).

groove.

excluded.

**4.3.2 Time schedule** 

Patients not treated according to the SPC were excluded from the study.

study.

Combination of Oxycodone + Naloxone in Low Back Pain Patients 309

II to a WHO-step III opioid or from one WHO-step III opiod to another WHO. The change of therapy was not allowed to be correlated to the study. Consequently, patients treated with oxycodone + naloxone or other WHO-step III opioids were eligible for the

For all patients, the summary of product characteristics (SPC) was considered with regard to

 Therapy with oxycodone + naloxone or another WHO-step III opioid was documented for all patients over an observation period of approximately twelve months, including prescription and administration of the medication (regular daily administration, period

Patients were informed about the study and agreed to participate by signing and dating

 Patients were able to comprehend the language as well as the contents of the study materials (patient information, informed consent form and patient questionnaires). Patients suffered from chronic back pain below the costal arch and above the gluteal

Patients with tumor pain, herniated vertebral disks, or pain caused by an accident, were

Administration of oxycodone + naloxone or another WHO-step III opioid was not in

200 general practitioners and orthopedics, some of them specializing in pain therapy, should be achieved to participate at in this nation-wide, multi-center, non-interventional study. As stated in the observational plan, the enrolment of 2,000 patients (10 patients per physician, 5 patients per cohort) with chronic back pain was required to document patients at baseline

Screening and recruitment of the participating physicians were conducted by the Institute of Empirical Health Economics (IfEG) prior to the start of the study. IfEG CRAs started to visit the physicians´ medical centers in September 2008. Patients were enrolled by the physicians and observed for one year. Documentation started according to the project schedule after the patients had signed the informed consent form (ICF). An interim analysis was scheduled

(V1), after one week (V2), four weeks (V3), six months (V4) and after 12 months.

oxycodone + naloxone or another WHO-step III opioids were not contraindicated.

#### **2. Primary objective**

The primary objective of this health services research study was to assess the health-related quality of life and the total costs (direct and indirect) of patients in Germany suffering from chronic back pain. Therapy with oxycodone + naloxone1 was compared to therapy with other strong opioids (WHO-step III opioids).

Main aims are:


### **3. Secondary objective**

The secondary objective of the study was to evaluate the data for effectiveness under daily routine conditions of the therapy with oxycodone + naloxone or other WHO-step III opioids (strong opioids).

Main issues were:


### **4. Methods**

In order to portray the actual costs ("true costs") incurred for patients suffering from chronic back pain, data had to be documented under daily routine conditions ("realworld-design"). Therefore, a cohort study design was chosen. Two cohorts were observed: Patients in the first cohort were treated with oxycodone + naloxone (cohort 1). Patients in the second cohort were treated with another WHO-step III opioid (cohort 2). In accordance with the statistical analysis plan, each participating physician was asked to document five patients per cohort. Because of the non-interventional study design, individual site-specific imbalances due to the cohort recruitment will be discussed from a statistical point of view.

#### **4.1 Patient population**

Opioid-naive and opioid-pretreated female and male adults (> 18 years) who suffered from chronic back pain below the costal arch and above the gluteal groove, who require a round-a-clock-treatment with WHO-step III opioids, were considered. Patients with cancer pain, herniated vertebral disks, or pain caused by an accident, were excluded. Patients who recently started therapy with oxycodone + naloxone or another WHO-step III opioid were also considered, as well as patients, who were switched from a WHO-step

 <sup>1</sup> Targin®

II to a WHO-step III opioid or from one WHO-step III opiod to another WHO. The change of therapy was not allowed to be correlated to the study. Consequently, patients treated with oxycodone + naloxone or other WHO-step III opioids were eligible for the study.

For all patients, the summary of product characteristics (SPC) was considered with regard to patient's safety and need to perform daily activities.

Patients not treated according to the SPC were excluded from the study.

#### **4.2 Inclusion and exclusion criteria**

308 Pain Management – Current Issues and Opinions

The primary objective of this health services research study was to assess the health-related quality of life and the total costs (direct and indirect) of patients in Germany suffering from chronic back pain. Therapy with oxycodone + naloxone1 was compared to therapy with

 Health related quality of life over a period of one year – patients on therapy with oxycodone + naloxone compared to therapy with other WHO-step III opioids.

The incidence of early retirement due to chronic back pain and the average age of these

The secondary objective of the study was to evaluate the data for effectiveness under daily routine conditions of the therapy with oxycodone + naloxone or other WHO-step III opioids

 The long-term effectiveness of treatment of chronic back pain under daily routine conditions with oxycodone + naloxone or other strong opioids (WHO-step III opioids). Frequency of the administration of rescue-medication (drugs additionally taken once only, as an emergency treatment of pain) under therapy with oxycodone + naloxone

In order to portray the actual costs ("true costs") incurred for patients suffering from chronic back pain, data had to be documented under daily routine conditions ("realworld-design"). Therefore, a cohort study design was chosen. Two cohorts were observed: Patients in the first cohort were treated with oxycodone + naloxone (cohort 1). Patients in the second cohort were treated with another WHO-step III opioid (cohort 2). In accordance with the statistical analysis plan, each participating physician was asked to document five patients per cohort. Because of the non-interventional study design, individual site-specific imbalances due to the cohort recruitment will be discussed from a

Opioid-naive and opioid-pretreated female and male adults (> 18 years) who suffered from chronic back pain below the costal arch and above the gluteal groove, who require a round-a-clock-treatment with WHO-step III opioids, were considered. Patients with cancer pain, herniated vertebral disks, or pain caused by an accident, were excluded. Patients who recently started therapy with oxycodone + naloxone or another WHO-step III opioid were also considered, as well as patients, who were switched from a WHO-step

 Costs for the pain therapy and therapy of AE/ADR in in- and out-patients. Patients' inability to work, days off work compared between both cohorts.

compared to other strong opioids (WHO-step III opioids).

**2. Primary objective** 

Main aims are:

patients.

(strong opioids). Main issues were:

**4. Methods** 

statistical point of view.

**4.1 Patient population** 

 <sup>1</sup> Targin®

**3. Secondary objective** 

other strong opioids (WHO-step III opioids).


Patients were excluded from the study if any of the following applied:


#### **4.3 Duration and conduct of the study**

#### **4.3.1 Study sites and number of patients**

200 general practitioners and orthopedics, some of them specializing in pain therapy, should be achieved to participate at in this nation-wide, multi-center, non-interventional study. As stated in the observational plan, the enrolment of 2,000 patients (10 patients per physician, 5 patients per cohort) with chronic back pain was required to document patients at baseline (V1), after one week (V2), four weeks (V3), six months (V4) and after 12 months.

#### **4.3.2 Time schedule**

Screening and recruitment of the participating physicians were conducted by the Institute of Empirical Health Economics (IfEG) prior to the start of the study. IfEG CRAs started to visit the physicians´ medical centers in September 2008. Patients were enrolled by the physicians and observed for one year. Documentation started according to the project schedule after the patients had signed the informed consent form (ICF). An interim analysis was scheduled

Pain Management and Costs of a

The following clinical data were collected at V1:

medical pre-treatment outside of pain therapy

diagnosis of chronic back pain (back pain causing disease)

average period of analgesia experienced by the patient

adverse events or adverse drug reactions were also included.

size) of prescribed and recommended drugs

previous and current drug therapy for chronic back pain treatment

**4.4.2 Clinical variables** 

concomitant diseases

pretreated patients)

opioid of WHO-step III

opioid of WHO-step III concomitant medication rescue-medication

diary)

**4.4.3 Variables of costs** 

non-medicinal therapies

observation period

emergency treatments

reduction in earning capacity

 other medicinal interventions remedies and medical devices consultations at other physicians

**4.5 Quality of life questionnaires** 

early retirement

hospitalizations

Combination of Oxycodone + Naloxone in Low Back Pain Patients 311

 assessment of previous pain therapy prior to enrolment (by physician and patient) other disorders apart from pain indication experienced within the last week before the beginning of observational study (separately for opioid-naive patients and opioid-

change/adjustment/withdrawal of therapy with oxycodone + naloxone or another

dosage and application times of the therapy with oxycodone + naloxone or another

assessment of pain, intensity of pain and general mobility of the patient (patient

The following variables of costs were included in the cost calculation. For all costs, a causal correlation to the underlying chronic back pain had to exist. Costs for the treatment of

ambulatory treatment costs (consultations including house calls, emergency treatments

type (trade name and active ingredient) and amount (number of packages and package

inability to work within the last twelve months before the start and during the

The SF-36 is a multi-purpose, short-form health survey with 36 questions. It provides an 8 scale profile of functional health and well-being scores, as well as a psychometrically-based physical and mental health summary and a preference-based health utility index. It is a

and medical specialist consultation) contributable to chronic back pain

additional acquisitions or measures taken (e.g. conversion of an apartment)

**4.5.1 Quality of life questionnaires (SF-36 v2 Health Survey)** 

approximately six months after the beginning of the observation period. The study-report was due three months after last patient last visit (LPLV).

#### **4.3.3 Patient information and informed consent form (ICF)**

Prior to their participation, patients had to sign the ICF. The patient information describes the objectives, contents and risks of the study. Furthermore, the patients were informed that withdrawal from the observational study was possible at any point in time without further consequences. The patient obtained a copy of the patient information and the ICF. The physician is obligated to keep the signed ICF records at least for 15 years.

#### **4.3.4 Documentation of treatment**

Socio-demographic data, the clinical variables regarding progress of the disease, as well as the treatment costs incurred for the attending physician were documented on standardized case report forms (CRF). All consultations during the observation period due to chronic back pain were documented. The consultations took place as they would within the scope of the treatment of chronic back pain and no study-specific visits were indicated. Physicians sent the completed CRF by postal service to IfEG.

#### **4.3.5 Documentation by patients**

During the observation period, patients actively participated in the documentation by completing standardized health-related quality of life questionnaires (SF-36 v2 Health Survey) at four points in time. Visits took place every quarter and the quality of life questionnaires were completed during the visits.

Intensity of pain and stool consistency was recorded daily for the first four weeks, followed by recording every two weeks on patient diaries.

The patients also completed standardized questionnaires regarding constipation and the pain intensity of the last seven days during each consultation.

#### **4.4 Variables**

The variables considered for this report are described in the following sections.

#### **4.4.1 Socio-demographic and administrative variables**

The following data were collected regarding at the first visit (V1):


#### **4.4.2 Clinical variables**

310 Pain Management – Current Issues and Opinions

approximately six months after the beginning of the observation period. The study-report

Prior to their participation, patients had to sign the ICF. The patient information describes the objectives, contents and risks of the study. Furthermore, the patients were informed that withdrawal from the observational study was possible at any point in time without further consequences. The patient obtained a copy of the patient information and the ICF. The

Socio-demographic data, the clinical variables regarding progress of the disease, as well as the treatment costs incurred for the attending physician were documented on standardized case report forms (CRF). All consultations during the observation period due to chronic back pain were documented. The consultations took place as they would within the scope of the treatment of chronic back pain and no study-specific visits were indicated. Physicians

During the observation period, patients actively participated in the documentation by completing standardized health-related quality of life questionnaires (SF-36 v2 Health Survey) at four points in time. Visits took place every quarter and the quality of life

Intensity of pain and stool consistency was recorded daily for the first four weeks, followed

The patients also completed standardized questionnaires regarding constipation and the

The variables considered for this report are described in the following sections.

patient's ability to comprehend the patient information and informed consent

status of ability to work (and correlation with chronic back pain)

physicians' specialization and additional pain therapy qualifications

was due three months after last patient last visit (LPLV).

**4.3.4 Documentation of treatment** 

**4.3.5 Documentation by patients** 

**4.4 Variables** 

gender

 height weight ethnic group

family status

status of occupation

type of health insurance

date of birth (month/year)

sent the completed CRF by postal service to IfEG.

questionnaires were completed during the visits.

by recording every two weeks on patient diaries.

educational school level and training level

exemption from additional payments

pain intensity of the last seven days during each consultation.

**4.4.1 Socio-demographic and administrative variables**  The following data were collected regarding at the first visit (V1):

**4.3.3 Patient information and informed consent form (ICF)** 

physician is obligated to keep the signed ICF records at least for 15 years.

The following clinical data were collected at V1:


#### **4.4.3 Variables of costs**

The following variables of costs were included in the cost calculation. For all costs, a causal correlation to the underlying chronic back pain had to exist. Costs for the treatment of adverse events or adverse drug reactions were also included.


#### **4.5 Quality of life questionnaires**

#### **4.5.1 Quality of life questionnaires (SF-36 v2 Health Survey)**

The SF-36 is a multi-purpose, short-form health survey with 36 questions. It provides an 8 scale profile of functional health and well-being scores, as well as a psychometrically-based physical and mental health summary and a preference-based health utility index. It is a

Pain Management and Costs of a

**4.6.2 Handling of dropouts** 

**4.6.3 Study population** 

**4.6.4 Statistical analysis** 

**5. Analysis and results** 

**5.1 Description of the study population** 

only.

cohorts.

completely excluded from the effectiveness analysis.

**4.6 Statistical analysis 4.6.1 Data entry** 

received.

Combination of Oxycodone + Naloxone in Low Back Pain Patients 313

A data entry template for the complete documentation was designed by IfEG by using the program Oracle 11.1.06G. Data entry was conducted successively after CRFs were

Patients were defined as dropouts if they were enrolled although the population criteria were not fulfilled, andif they did not receive any study-related medication. Dropouts were

Withdrawal patients were defined as patients who also include those patients who discontinued the therapy with oxycodone + naloxone or another WHO-step III opioid before the end of the observation period, withdrew their consent, or who became pregnant during the observation period. These patients are included in the effectiveness and efficacy analysis and are not considered to be dropouts, unless the therapy with oxycodone + naloxone or

Safety-Population (SP): all patients who were included in the observational study and

Intent-to-Treat-Population (ITT-P): all patients for whom at least one examination

Per-Protocol-Population (PPP): all patients for whom all quarter and all BPI-SF

For the Per-Protocol-Population, only the CRFs completed for the whole observation period were considered, whereas for the Intent-To-Treat-Population, all available data were considered. Data in this paper refer to safety-population and intent-to-treat population

The data analyses are conducted with the software PASW 18.0 for Windows, as well as MS-Excel 2007 and MS-Access 2007. The evaluation is descriptive, based on the character of the documentation. An inferential statistic is performed for the comparison of the

A total of 1.013 patients from 134 physicians were entered into the database (figure 1). 43 patients had to be excluded from the analysis: Of these, 24 patients did not receive any study-related medication and for 19 patients the physicians did not complete documentation to the end of the study. Therefore, 970 patients were included in the safety population (SP) comprising 583 patients from the cohort "oxycodone + naloxone" (cohort 1) and 371 from the cohort "other WHO-step III opioids" (cohort 2). No cohort classification was possible for 16 patients, because these patients did not take any strong opioid (oxycodone + naloxone or

another WHO-step III opioid was administered for less than three months

regarding effectiveness (pain and bowel function) was conducted

The following populations were defined before data analysis:

attended at least one follow-up visit

assessment were completely documented

generic measure, as opposed to surveys that target a specific age, disease, or treatment group [16].

The taxonomy has three levels: (1) items; (2) eight scales with 2-10 items each; and (3) two summaries. All but one of the 36 items (self-reported health transition) are used to score the eight SF-36 scales. Each item is used in scoring only one scale.

The SF-36 has the following composition:


The calculations (pole reversal and recalibration of items, missing values, and transformation of scales) of the SF-36-subscales and the physical and mental summation scales are performed with the SSPS-program by Mogens Trab Damsgaard. The SSPSprogram is described in the SF-36 manual. The totals from the 8 subscales are subsequently transformed to a percentage scale (co-domain 0-100). Norm-based scoring (NBS) algorithms are introduced for all eight scales and employ a linear T-score transformation with mean = 50 and standard deviation = 10. The weightings of subscales within summation scales are performed with the weight factor used in the American standard sample.

The SF-36 was completed for V1, V3 (after 4 weeks), V4 (after 6 months) and V5 (after 12 months).

#### **4.5.2 Brief Pain Inventory Short Form (BPI-SF)**

The Brief Pain Inventory is a standardized method applied for self assessment of pain and its outcomes in an abbreviated form. This inventory encompasses numeric rating scales for pain intensity and reduction in pain contributable to the treatment, as well as a graphic picture. Emphasise is placed on sensory pain components and the documentation of painrelated impairments.

The sum scale for pain intensity contains four questions: to most severe, minimum, and average pain severity experienced during the last 24 hours and at that moment (range 0-10 points per questions, total range 0-40 points). An increase in point score implies an increase in pain.

The sum scale for pain-related impairment consists of seven questions to self assessment of impairment in the daily routine (activity, mood, movement, occupation, relationships, sleep and vitality) within the last 24 hours (range 0-10 points per question, total range 0-70 points).

Cumulative values for pain intensity and pain-related impairment were calculated. An increase in cumulative values implies an increase in pain.

The third factor evaluated pain relief due to the analgesic therapy expressed as a percentage from the baseline value.

The BPI-SF was completed for V1 (beginning), V3 (after 4 weeks), V4 (after 6 months) and V5 (after 12 months).

#### **4.6 Statistical analysis**

#### **4.6.1 Data entry**

312 Pain Management – Current Issues and Opinions

generic measure, as opposed to surveys that target a specific age, disease, or treatment

The taxonomy has three levels: (1) items; (2) eight scales with 2-10 items each; and (3) two summaries. All but one of the 36 items (self-reported health transition) are used to score the

The calculations (pole reversal and recalibration of items, missing values, and transformation of scales) of the SF-36-subscales and the physical and mental summation scales are performed with the SSPS-program by Mogens Trab Damsgaard. The SSPSprogram is described in the SF-36 manual. The totals from the 8 subscales are subsequently transformed to a percentage scale (co-domain 0-100). Norm-based scoring (NBS) algorithms are introduced for all eight scales and employ a linear T-score transformation with mean = 50 and standard deviation = 10. The weightings of subscales within summation scales are

The SF-36 was completed for V1, V3 (after 4 weeks), V4 (after 6 months) and V5 (after 12

The Brief Pain Inventory is a standardized method applied for self assessment of pain and its outcomes in an abbreviated form. This inventory encompasses numeric rating scales for pain intensity and reduction in pain contributable to the treatment, as well as a graphic picture. Emphasise is placed on sensory pain components and the documentation of pain-

The sum scale for pain intensity contains four questions: to most severe, minimum, and average pain severity experienced during the last 24 hours and at that moment (range 0-10 points per questions, total range 0-40 points). An increase in point score implies an increase

The sum scale for pain-related impairment consists of seven questions to self assessment of impairment in the daily routine (activity, mood, movement, occupation, relationships, sleep and vitality) within the last 24 hours (range 0-10 points per question, total range 0-70

Cumulative values for pain intensity and pain-related impairment were calculated. An

The third factor evaluated pain relief due to the analgesic therapy expressed as a percentage

The BPI-SF was completed for V1 (beginning), V3 (after 4 weeks), V4 (after 6 months) and

performed with the weight factor used in the American standard sample.

**4.5.2 Brief Pain Inventory Short Form (BPI-SF)** 

increase in cumulative values implies an increase in pain.

eight SF-36 scales. Each item is used in scoring only one scale.

The SF-36 has the following composition:

Physical Functioning

 Social Functioning Role-Emotional Mental Health

 Role-Physical Physical Pain General Health

Vitality

months).

in pain.

points).

related impairments.

from the baseline value.

V5 (after 12 months).

group [16].

A data entry template for the complete documentation was designed by IfEG by using the program Oracle 11.1.06G. Data entry was conducted successively after CRFs were received.

#### **4.6.2 Handling of dropouts**

Patients were defined as dropouts if they were enrolled although the population criteria were not fulfilled, andif they did not receive any study-related medication. Dropouts were completely excluded from the effectiveness analysis.

Withdrawal patients were defined as patients who also include those patients who discontinued the therapy with oxycodone + naloxone or another WHO-step III opioid before the end of the observation period, withdrew their consent, or who became pregnant during the observation period. These patients are included in the effectiveness and efficacy analysis and are not considered to be dropouts, unless the therapy with oxycodone + naloxone or another WHO-step III opioid was administered for less than three months

#### **4.6.3 Study population**

The following populations were defined before data analysis:


For the Per-Protocol-Population, only the CRFs completed for the whole observation period were considered, whereas for the Intent-To-Treat-Population, all available data were considered. Data in this paper refer to safety-population and intent-to-treat population only.

#### **4.6.4 Statistical analysis**

The data analyses are conducted with the software PASW 18.0 for Windows, as well as MS-Excel 2007 and MS-Access 2007. The evaluation is descriptive, based on the character of the documentation. An inferential statistic is performed for the comparison of the cohorts.

#### **5. Analysis and results**

#### **5.1 Description of the study population**

A total of 1.013 patients from 134 physicians were entered into the database (figure 1). 43 patients had to be excluded from the analysis: Of these, 24 patients did not receive any study-related medication and for 19 patients the physicians did not complete documentation to the end of the study. Therefore, 970 patients were included in the safety population (SP) comprising 583 patients from the cohort "oxycodone + naloxone" (cohort 1) and 371 from the cohort "other WHO-step III opioids" (cohort 2). No cohort classification was possible for 16 patients, because these patients did not take any strong opioid (oxycodone + naloxone or

Pain Management and Costs of a

7% were ensured privately.

**5.2 Quality of life 5.2.1 SF-36** 

Standardized physical health

health (Figure 3).

Fig. 2. Standardized physical health SF-36 (means)

Combination of Oxycodone + Naloxone in Low Back Pain Patients 315

Almost all patients were classified as caucasians, more than half of the patients were married and app. 50% had an educational level above secondary general school. Less than

At visit 1 924 days off work in the last year were documented for both cohorts (560 in cohort 1). 17% of the included patients reported a reduction in earning capacity. 14,6% in cohort 1

**cohort 1 cohort 2** 

The difference between the physical health of cohort 1 compared to cohort 2 were significant for the periods V5>V3, V3>V1, V4 >V1 and V4>V1 but not for V4>V3 and V5>V4. The results for both cohorts indicate a continuous improvement, which was more pronounced in cohort 1. This result is also mirrored by the data on standardized mental

**number mean SD number mean SD p-value** 

356 9,65 10,29 244 4,55 8,90 p < 0,001

Nearly 45% (!) of all patients reported a poor effectiveness of the applied pain therapies. During the course of the study both physicians and patients assessed a higher effectiveness

and 16,8% in cohort 2 had been retired early due to chronic back pain.

increase in cohort 1 compared to cohort 2. This refers also to tolerability.

Figure 2 shows the results of the SF-36 evaluation for physical health.

other WHO-step III opioids). 560 cohort 1 and 364 cohort 2 patients were feasible for the Intent-To-Treat-Population. For the Per-Protocol-Population, 569 patients were included: 345 of cohort 1 and 224 of cohort 2.

Fig. 1. Organigram of the study population

The majority of the patients were female (~60%) which refers to the epidemiological distribution in Germany within an aging population: the average age was around 64 years and by this most patients had been retired or were of least unable to work. Only 20% of the patients were employed (Table 1).


Table 1. Gender and age of the population

Almost all patients were classified as caucasians, more than half of the patients were married and app. 50% had an educational level above secondary general school. Less than 7% were ensured privately.

At visit 1 924 days off work in the last year were documented for both cohorts (560 in cohort 1). 17% of the included patients reported a reduction in earning capacity. 14,6% in cohort 1 and 16,8% in cohort 2 had been retired early due to chronic back pain.

Nearly 45% (!) of all patients reported a poor effectiveness of the applied pain therapies.

During the course of the study both physicians and patients assessed a higher effectiveness increase in cohort 1 compared to cohort 2. This refers also to tolerability.

#### **5.2 Quality of life**

#### **5.2.1 SF-36**

314 Pain Management – Current Issues and Opinions

other WHO-step III opioids). 560 cohort 1 and 364 cohort 2 patients were feasible for the Intent-To-Treat-Population. For the Per-Protocol-Population, 569 patients were included:

The majority of the patients were female (~60%) which refers to the epidemiological distribution in Germany within an aging population: the average age was around 64 years and by this most patients had been retired or were of least unable to work. Only 20% of the

**cohort 1 cohort 2** 

P= 0,585 male 210 37,5% 143 39,3%

age 560 63,4 364 64,9 p = 0,084 employed 121 21,6% 62 17,0% p = 0,088

female 350 62,5% 221 60,7%

**N rate N rate p-value** 

81 75,0 40 95,4 p = 0,496

345 of cohort 1 and 224 of cohort 2.

Fig. 1. Organigram of the study population

Table 1. Gender and age of the population

patients were employed (Table 1).

number of days off work 12 months before inclusion Figure 2 shows the results of the SF-36 evaluation for physical health.


Fig. 2. Standardized physical health SF-36 (means)

The difference between the physical health of cohort 1 compared to cohort 2 were significant for the periods V5>V3, V3>V1, V4 >V1 and V4>V1 but not for V4>V3 and V5>V4. The results for both cohorts indicate a continuous improvement, which was more pronounced in cohort 1. This result is also mirrored by the data on standardized mental health (Figure 3).

Pain Management and Costs of a

the time periods V3 to V5 and V3 to V4.

Fig. 4. Sum scale of pain intensity (means) Brief Pain Inventory (BPI-Shortform)

Fig. 5. Worst pain in the last 24 hours (means)

Brief Pain Inventory (BPI-Shortform)

Combination of Oxycodone + Naloxone in Low Back Pain Patients 317

the total scores of pain intensity. Significant differences were found between cohort 1 and cohort 2 at V5, V4 and V3 compared to V1. Significant differences were also determined for

Worst pain in the last 24 hours decreased in cohort 1 more over all periods than in cohort 2

although worst pain was significantly higher in cohort 1 at baseline (V1).

After 12 months (V5) both cohorts revealed highly significant differences (Fig. 5).


Fig. 3. Standardized mental health SF-36 (means)

In total statistical power reached significant level for all SF-36 positions except "Roleemotional" (Table 2). All items and positions of the SF-36 were in favour of the combination of oxycodone + naloxone.


Table 2. Summary of SF-36 positions

#### **5.2.2 Brief Pain Inventory Short Form (BPI-SF)**

The Brief Pain Inventory Short Form (BPI-SF) contains numeric rating scales for pain intensity and pain impairment as well as for pain relief. Fig. 4 shows the differences between

**cohort 1 cohort 2** 

mental health 356 6,34 12,82 244 2,58 12,33 p < 0,001

In total statistical power reached significant level for all SF-36 positions except "Roleemotional" (Table 2). All items and positions of the SF-36 were in favour of the combination

1 Physical function 392 23,09 29,79 272 8,52 26,36 < 0,001 2 Role-physical 370 31,28 44,62 261 16,44 41,15 < 0,001 3 Bodily Pain 379 25,66 25,97 263 11,97 19,10 < 0,001 4 General health 375 13,32 22,64 257 6,16 17,76 < 0,001 5 Vitality 376 16,21 22,64 261 5,77 18,69 < 0,001 6 Social functioning 377 19,46 28,50 263 6,65 25,91 < 0,001 7 Role-emotional 363 22,87 56,34 252 14,02 54,19 0,057 8 Mental health 376 15,13 22,88 261 6,27 19,75 < 0,001

The Brief Pain Inventory Short Form (BPI-SF) contains numeric rating scales for pain intensity and pain impairment as well as for pain relief. Fig. 4 shows the differences between

Standardized

of oxycodone + naloxone.

Table 2. Summary of SF-36 positions

**5.2.2 Brief Pain Inventory Short Form (BPI-SF)** 

**SF-36 Positions** 

Fig. 3. Standardized mental health SF-36 (means)

**number mean SD number mean SD p-value** 

**cohort 1 cohort 2** 

**p-value number mean SD number mean SD** 

the total scores of pain intensity. Significant differences were found between cohort 1 and cohort 2 at V5, V4 and V3 compared to V1. Significant differences were also determined for the time periods V3 to V5 and V3 to V4.

Fig. 4. Sum scale of pain intensity (means) Brief Pain Inventory (BPI-Shortform)

Worst pain in the last 24 hours decreased in cohort 1 more over all periods than in cohort 2 although worst pain was significantly higher in cohort 1 at baseline (V1). After 12 months (V5) both cohorts revealed highly significant differences (Fig. 5).

Fig. 5. Worst pain in the last 24 hours (means) Brief Pain Inventory (BPI-Shortform)

Pain Management and Costs of a

Combination of Oxycodone + Naloxone in Low Back Pain Patients 319

Fig. 7 shows the indirect costs for the cohorts. Higher averaged indirect costs per patient were calculated for cohort 2. The higher indirect costs resulted from higher costs due to reduction in earning capacity. Approximately 26 % less costs were documented for cohort 1

The incremental cost-effectiveness ratio (ICER) represents the ratio between the differences in treatment costs (ΔC) and treatment effects (ΔE) for cohort OXN and cohort "other strong opioids". It presents the cost of an additional effect unit. The ICER was tested against the

 **CER CER** direct costs (C) --- -370 € SF-36 (physical health) 9.65 249 € 4.55 610 € -72 € -370 €/5.10 SF-36 (mental health) 6.34 379 € 2.58 1,074 € -98 € -370 €/3.76 BPI-SF (pain relief) 24.14 100 € 12.44 223 € -32 € -370 €/11.7

2,403 € 2,773 €

The following formula was used for the calculation of the incremental cost-effectiveness

*ICER* (costs of cohort OXN)-(costs of cohort "other strong opioids") cost difference (effect of cohort OXN)-(effect of cohort "other strong opioids") effect difference

*C C <sup>C</sup> ICER*

Negative values were calculated for the ICER of the main parameters, which implies more effectiveness at a lower price for the alternative therapy with Oxycodone + Naloxone (Fig. 8).

*E E E* cohort OXN cohort "other strong opioids" cohort OXN cohort "other strong opioids" 

**ICER C/E**

**cohort 1 cohort 2**

CER: Cost-Effectiveness Ratio; ICER: Incremental Cost-Effectiveness Ratio

patients than for cohort 2 patients in this part of indirect costs.

Fig. 7. Indirect cost categories for the cohorts

main parameters (Tab. 4).

Table 4. Cost-effectiveness ratio

**parameter**

ratio:

Pain relief treatments or medications administered were also recorded. The patients had to mark the percentage that represents how much pain relief they have experienced (0%=no relief, 100%=complete relief). The pain relief of cohort 1 patients compared to cohort 2 was significant at V1 (p < 0.001) and at V5 (p = 0.001). At visit 1 the pain relief on average amounted to 39.2 % in cohort 1 and to 46.02 % in cohort 2. At the end of the study (V5) the averaged pain relief was 64.2 % in cohort 1 and 58.9 % in cohort 2 (Fig. 6).

Fig. 6. Pain relief (means) Brief Pain Inventory (BPI-Shortform)

#### **6. Costs**

Annual average direct costs of 2,403.45 € accumulated per patient in cohort 1 and 2,772.98 € per patient in cohort 2. The difference in annual average costs was not significant (p = 0.195). The approximately 13 % lower amount incurred in cohort 1 can be attributed to drug expenses, emergency treatment and hospitalisation/rehabilitation. The differences between both cohorts were significant for co-medication (p < 0.001) and rescue-medication (p = 0.021) (Tab. 3).


Table 3. Direct costs categories

Pain relief treatments or medications administered were also recorded. The patients had to mark the percentage that represents how much pain relief they have experienced (0%=no relief, 100%=complete relief). The pain relief of cohort 1 patients compared to cohort 2 was significant at V1 (p < 0.001) and at V5 (p = 0.001). At visit 1 the pain relief on average amounted to 39.2 % in cohort 1 and to 46.02 % in cohort 2. At the end of the study (V5) the

Annual average direct costs of 2,403.45 € accumulated per patient in cohort 1 and 2,772.98 € per patient in cohort 2. The difference in annual average costs was not significant (p = 0.195). The approximately 13 % lower amount incurred in cohort 1 can be attributed to drug expenses, emergency treatment and hospitalisation/rehabilitation. The differences between both cohorts

were significant for co-medication (p < 0.001) and rescue-medication (p = 0.021) (Tab. 3).

**cost category total cohort 1 cohort 2**  out-patient treatment 477,03 € 481,79 € 469,71 € drug expenses 1.653,73 € 1.532,69 € 1.839,93 € oxycodone + naloxone 812,17 € 1.270,16 € 107,57 € opioid WHO-III 611,68 € 65,04 € 1.452,67 € comedication 211,51 € 181,83 € 257,16 € rescue medication 18,37 € 15,67 € 22,54 € remedies 34,20 € 31,07 € 39,03 € non-medical therapy 54,95 € 53,11 € 57,79 € emergency treatments 64,76 € 52,57 € 83,52 € hospitalization/rehabilitation 264,35 € 252,22 € 283,01 € direct costs 2.549,02 € 2.403,45 € 2.772,98 €

averaged pain relief was 64.2 % in cohort 1 and 58.9 % in cohort 2 (Fig. 6).

Fig. 6. Pain relief (means)

**6. Costs** 

Brief Pain Inventory (BPI-Shortform)

Table 3. Direct costs categories

Fig. 7 shows the indirect costs for the cohorts. Higher averaged indirect costs per patient were calculated for cohort 2. The higher indirect costs resulted from higher costs due to reduction in earning capacity. Approximately 26 % less costs were documented for cohort 1 patients than for cohort 2 patients in this part of indirect costs.

Fig. 7. Indirect cost categories for the cohorts

The incremental cost-effectiveness ratio (ICER) represents the ratio between the differences in treatment costs (ΔC) and treatment effects (ΔE) for cohort OXN and cohort "other strong opioids". It presents the cost of an additional effect unit. The ICER was tested against the main parameters (Tab. 4).


Table 4. Cost-effectiveness ratio

The following formula was used for the calculation of the incremental cost-effectiveness ratio:

$$\text{ICER} = \frac{\text{(costs of cohort OXN)} \text{(costs of cohort \text{"other strong opoids"})}}{\text{(effect of cohort OXN)} \text{(effect of cohort \text{"other strong opoids"})}} = \frac{\text{cost difference}}{\text{effect difference}}$$

$$ICER = \frac{\overline{C}\_{\text{cohort ONN}} - \overline{C}\_{\text{cohort \textquotedblleft other\textquotedblright strong\textquotedblright}\text{opoids}}}{\overline{E}\_{\text{cohort ONN}} - \overline{E}\_{\text{cohort \textquotedblleft other\textquotedblright strong\textquotedblright}\text{opoids}}} = \frac{\Delta \overline{C}}{\Delta \overline{E}}$$

Negative values were calculated for the ICER of the main parameters, which implies more effectiveness at a lower price for the alternative therapy with Oxycodone + Naloxone (Fig. 8).

**16** 

*Poland* 

Wojciech Leppert

*Chair and Department of Palliative Medicine, Poznan University of Medical Sciences, Poznan,* 

**The Role of Opioid Analgesics in the Treatment of Pain in Cancer Patients** 

Cancer pain treatment is based on the analgesic ladder, established in 1986 by the World Health Organization (WHO; see Fig. 1) (WHO, 1996). Cancer pain management guidelines in Europe are based on EAPC (European Association for Palliative Care) recommendations. Oral morphine is recommended by the Expert Working Group of the EAPC at the third step of the WHO analgesic ladder, which comprises additional opioids (i.e. oxycodone, fentanyl, buprenorphine, methadone, and hydromorphone) for the treatment of moderate-to-severe pain intensity (Hanks et al., 2001). The use of an analgesic ladder should be individualized with an appropriate application of supportive drugs (laxatives and antiemetics) for the prevention and treatment of opioid adverse effects (Leppert, 2009a) and nonpharmacological measures, such as radiotherapy and invasive procedures (nerve

blockades and neurolytic blocks) (Eidelman et al., 2007).

 +/- non opioid analgesics +/- adjuvant analgesics

Fig. 1. World Health Organization three-step analgesic ladder

 *Io* Mild to moderate non opioid analgesics pain intensity

+/- adjuvant analgesics

Mild pain intensity

*IIIo* 

strong opioids

 +/- non opioid analgesics +/- adjuvant analgesics

 *IIo* Moderate to severe weak opioids pain intensity

**1. Introduction** 

Fig. 8. Cost-effectiveness area

#### **7. Conclusion**

As a final conclusion it can be stated that patients of cohort 1 (oxycodone + naloxone) experienced a better quality of life and less back pain after twelve months compared to patients of cohort 2 (other WHO-step III opioids). According to the cost effectiveness-analysis therapy with oxycodone + naloxone is more effective and generates lower costs than cohort 2. These results and findings should be confirmed by a randomized, blinded controlled trial.

#### **8. References**


## **The Role of Opioid Analgesics in the Treatment of Pain in Cancer Patients**

#### Wojciech Leppert

*Chair and Department of Palliative Medicine, Poznan University of Medical Sciences, Poznan, Poland* 

#### **1. Introduction**

320 Pain Management – Current Issues and Opinions

As a final conclusion it can be stated that patients of cohort 1 (oxycodone + naloxone) experienced a better quality of life and less back pain after twelve months compared to patients of cohort 2 (other WHO-step III opioids). According to the cost effectiveness-analysis therapy with oxycodone + naloxone is more effective and generates lower costs than cohort 2. These results and findings should be confirmed by a randomized, blinded controlled trial.

[1] http://www.ninds.nih.gov/disorders/backpain/detail-backpain.htm, stand 16.06.2008 [2] Arzneimittelkommission der deutschen Ärzteschaft: Therapieempfehlungen der

[3] Diemer W, Burchert H: Chronische Schmerzen – Kopf- und Rückenschmerzen,

[4] Roth SH, Fleischmann RM, Burch FX et al.: Around-the-clock, Controlled-Release Oxycodone Therapy for Osteoarthritis-Related Pain. Arch Intern Med. 160, 853-860 (2000) [5] Furlan AD, Sandoval JA, Mailis-Gagnon A et al.: Opioids for Chronic Noncancer Pain: A Metaanalysis of Effectiveness and Side Effects. CMAJ. 174 (11), 1589-1594 (2006) [6] Panchal SJ, Müller-Schwefe P, Wurzelmann JI: Opioid-Induced Bowel Dysfunction: Prevalence, Pathophysiology and Burden. Int J Clin Pract. 61 (7), 1181-1187 (2007)

[12] Average of 2, 100 hospitals based on data oft he TK, stand 21.19.2009; http://www.tk-

[13] Schulenburg JM et al. Deutsche Empfehlung zur gesundheitsökonomischen Evaluation – dritte und aktualisierte Fassung. Gesundh ökon Qual manag. 12, 285-290 (2007)

Tumorschmerzen. Gesundheitsberichterstattung. Heft 7 (2002)

[10] http://www.e-bis.de/ebm/; http://e-bis.de/goae/defaultFrame.htm [11] http://drg.uni-muenster.de/de/webground/m.webground.php?menu=6

Arzneimittelkommission der deutschen Ärzteschaft: Kreuzschmerzen. Arzneiverordnung

Fig. 8. Cost-effectiveness area

in der Praxis; 3. Auflage 2007.

[7] Rote Liste Win®, Ausgabe 2007/I, Version 3.3

[8] http://www.gelbe-liste.de (12/2007) [9] http.//kbv.de/ebm2009/ebmgesamt.htm

online.de

[14] RVaktuell. 11, 470 (2006)

**7. Conclusion** 

**8. References** 

Cancer pain treatment is based on the analgesic ladder, established in 1986 by the World Health Organization (WHO; see Fig. 1) (WHO, 1996). Cancer pain management guidelines in Europe are based on EAPC (European Association for Palliative Care) recommendations. Oral morphine is recommended by the Expert Working Group of the EAPC at the third step of the WHO analgesic ladder, which comprises additional opioids (i.e. oxycodone, fentanyl, buprenorphine, methadone, and hydromorphone) for the treatment of moderate-to-severe pain intensity (Hanks et al., 2001). The use of an analgesic ladder should be individualized with an appropriate application of supportive drugs (laxatives and antiemetics) for the prevention and treatment of opioid adverse effects (Leppert, 2009a) and nonpharmacological measures, such as radiotherapy and invasive procedures (nerve blockades and neurolytic blocks) (Eidelman et al., 2007).

Fig. 1. World Health Organization three-step analgesic ladder

The Role of Opioid Analgesics in the Treatment of Pain in Cancer Patients 323

syndrome may appear with monoamine oxidase (MAO) inhibitors, olanzapine, risperidone,

The inhibition of tramadol metabolism to (+)M1 may attenuate tramadol analgesia. For example, coadministration of ondansetron (selective 5-HT3 [hydroxytryptamine] receptor antagonist) blocks spinal 5-HT3 receptors and competitively inhibits CYP2D6 although recent studies did not confirm such interaction (Rauers et al., 2010). Tramadol analgesia also may be impaired by coadministration of carbamazepine, which accelerates tramadol and M1 metabolism. Concomitant administration of tricyclic antidepressants increases the risk of seizures. Tramadol should be avoided in patients with history of epilepsy. In rats and mice, concomitant administration of tramadol and β-blocker and the 5-

Respiratory depression is rare in the chronic use of tramadol. When it does occur, respiratory depression is connected with the opioid mode of tramadol action, so naloxone should be administered. For example, respiratory depression was reported in a cancer patient with renal impairment (creatinine clearance 30 mL/min) and with UM genotype after renal carcinoma resection. As respiratory symptoms appeared more than 10 hours after the first tramadol dose, the accumulation of M1 was the cause. The patient recovered after intravenous (IV) naloxone bolus administration (0.4 mg). This case highlights that tramadol should not be prescribed in patients with UM genotype and renal impairment (Stamer et al.,

Codeine is a methylated morphine derivative that is found naturally, along with morphine, in the poppy seed. Codeine displays analgesic and antitussive activity. Codeine is available as IR and CR formulations but also in the form of paracetamol combined preparations. IR codeine is administered every 4-6 h in chronic pain with a starting single dose of about 30 mg. The daily doses of dihydrocodeine and codeine usually do not exceed 240 mg and 300 mg, respectively; when these analgesics are ineffective, opioids for moderate-to-severe

Codeine is metabolized in the liver and its bioavailability is 30% to 40% after oral administration. After oral administration of codeine, maximal plasma concentration is attained within 1 to 2 hours with plasma half-life of 2.5 to 3.5 hours and analgesia maintained for 4 to 6 hours (IR formulations). Codeine is partially metabolized to morphine and its metabolites and to codeine metabolites norcodeine (NORC) and codeine-6 glucuronide (C-6-G) (Lötsch et al., 2006). The analgesic effect of codeine is about equal to 1/10th of morphine analgesia. Polymorphism of CYP2D6 is responsible for the formation of morphine, and its metabolites may affect codeine analgesia. Other codeine metabolites, C-6- G predominantly, also display analgesic activity and contribute to codeine analgesia (Vree et al., 2000). In healthy volunteers, codeine is metabolized to C-6-G (81.0% ± 9.3%), NORC (2.16% ± 1.44%), morphine (0.50% ± 0.39%), morphine-3-glucuronide (M-3-G; 2.10% ± 1.24%), morphine-6-glucuronide (M-6-G; 0.80% ± 0.63%), and normorphine (NORM; 2.44% ± 2.42%). The half-life of codeine is 1.47 hours ± 0.32 hours, and that of C-6-G is 2.75 hours ± 0.79 hours. The plasma AUC of C-6-G is about tenfold higher than that of codeine. Protein binding of codeine and C-6-G in vivo is 56.1% ± 2.5% and 34.0% ± 3.6%, respectively (Vree &

Lötsch et al. explored the contributions from codeine and its metabolites to central nervous analgesic effects independent from O-demethylation of codeine to morphine. A

venlafaxine and mirtazapine (Davies and Glare, 2009).

2008).

**2.2 Codeine** 

pain (strong opioids) are introduced.

Verwey-van Wissen, 1992).

HT1A/1B antagonist pindolol enhances analgesia (Leppert, 2009b).

Each step of the WHO analgesic ladder: nonopioids (analgesics for mild pain, step 1 analgesics), weak opioids (analgesics for mild to moderate pain, step 2 opioid analgesics), and strong opioids (opioids for moderate-to-severe pain intensity, step 3 opioid analgesics) may be accompanied with adjuvant analgesics (coanalgesics), which can enhance opioid analgesia. In patients with bone pain, opioids may be combined with non-steroidal antiinflammatory drugs (NSAIDs), glucocorticoids, and bisphosphonates along with local or systemic radiotherapy (Lussier et al., 2004). In patients with very severe neuropathic pain, a combination of opioids and NMDA (*N*-methyl D-aspartate)-receptor antagonists (e.g. ketamine) are recommended (Leppert, 2010a). Patients with neuropathic pain along with opioids may also receive anticonvulsants, and antidepressants (Bennett, 2011). Other drug groups used in patients with neuropathic pain component comprise local anesthetics and antiarrhytmics (Freynhagen & Bennett, 2009). Opioid analgesics should be supplemented with spasmolytics in patients with visceral colicky pain, especially in the course of bowel obstruction (Ripamonti et al., 2008).

#### **2. Opioids for mild to moderate pain (weak opioids, step 2 opioid analgesics)**

#### **2.1 Tramadol**

Tramadol displays opioid properties and acts on neurotransmission of noradrenalin and serotonin. Both enantiomers act synergistically and improve analgesia without increasing adverse effects. Tramadol is metabolized in the liver and excreted by the kidneys. The main metabolite is O-desmethyltramadol (M1), which displays analgesic activity with a higher affinity to μ-opioid receptors than the parent compound; (+)-M1 has 300 to 400 times greater affinity to μ-opioid receptors than tramadol and (-)-M1 mainly inhibits noradrenalin reuptake. Apart from O,N-didesmethyltramadol (M5, which has weak analgesic activity) and M1, other metabolites are inactive (Leppert and Mikolajczak, 2011). The elimination half-life of tramadol is 5 to 6 hours and that if M1 is 8 hours. During oral administration, 90% of tramadol is excreted by the kidneys and 10% in feces. Patients with renal impairment show a decreased excretion of tramadol and M1. In patients with advanced cirrhosis, there is a decrease in tramadol metabolism with decrease of hepatic clearance and increase in blood serum levels. In these patients, elimination half-life is increased 2.5-fold. The starting dose of immediate-release (IR) tramadol is 25 to 50 mg every 4 to 6 hour and that of controlled-release (CR) tablets or capsules is 50 to 100 mg twice daily; the daily dose should not exceed 400 mg (Dickman, 2007).

Patients devoid of CYP2D6 activity (poor metabolizers) need a tramadol dose higher by 30% than those with normal CYP2D6 activity (extensive metabolizers) (Stamer et al., 2003). Tramadol analgesia depends on CYP2D6 genotype, with less analgesia in poor metabolizers being associated with lack of (+)-M1 formation (Stamer et al., 2007). Genotyping is helpful in patients with duplication of CYP2D6 gene (ultrarapid metabolizers [UM]) who are at greater risk to develop tramadol adverse effects. Tramadol metabolism through CYP2D6 may cause interactions with drugs inhibiting this enzyme (eg, cimetidine and ranitidine).

Serotonin syndrome has been reported in patients taking selective serotonin reuptake inhibitors (SSRIs) in conjunction with tramadol or opioids (Gnanadesigan et al., 2005). SSRIs (eg, fluoxetine, paroxetine, and, to less extent, sertraline) used in conjunction with tramadol may cause serotonin syndrome because SSRIs inhibit tramadol metabolism and increase serotonin level; generally, they should not be coadministered with tramadol. Serotonin syndrome may appear with monoamine oxidase (MAO) inhibitors, olanzapine, risperidone, venlafaxine and mirtazapine (Davies and Glare, 2009).

The inhibition of tramadol metabolism to (+)M1 may attenuate tramadol analgesia. For example, coadministration of ondansetron (selective 5-HT3 [hydroxytryptamine] receptor antagonist) blocks spinal 5-HT3 receptors and competitively inhibits CYP2D6 although recent studies did not confirm such interaction (Rauers et al., 2010). Tramadol analgesia also may be impaired by coadministration of carbamazepine, which accelerates tramadol and M1 metabolism. Concomitant administration of tricyclic antidepressants increases the risk of seizures. Tramadol should be avoided in patients with history of epilepsy. In rats and mice, concomitant administration of tramadol and β-blocker and the 5- HT1A/1B antagonist pindolol enhances analgesia (Leppert, 2009b).

Respiratory depression is rare in the chronic use of tramadol. When it does occur, respiratory depression is connected with the opioid mode of tramadol action, so naloxone should be administered. For example, respiratory depression was reported in a cancer patient with renal impairment (creatinine clearance 30 mL/min) and with UM genotype after renal carcinoma resection. As respiratory symptoms appeared more than 10 hours after the first tramadol dose, the accumulation of M1 was the cause. The patient recovered after intravenous (IV) naloxone bolus administration (0.4 mg). This case highlights that tramadol should not be prescribed in patients with UM genotype and renal impairment (Stamer et al., 2008).

#### **2.2 Codeine**

322 Pain Management – Current Issues and Opinions

Each step of the WHO analgesic ladder: nonopioids (analgesics for mild pain, step 1 analgesics), weak opioids (analgesics for mild to moderate pain, step 2 opioid analgesics), and strong opioids (opioids for moderate-to-severe pain intensity, step 3 opioid analgesics) may be accompanied with adjuvant analgesics (coanalgesics), which can enhance opioid analgesia. In patients with bone pain, opioids may be combined with non-steroidal antiinflammatory drugs (NSAIDs), glucocorticoids, and bisphosphonates along with local or systemic radiotherapy (Lussier et al., 2004). In patients with very severe neuropathic pain, a combination of opioids and NMDA (*N*-methyl D-aspartate)-receptor antagonists (e.g. ketamine) are recommended (Leppert, 2010a). Patients with neuropathic pain along with opioids may also receive anticonvulsants, and antidepressants (Bennett, 2011). Other drug groups used in patients with neuropathic pain component comprise local anesthetics and antiarrhytmics (Freynhagen & Bennett, 2009). Opioid analgesics should be supplemented with spasmolytics in patients with visceral colicky pain, especially in the course of bowel

**2. Opioids for mild to moderate pain (weak opioids, step 2 opioid analgesics)** 

Tramadol displays opioid properties and acts on neurotransmission of noradrenalin and serotonin. Both enantiomers act synergistically and improve analgesia without increasing adverse effects. Tramadol is metabolized in the liver and excreted by the kidneys. The main metabolite is O-desmethyltramadol (M1), which displays analgesic activity with a higher affinity to μ-opioid receptors than the parent compound; (+)-M1 has 300 to 400 times greater affinity to μ-opioid receptors than tramadol and (-)-M1 mainly inhibits noradrenalin reuptake. Apart from O,N-didesmethyltramadol (M5, which has weak analgesic activity) and M1, other metabolites are inactive (Leppert and Mikolajczak, 2011). The elimination half-life of tramadol is 5 to 6 hours and that if M1 is 8 hours. During oral administration, 90% of tramadol is excreted by the kidneys and 10% in feces. Patients with renal impairment show a decreased excretion of tramadol and M1. In patients with advanced cirrhosis, there is a decrease in tramadol metabolism with decrease of hepatic clearance and increase in blood serum levels. In these patients, elimination half-life is increased 2.5-fold. The starting dose of immediate-release (IR) tramadol is 25 to 50 mg every 4 to 6 hour and that of controlled-release (CR) tablets or capsules is 50 to 100 mg twice daily; the daily dose should

Patients devoid of CYP2D6 activity (poor metabolizers) need a tramadol dose higher by 30% than those with normal CYP2D6 activity (extensive metabolizers) (Stamer et al., 2003). Tramadol analgesia depends on CYP2D6 genotype, with less analgesia in poor metabolizers being associated with lack of (+)-M1 formation (Stamer et al., 2007). Genotyping is helpful in patients with duplication of CYP2D6 gene (ultrarapid metabolizers [UM]) who are at greater risk to develop tramadol adverse effects. Tramadol metabolism through CYP2D6 may cause

Serotonin syndrome has been reported in patients taking selective serotonin reuptake inhibitors (SSRIs) in conjunction with tramadol or opioids (Gnanadesigan et al., 2005). SSRIs (eg, fluoxetine, paroxetine, and, to less extent, sertraline) used in conjunction with tramadol may cause serotonin syndrome because SSRIs inhibit tramadol metabolism and increase serotonin level; generally, they should not be coadministered with tramadol. Serotonin

interactions with drugs inhibiting this enzyme (eg, cimetidine and ranitidine).

obstruction (Ripamonti et al., 2008).

not exceed 400 mg (Dickman, 2007).

**2.1 Tramadol** 

Codeine is a methylated morphine derivative that is found naturally, along with morphine, in the poppy seed. Codeine displays analgesic and antitussive activity. Codeine is available as IR and CR formulations but also in the form of paracetamol combined preparations. IR codeine is administered every 4-6 h in chronic pain with a starting single dose of about 30 mg. The daily doses of dihydrocodeine and codeine usually do not exceed 240 mg and 300 mg, respectively; when these analgesics are ineffective, opioids for moderate-to-severe pain (strong opioids) are introduced.

Codeine is metabolized in the liver and its bioavailability is 30% to 40% after oral administration. After oral administration of codeine, maximal plasma concentration is attained within 1 to 2 hours with plasma half-life of 2.5 to 3.5 hours and analgesia maintained for 4 to 6 hours (IR formulations). Codeine is partially metabolized to morphine and its metabolites and to codeine metabolites norcodeine (NORC) and codeine-6 glucuronide (C-6-G) (Lötsch et al., 2006). The analgesic effect of codeine is about equal to 1/10th of morphine analgesia. Polymorphism of CYP2D6 is responsible for the formation of morphine, and its metabolites may affect codeine analgesia. Other codeine metabolites, C-6- G predominantly, also display analgesic activity and contribute to codeine analgesia (Vree et al., 2000). In healthy volunteers, codeine is metabolized to C-6-G (81.0% ± 9.3%), NORC (2.16% ± 1.44%), morphine (0.50% ± 0.39%), morphine-3-glucuronide (M-3-G; 2.10% ± 1.24%), morphine-6-glucuronide (M-6-G; 0.80% ± 0.63%), and normorphine (NORM; 2.44% ± 2.42%). The half-life of codeine is 1.47 hours ± 0.32 hours, and that of C-6-G is 2.75 hours ± 0.79 hours. The plasma AUC of C-6-G is about tenfold higher than that of codeine. Protein binding of codeine and C-6-G in vivo is 56.1% ± 2.5% and 34.0% ± 3.6%, respectively (Vree & Verwey-van Wissen, 1992).

Lötsch et al. explored the contributions from codeine and its metabolites to central nervous analgesic effects independent from O-demethylation of codeine to morphine. A

The Role of Opioid Analgesics in the Treatment of Pain in Cancer Patients 325

depending on the dose, which suggests a lack of saturation effect of the O-demethylation process of DHC to DHM depending on CYP2D6 in patients normally metabolizing the substrates of this enzyme. Pharmacokinetic parameters were similar after single and multiple doses of 60 mg of DHC (Ammon et al., 1999). Single-dose and multiple-dose pharmacokinetics of IR and CR DHC formulations provide support for a twice-daily dosage schedule of CR DHC. DHC is metabolized in the liver to main metabolites: DHM, DHC-6-G, and nordihydrocodeine (NORDHC). NORDHC is further glucuronidated to NORDHC-6 glucuronide and O-demethylated to nordihydromorphine (NDHM). DHM undergoes glucuronidation to dihydromorphine-3-glucuronide (DHM-3-G) and dihydromorphine-6 glucuronide (DHM-6-G) and N-demethylation to NDHM. It may be concluded that DHC undergoes the first pass effect after oral administration, which is connected with the formation of significantly higher amount of metabolites after oral than after parenteral administration (Rowell et al., 1983). Studies performed to date (Schmidt et al., 2003; Webb et al., 2001) indicate that DHC analgesia is independent of CYP2D6 activity (Leppert and

**3. Opioids for moderate to severe pain (strong opioids, step 3 opioid** 

is little risk of pharmacokinetic interactions with other drugs.

possible management possibilities are showed in Table 1.

third of the morphine oral dose (Donnelly et al., 2002).

Morphine is the standard drug for the treatment of moderate to severe cancer pain and is a comparator for other strong opioids (Caraceni et al., 2011). This is predominantly due to large clinical experience and different routes of morphine administration (eg, oral, SC, IV, intrathecal, topical). Morphine is a hydrophilic opioid and a pure opioid agonist that acts predominantly through the activation of µ-opioid receptors (Flemming, 2010). Plasma halflife of IR formulations equals 2 to 3 hours and the bioavailability after oral morphine administration equals about 30% to 40%. Morphine undergoes glucuronidation; thus, there

The active metabolite responsible for analgesia is morphine-6-glucuronide (M-6-G). The accumulation of morphine and M-6-G may cause nausea and vomiting, sedation, and finally, respiratory depression. Morphine-3-glucuronide (M-3-G) is devoid of analgesic properties but may be responsible for neurotoxic effects and opioid hyperalgesia (paradoxical pain) (Gretton & Riley, 2008). The main drawback of morphine is the fact that M-3-G and M-6-G may accumulate especially in patients with renal impairment and renal failure, leading to possible intense adverse effects associated with accumulation of metabolites. In severe pain syndromes a change from oral to parenteral or intrathecal route of morphine administration may be beneficial. In case of renal problems, a switch from morphine to other opioids, such as fentanyl, methadone, or buprenorphine, is recommended. Similar to other opioids, morphine often causes constipation; therefore, the use of laxative prophylaxis is recommended. Common morphine adverse effects and

Numerous oral CR formulations of morphine, designed for 12-hour and 24-hour administration, were developed (Ridgway et al., 2010). Local administration of morphine prevents systemic adverse effects. The starting daily dose of oral morphine is usually 20 to 30 mg (for opioid-naïve patients) or 40 to 60 mg (for patients unsuccessfully treated with weak opioids) (Ripamonti et al., 2009). The dose of parenteral (SC or IV) morphine is one

Majkowicz, 2010).

**analgesics) 3.1 Morphine** 

pharmacokinetic/pharmacodynamic fit of the miotic effects by use of morphine as the only active compound was most significantly (*P* < 0.0001) improved when C-6-G as a second active moiety was added. CYP2D6-dependent formation of morphine does not explain exclusively the central nervous effects of codeine, and C-6-G is the most likely additional active moiety with possible contribution of NORC and the parent compound (Lötsch et al., 2006).

Gasche et al. depicted a patient who received oral codeine in a daily dose of 75 mg (25 mg three times a day) and who, after 4 days of treatment, experienced respiratory depression. The patient recovered after IV administration of naloxone (0.4 mg). The cause of the symptoms was CYP2D6 UM phenotype. The patient was concomitantly treated with clarithromycin and voriconazole, both known inhibitors of CYP3A4. This together with CYP2D6 gene duplication led to increased morphine formation. Blood concentrations of M-3-G and M-6-G were substantially elevated, also due to renal failure (Gasche et al., 2004). Recent reports (Kircheiner et al., 2007; Voronov et al., 2007) indicate that there is a significant risk of respiratory depression in infants whose mothers with CYP2D6 UM and UGT2B7•2/•2 genotypes taking codeine during breastfeeding (Madadi et al., 2009b). Guidelines for maternal codeine use during breastfeeding were issued in Canada (Madadi et al., 2009a) but it seems safer not to use codeine and substitute it with other analgesics in this patient group. Apart from morphine glucuronides, codeine and its metabolites (C-6-G and NORC) also contribute to codeine analgesic effects (Lötsch et al., 2006).

#### **2.3 Dihydrocodeine**

Dihydrocodeine (DHC) is a semi synthetic analogue of codeine. Apart from analgesic and antitussive activity, DHC also is used in the treatment of opioid addiction. After subcutaneous (sc) administration of DHC, 30 mg, analgesia is similar to that induced by 10 mg of morphine. After parenteral administration, DHC is twice as potent as codeine. Bioavailability of DHC after oral administration is 20%, which indicates that its analgesia after oral administration is slightly stronger than that of codeine (bioavailability after oral administration equals 30%–40%). After oral administration of DHC, the maximal serum concentration appears after 1.7 hours, plasma half-life varies 3.5 to 5.5 hours, and analgesia lasts 4-6 hours. DHC pharmacokinetics was assessed in 12 extensive metabolizers of CYP2D6 (Ammon et al., 1999). They received a single oral DHC dose of 60 mg, then after 60 hours, they were treated for 3 days with 60 mg dosed twice daily; for the next 3 days with 90 mg twice daily; and for 3 subsequent days 120 mg twice daily. In the 60 to 120 mg DHC dose range, pharmacokinetics of DHC and dihydromorphine (DHM) displayed linear characteristics: area under the curve (AUC), c max (maximum serum concentration), and cssmin (minimum serum concentration at steady state) for both compounds increased depending on the drug dose (Rowell et al., 1983). Even though DHM displays higher affinity (about 100-fold) to the µ-opioid receptors and exhibits higher analgesic activity in comparison to the parent compound, the role of DHM and its glucuronides in DHC analgesia has not been unequivocally established. The starting dose of IR DHC is usually 30 mg every 4 to 6 hours, and that of CR tablets is 60 mg twice daily (Leppert, 2010b).

Renal clearance and the clearance to DHC metabolites, glucuronidation, and Odemethylation to dihydrocodeine-6-glucuronide (DHC-6-G) and DHM, respectively, are not dose dependent, which indicates that metabolism and excretion of DHC and its metabolites are also not dose dependent. Moreover, the ratio of DHC to DHM for AUC does not change depending on the dose, which suggests a lack of saturation effect of the O-demethylation process of DHC to DHM depending on CYP2D6 in patients normally metabolizing the substrates of this enzyme. Pharmacokinetic parameters were similar after single and multiple doses of 60 mg of DHC (Ammon et al., 1999). Single-dose and multiple-dose pharmacokinetics of IR and CR DHC formulations provide support for a twice-daily dosage schedule of CR DHC. DHC is metabolized in the liver to main metabolites: DHM, DHC-6-G, and nordihydrocodeine (NORDHC). NORDHC is further glucuronidated to NORDHC-6 glucuronide and O-demethylated to nordihydromorphine (NDHM). DHM undergoes glucuronidation to dihydromorphine-3-glucuronide (DHM-3-G) and dihydromorphine-6 glucuronide (DHM-6-G) and N-demethylation to NDHM. It may be concluded that DHC undergoes the first pass effect after oral administration, which is connected with the formation of significantly higher amount of metabolites after oral than after parenteral administration (Rowell et al., 1983). Studies performed to date (Schmidt et al., 2003; Webb et al., 2001) indicate that DHC analgesia is independent of CYP2D6 activity (Leppert and Majkowicz, 2010).

#### **3. Opioids for moderate to severe pain (strong opioids, step 3 opioid analgesics)**

#### **3.1 Morphine**

324 Pain Management – Current Issues and Opinions

pharmacokinetic/pharmacodynamic fit of the miotic effects by use of morphine as the only active compound was most significantly (*P* < 0.0001) improved when C-6-G as a second active moiety was added. CYP2D6-dependent formation of morphine does not explain exclusively the central nervous effects of codeine, and C-6-G is the most likely additional active moiety with possible contribution of NORC and the parent compound (Lötsch et al.,

Gasche et al. depicted a patient who received oral codeine in a daily dose of 75 mg (25 mg three times a day) and who, after 4 days of treatment, experienced respiratory depression. The patient recovered after IV administration of naloxone (0.4 mg). The cause of the symptoms was CYP2D6 UM phenotype. The patient was concomitantly treated with clarithromycin and voriconazole, both known inhibitors of CYP3A4. This together with CYP2D6 gene duplication led to increased morphine formation. Blood concentrations of M-3-G and M-6-G were substantially elevated, also due to renal failure (Gasche et al., 2004). Recent reports (Kircheiner et al., 2007; Voronov et al., 2007) indicate that there is a significant risk of respiratory depression in infants whose mothers with CYP2D6 UM and UGT2B7•2/•2 genotypes taking codeine during breastfeeding (Madadi et al., 2009b). Guidelines for maternal codeine use during breastfeeding were issued in Canada (Madadi et al., 2009a) but it seems safer not to use codeine and substitute it with other analgesics in this patient group. Apart from morphine glucuronides, codeine and its metabolites (C-6-G and

Dihydrocodeine (DHC) is a semi synthetic analogue of codeine. Apart from analgesic and antitussive activity, DHC also is used in the treatment of opioid addiction. After subcutaneous (sc) administration of DHC, 30 mg, analgesia is similar to that induced by 10 mg of morphine. After parenteral administration, DHC is twice as potent as codeine. Bioavailability of DHC after oral administration is 20%, which indicates that its analgesia after oral administration is slightly stronger than that of codeine (bioavailability after oral administration equals 30%–40%). After oral administration of DHC, the maximal serum concentration appears after 1.7 hours, plasma half-life varies 3.5 to 5.5 hours, and analgesia lasts 4-6 hours. DHC pharmacokinetics was assessed in 12 extensive metabolizers of CYP2D6 (Ammon et al., 1999). They received a single oral DHC dose of 60 mg, then after 60 hours, they were treated for 3 days with 60 mg dosed twice daily; for the next 3 days with 90 mg twice daily; and for 3 subsequent days 120 mg twice daily. In the 60 to 120 mg DHC dose range, pharmacokinetics of DHC and dihydromorphine (DHM) displayed linear characteristics: area under the curve (AUC), c max (maximum serum concentration), and cssmin (minimum serum concentration at steady state) for both compounds increased depending on the drug dose (Rowell et al., 1983). Even though DHM displays higher affinity (about 100-fold) to the µ-opioid receptors and exhibits higher analgesic activity in comparison to the parent compound, the role of DHM and its glucuronides in DHC analgesia has not been unequivocally established. The starting dose of IR DHC is usually 30 mg every 4 to 6 hours, and that of CR tablets is 60 mg twice daily

Renal clearance and the clearance to DHC metabolites, glucuronidation, and Odemethylation to dihydrocodeine-6-glucuronide (DHC-6-G) and DHM, respectively, are not dose dependent, which indicates that metabolism and excretion of DHC and its metabolites are also not dose dependent. Moreover, the ratio of DHC to DHM for AUC does not change

NORC) also contribute to codeine analgesic effects (Lötsch et al., 2006).

2006).

**2.3 Dihydrocodeine** 

(Leppert, 2010b).

Morphine is the standard drug for the treatment of moderate to severe cancer pain and is a comparator for other strong opioids (Caraceni et al., 2011). This is predominantly due to large clinical experience and different routes of morphine administration (eg, oral, SC, IV, intrathecal, topical). Morphine is a hydrophilic opioid and a pure opioid agonist that acts predominantly through the activation of µ-opioid receptors (Flemming, 2010). Plasma halflife of IR formulations equals 2 to 3 hours and the bioavailability after oral morphine administration equals about 30% to 40%. Morphine undergoes glucuronidation; thus, there is little risk of pharmacokinetic interactions with other drugs.

The active metabolite responsible for analgesia is morphine-6-glucuronide (M-6-G). The accumulation of morphine and M-6-G may cause nausea and vomiting, sedation, and finally, respiratory depression. Morphine-3-glucuronide (M-3-G) is devoid of analgesic properties but may be responsible for neurotoxic effects and opioid hyperalgesia (paradoxical pain) (Gretton & Riley, 2008). The main drawback of morphine is the fact that M-3-G and M-6-G may accumulate especially in patients with renal impairment and renal failure, leading to possible intense adverse effects associated with accumulation of metabolites. In severe pain syndromes a change from oral to parenteral or intrathecal route of morphine administration may be beneficial. In case of renal problems, a switch from morphine to other opioids, such as fentanyl, methadone, or buprenorphine, is recommended. Similar to other opioids, morphine often causes constipation; therefore, the use of laxative prophylaxis is recommended. Common morphine adverse effects and possible management possibilities are showed in Table 1.

Numerous oral CR formulations of morphine, designed for 12-hour and 24-hour administration, were developed (Ridgway et al., 2010). Local administration of morphine prevents systemic adverse effects. The starting daily dose of oral morphine is usually 20 to 30 mg (for opioid-naïve patients) or 40 to 60 mg (for patients unsuccessfully treated with weak opioids) (Ripamonti et al., 2009). The dose of parenteral (SC or IV) morphine is one third of the morphine oral dose (Donnelly et al., 2002).

The Role of Opioid Analgesics in the Treatment of Pain in Cancer Patients 327

noroxymorphone through CYP2D6, and oxymorphone is metabolized to noroxymorphone by CYP3A4. However, analgesia observed after oxycodone administration relies primarily on the parent compound. Noroxycodone has 17% of the potency of oxycodone. Oxymorphone, in spite of high affinity for µ-opioid receptors, is produced in very small amounts. Noroxymorphone is produced in a significant amount and displays significant affinity for opioid receptors. However, the blood–brain barrier is extremely impermeable to noroxymorphone; thus, its role in analgesia is negligible. Low blood–brain barrier permeability is also characteristic of noroxycodone and oxymorphone

In patients with liver cirrhosis and hepatic diseases, the oxycodone dose should be reduced by half. Oxycodone is excreted through the kidneys. In patients with renal insufficiency, the oxycodone dose also should be reduced. In patients with renal failure, the oxycodone halflife is prolonged and ranges from 1.8 to 26 hours. The elimination of noroxycodone and oxymorphone also is impaired in patients with renal failure. CYP2D6 polymorphism probably does not influence oxycodone analgesia and adverse effects. Sertraline minimally inhibits CYP2D6 and intensifies adverse effects of oxycodone (eg, hallucinations, tremors), whereas fluoxetine and quinidine (significant CYP2D6 inhibitors) do not intensify oxycodone adverse effects. Oxycodone reduces oral bioavailability of cyclosporine by half. In healthy patients, rifampin, a CYP3A4 inducer, greatly decreased oral and IV oxycodone AUC by 86% and 53%, respectively (*P* < 0.001), and modestly reduced analgesia and increased plasma metabolite-to–parent compound ratios for noroxycodone and noroxymorphone (*P* < 0.001) (Nieminen et al., 2009). A pharmacodynamic interaction of oxycodone with other drugs acting on the central nervous system, such as benzodiazepines, neuroleptics, and antidepressants, may intensify oxycodone adverse effects, especially sedation, and respiratory depression may be intensified in the case of patients who are more

Oral hydromorphone is an alternative to oral morphine and oral oxycodone as a first choice opioid analgesic for the treatment of moderate to severe cancer pain (Pigni et al, 2011). Hydromorphone has about 5 to 10 times more potent analgesic effect than morphine and similar pharmacodynamic properties. Hydromorphone analgesia is mainly due to µ-opioid– receptor agonist effects; it also features some affinity for δ- but not for κ-opioid receptors (Murray & Hagen, 1995). After hydromorphone administration, analgesia lasts for about 4 to 6 hours and the plasma half-life is about 2.5 hours; sustained-release oral preparations

The drug is metabolized mainly to hydromorphone-3-glucuronide that is devoid of analgesic activity and may accumulate in patients with renal failure; it may induce neurotoxic adverse effects to larger extent than the respective morphine metabolite (morphine-3-glucuronide) (Wright et al., 2001). Hydromorphone in small amount is also metabolized to 6-hydroxy-hydromorphone, but its role is unknown. Due to glucuronidation, the risk of hydromorphone pharmacokinetic interactions with other drugs seems to be low (Sarhill et al., 2001). Adverse effects are similar to those of morphine; however, hydromorphone less frequently induces nausea and vomiting, constipation, itching, and probably more slowly develops tolerance to analgesia (Wirz et al., 2008). In comparative studies conducted in cancer patients with pain hydromorphone displays similar analgesic efficacy to morphine (Miller et al., 1999) and oxycodone (Hagen and Babul, 1997).

provide analgesia for 12-24 hours (Gardner-Nix & Mercadante, 2010).

(Leppert, 2010c).

sensitive to opioids.

**3.3 Hydromorphone** 


Table 1. Common adverse effects of morphine and management possibilities

#### **3.2 Oxycodone**

Oral oxycodone is along with oral morphine recommended as a first choice opioid analgesic for the treatment of moderate to severe cancer-related pain (King et al., 2011). It is a semi synthetic thebaine derivative, a strong opioid that displays a significant affinity to κ-opioid receptors along with agonistic effect mediated by µ-opioid receptors. Limited cross-tolerance is observed between oxycodone and morphine in rats and in clinical studies (Maddocks et al, 1996). In comparison to morphine, oxycodone possesses lower affinity to µ-opioid receptors and similar lipid solubility. Oxycodone permeates the blood–brain barrier very quickly, which may explain its stronger analgesic effect in comparison to other opioids. Oxycodone does not display immunosuppressive effects in experimental studies. It has high oral bioavailability (60%–87%); the plasma half-life is 2 to 3 hours after IV administration, 3 hours after treatment with IR oral solution, and 8 hours after CR tablets. The bioavailability of rectal administration is similar to oral route (61%), but it displays greater variability.

Oxycodone is metabolized in the liver primarily to noroxycodone through CYP3A4 and, to a much less extent, to oxymorphone via CYP2D6. Noroxycodone is metabolized to noroxymorphone through CYP2D6, and oxymorphone is metabolized to noroxymorphone by CYP3A4. However, analgesia observed after oxycodone administration relies primarily on the parent compound. Noroxycodone has 17% of the potency of oxycodone. Oxymorphone, in spite of high affinity for µ-opioid receptors, is produced in very small amounts. Noroxymorphone is produced in a significant amount and displays significant affinity for opioid receptors. However, the blood–brain barrier is extremely impermeable to noroxymorphone; thus, its role in analgesia is negligible. Low blood–brain barrier permeability is also characteristic of noroxycodone and oxymorphone (Leppert, 2010c).

In patients with liver cirrhosis and hepatic diseases, the oxycodone dose should be reduced by half. Oxycodone is excreted through the kidneys. In patients with renal insufficiency, the oxycodone dose also should be reduced. In patients with renal failure, the oxycodone halflife is prolonged and ranges from 1.8 to 26 hours. The elimination of noroxycodone and oxymorphone also is impaired in patients with renal failure. CYP2D6 polymorphism probably does not influence oxycodone analgesia and adverse effects. Sertraline minimally inhibits CYP2D6 and intensifies adverse effects of oxycodone (eg, hallucinations, tremors), whereas fluoxetine and quinidine (significant CYP2D6 inhibitors) do not intensify oxycodone adverse effects. Oxycodone reduces oral bioavailability of cyclosporine by half. In healthy patients, rifampin, a CYP3A4 inducer, greatly decreased oral and IV oxycodone AUC by 86% and 53%, respectively (*P* < 0.001), and modestly reduced analgesia and increased plasma metabolite-to–parent compound ratios for noroxycodone and noroxymorphone (*P* < 0.001) (Nieminen et al., 2009). A pharmacodynamic interaction of oxycodone with other drugs acting on the central nervous system, such as benzodiazepines, neuroleptics, and antidepressants, may intensify oxycodone adverse effects, especially sedation, and respiratory depression may be intensified in the case of patients who are more sensitive to opioids.

#### **3.3 Hydromorphone**

326 Pain Management – Current Issues and Opinions

Metoclopramide 10 mg

Promethazine or cyclizine

Stool softener (macrogol or lactulose) plus stimulant (senna or

If the symptom persists a switch to alternative opioid

If intractable consider levomepromazine

May be caused by coadministered medications

If no improvement consider

e.g. neuroleptics, benzodiazepines, antidepressants and co morbidities (hepatic/renal failure). Consider opioid

switch

opioid switch

If no effect consider switch to transdermal fentanyl or transdermal buprenorphine

may be useful

**Adverse effect Symptomatology Treatment Comments** 

25 mg t.i.d.

bisacodyl). If no effect rectal measures or methylnaltrexone

Reduce dose of morphine, consider methylphedindate 5-10

mg o.d.-b.d.

Reduce dose of

1 – 2 mg o.d.-b.d.

Oral oxycodone is along with oral morphine recommended as a first choice opioid analgesic for the treatment of moderate to severe cancer-related pain (King et al., 2011). It is a semi synthetic thebaine derivative, a strong opioid that displays a significant affinity to κ-opioid receptors along with agonistic effect mediated by µ-opioid receptors. Limited cross-tolerance is observed between oxycodone and morphine in rats and in clinical studies (Maddocks et al, 1996). In comparison to morphine, oxycodone possesses lower affinity to µ-opioid receptors and similar lipid solubility. Oxycodone permeates the blood–brain barrier very quickly, which may explain its stronger analgesic effect in comparison to other opioids. Oxycodone does not display immunosuppressive effects in experimental studies. It has high oral bioavailability (60%–87%); the plasma half-life is 2 to 3 hours after IV administration, 3 hours after treatment with IR oral solution, and 8 hours after CR tablets. The bioavailability of rectal administration is similar to oral route

Oxycodone is metabolized in the liver primarily to noroxycodone through CYP3A4 and, to a much less extent, to oxymorphone via CYP2D6. Noroxycodone is metabolized to

Table 1. Common adverse effects of morphine and management possibilities

morphine, haloperidol – 1 – 2 mg b.d. or risperidone

t.i.d.

Gastric stasis Epigastric

Sedation Drowsiness

Nausea/vomit ing induced by vestibular stimulation

Constipation

Neurotoxicity/ cognitive failure

**3.2 Oxycodone** 

fullness, nausea

Symptoms appear on movement

Flatulence, abdominal pain painful bowel movements,

Hyperalgesia, allodynia, myoclonic jerks/agitation, hallucinations

(61%), but it displays greater variability.

Oral hydromorphone is an alternative to oral morphine and oral oxycodone as a first choice opioid analgesic for the treatment of moderate to severe cancer pain (Pigni et al, 2011). Hydromorphone has about 5 to 10 times more potent analgesic effect than morphine and similar pharmacodynamic properties. Hydromorphone analgesia is mainly due to µ-opioid– receptor agonist effects; it also features some affinity for δ- but not for κ-opioid receptors (Murray & Hagen, 1995). After hydromorphone administration, analgesia lasts for about 4 to 6 hours and the plasma half-life is about 2.5 hours; sustained-release oral preparations provide analgesia for 12-24 hours (Gardner-Nix & Mercadante, 2010).

The drug is metabolized mainly to hydromorphone-3-glucuronide that is devoid of analgesic activity and may accumulate in patients with renal failure; it may induce neurotoxic adverse effects to larger extent than the respective morphine metabolite (morphine-3-glucuronide) (Wright et al., 2001). Hydromorphone in small amount is also metabolized to 6-hydroxy-hydromorphone, but its role is unknown. Due to glucuronidation, the risk of hydromorphone pharmacokinetic interactions with other drugs seems to be low (Sarhill et al., 2001). Adverse effects are similar to those of morphine; however, hydromorphone less frequently induces nausea and vomiting, constipation, itching, and probably more slowly develops tolerance to analgesia (Wirz et al., 2008). In comparative studies conducted in cancer patients with pain hydromorphone displays similar analgesic efficacy to morphine (Miller et al., 1999) and oxycodone (Hagen and Babul, 1997).

The Role of Opioid Analgesics in the Treatment of Pain in Cancer Patients 329

renal failure. Respiratory depression is rare; however, when the symptom appears, naloxone injection should be administered at a dose of 2 mg, followed by continuous infusion (4 mg/h). Buprenorphine displays antihyperalgesic activity and may be successfully used in

Buprenorphine is administered in transdermal patches (TB) releasing 35, 52.5, and 70 g/h, which corresponds to 0.8, 1.2, and 1.6 mg/d, respectively. The patches are changed every 84 to 96 hours. In some countries, patches releasing 5 and 10 g/h, changed weekly, are available. The starting dose for strong opioid–naïve patients is usually one patch of 35 g/h. However, opioid-naive patients and those with renal or hepatic impairment may start with a dose of 17.5 g/h. The treatment is usually well-tolerated. At doses up to 140 g/h, TB does not display ceiling analgesia (Kress, 2009). Breakthrough pain may be treated with sublingual buprenorphine tablets or with IR morphine administered by oral or parenteral

Methadone is a synthetic opioid and a racemate of dextrorotatory (S-methadone) and levorotatory (D-methadone) isomers. Methadone activates μ, κ, and Δ receptors (Dmethadone); it displays moderate antagonistic effect to NMDA receptors (both enantiomers) and strongly inhibits the reuptake of serotonin and noradrenalin in the central nervous system (S-methadone). In high doses, methadone blocks potassium channels required for rapid cardiac muscle repolarization, which may explain the risk of developing ventricular

Methadone is administered mostly to patients with cancer pain who undergo opioid switch; usually methadone is given every 8 hours. In comparison to morphine, 10 times less demand for laxatives and 2 times less nausea and vomiting were observed. Methadone may be administered as the first strong opioid to patients who have been treated with opioids for moderate pain or to opioid-naïve patients (the starting dose is usually 3–5 mg every 8 h) (Ripamonti et al., 1998) although EAPC recommends methadone as the second or the thirdline opioid. Methadone can be administered to patients with renal impairment. It has weak immunosuppressive effect and does not suppress the functioning of natural killer cells. Methadone is tenfold less expensive than the CR morphine and 25-fold cheaper than TF. Methadone is a highly lipophilic and basic drug with a high distribution volume (4.1 ± 0.65 L/kg) and a high affinity to tissues, where it cumulates after multiple administrations (in brain, lung, liver, gut, kidney, and muscles). The high affinity to tissues together with a gradual, retarded release to plasma is the cause of a prolonged half-life. The bioavailability of the drug after oral administration oscillates between 70% and 90%. The half-life is about 24 hours, but it occurs in the range of 8 to 120 hours. Analgesia lasts for 6 to 12 hours. A stable level is reached within 2 to 4 days. Methadone is metabolized mostly via liver enzymes, but also in the intestine wall via N-demethylation to inactive metabolites. The main enzyme responsible for methadone N-demethylation is CYP3A4 with a lesser CYP1A2 and CYP2D6 involvement and a significant CYP2B6 role. The drug is excreted mainly via the alimentary tract, but also through kidneys (depending on the urine pH). In chronic renal disease, methadone does not accumulate; in severe renal failure, a dose reduction may be considered. Methadone is not eliminated in the process of hemodialysis. Methadone is more difficult to use than other opioids due to complicated pharmacokinetics, numerous drug interactions, and possible QT prolongation; therefore, it should be used by physicians

the treatment of neuropathic pain (Mercadante et al., 2007).

experienced in chronic pain management (Leppert, 2009c).

route (Mercadante et al., 2006).

**3.6 Methadone** 

arrhythmia.

Hydromorphone is especially useful for patients requiring high opioid doses via parenteral route due to strong analgesic effects and increased solubility that enables the possibility administering small volumes of the drug in SC injections.

#### **3.4 Fentanyl**

Fentanyl is a lipophilic opioid, µ-opioid–receptor agonist, with analgesic effect about 100 times more potent than that of morphine. In chronic pain treatment, transdermal fentanyl (TF) patches are applied, usually on the upper trunk. There are five types of patches that release 12, 25, 50, 75, and 100 µg/h equal to approximately 0.3, 0.6, 1.2, 1.8, and 2.4 mg fentanyl dose per day, respectively. Patches are changed every 72 hours. Patients need access to short-acting opioid preparations (i.e. oral or parenteral morphine, buccal fentanyl tablets, oral transmucosal fentanyl citrate [OTFC] or fentanyl spray) during TF therapy to effectively manage breakthrough pain episodes. Fentanyl is metabolized mainly to inactive norfentanyl; thus, it may be used in patients with renal impairment. Because the fentanyl metabolic pathway is through CYP3A4, the drugs inhibiting or inducing this enzyme should be avoided. Caution is recommended when using drugs metabolized via CYP3A4. In comparison to morphine, the advantages of TF include milder constipation, nausea, and drowsiness (Ahmedzai & Brooks, 1997).

When starting TF in opioid-naive or strong opioid–naïve patients, one patch at a dose of 12 and 25 µg/h is recommended, respectively. TF also may be used in opioid switch, especially in patients treated with morphine who suffer from intractable constipation. In an open-label study of 16 patients with cancer pain unable to take oral opioids, TF was effective and well tolerated (Leppert et al., 2000). A good analgesic effect was achieved in 11 patients, with a partial effect in an additional 2 patients. TF was effective and welltolerated in patients formerly treated with weak opioids that did not provide satisfactory analgesia (Vielvoye-Kerkmeer et al., 2000). The indications for TF include patients' preferences, intense constipation during morphine treatment, morphine intolerance, nausea, and vomiting. TF should not be used in patients with unstable pain syndromes, especially with neuropathic pain component due to the long plasma half-life (20 h) of the drug, which hinders quick and effective dose titration. Fentanyl may be successfully used by other routes (e.g. SC, IV, intranasal inhaled, buccal) in the treatment of breakthrough pain (Slatkin et al., 2008).

#### **3.5 Buprenorphine**

Buprenorphine is a partial µ-opioid–receptor agonist and κ-receptor antagonist. A ceiling analgesic effect may be obtained at high doses (ie, 15 mg); however, such high doses are not used in clinical practice. The analgesic potency of buprenorphine is about 100 times greater than oral morphine (Likar et al., 2008). Buprenorphine may be administered sublingually due to low oral bioavailability at doses 0.2 to 0.8 mg, usually 3 times daily. It also may be administered by parenteral route (SC or IV).

Buprenorphine is metabolized to the active metabolite norbuprenorphine via CYP3A4. The parent compound and norbuprenorphine undergo glucuronidation; thus, the risk of pharmacokinetic interactions with other drugs is low. Compared with morphine, buprenorphine less frequently induces constipation, nausea, and vomiting, which is probably associated with higher lipophilicity. Buprenorphine is mainly excreted with feces (2/3) and 1/3 of the drug is excreted with urine therefore, it may be used in patients with renal failure. Respiratory depression is rare; however, when the symptom appears, naloxone injection should be administered at a dose of 2 mg, followed by continuous infusion (4 mg/h). Buprenorphine displays antihyperalgesic activity and may be successfully used in the treatment of neuropathic pain (Mercadante et al., 2007).

Buprenorphine is administered in transdermal patches (TB) releasing 35, 52.5, and 70 g/h, which corresponds to 0.8, 1.2, and 1.6 mg/d, respectively. The patches are changed every 84 to 96 hours. In some countries, patches releasing 5 and 10 g/h, changed weekly, are available. The starting dose for strong opioid–naïve patients is usually one patch of 35 g/h. However, opioid-naive patients and those with renal or hepatic impairment may start with a dose of 17.5 g/h. The treatment is usually well-tolerated. At doses up to 140 g/h, TB does not display ceiling analgesia (Kress, 2009). Breakthrough pain may be treated with sublingual buprenorphine tablets or with IR morphine administered by oral or parenteral route (Mercadante et al., 2006).

#### **3.6 Methadone**

328 Pain Management – Current Issues and Opinions

Hydromorphone is especially useful for patients requiring high opioid doses via parenteral route due to strong analgesic effects and increased solubility that enables the possibility

Fentanyl is a lipophilic opioid, µ-opioid–receptor agonist, with analgesic effect about 100 times more potent than that of morphine. In chronic pain treatment, transdermal fentanyl (TF) patches are applied, usually on the upper trunk. There are five types of patches that release 12, 25, 50, 75, and 100 µg/h equal to approximately 0.3, 0.6, 1.2, 1.8, and 2.4 mg fentanyl dose per day, respectively. Patches are changed every 72 hours. Patients need access to short-acting opioid preparations (i.e. oral or parenteral morphine, buccal fentanyl tablets, oral transmucosal fentanyl citrate [OTFC] or fentanyl spray) during TF therapy to effectively manage breakthrough pain episodes. Fentanyl is metabolized mainly to inactive norfentanyl; thus, it may be used in patients with renal impairment. Because the fentanyl metabolic pathway is through CYP3A4, the drugs inhibiting or inducing this enzyme should be avoided. Caution is recommended when using drugs metabolized via CYP3A4. In comparison to morphine, the advantages of TF include milder constipation, nausea, and

When starting TF in opioid-naive or strong opioid–naïve patients, one patch at a dose of 12 and 25 µg/h is recommended, respectively. TF also may be used in opioid switch, especially in patients treated with morphine who suffer from intractable constipation. In an open-label study of 16 patients with cancer pain unable to take oral opioids, TF was effective and well tolerated (Leppert et al., 2000). A good analgesic effect was achieved in 11 patients, with a partial effect in an additional 2 patients. TF was effective and welltolerated in patients formerly treated with weak opioids that did not provide satisfactory analgesia (Vielvoye-Kerkmeer et al., 2000). The indications for TF include patients' preferences, intense constipation during morphine treatment, morphine intolerance, nausea, and vomiting. TF should not be used in patients with unstable pain syndromes, especially with neuropathic pain component due to the long plasma half-life (20 h) of the drug, which hinders quick and effective dose titration. Fentanyl may be successfully used by other routes (e.g. SC, IV, intranasal inhaled, buccal) in the treatment of breakthrough

Buprenorphine is a partial µ-opioid–receptor agonist and κ-receptor antagonist. A ceiling analgesic effect may be obtained at high doses (ie, 15 mg); however, such high doses are not used in clinical practice. The analgesic potency of buprenorphine is about 100 times greater than oral morphine (Likar et al., 2008). Buprenorphine may be administered sublingually due to low oral bioavailability at doses 0.2 to 0.8 mg, usually 3 times daily. It also may be

Buprenorphine is metabolized to the active metabolite norbuprenorphine via CYP3A4. The parent compound and norbuprenorphine undergo glucuronidation; thus, the risk of pharmacokinetic interactions with other drugs is low. Compared with morphine, buprenorphine less frequently induces constipation, nausea, and vomiting, which is probably associated with higher lipophilicity. Buprenorphine is mainly excreted with feces (2/3) and 1/3 of the drug is excreted with urine therefore, it may be used in patients with

administering small volumes of the drug in SC injections.

drowsiness (Ahmedzai & Brooks, 1997).

pain (Slatkin et al., 2008).

administered by parenteral route (SC or IV).

**3.5 Buprenorphine** 

**3.4 Fentanyl** 

Methadone is a synthetic opioid and a racemate of dextrorotatory (S-methadone) and levorotatory (D-methadone) isomers. Methadone activates μ, κ, and Δ receptors (Dmethadone); it displays moderate antagonistic effect to NMDA receptors (both enantiomers) and strongly inhibits the reuptake of serotonin and noradrenalin in the central nervous system (S-methadone). In high doses, methadone blocks potassium channels required for rapid cardiac muscle repolarization, which may explain the risk of developing ventricular arrhythmia.

Methadone is administered mostly to patients with cancer pain who undergo opioid switch; usually methadone is given every 8 hours. In comparison to morphine, 10 times less demand for laxatives and 2 times less nausea and vomiting were observed. Methadone may be administered as the first strong opioid to patients who have been treated with opioids for moderate pain or to opioid-naïve patients (the starting dose is usually 3–5 mg every 8 h) (Ripamonti et al., 1998) although EAPC recommends methadone as the second or the thirdline opioid. Methadone can be administered to patients with renal impairment. It has weak immunosuppressive effect and does not suppress the functioning of natural killer cells. Methadone is tenfold less expensive than the CR morphine and 25-fold cheaper than TF.

Methadone is a highly lipophilic and basic drug with a high distribution volume (4.1 ± 0.65 L/kg) and a high affinity to tissues, where it cumulates after multiple administrations (in brain, lung, liver, gut, kidney, and muscles). The high affinity to tissues together with a gradual, retarded release to plasma is the cause of a prolonged half-life. The bioavailability of the drug after oral administration oscillates between 70% and 90%. The half-life is about 24 hours, but it occurs in the range of 8 to 120 hours. Analgesia lasts for 6 to 12 hours. A stable level is reached within 2 to 4 days. Methadone is metabolized mostly via liver enzymes, but also in the intestine wall via N-demethylation to inactive metabolites. The main enzyme responsible for methadone N-demethylation is CYP3A4 with a lesser CYP1A2 and CYP2D6 involvement and a significant CYP2B6 role. The drug is excreted mainly via the alimentary tract, but also through kidneys (depending on the urine pH). In chronic renal disease, methadone does not accumulate; in severe renal failure, a dose reduction may be considered. Methadone is not eliminated in the process of hemodialysis. Methadone is more difficult to use than other opioids due to complicated pharmacokinetics, numerous drug interactions, and possible QT prolongation; therefore, it should be used by physicians experienced in chronic pain management (Leppert, 2009c).

The Role of Opioid Analgesics in the Treatment of Pain in Cancer Patients 331

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760

391-395.

#### **3.7 Tapentadol**

Tapentadol chloride ([-]-[1*R,*2*R*]-3-[3-Dimethylamino-1-ethyl-2-methyl-propyl]-phenol hydrochloride) is an opioid with two analgesic mechanisms: agonist of µ-opioid receptors with 50 times less affinity than morphine, and inhibition of norepinephrine reuptake (Tzschentke et al., 2007). Bioavailability after oral administration is over 30%, the drug is metabolized to inactive metabolites through glucuronidation and excreted via kidneys (Kneip et al., 2008). In experimental studies tapentadol is effective in the treatment of neuropathic pain and in inflammatory pain. In clinical studies conducted in patients with low back pain, those with postoperative pain, and those with osteoarthritis, IR tapentadol at doses 50, 75, and 100 mg had more favorable adverse-effects profiles with less intense gastrointestinal adverse effects (ie, nausea, vomiting, constipation) in comparison to IR oxycodone at doses 10 and 15 mg. Clinical studies on tapentadol use in patients with cancer pain are ongoing.

#### **4. Conclusions**

Opioids are usually effective when administered alone or with adjuvant analgesics. The traditional WHO step-by-step approach should be used individually, based on the clinical assessment of pain type and intensity. Patients with severe pain intensity should use strong opioids (opioids for moderate-to-severe pain) without climbing up the analgesic ladder. Opioids may be combined with nonopioid analgesics and adjuvant analgesics appropriate for a given pain type. Understanding important attributes of commonly used opioids can help assist selection.

In case of lack of efficacy of orally or transdermally administered opioids, it may be beneficial to change the route of administration to parenteral or intrathecal (Enting et al., 2002). Another possibility is opioid switch that may improve analgesia and reduce adverse effects (Mercadante & Bruera, 2006). A good example may be patients suffering from severe constipation who may benefit when switching from morphine to TF (Ahmedzai & Brooks, 1997) and from codeine or DHC to tramadol (Leppert & Majkowicz, 2010). A newer approach is the concomitant use of two opioids, although little evidence supports such procedure (Fallon & Laird, 2011). Future studies may address genetic disposition responsible for individual patients' response to opioid analgesics (Lötsch et al., 2009).

#### **5. References**


Tapentadol chloride ([-]-[1*R,*2*R*]-3-[3-Dimethylamino-1-ethyl-2-methyl-propyl]-phenol hydrochloride) is an opioid with two analgesic mechanisms: agonist of µ-opioid receptors with 50 times less affinity than morphine, and inhibition of norepinephrine reuptake (Tzschentke et al., 2007). Bioavailability after oral administration is over 30%, the drug is metabolized to inactive metabolites through glucuronidation and excreted via kidneys (Kneip et al., 2008). In experimental studies tapentadol is effective in the treatment of neuropathic pain and in inflammatory pain. In clinical studies conducted in patients with low back pain, those with postoperative pain, and those with osteoarthritis, IR tapentadol at doses 50, 75, and 100 mg had more favorable adverse-effects profiles with less intense gastrointestinal adverse effects (ie, nausea, vomiting, constipation) in comparison to IR oxycodone at doses 10 and 15 mg. Clinical studies on tapentadol use in patients with cancer

Opioids are usually effective when administered alone or with adjuvant analgesics. The traditional WHO step-by-step approach should be used individually, based on the clinical assessment of pain type and intensity. Patients with severe pain intensity should use strong opioids (opioids for moderate-to-severe pain) without climbing up the analgesic ladder. Opioids may be combined with nonopioid analgesics and adjuvant analgesics appropriate for a given pain type. Understanding important attributes of commonly used opioids can

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**3.7 Tapentadol** 

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**4. Conclusions** 

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**5. References** 

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**Chronic Pain** 

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**17** 

*USA* 

**Epidural Lysis of** 

**Adhesions and Percutaneous Neuroplasty** 

Jeffrey P. Smith1, Jared Scott2, Carl E. Noe3, Laslo Nagy4 and Hana Ilner1

Chances are relatively high that each of us will experience low back pain at some point in our lives. The usual course is rapid improvement with 5% to 10% developing persistent symptoms.1 In the 1990s the estimated cost of low back pain to the health industry was in the billions of dollars, and with a larger proportion of our population now reported to be older, this number can only be expected to increase. 2, 3 Treatment typically begins with conservative measures such as medication and physical therapy and may even include minimally and highly invasive pain management interventions. Surgery is sometimes required in patients who have progressive neurologic deficits or those who do not respond to conservative treatment sometimes chose surgery. A quandary sometimes arises, following a primary surgery, as to whether repeat surgery should be attempted or another alternative technique should be tried. This is the exact problem that the epidural adhesiolysis procedure was designed to address. Failed back surgery or postlaminectomy

It was shown to be effective in many patients with chronic pain after back surgery presumably by freeing up nerves and breaking down scar formation, delivering site-specific corticosteroids and local anesthetics, and reducing edema with the use of hyaluronidase and hypertonic saline. Epidural adhesiolysis has afforded patients a reduction in pain and neurologic symptoms without the expense and occasional long recovery period associated with repeat surgery, and often prevents the need for surgical intervention. Epidural adhesiolysis was given an evidence rating of strong correlating to a 1B or 1C evidence level for post–lumbar surgery syndrome in the most recent American Society of Interventional Pain Physicians evidence-based guidelines. The therapy is supported by observational studies and case series along with randomized-control trials. The recommendation was also made that this therapy could apply to most patients with post laminectomy syndrome or failed back syndrome in many circumstances with informed consent.4 Additionally, current procedural terminology (CPT) codes have been assigned to the two different kinds of adhesiolysis: CPT 62263 for the three-times injections over 2 to 3 days, usually done in an

syndrome led to the development of the epidural adhesiolysis procedure.

**1. Introduction** 

Gabor B. Racz1, Miles R. Day1, James E. Heavner1,

*2Advanced Pain Medicine Associates, Wichita, Kansas* 

*4Texas Tech University Health Sciences Center and* 

*1Texas Tech University Health Sciences Center, Lubbock, Texas* 

*3University of Texas Southwestern Medical Center, Dallas, Texas* 

*Covenant Medical Center, Department of Pediatric Neurosurgery* 

### **Epidural Lysis of Adhesions and Percutaneous Neuroplasty**

Gabor B. Racz1, Miles R. Day1, James E. Heavner1,

Jeffrey P. Smith1, Jared Scott2, Carl E. Noe3, Laslo Nagy4 and Hana Ilner1

*1Texas Tech University Health Sciences Center, Lubbock, Texas* 

*2Advanced Pain Medicine Associates, Wichita, Kansas* 

*3University of Texas Southwestern Medical Center, Dallas, Texas* 

*4Texas Tech University Health Sciences Center and Covenant Medical Center, Department of Pediatric Neurosurgery* 

*USA* 

#### **1. Introduction**

Chances are relatively high that each of us will experience low back pain at some point in our lives. The usual course is rapid improvement with 5% to 10% developing persistent symptoms.1 In the 1990s the estimated cost of low back pain to the health industry was in the billions of dollars, and with a larger proportion of our population now reported to be older, this number can only be expected to increase. 2, 3 Treatment typically begins with conservative measures such as medication and physical therapy and may even include minimally and highly invasive pain management interventions. Surgery is sometimes required in patients who have progressive neurologic deficits or those who do not respond to conservative treatment sometimes chose surgery. A quandary sometimes arises, following a primary surgery, as to whether repeat surgery should be attempted or another alternative technique should be tried. This is the exact problem that the epidural adhesiolysis procedure was designed to address. Failed back surgery or postlaminectomy syndrome led to the development of the epidural adhesiolysis procedure.

It was shown to be effective in many patients with chronic pain after back surgery presumably by freeing up nerves and breaking down scar formation, delivering site-specific corticosteroids and local anesthetics, and reducing edema with the use of hyaluronidase and hypertonic saline. Epidural adhesiolysis has afforded patients a reduction in pain and neurologic symptoms without the expense and occasional long recovery period associated with repeat surgery, and often prevents the need for surgical intervention. Epidural adhesiolysis was given an evidence rating of strong correlating to a 1B or 1C evidence level for post–lumbar surgery syndrome in the most recent American Society of Interventional Pain Physicians evidence-based guidelines. The therapy is supported by observational studies and case series along with randomized-control trials. The recommendation was also made that this therapy could apply to most patients with post laminectomy syndrome or failed back syndrome in many circumstances with informed consent.4 Additionally, current procedural terminology (CPT) codes have been assigned to the two different kinds of adhesiolysis: CPT 62263 for the three-times injections over 2 to 3 days, usually done in an

Epidural Lysis of Adhesions and Percutaneous Neuroplasty 339

This evidence also parallels a new study by Gilbert et al20 in which lumbosacral nerve roots were identified as undergoing less strain than previously published during straight leg raise and in which hip motion greater than 60 degrees was determined to cause displacement of

Relative or functional foraminal root entrapment syndrome secondary to epidural fibrosis with corresponding nerve root entrapment is frequently evident after an epidurogram and signified by lack of epidural contrast flow into epidural finger projections at those levels. The lysis procedure effectively serves as a fluid foraminotomy reducing foraminal stenosis caused by epidural fibrosis. In addition to increasing foraminal cross-sectional area, adhesiolysis serves to decompress distended epidural venous structures that may exert compression at nearby spinal levels (Fig. 1) and inevitably cause needle stick related epidural hematomas. Adhesiolysis has led to the development of flexible epiduroscopy that is being pioneered by,

**3. Fluid foraminotomy: Foraminal adhesiolysis or disentrapment** 

primarily initiated, pursued and to this day supported by Dr. James Heavner.21,22

Fig. 1. Engorged blood vessels in the epidural cavity as observed during epiduroscopy. Insert in upper right corner is fluoroscopy showing location for epiduroscopy tip (left

As with any patient, a thorough musculoskeletal and neurologic examination should be performed. In addition to standard dural tension provocative tests, we recommend a provocative test called 'dural tug'. To perform the test, the patient should be instructed to sit

**4. Diagnosis and radiologic diagnosis of epidural fibrosis** 

the nerve root in the lateral recess.

anterior border of L5)

inpatient hospital setting, and CPT 62264 for the one-time injection series surgery-center model that may need to be repeated 3 to 3.5 times in a 12-month period.

#### **2. Pathophysiology of epidural fibrosis (scar tissue) as a cause of low back pain with radiculopathy**

The etiology of chronic low back pain with radiculopathy after appropriate surgery is not well understood. Kuslich et al5 addressed this issue when they studied 193 patients who had undergone lumbar spine operations given local anesthesic int the epidural space. It was postulated that sciatica could only be produced by stimulation of a swollen, stretched, restricted (i.e., scarred) or compressed nerve root.5 Back pain could be produced by stimulation of several tissues, but the most common tissue of origin was the outer layer of the annulus fibrosus and the posterior longitudinal ligament. Stimulation for pain generation of the facet joint capsule rarely generated low back pain, and facet synovium and cartilage surfaces of the facet or muscles were never tender.6

The contribution of fibrosis to the etiology of low back pain has been debated.7–9 There are many possible etiologies of epidural fibrosis, including surgical trauma, an annular tear, infection, hematoma, or intrathecal contrast material.10 These etiologies have been well documented in the literature. LaRocca and Macnab11 demonstrated the invasion of fibrous connective tissue into postoperative hematoma as a cause of epidural fibrosis, and Cooper et al12 reported periradicular fibrosis and vascular abnormalities occurring with herniated intervertebral disks. McCarron et al13 investigated the irritative effect of nucleus pulposus on the dural sac, adjacent nerve roots, and nerve root sleeves independent of the influence of direct compression on these structures. Evidence of an inflammatory reaction was identified by gross inspection and microscopic analysis of spinal cord sections after homogenized autogenous nucleus pulposus was injected into the lumbar epidural space of four dogs. In the control group consisting of four dogs injected with normal saline, the spinal cord sections were grossly normal. Parke and Watanabe14 showed significant evidence of adhesions in cadavers with lumbar disk herniation.

It is widely accepted that postoperative scar renders the nerve susceptible to injury by a compressive phenomena.9 It is natural for connective tissue or any kind of scar tissue to form fibrous layers (scar tissue) as a part of the process that transpires after disruption of the intact milieu.15 Scar tissue is generally found in three components of the epidural space. Dorsal epidural scar tissue is formed by reabsorption of surgical hematoma and may be involved in pain generation.16 In the ventral epidural space, dense scar tissue is formed by ventral defects in the disk, which may persist despite surgical treatment and continue to produce low back pain and radiculopathy past the surgical healing phase.17 The lateral epidural space includes the epiradicular structures outside the root canals, known as the lateral recesses or "sleeves," which are susceptible to lateral disk defects, facet hypertrophy, and neuroforaminal stenosis.18

Although scar tissue itself is not tender, an entrapped nerve root is. Kuslich et al5 surmised that the presence of scar tissue compounded the pain associated with the nerve root by fixing it in one position and thus increasing the susceptibility of the nerve root to tension or compression. They also concluded that no other tissues in the spine are capable of producing leg pain. In a study of the relationship between peridural scar evaluated by magnetic resonance imaging (MRI) and radicular pain after lumbar diskectomy, Ross et al19 demonstrated that subjects with extensive peridural scarring were 3.2 times more likely to experience recurrent radicular pain.

inpatient hospital setting, and CPT 62264 for the one-time injection series surgery-center

**2. Pathophysiology of epidural fibrosis (scar tissue) as a cause of low back** 

The etiology of chronic low back pain with radiculopathy after appropriate surgery is not well understood. Kuslich et al5 addressed this issue when they studied 193 patients who had undergone lumbar spine operations given local anesthesic int the epidural space. It was postulated that sciatica could only be produced by stimulation of a swollen, stretched, restricted (i.e., scarred) or compressed nerve root.5 Back pain could be produced by stimulation of several tissues, but the most common tissue of origin was the outer layer of the annulus fibrosus and the posterior longitudinal ligament. Stimulation for pain generation of the facet joint capsule rarely generated low back pain, and facet synovium and

The contribution of fibrosis to the etiology of low back pain has been debated.7–9 There are many possible etiologies of epidural fibrosis, including surgical trauma, an annular tear, infection, hematoma, or intrathecal contrast material.10 These etiologies have been well documented in the literature. LaRocca and Macnab11 demonstrated the invasion of fibrous connective tissue into postoperative hematoma as a cause of epidural fibrosis, and Cooper et al12 reported periradicular fibrosis and vascular abnormalities occurring with herniated intervertebral disks. McCarron et al13 investigated the irritative effect of nucleus pulposus on the dural sac, adjacent nerve roots, and nerve root sleeves independent of the influence of direct compression on these structures. Evidence of an inflammatory reaction was identified by gross inspection and microscopic analysis of spinal cord sections after homogenized autogenous nucleus pulposus was injected into the lumbar epidural space of four dogs. In the control group consisting of four dogs injected with normal saline, the spinal cord sections were grossly normal. Parke and Watanabe14 showed significant evidence of

It is widely accepted that postoperative scar renders the nerve susceptible to injury by a compressive phenomena.9 It is natural for connective tissue or any kind of scar tissue to form fibrous layers (scar tissue) as a part of the process that transpires after disruption of the intact milieu.15 Scar tissue is generally found in three components of the epidural space. Dorsal epidural scar tissue is formed by reabsorption of surgical hematoma and may be involved in pain generation.16 In the ventral epidural space, dense scar tissue is formed by ventral defects in the disk, which may persist despite surgical treatment and continue to produce low back pain and radiculopathy past the surgical healing phase.17 The lateral epidural space includes the epiradicular structures outside the root canals, known as the lateral recesses or "sleeves," which are susceptible to lateral disk defects, facet hypertrophy,

Although scar tissue itself is not tender, an entrapped nerve root is. Kuslich et al5 surmised that the presence of scar tissue compounded the pain associated with the nerve root by fixing it in one position and thus increasing the susceptibility of the nerve root to tension or compression. They also concluded that no other tissues in the spine are capable of producing leg pain. In a study of the relationship between peridural scar evaluated by magnetic resonance imaging (MRI) and radicular pain after lumbar diskectomy, Ross et al19 demonstrated that subjects with extensive peridural scarring were 3.2 times more likely to

model that may need to be repeated 3 to 3.5 times in a 12-month period.

cartilage surfaces of the facet or muscles were never tender.6

adhesions in cadavers with lumbar disk herniation.

and neuroforaminal stenosis.18

experience recurrent radicular pain.

**pain with radiculopathy** 

This evidence also parallels a new study by Gilbert et al20 in which lumbosacral nerve roots were identified as undergoing less strain than previously published during straight leg raise and in which hip motion greater than 60 degrees was determined to cause displacement of the nerve root in the lateral recess.

### **3. Fluid foraminotomy: Foraminal adhesiolysis or disentrapment**

Relative or functional foraminal root entrapment syndrome secondary to epidural fibrosis with corresponding nerve root entrapment is frequently evident after an epidurogram and signified by lack of epidural contrast flow into epidural finger projections at those levels. The lysis procedure effectively serves as a fluid foraminotomy reducing foraminal stenosis caused by epidural fibrosis. In addition to increasing foraminal cross-sectional area, adhesiolysis serves to decompress distended epidural venous structures that may exert compression at nearby spinal levels (Fig. 1) and inevitably cause needle stick related epidural hematomas. Adhesiolysis has led to the development of flexible epiduroscopy that is being pioneered by, primarily initiated, pursued and to this day supported by Dr. James Heavner.21,22

Fig. 1. Engorged blood vessels in the epidural cavity as observed during epiduroscopy. Insert in upper right corner is fluoroscopy showing location for epiduroscopy tip (left anterior border of L5)

#### **4. Diagnosis and radiologic diagnosis of epidural fibrosis**

As with any patient, a thorough musculoskeletal and neurologic examination should be performed. In addition to standard dural tension provocative tests, we recommend a provocative test called 'dural tug'. To perform the test, the patient should be instructed to sit

Epidural Lysis of Adhesions and Percutaneous Neuroplasty 341

Fig. 2. D-E. D) There is decreased spine flexion prior to treatment secondary to dural adhesions. E) After treatment, the same patient demonstrates increased painless flexion of

techniques would undoubtedly increase the ability to identify epidural fibrosis.

**5. Current Procedural Terminology or CPT codes** 

MRI and computed tomography (CT) are diagnostic tools; sensitivity and specificity are 50% and 70%, respectively.15 CT myelography may also be helpful, although none of the aforementioned modalities can identify epidural fibrosis with 100% reliability. In contrast, epidurography is a technique used with considerable success and it is believed that epidural fibrosis is best diagnosed by performing an epidurogram.23–26 It can detect filling defects in good correlation with a patient's symptoms in real time.26 A combination of several of these

The American Medical Association has developed Current Procedural Terminology codes for epidural adhesiolysis, which include 62264 for a single infusion and 62263 for a staged

the spine.

three-series infusion.

up with a straight leg, bend forward flexing the lumbar spine until their back pain starts to become evident, and the head and neck flexed rapidly forward. During this maneuver, the dura is stretched cephalad and if adhered to structures such as the posterior longitudinal ligament, the most heavily innervated spinal canal structure, the movement of the dura will elicit back pain that is localized to the pain generator. A positive dural tug maneuver has been observed to resolve after percutaneous neuroplasty. (Fig 2 A-E)

Fig. 2. A-C. A) The 'dural tug' maneuver being performed prior to percutaneous neuroplasty. B) Note pain reproduction prior to full neck flexion secondary to dural adhesions. C) Patient after percutaneous neuroplasty with pain free neck and back flexion due to treatment of dural adhesions.

up with a straight leg, bend forward flexing the lumbar spine until their back pain starts to become evident, and the head and neck flexed rapidly forward. During this maneuver, the dura is stretched cephalad and if adhered to structures such as the posterior longitudinal ligament, the most heavily innervated spinal canal structure, the movement of the dura will elicit back pain that is localized to the pain generator. A positive dural tug maneuver has

been observed to resolve after percutaneous neuroplasty. (Fig 2 A-E)

A B

C

due to treatment of dural adhesions.

Fig. 2. A-C. A) The 'dural tug' maneuver being performed prior to percutaneous neuroplasty. B) Note pain reproduction prior to full neck flexion secondary to dural adhesions. C) Patient after percutaneous neuroplasty with pain free neck and back flexion

Fig. 2. D-E. D) There is decreased spine flexion prior to treatment secondary to dural adhesions. E) After treatment, the same patient demonstrates increased painless flexion of the spine.

MRI and computed tomography (CT) are diagnostic tools; sensitivity and specificity are 50% and 70%, respectively.15 CT myelography may also be helpful, although none of the aforementioned modalities can identify epidural fibrosis with 100% reliability. In contrast, epidurography is a technique used with considerable success and it is believed that epidural fibrosis is best diagnosed by performing an epidurogram.23–26 It can detect filling defects in good correlation with a patient's symptoms in real time.26 A combination of several of these techniques would undoubtedly increase the ability to identify epidural fibrosis.

#### **5. Current Procedural Terminology or CPT codes**

The American Medical Association has developed Current Procedural Terminology codes for epidural adhesiolysis, which include 62264 for a single infusion and 62263 for a staged three-series infusion.

Epidural Lysis of Adhesions and Percutaneous Neuroplasty 343

stopping any of these medications, particularly in patients who require chronic anticoagulation such as those with drug-eluting heart stents or prosthetic heart valves. Nonsteroidal anti-inflammatory drugs and aspirin, respectively, should be withheld 4 days and 7 to 10 days before the procedure. Although there is much debate regarding these medications and neuraxial procedures, we tend to be on the conservative side. Clopidogrel (Plavix) should be stopped 7 days before, whereas ticlopidine (Ticlid) is withheld 10 to 14 days before the adhesiolysis.28 Warfarin (Coumadin) stoppage is variable but 5 days is usually adequate.27 Patients on subcutaneous heparin should have it withheld a minimum of 12 hours before the procedure, whereas those on low-molecular-weight heparin require a minimum of 24 hours.28 Over-the-counter homeopathic medications that prolong bleeding parameters should also be withheld. These include fish oil, vitamin E, gingko biloba, garlic, ginseng, and St. John's Wort. Adequate coagulation status can be confirmed by the history, INR, prothrombin time, partial thromboplastin time, and a platelet function assay or bleeding time. The tests should be performed as close to the day of the procedure as possible. Tests performed only a few days after stopping the anticoagulant medication may come back elevated because not enough time has elapsed to allow the anticoagulant effects of the medication to resolve. The benefits of the procedure must be weighed against the potential sequelae of stopping the anticoagulant medication and this should be discussed

Before the procedure, a complete blood count and a clean-catch urinalysis are obtained to check for any undiagnosed infections. An elevated white count and/or a positive urinalysis should prompt the physician to postpone the procedure and refer the patient to the primary care physician for further workup and treatment. In addition, history of bleeding, abnormalities a prothrombin time, partial thromboplastin time, and platelet function assay or bleeding time, are obtained to check for coagulation abnormalities. Any elevated value warrants further investigation and postponement of the procedure until those studies are

This procedure can be performed in the cervical, thoracic, lumbar, and caudal regions of the spine. The caudal and transforaminal placement of catheters will be described in detail, whereas highlights and slight changes in protocol will be provided for cervical and thoracic catheters. Our policy is to perform this procedure under strict sterile conditions in the operating room. Prophylactic antibiotics with broad neuraxial coverage are given before the procedure. Patients will receive either ceftriaxone 1 g intravenously or Levaquin 500 mg orally in those allergic to penicillin. The same dose is also given on day 2. An

The patient is placed in the prone position with a pillow placed under the abdomen to correct the lumbar lordosis and a pillow under the ankles for patient comfort. The patient is asked to put his or her toes together and heels apart. This relaxes the gluteal muscles and

anesthesiologist or nurse anesthetist provides monitored anesthesia care.

thoroughly with the patient.

complete.

**11. Technique** 

**12. Caudal approach** 

**10. Preoperative laboratory** 

#### **6. Indications for epidural adhesiolysis**

Although originally designed to treat radiculopathy secondary to epidural fibrosis following surgery, the use of epidural adhesiolysis has been expanded to treat a multitude of pain etiologies. These include the following27:


### **7. Contraindications**

The following are absolute contraindications for performing epidural adhesiolysis:


A relative contraindication is the presence of arachnoiditis. With arachnoiditis, the tissue planes may be adherent to one another, increasing the chance of loculation of contrast or medication. It may also increase the chance of spread of the medications to the subdural or subarachnoid space, which can increase the chance of complications. Practitioners with limited experience with epidural adhesiolysis should consider referring these patients to a clinician with more training and experience.

#### **8. Patient preparation**

When epidural adhesiolysis has been deemed an appropriate treatment modality, the risks and benefits of the procedure should be discussed with the patient and informed consent obtained. The benefits are pain relief, improved physical function, and possible reversal of neurologic symptoms. Risks include, but are not limited to, bruising, bleeding, infection, reaction to medications used (i.e., hyaluronidase, local anesthetic, corticosteroids, hypertonic saline), damage to nerves or blood vessels, no or little pain relief, bowel/bladder incontinence, worsening of pain, and paralysis. Patients with a history of urinary incontinence should have a urodynamic evaluation by a urologist before the procedure to document the preexisting urodynamic etiology and pathology.

#### **9. Anticoagulant medication**

Medications that prolong bleeding and clotting parameters should be withheld before performing epidural adhesiolysis. The length of time varies depending on the medication taken. A consultation with the patient's primary physician should be obtained before

Although originally designed to treat radiculopathy secondary to epidural fibrosis following surgery, the use of epidural adhesiolysis has been expanded to treat a multitude of pain

**6. Indications for epidural adhesiolysis** 

2. Postlaminectomy syndrome of the neck and back after surgery

4. Metastatic carcinoma of the spine leading to compression fracture

8. Pain unresponsive to spinal cord stimulation and spinal opioids 9. Thoracic disk related chest wall and abdominal pain (after mapping)

The following are absolute contraindications for performing epidural adhesiolysis:

A relative contraindication is the presence of arachnoiditis. With arachnoiditis, the tissue planes may be adherent to one another, increasing the chance of loculation of contrast or medication. It may also increase the chance of spread of the medications to the subdural or subarachnoid space, which can increase the chance of complications. Practitioners with limited experience with epidural adhesiolysis should consider referring these patients to a

When epidural adhesiolysis has been deemed an appropriate treatment modality, the risks and benefits of the procedure should be discussed with the patient and informed consent obtained. The benefits are pain relief, improved physical function, and possible reversal of neurologic symptoms. Risks include, but are not limited to, bruising, bleeding, infection, reaction to medications used (i.e., hyaluronidase, local anesthetic, corticosteroids, hypertonic saline), damage to nerves or blood vessels, no or little pain relief, bowel/bladder incontinence, worsening of pain, and paralysis. Patients with a history of urinary incontinence should have a urodynamic evaluation by a urologist before the procedure to

Medications that prolong bleeding and clotting parameters should be withheld before performing epidural adhesiolysis. The length of time varies depending on the medication taken. A consultation with the patient's primary physician should be obtained before

etiologies. These include the following27: 1. Failed back surgery syndrome

5. Multilevel degenerative arthritis

4. Local infection at the procedure site

clinician with more training and experience.

document the preexisting urodynamic etiology and pathology.

3. Disk disruption

**7. Contraindications** 

2. Chronic infection 3. Coagulopathy

5. Patient refusal 6. Syrinx formation

**8. Patient preparation** 

**9. Anticoagulant medication** 

6. Facet pain 7. Spinal stenosis

1. Sepsis

stopping any of these medications, particularly in patients who require chronic anticoagulation such as those with drug-eluting heart stents or prosthetic heart valves. Nonsteroidal anti-inflammatory drugs and aspirin, respectively, should be withheld 4 days and 7 to 10 days before the procedure. Although there is much debate regarding these medications and neuraxial procedures, we tend to be on the conservative side. Clopidogrel (Plavix) should be stopped 7 days before, whereas ticlopidine (Ticlid) is withheld 10 to 14 days before the adhesiolysis.28 Warfarin (Coumadin) stoppage is variable but 5 days is usually adequate.27 Patients on subcutaneous heparin should have it withheld a minimum of 12 hours before the procedure, whereas those on low-molecular-weight heparin require a minimum of 24 hours.28 Over-the-counter homeopathic medications that prolong bleeding parameters should also be withheld. These include fish oil, vitamin E, gingko biloba, garlic, ginseng, and St. John's Wort. Adequate coagulation status can be confirmed by the history, INR, prothrombin time, partial thromboplastin time, and a platelet function assay or bleeding time. The tests should be performed as close to the day of the procedure as possible. Tests performed only a few days after stopping the anticoagulant medication may come back elevated because not enough time has elapsed to allow the anticoagulant effects of the medication to resolve. The benefits of the procedure must be weighed against the potential sequelae of stopping the anticoagulant medication and this should be discussed thoroughly with the patient.

#### **10. Preoperative laboratory**

Before the procedure, a complete blood count and a clean-catch urinalysis are obtained to check for any undiagnosed infections. An elevated white count and/or a positive urinalysis should prompt the physician to postpone the procedure and refer the patient to the primary care physician for further workup and treatment. In addition, history of bleeding, abnormalities a prothrombin time, partial thromboplastin time, and platelet function assay or bleeding time, are obtained to check for coagulation abnormalities. Any elevated value warrants further investigation and postponement of the procedure until those studies are complete.

#### **11. Technique**

This procedure can be performed in the cervical, thoracic, lumbar, and caudal regions of the spine. The caudal and transforaminal placement of catheters will be described in detail, whereas highlights and slight changes in protocol will be provided for cervical and thoracic catheters. Our policy is to perform this procedure under strict sterile conditions in the operating room. Prophylactic antibiotics with broad neuraxial coverage are given before the procedure. Patients will receive either ceftriaxone 1 g intravenously or Levaquin 500 mg orally in those allergic to penicillin. The same dose is also given on day 2. An anesthesiologist or nurse anesthetist provides monitored anesthesia care.

#### **12. Caudal approach**

The patient is placed in the prone position with a pillow placed under the abdomen to correct the lumbar lordosis and a pillow under the ankles for patient comfort. The patient is asked to put his or her toes together and heels apart. This relaxes the gluteal muscles and

Epidural Lysis of Adhesions and Percutaneous Neuroplasty 345

Fig. 4. Roll palpating index finger to identify the sacral cornu and thus the target sacral

An epidurogram is performed using 10 mL of a non-ionic, water-soluble contrast agent. Confirm a negative aspiration for blood or cerebrospinal fluid before any injection of the contrast or medication. Omnipaque and Isovue are the two agents most frequently used and are suitable for myelography.29, 30 Do not use ionic, water-insoluble agents such as Hypopaque or Renografin or ionic, water-soluble agents such as Conray. 31,32 These agents are not indicated for myelography. Accidental subarachnoid injections can lead to serious untoward events such as seizure and possibly death. Slowly inject the contrast agent and observe for filling defects. A normal epidurogram will have a "Christmas tree" pattern with the central canal being the trunk and the outline of the nerve roots making up the branches. An abnormal epidurogram will have areas where the contrast does not fill (Fig. 5). These are the areas of presumed scarring and typically correspond to the patient's radicular complaints. If vascular uptake is observed, the needle needs to be

hiatus.

redirected.

facilitates identification of the sacral hiatus. After sterile preparation and draping, the sacral hiatus is identified via palpation just caudal to the sacral cornu or with fluoroscopic guidance. A skin wheal is raised with local anesthetic 1-inch lateral and 2 inches caudal to the sacral hiatus on the side opposite the documented radiculopathy. A distal subcutaneous approach theoretically provides some protection from meningitis, as a local skin infection would be much preferred over infection closer to the caudal epidural space. The skin is nicked with an 18-gauge cutting needle, and a 15- or 16-gauge RX Coudé (Epimed International) epidural needle is inserted through the nick at a 45-degree angle and guided fluoroscopically or by palpation to the sacral hiatus (Figs. 3 and 4).

When the needle is through the hiatus, the angle of the needle is dropped to approximately 30 degrees and advanced. The advantages of the RX Coudé needle over other needles are the angled tip, which enables easier direction of the catheter, and the tip of the needle is less sharp. The back edge of the distal opening of the needle is designed to be a noncutting surface that allows manipulation of the catheter in and out of the needle. A Touhy needle has the back edge of the distal opening, which is a cutting surface and can more easily shear a catheter. A properly placed needle will be inside the caudal canal below the level of the S3 foramen on anteroposterior (AP) and later fluoroscopic images. A needle placed above the level of the S3 foramen could potentially puncture a low-lying dura. The needle tip should cross the midline of the sacrum toward the side of the radiculopathy.

Fig. 3. Caudal lysis sequence—first find sacral hiatus and tip of coccyx.

facilitates identification of the sacral hiatus. After sterile preparation and draping, the sacral hiatus is identified via palpation just caudal to the sacral cornu or with fluoroscopic guidance. A skin wheal is raised with local anesthetic 1-inch lateral and 2 inches caudal to the sacral hiatus on the side opposite the documented radiculopathy. A distal subcutaneous approach theoretically provides some protection from meningitis, as a local skin infection would be much preferred over infection closer to the caudal epidural space. The skin is nicked with an 18-gauge cutting needle, and a 15- or 16-gauge RX Coudé (Epimed International) epidural needle is inserted through the nick at a 45-degree angle and guided

When the needle is through the hiatus, the angle of the needle is dropped to approximately 30 degrees and advanced. The advantages of the RX Coudé needle over other needles are the angled tip, which enables easier direction of the catheter, and the tip of the needle is less sharp. The back edge of the distal opening of the needle is designed to be a noncutting surface that allows manipulation of the catheter in and out of the needle. A Touhy needle has the back edge of the distal opening, which is a cutting surface and can more easily shear a catheter. A properly placed needle will be inside the caudal canal below the level of the S3 foramen on anteroposterior (AP) and later fluoroscopic images. A needle placed above the level of the S3 foramen could potentially puncture a low-lying dura. The needle tip should cross the midline of the sacrum toward the side of the

fluoroscopically or by palpation to the sacral hiatus (Figs. 3 and 4).

Fig. 3. Caudal lysis sequence—first find sacral hiatus and tip of coccyx.

radiculopathy.

An epidurogram is performed using 10 mL of a non-ionic, water-soluble contrast agent. Confirm a negative aspiration for blood or cerebrospinal fluid before any injection of the contrast or medication. Omnipaque and Isovue are the two agents most frequently used and are suitable for myelography.29, 30 Do not use ionic, water-insoluble agents such as Hypopaque or Renografin or ionic, water-soluble agents such as Conray. 31,32 These agents are not indicated for myelography. Accidental subarachnoid injections can lead to serious untoward events such as seizure and possibly death. Slowly inject the contrast agent and observe for filling defects. A normal epidurogram will have a "Christmas tree" pattern with the central canal being the trunk and the outline of the nerve roots making up the branches. An abnormal epidurogram will have areas where the contrast does not fill (Fig. 5). These are the areas of presumed scarring and typically correspond to the patient's radicular complaints. If vascular uptake is observed, the needle needs to be redirected.

Epidural Lysis of Adhesions and Percutaneous Neuroplasty 347

Fig. 7. The Epimed Racz catheter is marked for the location of the bend, or use the thumb as

Fig. 8. The direction of the catheter is just near the midline; direct the curve under continuous fluoroscopic guidance to the ventral lateral target site. The needle rotation, as

well as the catheter navigation, may need to be used to reach the target

reference for the 15-degree angle bend

Fig. 5. Initial dye injection Omnipaque 240 (10 mL) showing sacral S3 runoff and filling defects at S2, S1, and right L5

After turning the distal opening of the needle ventral lateral, insert a TunL Kath or TunL-XL (stiffer) catheter (Epimed International) with a bend on the distal tip through the needle (Figs. 6 and 7). The bend should be 2.5 cm from the tip of the catheter and at a 30-degree angle. The bend will enable the catheter to be steered to the target level (Fig 8). Under continuous AP fluoroscopic guidance, advance the tip of the catheter toward the ventrallateral epidural space of the desired level. The catheter can be steered by gently twisting the catheter in a clockwise or counterclockwise direction. Avoid "propellering" the tip (i.e., twisting the tip in circles) because this makes it more difficult to direct the catheter. Do not advance the catheter up the middle of the sacrum because this makes guiding the catheter to the ventral-lateral epidural space more difficult. Ideal location of the tip of the catheter in the AP projection is in the foramen just below the midportion of the pedicle shadow (Figs 9 and 10). Check a lateral projection to confirm that the catheter tip is in the ventral epidural space.

Fig. 6. The needle is placed through the sacral hiatus into the sacral canal and rotated in the direction of the target. Do not advance beyond the S3 foramen.

Fig. 5. Initial dye injection Omnipaque 240 (10 mL) showing sacral S3 runoff and filling

After turning the distal opening of the needle ventral lateral, insert a TunL Kath or TunL-XL (stiffer) catheter (Epimed International) with a bend on the distal tip through the needle (Figs. 6 and 7). The bend should be 2.5 cm from the tip of the catheter and at a 30-degree angle. The bend will enable the catheter to be steered to the target level (Fig 8). Under continuous AP fluoroscopic guidance, advance the tip of the catheter toward the ventrallateral epidural space of the desired level. The catheter can be steered by gently twisting the catheter in a clockwise or counterclockwise direction. Avoid "propellering" the tip (i.e., twisting the tip in circles) because this makes it more difficult to direct the catheter. Do not advance the catheter up the middle of the sacrum because this makes guiding the catheter to the ventral-lateral epidural space more difficult. Ideal location of the tip of the catheter in the AP projection is in the foramen just below the midportion of the pedicle shadow (Figs 9 and 10). Check a lateral projection to confirm that the catheter tip is in the ventral epidural

Fig. 6. The needle is placed through the sacral hiatus into the sacral canal and rotated in the

direction of the target. Do not advance beyond the S3 foramen.

defects at S2, S1, and right L5

space.

Fig. 7. The Epimed Racz catheter is marked for the location of the bend, or use the thumb as reference for the 15-degree angle bend

Fig. 8. The direction of the catheter is just near the midline; direct the curve under continuous fluoroscopic guidance to the ventral lateral target site. The needle rotation, as well as the catheter navigation, may need to be used to reach the target

Epidural Lysis of Adhesions and Percutaneous Neuroplasty 349

Under real-time fluoroscopy, inject 2 to 3 mL of additional contrast through the catheter in an attempt to outline the "scarred in" nerve root (Fig 11). If vascular uptake is noted, reposition the catheter and reinject contrast. Preferably there should not be vascular runoff, but infrequently secondary to venous congestion, an epidural pattern is seen with a small amount of vascular spread. This is acceptable as long as the vascular uptake is venous in nature and not arterial. Extra caution should be taken when injecting the local anesthetic to prevent local anesthetic toxicity. Toxicity is volume and dose related and so far there has not been any reported complications from small volume venous spread. Any arterial spread of contrast always warrants repositioning of the catheter. We have never observed intra-

Fig. 11. Contrast injection Omnipaque 240, additional 5 mL opening right L5, S1, S2, and S3 perineural spaces; also left L5, S1, S2, and S3 in addition to right L4 spread in cephalad

Inject 1500 U of hyaluronidase dissolved in 10 mL of preservative-free normal saline. A newer development is the use of Hylenex or human-recombinant hyaluronidase, which carries the advantage of a reportedly increased effectiveness at the body's normal pH compared to bovine-recombinant hyaluronidase.33 This injection may cause some discomfort, so a slow injection is preferable. Observe for "opening up"(i.e. visualization) of the "scarred in" nerve root (Figs 12 and 13 ; see also Fig. 11). A 3 mL test dose of a 10 mL local anesthetic/steroid (LA/S) solution is then given. Our institution used 4 mg of dexamethasone mixed with 9 mL of 0.2% ropivacaine. Ropivacaine is used instead of bupivacaine for two reasons: the former produces a preferential sensory versus a motor block, and it is less cardiotoxic than a racemic bupivacaine. Doses for other corticosteroids commonly used are 40 to 80 mg of methylprednisolone (Depo-Medrol), 25 to 50 mg of triamcinolone diacetate (Aristocort), 40 to 80 mg of triamcinolone acetonide (Kenalog), and 6 to 12 mg of betamethasone (Celestone Solu span). If, after 5 minutes, there is no evidence of intrathecal or intravascular injection of

medication, inject the remaining 7 mL of the LA/S solution.

direction

arterial placement in 25 years of placing soft, spring-tipped catheters.

Fig. 9. The needle is removed, and the catheter is placed in the ventral lateral epidural space ventral to the nerve root

Fig. 10. Catheter (24xL) is threaded to lateral L5 neural foramen

Fig. 9. The needle is removed, and the catheter is placed in the ventral lateral epidural space

Fig. 10. Catheter (24xL) is threaded to lateral L5 neural foramen

ventral to the nerve root

Under real-time fluoroscopy, inject 2 to 3 mL of additional contrast through the catheter in an attempt to outline the "scarred in" nerve root (Fig 11). If vascular uptake is noted, reposition the catheter and reinject contrast. Preferably there should not be vascular runoff, but infrequently secondary to venous congestion, an epidural pattern is seen with a small amount of vascular spread. This is acceptable as long as the vascular uptake is venous in nature and not arterial. Extra caution should be taken when injecting the local anesthetic to prevent local anesthetic toxicity. Toxicity is volume and dose related and so far there has not been any reported complications from small volume venous spread. Any arterial spread of contrast always warrants repositioning of the catheter. We have never observed intraarterial placement in 25 years of placing soft, spring-tipped catheters.

Fig. 11. Contrast injection Omnipaque 240, additional 5 mL opening right L5, S1, S2, and S3 perineural spaces; also left L5, S1, S2, and S3 in addition to right L4 spread in cephalad direction

Inject 1500 U of hyaluronidase dissolved in 10 mL of preservative-free normal saline. A newer development is the use of Hylenex or human-recombinant hyaluronidase, which carries the advantage of a reportedly increased effectiveness at the body's normal pH compared to bovine-recombinant hyaluronidase.33 This injection may cause some discomfort, so a slow injection is preferable. Observe for "opening up"(i.e. visualization) of the "scarred in" nerve root (Figs 12 and 13 ; see also Fig. 11). A 3 mL test dose of a 10 mL local anesthetic/steroid (LA/S) solution is then given. Our institution used 4 mg of dexamethasone mixed with 9 mL of 0.2% ropivacaine. Ropivacaine is used instead of bupivacaine for two reasons: the former produces a preferential sensory versus a motor block, and it is less cardiotoxic than a racemic bupivacaine. Doses for other corticosteroids commonly used are 40 to 80 mg of methylprednisolone (Depo-Medrol), 25 to 50 mg of triamcinolone diacetate (Aristocort), 40 to 80 mg of triamcinolone acetonide (Kenalog), and 6 to 12 mg of betamethasone (Celestone Solu span). If, after 5 minutes, there is no evidence of intrathecal or intravascular injection of medication, inject the remaining 7 mL of the LA/S solution.

Epidural Lysis of Adhesions and Percutaneous Neuroplasty 351

Remove the needle under continuous fluoroscopic guidance to ensure the catheter remains at the target level (Fig 14). Secure the catheter to the skin using nonabsorbable suture and coat the skin puncture site with antimicrobial ointment. Apply a sterile dressing and attach a 0.2 μ m filter to the end of the catheter. Affix the exposed portion of the catheter to the

Fig. 14. Five picture sequence of removal of the needle to prevent dislodging the catheter

A 20- to 30-minute period should elapse between the last injection of the LA/S solution and the start of the hypertonic saline (10%) infusion. This is necessary to ensure that a subdural injection of the LA/S solution has not occurred. A subdural block mimics a subarachnoid block but it takes longer to establish, usually 16 to 18 minutes. Evidence for subdural or subarachnoid spread is the development of motor block. If the patient develops a subarachnoid or subdural block at any point during the procedure, the catheter should be removed and the remainder of the adhesiolysis canceled. The patient needs to be observed to document the resolution of the motor and sensory block and to document that 10 mL of

from target site before suturing and application of dressing.

patient with tape and transport the patient to the recovery area.

Fig. 12. Additional contrast and hyaluronidase injection opens up bilaterally formerly scarred areas. The Christmas tree appearance is obvious.

Fig. 13. Catheter advances to the desired symptomatic level of right L5 in the ventral lateral epidural space. Injection of contrast followed by 10 mL hyaluronidase 1,500 units opens up bilaterally L3-5, S1, S2, and S3 neural foramina.

Fig. 12. Additional contrast and hyaluronidase injection opens up bilaterally formerly

Fig. 13. Catheter advances to the desired symptomatic level of right L5 in the ventral lateral epidural space. Injection of contrast followed by 10 mL hyaluronidase 1,500 units opens up

scarred areas. The Christmas tree appearance is obvious.

bilaterally L3-5, S1, S2, and S3 neural foramina.

Remove the needle under continuous fluoroscopic guidance to ensure the catheter remains at the target level (Fig 14). Secure the catheter to the skin using nonabsorbable suture and coat the skin puncture site with antimicrobial ointment. Apply a sterile dressing and attach a 0.2 μ m filter to the end of the catheter. Affix the exposed portion of the catheter to the patient with tape and transport the patient to the recovery area.

Fig. 14. Five picture sequence of removal of the needle to prevent dislodging the catheter from target site before suturing and application of dressing.

A 20- to 30-minute period should elapse between the last injection of the LA/S solution and the start of the hypertonic saline (10%) infusion. This is necessary to ensure that a subdural injection of the LA/S solution has not occurred. A subdural block mimics a subarachnoid block but it takes longer to establish, usually 16 to 18 minutes. Evidence for subdural or subarachnoid spread is the development of motor block. If the patient develops a subarachnoid or subdural block at any point during the procedure, the catheter should be removed and the remainder of the adhesiolysis canceled. The patient needs to be observed to document the resolution of the motor and sensory block and to document that 10 mL of

Epidural Lysis of Adhesions and Percutaneous Neuroplasty 353

Fig. 16. Following bony contact with SAP. Lateral rotation of 180 degrees to allow passage

Fig. 17. Note the intertransverse ligament. The needle tip with the RX Coude 2 that has 1 mm protruding blunt stylet will pass through the ligament and will be less likely to damage

the tip should be just short of the middle of the spinal canal (Fig 18 to 20).

Fig. 18. The distal tip of the catheter may be bent 15-degrees, 3/4 inch length.

As the needle is advanced slowly, a clear "pop" is felt as the needle penetrates the inter transverse ligament. Obtain a lateral fluoroscopic image. The tip of the needle should be just past the SAP in the posterior foramen. In the AP plane, the tip of the needle under continuous AP fluoroscopy, insert the catheter slowly into the foramen and advance until

toward the target.

the nerve.

the hypertonic saline is then infused through the catheter over 15 to 30 minutes. If the patient complains of discomfort, the infusion is stopped and an additional 2 to 3 mL of 0.2% ropivacaine is injected and the infusion is restarted. Alternatively, 50 to 75 μ g of fentanyl can be injected epidurally in lieu of the local anesthetic. After completion of the hypertonic saline infusion, the catheter is slowly flushed with 2 mL of preservative-free normal saline and the catheter is capped.

Our policy is to admit the patient for 24-hour observation status and do a second and a third hypertonic saline infusion the following day. On post–catheter insertion day 2, the catheter is twice injected (separated by 4- to 6-hour increments) with 10 mL of 0.2% ropivacaine without steroid and infused with 10 mL of hypertonic saline (10%) using the same technique and precautions as the day 1 infusion. At the end of the third infusion, the catheter is removed and a sterile dressing applied. The patient is discharged home with 5 days of oral cephalexin at 500 mg twice a day or oral levofloxacin (Levaquin) at 500 mg once a day for penicillin-allergic patients. Clinic follow-up is in 30 days.

#### **13. Transforaminal catheters**

Patients with an additional level of radiculopathy or those in whom the target level cannot be reached by the caudal approach may require placement of a second catheter. The second catheter is placed into the ventral epidural space via a transforaminal approach.

After the target level is identified with an AP fluoroscopic image, the superior endplate of the vertebra that comprises the caudal portion of the foramina is "squared," that is, the anterior and posterior shadows of the vertebral endplate are superimposed. The angle is typically 15 to 20 degrees in a caudocephalad direction. The fluoroscope is then oblique approximately 15 degrees to the side of the radiculopathy and adjusted until the spinous process is rotated to the opposite side. This fluoroscope positioning allows the best visualization of the superior articular process (SAP) that forms the inferoposterior portion of the targeted foramen. The image of the SAP should be superimposed on the shadow of the disk space on the oblique view. The tip of the SAP is the target for the needle placement (Fig 15). Raise a skin wheal slightly lateral to the shadow of the tip of the SAP. Pierce the skin with an 18-gauge needle and then insert a 15- or 16-gauge RX Coudé needle and advance using gun-barrel technique toward the tip of the SAP. Continue to advance the needle medially toward the SAP until the tip contacts bone. Rotate the tip of the needle 180 degrees laterally and advance about 5 mm (Fig 16). Rotate the needle back medially 180 degrees (Fig 17).

Fig. 15. Transforaminal lateral-oblique view. Target the SAP with the advancing RX Coude needle.

the hypertonic saline is then infused through the catheter over 15 to 30 minutes. If the patient complains of discomfort, the infusion is stopped and an additional 2 to 3 mL of 0.2% ropivacaine is injected and the infusion is restarted. Alternatively, 50 to 75 μ g of fentanyl can be injected epidurally in lieu of the local anesthetic. After completion of the hypertonic saline infusion, the catheter is slowly flushed with 2 mL of preservative-free normal saline

Our policy is to admit the patient for 24-hour observation status and do a second and a third hypertonic saline infusion the following day. On post–catheter insertion day 2, the catheter is twice injected (separated by 4- to 6-hour increments) with 10 mL of 0.2% ropivacaine without steroid and infused with 10 mL of hypertonic saline (10%) using the same technique and precautions as the day 1 infusion. At the end of the third infusion, the catheter is removed and a sterile dressing applied. The patient is discharged home with 5 days of oral cephalexin at 500 mg twice a day or oral levofloxacin (Levaquin) at 500 mg once a day for

Patients with an additional level of radiculopathy or those in whom the target level cannot be reached by the caudal approach may require placement of a second catheter. The second

After the target level is identified with an AP fluoroscopic image, the superior endplate of the vertebra that comprises the caudal portion of the foramina is "squared," that is, the anterior and posterior shadows of the vertebral endplate are superimposed. The angle is typically 15 to 20 degrees in a caudocephalad direction. The fluoroscope is then oblique approximately 15 degrees to the side of the radiculopathy and adjusted until the spinous process is rotated to the opposite side. This fluoroscope positioning allows the best visualization of the superior articular process (SAP) that forms the inferoposterior portion of the targeted foramen. The image of the SAP should be superimposed on the shadow of the disk space on the oblique view. The tip of the SAP is the target for the needle placement (Fig 15). Raise a skin wheal slightly lateral to the shadow of the tip of the SAP. Pierce the skin with an 18-gauge needle and then insert a 15- or 16-gauge RX Coudé needle and advance using gun-barrel technique toward the tip of the SAP. Continue to advance the needle medially toward the SAP until the tip contacts bone. Rotate the tip of the needle 180 degrees laterally and advance about 5 mm

Fig. 15. Transforaminal lateral-oblique view. Target the SAP with the advancing RX Coude

catheter is placed into the ventral epidural space via a transforaminal approach.

and the catheter is capped.

**13. Transforaminal catheters** 

needle.

penicillin-allergic patients. Clinic follow-up is in 30 days.

(Fig 16). Rotate the needle back medially 180 degrees (Fig 17).

Fig. 16. Following bony contact with SAP. Lateral rotation of 180 degrees to allow passage toward the target.

Fig. 17. Note the intertransverse ligament. The needle tip with the RX Coude 2 that has 1 mm protruding blunt stylet will pass through the ligament and will be less likely to damage the nerve.

As the needle is advanced slowly, a clear "pop" is felt as the needle penetrates the inter transverse ligament. Obtain a lateral fluoroscopic image. The tip of the needle should be just past the SAP in the posterior foramen. In the AP plane, the tip of the needle under continuous AP fluoroscopy, insert the catheter slowly into the foramen and advance until the tip should be just short of the middle of the spinal canal (Fig 18 to 20).

Fig. 18. The distal tip of the catheter may be bent 15-degrees, 3/4 inch length.

Epidural Lysis of Adhesions and Percutaneous Neuroplasty 355

Fig. 21. Lateral view of Fig. 169-13 . Transforaminal-ventral-anterior catheter dye spread to

Fig. 22. Anteroposterior view. The catheter is in optimal position near midline via the

Inject 1 to 2 mL of contrast to confirm epidural spread. When a caudal and a transforaminal catheter are placed, the 1500 U of hyaluronidase are divided evenly between the two catheters (5 mL of the hyaluronidase/saline solution into each). The LA/S solution is also divided evenly, but a volume of 15 mL (1 mL steroid and 14 mL 0.2% ropivacaine; of the total volume, 5 mL is transforaminal and 10 mL is caudal) is used instead of 10 mL. Remove the needle under fluoroscopic guidance to make sure the catheter does not move from the original position in the epidural space. Secure and cover the catheter as described previously. The hypertonic saline solution is infused at a volume of 4 to 5 mL per

epidural and L3-4 intradiscal area (through annular tear).

transforaminal placement.

Fig. 19. Once the intertransverse ligament is perforated, the catheter is steered to the ventral lateral epidural space (lateral view).

Fig. 20. Transforaminal 15-gauge RX-Coude 2 (Epimed International, Johnstown, NY) catheter at left L3-4 threaded almost to near *midcanal* position (anteroposterior view).

Confirm that the catheter is in the anterior epidural space with a lateral image (Fig 21). Anatomically, the catheter is in the foramen above or below the exiting nerve root (Fig 22). If the catheter cannot be advanced, it usually means the needle is either too posterior or too lateral to the foramen. It can also indicate that the foramen is too stenotic to allow passage of the catheter. The needle can be advanced a few millimeters anteriorly in relation to the foramen, and that will also move it slightly medial into the foramen. If the catheter still will not pass, the initial insertion of the needle will need to be more lateral. Therefore the fluoroscope angle will be about 20 degrees instead of 15 degrees. The curve of the needle usually facilitates easy catheter placement. The final position of the catheter tip is just short of the midline.

Fig. 19. Once the intertransverse ligament is perforated, the catheter is steered to the ventral

Fig. 20. Transforaminal 15-gauge RX-Coude 2 (Epimed International, Johnstown, NY) catheter at left L3-4 threaded almost to near *midcanal* position (anteroposterior view).

Confirm that the catheter is in the anterior epidural space with a lateral image (Fig 21). Anatomically, the catheter is in the foramen above or below the exiting nerve root (Fig 22). If the catheter cannot be advanced, it usually means the needle is either too posterior or too lateral to the foramen. It can also indicate that the foramen is too stenotic to allow passage of the catheter. The needle can be advanced a few millimeters anteriorly in relation to the foramen, and that will also move it slightly medial into the foramen. If the catheter still will not pass, the initial insertion of the needle will need to be more lateral. Therefore the fluoroscope angle will be about 20 degrees instead of 15 degrees. The curve of the needle usually facilitates easy catheter placement. The final position of the catheter tip is just short

lateral epidural space (lateral view).

of the midline.

Fig. 21. Lateral view of Fig. 169-13 . Transforaminal-ventral-anterior catheter dye spread to epidural and L3-4 intradiscal area (through annular tear).

Fig. 22. Anteroposterior view. The catheter is in optimal position near midline via the transforaminal placement.

Inject 1 to 2 mL of contrast to confirm epidural spread. When a caudal and a transforaminal catheter are placed, the 1500 U of hyaluronidase are divided evenly between the two catheters (5 mL of the hyaluronidase/saline solution into each). The LA/S solution is also divided evenly, but a volume of 15 mL (1 mL steroid and 14 mL 0.2% ropivacaine; of the total volume, 5 mL is transforaminal and 10 mL is caudal) is used instead of 10 mL. Remove the needle under fluoroscopic guidance to make sure the catheter does not move from the original position in the epidural space. Secure and cover the catheter as described previously. The hypertonic saline solution is infused at a volume of 4 to 5 mL per

Epidural Lysis of Adhesions and Percutaneous Neuroplasty 357

A B

C D

E

through the enlarged neural foramina (Fig 24)34

inserted.

Fig. 23. Sequence of stages to place a catheter using the R-X Coude. **A** and **B.** The needle is inserted into the epidural space with the tip directed as shown. **C.** The protruding stylet is inserted. **D.** Then the needle is rotated so the tip is parallel to the dura. **E.** The catheter is

Inject an additional small volume as needed to complete the epidurogram. If there is no free flow of injected contrast, pressure may build up in the lateral epidural space. Characteristic fluid spread by the path of least resistance can be recognized as *perivenous counter spread*  (PVCS). Presence of PVCS means pressure builds up in the lateral epidural space that is unable to spread laterally to decompress. The dye spread picks the path of least resistance to the opposite side. Pressure may build up and lead to ischemic spinal cord injury. Flexion and rotation of the head and neck can open up lateral runoff and release the pressure

transforaminal and 8 to 10 mL per caudal catheter over 30 minutes. The hypertonic saline injection volume should always be less than or equal to the local anesthetic volume injected to avoid pain from injection. It behooves the practitioner to check the position of the transforaminal catheter under fluoroscopy before performing the second and third infusions. The catheter may advance across the epidural space into the contralateral foramen or paraspinous muscles or more commonly back out of the epidural space into the ipsilateral paraspinous muscles.

This results in deposition of the medication in the paravertebral tissue rather than in the epidural space. As with the caudal approach, remove the transforaminal catheter after the third infusion. A recent development is the R-X Coude 2 needle in which a second protruding stylet may allow closer needle placement and less chance of nerve injury.

#### **14. Cervical lysis of adhesions**

The success of the caudal approach for lysis of adhesions led to the application of the same technique to the cervical epidural space. The indications and preprocedure workup are the same as those for the caudal lysis technique, but there are a few differences in technique and volumes of medication used.

The epidural space should be entered via the upper thoracic interspaces using a paramedian approach on the contralateral side. The most common levels are T1-2 and T2-3. Entry at these levels allows for a sufficient length of the catheter to remain in the epidural space after the target level has been reached. If the target is the lower cervical nerve roots, a more caudal interspace should be selected. We place the patient in the left lateral decubitus position, but use a prone approach in larger patients.

A technique referred to as the "3-D technique" is used to facilitate entry into the epidural space. The "3-D" stands for *direction, depth,* and *direction.* Using an AP fluoroscopic image, the initial *direction* of the 15- or 16-gauge RX Coudé needle is determined. Using a modified paramedian approach with the skin entry one and a half levels below the target interlaminar space, advance and direct the needle toward the midpoint of the chosen interlaminar space with the opening of the needle pointing medial. Once the needle engages the deeper tissue planes (usually at 2 to 3 cm), check the depth of the needle with a lateral image. Advance the needle toward the epidural space and check repeat images to confirm the *depth.* The posterior border of the dorsal epidural space can be visualized by identifying the junction of the base of the spinous process of the vertebra with its lamina. This junction creates a distinct radiopaque "straight line." Once the needle is close to the epidural space, obtain an AP fluoroscopic image to recheck the *direction* of the needle. If the tip of the needle has crossed the midline as defined by the spinous processes of the vertebral bodies, pull the needle back and redirect. The "3-D" process can be repeated as many times as is necessary to get the needle into the perfect position.

Using loss-of-resistance technique, advance the needle into the epidural space with the tip of the RX-Coudé needle, pointed caudally. Once the tip is in the epidural space, rotate the tip cephalad, and inject 1 to 2 mL of contrast to confirm entry. Rotation or movement of any needle in the epidural space can cut the dura. This technique has been improved with the advent of the RX Coudé 2 needle, which has a second interlocking stylet that protrudes slightly beyond the tip of the needle and functions to push the dura away from the needle tip as it is turned 180 degrees cephalad (Fig. 23 A-E).

transforaminal and 8 to 10 mL per caudal catheter over 30 minutes. The hypertonic saline injection volume should always be less than or equal to the local anesthetic volume injected to avoid pain from injection. It behooves the practitioner to check the position of the transforaminal catheter under fluoroscopy before performing the second and third infusions. The catheter may advance across the epidural space into the contralateral foramen or paraspinous muscles or more commonly back out of the epidural space into the

This results in deposition of the medication in the paravertebral tissue rather than in the epidural space. As with the caudal approach, remove the transforaminal catheter after the third infusion. A recent development is the R-X Coude 2 needle in which a second

The success of the caudal approach for lysis of adhesions led to the application of the same technique to the cervical epidural space. The indications and preprocedure workup are the same as those for the caudal lysis technique, but there are a few differences in technique and

The epidural space should be entered via the upper thoracic interspaces using a paramedian approach on the contralateral side. The most common levels are T1-2 and T2-3. Entry at these levels allows for a sufficient length of the catheter to remain in the epidural space after the target level has been reached. If the target is the lower cervical nerve roots, a more caudal interspace should be selected. We place the patient in the left lateral decubitus

A technique referred to as the "3-D technique" is used to facilitate entry into the epidural space. The "3-D" stands for *direction, depth,* and *direction.* Using an AP fluoroscopic image, the initial *direction* of the 15- or 16-gauge RX Coudé needle is determined. Using a modified paramedian approach with the skin entry one and a half levels below the target interlaminar space, advance and direct the needle toward the midpoint of the chosen interlaminar space with the opening of the needle pointing medial. Once the needle engages the deeper tissue planes (usually at 2 to 3 cm), check the depth of the needle with a lateral image. Advance the needle toward the epidural space and check repeat images to confirm the *depth.* The posterior border of the dorsal epidural space can be visualized by identifying the junction of the base of the spinous process of the vertebra with its lamina. This junction creates a distinct radiopaque "straight line." Once the needle is close to the epidural space, obtain an AP fluoroscopic image to recheck the *direction* of the needle. If the tip of the needle has crossed the midline as defined by the spinous processes of the vertebral bodies, pull the needle back and redirect. The "3-D" process can be repeated as many times as is necessary

Using loss-of-resistance technique, advance the needle into the epidural space with the tip of the RX-Coudé needle, pointed caudally. Once the tip is in the epidural space, rotate the tip cephalad, and inject 1 to 2 mL of contrast to confirm entry. Rotation or movement of any needle in the epidural space can cut the dura. This technique has been improved with the advent of the RX Coudé 2 needle, which has a second interlocking stylet that protrudes slightly beyond the tip of the needle and functions to push the dura away from the needle

protruding stylet may allow closer needle placement and less chance of nerve injury.

ipsilateral paraspinous muscles.

**14. Cervical lysis of adhesions** 

position, but use a prone approach in larger patients.

to get the needle into the perfect position.

tip as it is turned 180 degrees cephalad (Fig. 23 A-E).

volumes of medication used.

Fig. 23. Sequence of stages to place a catheter using the R-X Coude. **A** and **B.** The needle is inserted into the epidural space with the tip directed as shown. **C.** The protruding stylet is inserted. **D.** Then the needle is rotated so the tip is parallel to the dura. **E.** The catheter is inserted.

Inject an additional small volume as needed to complete the epidurogram. If there is no free flow of injected contrast, pressure may build up in the lateral epidural space. Characteristic fluid spread by the path of least resistance can be recognized as *perivenous counter spread*  (PVCS). Presence of PVCS means pressure builds up in the lateral epidural space that is unable to spread laterally to decompress. The dye spread picks the path of least resistance to the opposite side. Pressure may build up and lead to ischemic spinal cord injury. Flexion and rotation of the head and neck can open up lateral runoff and release the pressure through the enlarged neural foramina (Fig 24)34

Epidural Lysis of Adhesions and Percutaneous Neuroplasty 359

minutes. At the end of the infusion, flush the catheter with 1 to 2 mL of preservative-free

Fig. 25. A & B. **A** Cervical left ventral lateral catheter to the upper level of fusion C5-7. **B** Cervical-left ventral lateral catheter threaded to above level of fusion of C4. The dye

injection spreads cephalad and lateral.

normal saline and cap the catheter.

Fig. 24. Flexion rotation, left to right regardless patient position. The neural foramen enlarges on flexion rotation and gets smaller with extension. The inferior pars slides forward over the superior pars to enlarge the foramen. This allows lateral run off and pressure release with PVCS.

As with the caudal epidurogram, look for filling defects. It is extremely important to visualize spread of the contrast in the cephalad and caudal directions. Loculation of contrast in a small area must be avoided as this can significantly increase the pressure in the epidural space and can compromise the already tenuous arterial blood supply to the spinal cord. Place a bend on the catheter as previously described for the caudal approach and insert it through the needle (Fig 23E). The opening of the needle should be directed toward the target side. Slowly advance the catheter to the lateral gutter and direct it cephalad. Redirect the catheter as needed and once the target level has been reached, turn the tip of the catheter toward the foramen (Fig 25A). Inject 0.5 to 1 mL of contrast to visualize the target nerve root. Make sure there is runoff of contrast out of the foramen (Fig 25B). Slowly instill 150 U of Hylenex dissolved in 5 mL of preservative-free normal saline. Follow this with 1 to 2 mL of additional contrast and observe for "opening up" of the "scarred in" nerve root. Give a 2 mL test dose of a 6 mL solution of LA/S. Our combination is 5 mL of 0.2% ropivicaine and 4 mg of dexamethasone. If after 5 minutes there is no evidence of intrathecal or intravascular spread, inject the remaining 4 mL. Remove the needle, and secure and dress the catheter as previously described. Once 20 minutes have passed since the last dose of LA/S solution and there is no evidence of a subarachnoid or subdural block, start an infusion of 5 mL of hypertonic saline over 30

Fig. 24. Flexion rotation, left to right regardless patient position. The neural foramen

release with PVCS.

enlarges on flexion rotation and gets smaller with extension. The inferior pars slides forward over the superior pars to enlarge the foramen. This allows lateral run off and pressure

As with the caudal epidurogram, look for filling defects. It is extremely important to visualize spread of the contrast in the cephalad and caudal directions. Loculation of contrast in a small area must be avoided as this can significantly increase the pressure in the epidural space and can compromise the already tenuous arterial blood supply to the spinal cord. Place a bend on the catheter as previously described for the caudal approach and insert it through the needle (Fig 23E). The opening of the needle should be directed toward the target side. Slowly advance the catheter to the lateral gutter and direct it cephalad. Redirect the catheter as needed and once the target level has been reached, turn the tip of the catheter toward the foramen (Fig 25A). Inject 0.5 to 1 mL of contrast to visualize the target nerve root. Make sure there is runoff of contrast out of the foramen (Fig 25B). Slowly instill 150 U of Hylenex dissolved in 5 mL of preservative-free normal saline. Follow this with 1 to 2 mL of additional contrast and observe for "opening up" of the "scarred in" nerve root. Give a 2 mL test dose of a 6 mL solution of LA/S. Our combination is 5 mL of 0.2% ropivicaine and 4 mg of dexamethasone. If after 5 minutes there is no evidence of intrathecal or intravascular spread, inject the remaining 4 mL. Remove the needle, and secure and dress the catheter as previously described. Once 20 minutes have passed since the last dose of LA/S solution and there is no evidence of a subarachnoid or subdural block, start an infusion of 5 mL of hypertonic saline over 30 minutes. At the end of the infusion, flush the catheter with 1 to 2 mL of preservative-free normal saline and cap the catheter.

Fig. 25. A & B. **A** Cervical left ventral lateral catheter to the upper level of fusion C5-7. **B** Cervical-left ventral lateral catheter threaded to above level of fusion of C4. The dye injection spreads cephalad and lateral.

Epidural Lysis of Adhesions and Percutaneous Neuroplasty 361

localization.35 The TunL Kath and the TunL-XL catheter can be used as stimulating catheters

Fig. 26. **A-F Neural flossing exercises. A,** Standing erect, firmly grasp a stable surface (e.g., a door frame) with outstretched arm. Press elbow and shoulder forward. **B,** Next, slowly tilt head in opposite direction from outstretched arm to achieve gentle tension. **C,** Finally, rotate chin toward opposite shoulder as is comfortable. Hold this final position for approximately 20 to 30 seconds. **D,** Lay down supine on an exercise mat without a pillow. Slowly bring both knees close to the chest with bent legs and hold this position for 20 seconds. Release and assume a neutral position. **E,** Again in supine position, raise both legs to 90 degrees, with knees straight while laying flat on a firm surface. Hold for 20 seconds. Assume a neutral position and rest briefly. **F,** Bring both legs to a 90-degree angle while lying supine. Slowly spread legs in a V shape, as much as is comfortable, and hold for

After entering the epidural space, advance the catheter into the ventrolateral epidural space past the suspected target level. Make sure the tip of the catheter is pointing laterally toward the foramina, just below the pedicle. Pull the catheter stylet back approximately 1 cm. Using alligator clips, attach the cathode to the stylet and ground the anode on the needle or ground pad or a 22-gauge needle inserted into the skin. Apply electrical stimulation with a stimulator box with a rate of 50 pulses per second and a pulse width of 450 milliseconds, dialing up the amplitude until a paresthesia is perceived in small increments, usually less than 2 or 3 volts. Inquire of the patient as to whether or not the paresthesia is felt in the area of the patient's recognized greatest pain. This process is repeated at each successive level until the most painful nerve root is identified. Once

to identify the nerve root(s).

20 seconds.**Epidural Mapping** 

The second and third infusions are performed on the next day with 6 mL of 0.2% ropivacaine without spread and 5 mL of hypertonic saline using the same technique and precautions described for the first infusion. The catheter is removed and prophylactic antibiotics are prescribed. Clinic follow-up is 30 days.

#### **15. Thoracic lysis of adhesions**

The technique for entry into the thoracic epidural space for adhesiolysis is identical to that for the cervical region. Always remember the 3-D technique. Make sure to get a true lateral when checking the depth of the needle. This can be obtained by superimposing the rib shadows on one another. The target is still the ventrolateral epidural space with the tip of the catheter in the foramen of the desired level. The major difference for thoracic lysis compared to the caudal and cervical techniques is the volumes of the various injectates. Volumes of 8 mL are used for the contrast, Hylenex, LA/S, and hypertonic saline. **(**Table 1**)**  lists typical infusion volumes for epidural adhesiolysis.


Table 1. Typical Infusion Volumes for Epidural Adhesiolysis

#### **16. Neural flossing**

The protocol for epidural adhesiolysis has been aided by neural flossing exercises that were designed to mobilize nerve roots by "sliding" them in and out of the foramen (Fig 26). This breaks up weakened scar tissue from the procedure and prevents further scar tissue deposition. If these exercises are done effectively three to four times per day for a few months after the procedure, the formation of scar tissue will be severely restricted.

In patients with multilevel radiculopathy and complex pain, it can be difficult to determine from where the majority of the pain is emanating. We have been using a technique that we have termed *mapping* to locate the most painful nerve root with stimulation and then carry out the adhesiolysis at that level. There are several references in the literature regarding the use of stimulation to confirm epidural placement of a catheter and for nerve root

The second and third infusions are performed on the next day with 6 mL of 0.2% ropivacaine without spread and 5 mL of hypertonic saline using the same technique and precautions described for the first infusion. The catheter is removed and prophylactic

The technique for entry into the thoracic epidural space for adhesiolysis is identical to that for the cervical region. Always remember the 3-D technique. Make sure to get a true lateral when checking the depth of the needle. This can be obtained by superimposing the rib shadows on one another. The target is still the ventrolateral epidural space with the tip of the catheter in the foramen of the desired level. The major difference for thoracic lysis compared to the caudal and cervical techniques is the volumes of the various injectates. Volumes of 8 mL are used for the contrast, Hylenex, LA/S, and hypertonic saline. **(**Table 1**)** 

> Hyaluronidase and Normal Saline

Caudal 10 mL 10 mL 10 mL 10 mL

Thoracic 8 mL 8 mL 8 mL 8 mL

Cervical 5 mL 6 mL 6 mL 5 mL

months after the procedure, the formation of scar tissue will be severely restricted.

The protocol for epidural adhesiolysis has been aided by neural flossing exercises that were designed to mobilize nerve roots by "sliding" them in and out of the foramen (Fig 26). This breaks up weakened scar tissue from the procedure and prevents further scar tissue deposition. If these exercises are done effectively three to four times per day for a few

In patients with multilevel radiculopathy and complex pain, it can be difficult to determine from where the majority of the pain is emanating. We have been using a technique that we have termed *mapping* to locate the most painful nerve root with stimulation and then carry out the adhesiolysis at that level. There are several references in the literature regarding the use of stimulation to confirm epidural placement of a catheter and for nerve root

5 mL in each catheter

Local Anesthetic and Steroid

5 mL in each catheter

10% Hypertonic Saline Infusion

8 mL in caudal catheter and 4 mL in transforaminal catheter

antibiotics are prescribed. Clinic follow-up is 30 days.

lists typical infusion volumes for epidural adhesiolysis.

Contrast

5 mL in each catheter

Table 1. Typical Infusion Volumes for Epidural Adhesiolysis

Caudal and transforaminal

**16. Neural flossing** 

**15. Thoracic lysis of adhesions** 

localization.35 The TunL Kath and the TunL-XL catheter can be used as stimulating catheters to identify the nerve root(s).

Fig. 26. **A-F Neural flossing exercises. A,** Standing erect, firmly grasp a stable surface (e.g., a door frame) with outstretched arm. Press elbow and shoulder forward. **B,** Next, slowly tilt head in opposite direction from outstretched arm to achieve gentle tension. **C,** Finally, rotate chin toward opposite shoulder as is comfortable. Hold this final position for approximately 20 to 30 seconds. **D,** Lay down supine on an exercise mat without a pillow. Slowly bring both knees close to the chest with bent legs and hold this position for 20 seconds. Release and assume a neutral position. **E,** Again in supine position, raise both legs to 90 degrees, with knees straight while laying flat on a firm surface. Hold for 20 seconds. Assume a neutral position and rest briefly. **F,** Bring both legs to a 90-degree angle while lying supine. Slowly spread legs in a V shape, as much as is comfortable, and hold for 20 seconds.**Epidural Mapping** 

After entering the epidural space, advance the catheter into the ventrolateral epidural space past the suspected target level. Make sure the tip of the catheter is pointing laterally toward the foramina, just below the pedicle. Pull the catheter stylet back approximately 1 cm. Using alligator clips, attach the cathode to the stylet and ground the anode on the needle or ground pad or a 22-gauge needle inserted into the skin. Apply electrical stimulation with a stimulator box with a rate of 50 pulses per second and a pulse width of 450 milliseconds, dialing up the amplitude until a paresthesia is perceived in small increments, usually less than 2 or 3 volts. Inquire of the patient as to whether or not the paresthesia is felt in the area of the patient's recognized greatest pain. This process is repeated at each successive level until the most painful nerve root is identified. Once

Epidural Lysis of Adhesions and Percutaneous Neuroplasty 363

Fig. 28. A 22-gauge spinal needle and extension set with syringe placed in the subdural space and 12 mL fluid aspirated. The patient reported immediate reversal of bilateral leg

Initially in the early 1980s the protocol was designed to direct site-specific medication onto the dorsal root ganglion; however, after performing a number of the procedures, it was found that the dorsal root ganglion was exceptionally hard to reach secondary to developing scar tissue or adhesions. In the early days, our understanding was coming from the use of local anesthetics for surgery giving a 2- to 4-hour block for the surgeon to operate. It was gratifying to see chronic pain patients get months and years of pain relief following the placement of the new steerable x-ray visible catheter. The early report in 1985 by Racz et al36 described the use of phenol at the dorsal root ganglion followed by an observational listing of outcomes that were clearly not as good as the latest studies on failed back surgery and spinal stenosis showing 75% to 80% improvement at 12 months' follow-up by Manchikanti.34 Initially we were pleased to see some patients getting 3 to 4 months of relief and report seeing recovery of footdrops. This philosophy still proves to be true even in studies in 2008 by Sakai et al 37 in which they found that adhesiolysis with catheter-directed steroid and local anesthetic injection during epiduroscopy alleviated pain and reduced sensory nerve dysfunction in patients with chronic sciatica. The evolution of these findings has changed the process into what it is today.38 Racz and Holubec first reported on epidural adhesiolysis in 1989.39 There were slight variations in the protocol compared to today's protocol, namely the dose of local anesthetic and the fact that hyaluronidase was not used. Catheter placement was lesion-specific (i.e., the tip of the catheter was placed in the foramen corresponding to the vertebral level and side of the suspected adhesions). The retrospective

pain. Note the dye in the extension tubing and syringe at the 7-o'clock position.

**18. Outcomes** 

identified, the adhesiolysis is carried out at that level. The mapping procedure is also useful to identify the optimal site of surgery either before the first surgery or when surgery has failed one or more times.

#### **17. Complications**

As with any invasive procedure, complications are possible. These include bleeding, infection, headache, damage to nerves or blood vessels, catheter shearing, bowel/bladder dysfunction, paralysis, spinal cord compression from loculation of the injected fluids or hematoma, subdural or subarachnoid injection of local anesthetic or hypertonic saline, and reactions to the medications used. We also include on the consent form that the patient may experience an increase in pain or no pain relief at all. Although the potential list of complications is long, the frequency of complications is very rare. However, there is clearly a learning curve, and recent studies reflect this by the significantly improved long-term outcome and the very rare publications of complications and medicolegal consequences when one considers the ever-increasing clinical experience.

Subdural spread is a complication that should always be watched for when injecting local anesthetic. During the caudal adhesiolysis, particularly if the catheter is advanced along the midline, subdural catheter placement is a risk (Figs 27 and 28). Identification of the subdural motor block should occur within 16 to 18 minutes. Catheters used for adhesiolysis should never be directed midline in the epidural space.

Fig. 27. Midline catheter placement enters subdural space. There is also some epidural dye spread. But the patient starts to complain of bilateral leg pain.

Fig. 28. A 22-gauge spinal needle and extension set with syringe placed in the subdural space and 12 mL fluid aspirated. The patient reported immediate reversal of bilateral leg pain. Note the dye in the extension tubing and syringe at the 7-o'clock position.

#### **18. Outcomes**

362 Pain Management – Current Issues and Opinions

identified, the adhesiolysis is carried out at that level. The mapping procedure is also useful to identify the optimal site of surgery either before the first surgery or when

As with any invasive procedure, complications are possible. These include bleeding, infection, headache, damage to nerves or blood vessels, catheter shearing, bowel/bladder dysfunction, paralysis, spinal cord compression from loculation of the injected fluids or hematoma, subdural or subarachnoid injection of local anesthetic or hypertonic saline, and reactions to the medications used. We also include on the consent form that the patient may experience an increase in pain or no pain relief at all. Although the potential list of complications is long, the frequency of complications is very rare. However, there is clearly a learning curve, and recent studies reflect this by the significantly improved long-term outcome and the very rare publications of complications and medicolegal consequences

Subdural spread is a complication that should always be watched for when injecting local anesthetic. During the caudal adhesiolysis, particularly if the catheter is advanced along the midline, subdural catheter placement is a risk (Figs 27 and 28). Identification of the subdural motor block should occur within 16 to 18 minutes. Catheters used for adhesiolysis should

Fig. 27. Midline catheter placement enters subdural space. There is also some epidural dye

spread. But the patient starts to complain of bilateral leg pain.

surgery has failed one or more times.

when one considers the ever-increasing clinical experience.

never be directed midline in the epidural space.

**17. Complications** 

Initially in the early 1980s the protocol was designed to direct site-specific medication onto the dorsal root ganglion; however, after performing a number of the procedures, it was found that the dorsal root ganglion was exceptionally hard to reach secondary to developing scar tissue or adhesions. In the early days, our understanding was coming from the use of local anesthetics for surgery giving a 2- to 4-hour block for the surgeon to operate. It was gratifying to see chronic pain patients get months and years of pain relief following the placement of the new steerable x-ray visible catheter. The early report in 1985 by Racz et al36 described the use of phenol at the dorsal root ganglion followed by an observational listing of outcomes that were clearly not as good as the latest studies on failed back surgery and spinal stenosis showing 75% to 80% improvement at 12 months' follow-up by Manchikanti.34 Initially we were pleased to see some patients getting 3 to 4 months of relief and report seeing recovery of footdrops. This philosophy still proves to be true even in studies in 2008 by Sakai et al 37 in which they found that adhesiolysis with catheter-directed steroid and local anesthetic injection during epiduroscopy alleviated pain and reduced sensory nerve dysfunction in patients with chronic sciatica. The evolution of these findings has changed the process into what it is today.38 Racz and Holubec first reported on epidural adhesiolysis in 1989.39 There were slight variations in the protocol compared to today's protocol, namely the dose of local anesthetic and the fact that hyaluronidase was not used. Catheter placement was lesion-specific (i.e., the tip of the catheter was placed in the foramen corresponding to the vertebral level and side of the suspected adhesions). The retrospective

Epidural Lysis of Adhesions and Percutaneous Neuroplasty 365

decreasing to 22% and 11% at 3 months, 8% and 7% at 6 months, and 2% and 3% at 1 year. Of significant interest is that the percentage of patients receiving greater than 50% pain relief after four procedures increased to 79% and 90% at 1 month, 50% and 36% at 3 months, 29% and 19% at 6 months, and 7% and 8% at 1 year for groups 1 and 2, respectively. Short-term

Manchikanti, in 1999, evaluated two groups of randomly pulled, 150 patients for a 2-day reinjection procedure, and a second 150 patients for a one-day procedure out of a pool of 536 patients. It was concluded that repeat use of the one-day procedure is also cost effective when evaluated on a 12-month follow-up. The cost effectiveness indicated the lysis

In a randomized, prospective study, Manchikanti et al46 evaluated a 1-day epidural adhesiolysis procedure against a control group of patients who received conservative therapy. Results showed that cumulative relief, defined as relief greater than 50% with one to three injections, in the treatment group was 97% at 3 months, 93% at 6 months, and 47% at 1 year. The study also showed that overall health status improved significantly in the adhesiolysis group. Conservative therapy consisted of physical therapy and

In 2004 Manchikanti et al47 published their results of a randomized, double-blind, controlled study on the effectiveness of 1-day lumbar adhesiolysis and hypertonic saline neurolysis in treatment of chronic low back pain. Seventy-five patients whose pain was unresponsive to conservative modalities were randomized into one of three treatment groups. Group 1 (control group) underwent catheterization where the catheter was in the sacral canal without adhesiolysis, followed by injection of local anesthetic, normal saline, and steroid. Group 2 consisted of catheterization with site-specific catheter placement being ventral-lateral for adhesiolysis, followed by injection of local anesthetic, normal saline, and steroid. Group 3 consisted of site-specific catheter placement for adhesiolysis, followed by injection of local anesthetic, hypertonic saline, and steroid. Patients were allowed to have additional injections based on the response, either after unblinding or without unblinding after 3 months. Patients without unblinding were offered either the assigned treatment or another treatment based on their response. If the patients in group 1 or 2 received adhesiolysis and injection and injection of hypertonic saline, they were considered withdrawn, and no subsequent data were collected. Outcomes were assessed at 3, 6, and 12 months using visual analog scale pain scores, Oswestry Disability Index, opioid intake, range-of-motion measurement, and P-3. Significant pain relief was defined as average relief of 50% or greater. Seventy-two percent of patients in group 3, 60% of patients in group 2, and 0% of patients in group 1 showed significant pain relief at 12 months. The average number of treatments for 1 year was 2.76 in group 2 and 2.16 in group 3. Duration of significant relief with the first procedure was 2.8 + 1.49 months and 3.8 + 3.37 months in groups 2 and 3, respectively. Significant pain relief (>50%) was also associated with improvement in Oswestry Disability Index, range of motion, and

Manchikanti et al48,49, furthered this research using comparisons of percutaneous adhesiolysis versus fluoroscopically guided caudal epidural steroid injections. The first study involved a population of patients with chronic low back pain and known spinal stenosis. The results showed a 76% reduction in pain relief at 1 year with epidural adhesiolysis compared to 4% in the control group. The second study performed in a population of patients with post–lumbar surgery syndrome showed a reduction in pain and

relief of pain was demonstrated, but long-term relief was not.

medications.

psychologic status.

procedure to be superior to surgery or the rehabilitation activity program.45

analysis conducted 6 to 12 months after the procedure reported initial pain relief in 72.2% of patients ( *N* = 72) at time of discharge. Relief was sustained in 37.5% and 30.5% of patients at 1 and 3 months, respectively. Forty-three percent decreased their frequency and dosage of medication use and 16.7% discontinued their medications altogether. In total, 30.6% of patients returned to work or returned to daily functions. In April 1990, at a presentation of the 7th IASP World Congress on Pain in Adelaide, Austraila, Arthur et al40 reported on epidural adhesiolysis in 100 patients, 50 of whom received hyaluronidase as part of the procedure. In the hyaluronidase group, 81.6% of the participants had initial pain relief, with 12.3% having persistent relief; 68% of the no hyaluronidase group had relief of pain, with 14% having persistent relief at the end of the 3-year follow-up period from which the study sample was randomly selected.

In 1994 Stolker et al41 added hyaluronidase to the procedure, but omitted the hypertonic saline. In a study of 28 patients, they reported greater than 50% pain reduction in 64% of patients at 1 year. They stressed the importance of the patient selection and believed that the effectiveness of adhesiolysis was based on the effect of the hyaluronidase on the adhesions and the action of the local anesthetic and steroids on the sinuvertebral nerve.

Devulder et al42 published a study of 34 patients with failed back surgery syndrome in whom epidural fibrosis was suspected or proved with MRI.42 An epidural catheter was inserted via the sacral hiatus to a distance of 10 cm into the caudal canal. Injections of contrast dye, local anesthetic, corticosteroid, and hypertonic saline (10%) were carried out daily for 3 days. No hyaluronidase was used. Filling defects were noted in 30 of 34 patients, but significant pain relief was noted in only 7 patients at 1 month, 2 patients at 3 months, and no patients at 12 months. They concluded that epidurography may confirm epidural filling defects for contrast dye in patients with filling defects, but a better contrast dye spread, assuming scar lysis does not guarantee sustained pain relief. This study was criticized for lack of lesion-specific catheter placement resulting in nonspecific drug delivery.43 The catheter was never directed to the ventral lateral epidural space where the dorsal root ganglion is located and the lateral recess scarring occurs.

Heavner et al44 performed a prospective randomized trial of lesion-specific epidural adhesiolysis on 59 patients with chronic intractable low back pain. The patients were assigned to one of four epidural adhesiolysis treatment groups: (1) hypertonic (10%) saline plus hyaluronidase, (2) hypertonic saline, (3) isotonic (0.9%) saline, or (4) isotonic saline plus hyaluronidase. All treatment groups received corticosteroid and local anesthetic. Overall, across all four treatment groups, 83% of patients had significant pain relief at 1 month compared to 49% at 3 months, 43% at 6 months, and 49% at 12 months. The hyaluronidase and the hypertonic saline study group had a much lower incidence of additional need for pain procedures than the placebo groups, showing that site-specific catheter placement is important. Active substances and preservative free normal saline were blinded for the placebo effect.

Manchikanti et al45 performed a retrospective randomized evaluation of a modified Racz adhesiolysis protocol in 232 patients with low back pain. The study involved lesion specific catheter placement, but the usual 3-day procedure was reduced to a 2-day (group 1) or a 1 day (group 2) procedure. Group 1 had 103 patients and group 2 had 129 patients. Other changes included changing the local anesthetic from bupivacaine to lidocaine, substituting methylprednisolone acetate or betamethasone acetate and phosphate for triamcinolone diacetate, and reduction of the volume of injectate. Of the patients in groups 1 and 2, 62% and 58% had greater than 50% pain relief at 1 month, respectively, with these percentages

analysis conducted 6 to 12 months after the procedure reported initial pain relief in 72.2% of patients ( *N* = 72) at time of discharge. Relief was sustained in 37.5% and 30.5% of patients at 1 and 3 months, respectively. Forty-three percent decreased their frequency and dosage of medication use and 16.7% discontinued their medications altogether. In total, 30.6% of patients returned to work or returned to daily functions. In April 1990, at a presentation of the 7th IASP World Congress on Pain in Adelaide, Austraila, Arthur et al40 reported on epidural adhesiolysis in 100 patients, 50 of whom received hyaluronidase as part of the procedure. In the hyaluronidase group, 81.6% of the participants had initial pain relief, with 12.3% having persistent relief; 68% of the no hyaluronidase group had relief of pain, with 14% having persistent relief at the end of the 3-year follow-up period from which the study

In 1994 Stolker et al41 added hyaluronidase to the procedure, but omitted the hypertonic saline. In a study of 28 patients, they reported greater than 50% pain reduction in 64% of patients at 1 year. They stressed the importance of the patient selection and believed that the effectiveness of adhesiolysis was based on the effect of the hyaluronidase on the adhesions

Devulder et al42 published a study of 34 patients with failed back surgery syndrome in whom epidural fibrosis was suspected or proved with MRI.42 An epidural catheter was inserted via the sacral hiatus to a distance of 10 cm into the caudal canal. Injections of contrast dye, local anesthetic, corticosteroid, and hypertonic saline (10%) were carried out daily for 3 days. No hyaluronidase was used. Filling defects were noted in 30 of 34 patients, but significant pain relief was noted in only 7 patients at 1 month, 2 patients at 3 months, and no patients at 12 months. They concluded that epidurography may confirm epidural filling defects for contrast dye in patients with filling defects, but a better contrast dye spread, assuming scar lysis does not guarantee sustained pain relief. This study was criticized for lack of lesion-specific catheter placement resulting in nonspecific drug delivery.43 The catheter was never directed to the ventral lateral epidural space where the

Heavner et al44 performed a prospective randomized trial of lesion-specific epidural adhesiolysis on 59 patients with chronic intractable low back pain. The patients were assigned to one of four epidural adhesiolysis treatment groups: (1) hypertonic (10%) saline plus hyaluronidase, (2) hypertonic saline, (3) isotonic (0.9%) saline, or (4) isotonic saline plus hyaluronidase. All treatment groups received corticosteroid and local anesthetic. Overall, across all four treatment groups, 83% of patients had significant pain relief at 1 month compared to 49% at 3 months, 43% at 6 months, and 49% at 12 months. The hyaluronidase and the hypertonic saline study group had a much lower incidence of additional need for pain procedures than the placebo groups, showing that site-specific catheter placement is important. Active substances and preservative free normal saline were blinded for the

Manchikanti et al45 performed a retrospective randomized evaluation of a modified Racz adhesiolysis protocol in 232 patients with low back pain. The study involved lesion specific catheter placement, but the usual 3-day procedure was reduced to a 2-day (group 1) or a 1 day (group 2) procedure. Group 1 had 103 patients and group 2 had 129 patients. Other changes included changing the local anesthetic from bupivacaine to lidocaine, substituting methylprednisolone acetate or betamethasone acetate and phosphate for triamcinolone diacetate, and reduction of the volume of injectate. Of the patients in groups 1 and 2, 62% and 58% had greater than 50% pain relief at 1 month, respectively, with these percentages

and the action of the local anesthetic and steroids on the sinuvertebral nerve.

dorsal root ganglion is located and the lateral recess scarring occurs.

sample was randomly selected.

placebo effect.

decreasing to 22% and 11% at 3 months, 8% and 7% at 6 months, and 2% and 3% at 1 year. Of significant interest is that the percentage of patients receiving greater than 50% pain relief after four procedures increased to 79% and 90% at 1 month, 50% and 36% at 3 months, 29% and 19% at 6 months, and 7% and 8% at 1 year for groups 1 and 2, respectively. Short-term relief of pain was demonstrated, but long-term relief was not.

Manchikanti, in 1999, evaluated two groups of randomly pulled, 150 patients for a 2-day reinjection procedure, and a second 150 patients for a one-day procedure out of a pool of 536 patients. It was concluded that repeat use of the one-day procedure is also cost effective when evaluated on a 12-month follow-up. The cost effectiveness indicated the lysis procedure to be superior to surgery or the rehabilitation activity program.45

In a randomized, prospective study, Manchikanti et al46 evaluated a 1-day epidural adhesiolysis procedure against a control group of patients who received conservative therapy. Results showed that cumulative relief, defined as relief greater than 50% with one to three injections, in the treatment group was 97% at 3 months, 93% at 6 months, and 47% at 1 year. The study also showed that overall health status improved significantly in the adhesiolysis group. Conservative therapy consisted of physical therapy and medications.

In 2004 Manchikanti et al47 published their results of a randomized, double-blind, controlled study on the effectiveness of 1-day lumbar adhesiolysis and hypertonic saline neurolysis in treatment of chronic low back pain. Seventy-five patients whose pain was unresponsive to conservative modalities were randomized into one of three treatment groups. Group 1 (control group) underwent catheterization where the catheter was in the sacral canal without adhesiolysis, followed by injection of local anesthetic, normal saline, and steroid. Group 2 consisted of catheterization with site-specific catheter placement being ventral-lateral for adhesiolysis, followed by injection of local anesthetic, normal saline, and steroid. Group 3 consisted of site-specific catheter placement for adhesiolysis, followed by injection of local anesthetic, hypertonic saline, and steroid. Patients were allowed to have additional injections based on the response, either after unblinding or without unblinding after 3 months. Patients without unblinding were offered either the assigned treatment or another treatment based on their response. If the patients in group 1 or 2 received adhesiolysis and injection and injection of hypertonic saline, they were considered withdrawn, and no subsequent data were collected. Outcomes were assessed at 3, 6, and 12 months using visual analog scale pain scores, Oswestry Disability Index, opioid intake, range-of-motion measurement, and P-3. Significant pain relief was defined as average relief of 50% or greater. Seventy-two percent of patients in group 3, 60% of patients in group 2, and 0% of patients in group 1 showed significant pain relief at 12 months. The average number of treatments for 1 year was 2.76 in group 2 and 2.16 in group 3. Duration of significant relief with the first procedure was 2.8 + 1.49 months and 3.8 + 3.37 months in groups 2 and 3, respectively. Significant pain relief (>50%) was also associated with improvement in Oswestry Disability Index, range of motion, and psychologic status.

Manchikanti et al48,49, furthered this research using comparisons of percutaneous adhesiolysis versus fluoroscopically guided caudal epidural steroid injections. The first study involved a population of patients with chronic low back pain and known spinal stenosis. The results showed a 76% reduction in pain relief at 1 year with epidural adhesiolysis compared to 4% in the control group. The second study performed in a population of patients with post–lumbar surgery syndrome showed a reduction in pain and

Epidural Lysis of Adhesions and Percutaneous Neuroplasty 367

Facet pain is commonly associated with the postlysis period or after provocative testing a month or so later if two-facet diagnostic blocks show efficacy. In addition to epidural lysis of adhesions, the combined use of radiofrequency facet denervation gives us the best long-

Epidural adhesiolysis has been accepted as a treatment for post laminectomy syndrome, failed back syndrome, and cervical and thoracic radicular syndromes. Additional studies are underway to further refine the technique and indications. The combined use of long term patient education for neural flossing exercises and the inclusion of the facet delayed treatment in the algorithm further improves patient outcome. The identification of back pain provocation by saline injection and the successful use of percutaneous neuroplasty in the

Racz GB, Day MR, Heavner JE, Scott J. *Lysis of Epidural Adhesions.* In: Waldman S, ed. *Pain* 

Racz GB, Day MR, Heavner JE, Smith JP. The Racz Procedure: Lysis of Epidural Adhesions (Percutaneous Neuroplasty). In: Deer T, ed. The AAPM Text of Pain Medicine. Springer; 2011. The authors would also like to thank Marzieh N. Brown and Paula Brashear for their

[1] Lawrence R., Helmick C., Arnett F., et al: Estimates of the prevalence of arthritis and

[2] Straus B.: Chronic pain of spinal origin: the costs of intervention. *Spine* 2002; 27(22):2614-

[3] National Center for Health Statistics : *National hospital discharge survey*, Washington, DC,

[5] Kuslich S., Ulstrom C., Michael C.: The tissue origin of low back pain and sciatica. *Orthop* 

[6] Racz G., Noe C., Heavner J.: Selective spinal injections for lower back pain. *Curr Rev Pain*

[7] Anderson S.: A rationale for the treatment algorithm of failed back surgery syndrome.

[8] Pawl R.: Arachnoiditis and epidural fibrosis: the relationship to chronic pain. *Curr Rev* 

[9] Cervellini P., Curri D., Volpin L., et al: Computed tomography of epidural fibrosis after

[10] Manchikanti L., Staats P., Singh V.: Evidence-based practice guidelines for

discectomy: a comparison between symptomatic and asymptomatic patients.

interventional techniques in the management of chronic spinal pain. *Pain Phys* 2003;

selected musculoskeletal disorders in the United States. *Arthritis Rheum* 1998;

US Department of Health and Human Services, Centers for Disease Control and

treatment represents hopeful promise for a cost effective treatment of back pain.

term outcome.

**20. Acknowledgements** 

**21. References** 

*Management, 2nd Edition*. Elsevier; 2011: 1258-1272.

Prevention, 1990. Report no. PB92-500818

[4] Van Zundert J.: *Personal communication*. 2005.

*Clin North Am* 1991; 22:181-187.

*Curr Rev Pain* 2000; 4:396-406.

*Neurosurgery* 1988; 23(6):710-713.

assistance in the editing of this chapter.

41(5):778-799.

1999; 3:333-341.

*Pain* 1998; 2:93-99.

6:3-81.

2619.

improvement in functional status in 73% of the epidural adhesiolysis group compared to 12% in the control group.

In 2006 a study by Veihelmann et al50 evaluated patients with a history of chronic low back pain and sciatica. Inclusion criteria were radicular pain with a corresponding nerve root compressing substrate found on MRI or CT. All patients were randomized to receive physiotherapy, analgesics, or lysis of adhesions. The lysis group had statistically significantly better outcome than the physical therapy treatment group.

Two other prospective evaluations by Chopra et al and Gerdesmeyer et al51, 52 evaluated patients with monosegmental radiculopathy of the lumbar spine. All the patients suffered from chronic disk herniations or failed back syndrome. All these randomized trials showed positive short-term and long-term relief. Two prospective evaluations also showed positive short- and long-term relief.51,52

#### **19. Conclusion**

Epidural adhesiolysis has evolved over the years as an important treatment option for patients with intractable cervical, thoracic, and low back and leg pain. Studies show that patients are able to experience significant pain relief and restoration of function. Manchikanti's studies show that the amount and duration of relief can be achieved by repeat procedures. Recent prospective randomized double-blind studies on failed back surgery and spinal stenosis show 75% and 80% improvement in visual analog scale scores and functional improvements at 12 months' follow-up. There have been no negative studies to date where the lysis target was the ventral-lateral epidural space. The one negative study used a 10 cm sacral mid-canal catheter placement which was non-target specific.43 This negative study was subsequently used as the placebo group in a study performed by Manchikanti.47 Manchikanti's study consisted of 3 treatment groups: placebo (sacral mid-canal catheter placement), target specific ventral-lateral epidural without hypertonic saline and target specific ventral-lateral epidural with hypertonic saline . The later two treatment groups had positive outcomes with the hypertonic saline group superior; whereas, the placebo group did not. 47 The evolution in the recognition of the site-specific importance of the catheter and medication delivery together with the fact that physicians need to acquire the skills to be able to carry out the procedure led to the improved outcomes seen in recent prospective randomized studies.

The management of failed back surgery syndrome and post laminectomy syndrome will likely continue to be controversial among the multitude of practitioners who treat these patients. However, in experienced hands, it is established as a reasonable option for many patients.

Percutaneous neuroplasty via a transforaminal approach evolved from the caudal approach. Lysis of adhesions via the caudal approach involves introducing a catheter through the sacral hiatus and advancing it to the affected nerve root in the ventral-lateral epidural space. On the other hand, transforaminal percutaneous neuroplasty achieves a midline catheter placement in the epidural space that is able to target the two most heavily innervated structures in the spine—the posterior annulus fibrosus and the posterior longitudinal ligament.5 Apart from a surgical approach, the ventral epidural structures have been otherwise inaccessible.

Endoscopy offers direct visualization of the affected nerve roots in addition to mechanical adhesiolysis, and may become more mainstream as the technique is refined.

Facet pain is commonly associated with the postlysis period or after provocative testing a month or so later if two-facet diagnostic blocks show efficacy. In addition to epidural lysis of adhesions, the combined use of radiofrequency facet denervation gives us the best longterm outcome.

Epidural adhesiolysis has been accepted as a treatment for post laminectomy syndrome, failed back syndrome, and cervical and thoracic radicular syndromes. Additional studies are underway to further refine the technique and indications. The combined use of long term patient education for neural flossing exercises and the inclusion of the facet delayed treatment in the algorithm further improves patient outcome. The identification of back pain provocation by saline injection and the successful use of percutaneous neuroplasty in the treatment represents hopeful promise for a cost effective treatment of back pain.

#### **20. Acknowledgements**

366 Pain Management – Current Issues and Opinions

improvement in functional status in 73% of the epidural adhesiolysis group compared to

In 2006 a study by Veihelmann et al50 evaluated patients with a history of chronic low back pain and sciatica. Inclusion criteria were radicular pain with a corresponding nerve root compressing substrate found on MRI or CT. All patients were randomized to receive physiotherapy, analgesics, or lysis of adhesions. The lysis group had statistically

Two other prospective evaluations by Chopra et al and Gerdesmeyer et al51, 52 evaluated patients with monosegmental radiculopathy of the lumbar spine. All the patients suffered from chronic disk herniations or failed back syndrome. All these randomized trials showed positive short-term and long-term relief. Two prospective evaluations also showed positive

Epidural adhesiolysis has evolved over the years as an important treatment option for patients with intractable cervical, thoracic, and low back and leg pain. Studies show that patients are able to experience significant pain relief and restoration of function. Manchikanti's studies show that the amount and duration of relief can be achieved by repeat procedures. Recent prospective randomized double-blind studies on failed back surgery and spinal stenosis show 75% and 80% improvement in visual analog scale scores and functional improvements at 12 months' follow-up. There have been no negative studies to date where the lysis target was the ventral-lateral epidural space. The one negative study used a 10 cm sacral mid-canal catheter placement which was non-target specific.43 This negative study was subsequently used as the placebo group in a study performed by Manchikanti.47 Manchikanti's study consisted of 3 treatment groups: placebo (sacral mid-canal catheter placement), target specific ventral-lateral epidural without hypertonic saline and target specific ventral-lateral epidural with hypertonic saline . The later two treatment groups had positive outcomes with the hypertonic saline group superior; whereas, the placebo group did not. 47 The evolution in the recognition of the site-specific importance of the catheter and medication delivery together with the fact that physicians need to acquire the skills to be able to carry out the procedure led to the improved outcomes seen in recent prospective

The management of failed back surgery syndrome and post laminectomy syndrome will likely continue to be controversial among the multitude of practitioners who treat these patients. However, in experienced hands, it is established as a reasonable option for many

Percutaneous neuroplasty via a transforaminal approach evolved from the caudal approach. Lysis of adhesions via the caudal approach involves introducing a catheter through the sacral hiatus and advancing it to the affected nerve root in the ventral-lateral epidural space. On the other hand, transforaminal percutaneous neuroplasty achieves a midline catheter placement in the epidural space that is able to target the two most heavily innervated structures in the spine—the posterior annulus fibrosus and the posterior longitudinal ligament.5 Apart from a surgical approach, the ventral epidural structures have been

Endoscopy offers direct visualization of the affected nerve roots in addition to mechanical

adhesiolysis, and may become more mainstream as the technique is refined.

significantly better outcome than the physical therapy treatment group.

12% in the control group.

short- and long-term relief.51,52

**19. Conclusion** 

randomized studies.

otherwise inaccessible.

patients.

Racz GB, Day MR, Heavner JE, Scott J. *Lysis of Epidural Adhesions.* In: Waldman S, ed. *Pain Management, 2nd Edition*. Elsevier; 2011: 1258-1272.

Racz GB, Day MR, Heavner JE, Smith JP. The Racz Procedure: Lysis of Epidural Adhesions (Percutaneous Neuroplasty). In: Deer T, ed. The AAPM Text of Pain Medicine. Springer; 2011.

The authors would also like to thank Marzieh N. Brown and Paula Brashear for their assistance in the editing of this chapter.

#### **21. References**


Epidural Lysis of Adhesions and Percutaneous Neuroplasty 369

[34] Racz G.B., Heavner J.E.: Cervical spinal canal loculation and secondary ischemic cord

[35] Larkin T., Carragee E., Cohen S.: A novel technique for delivery of epidural steroids and

[36] Racz G.B., Sabonghy M., Gintautas J., et al: Intractable pain therapy using a new type of

[37] Sakai T., Aoki H., Hojo M., et al: Adhesiolysis and targeted steroid/local anesthetic

dysfunction in patients with chronic sciatica. *J Anesth* 2008; 22(3):242-247. [38] Anderson S., Racz G., Heavner J.: Evolution of epidural lysis of adhesions. *Pain* 

[39] Racz G., Holubec J.: *Lysis of adhesions in the epidural space*. In: Raj P., ed. *Techniques of* 

[40] Arthur J., Racz G., Heinrich R., et al: *Epidural space: identification of filling defects and lysis* 

[41] Stolker R., Vervest A., Gerbrand J.: The management of chronic spinal pain by

[42] Devulder J., Bogaert L., Castille F., et al: Relevance of epidurography and epidural adhesiolysis in chonic failed back surgery patients. *Clin J Pain* 1995; 11:147-150. [43] Racz G., Heavner J.: In response to article by Drs. Devulder et al. *Clin J Pain* 1995;

[44] Heavner J., Racz G., Raj P.: Percutaneous epidural neuroplasty: prospective evaluation

[45] Manchikanti L., Pakanati R., Bakhit C., et al: Role of adhesiolysis and hypertonic saline

[46] Manchikanti L., Pampati V., Fellow B., et al: Role of one day epidural adhesiolysis in

[47] Manchikanti L., Rivera J., Pampati V., et al: One day lumbar adhesiolysis and

[48] Manchikanti L., Cash K., McManus C., et al: The preliminary results of a comparative

low back pain secondary to spinal stenosis. *Pain Phys* 2009; 12(6):E341-E354. [49] Manchikanti L., Singh V., Cash K., et al: A comparative effectiveness evaluation of

[50] Veihelmann A., Devens C., Trouiller H., et al: Epidural neuroplasty versus

of 0.9% saline versus 10% saline with or without hyaluronidase. *Reg Anesth Pain* 

neurolysis in management of low back pain: evaluation of modification of the Racz

management of chronic low back pain: a randomized clinical trial. *Pain Phys* 2001;

hypertonic saline neurolysis in treatment of chronic low back pain: a randomized,

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physiotherapy to relieve pain in patients with sciatica: a prospective randomized

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diagnosing the level of nerve root pathology. *J Spinal Disord Tech* 2003; 16(2):186-

injection during epiduroscopy alleviates pain and reduces sensory nerve

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[11] LaRocca H., Macnab I.: The laminectomy membrane: studies in its evolution,

[12] Cooper R., Freemont A., Hoyland J., et al: Herniated intervertebral disc–associated

[13] McCarron R., Wimpee M., Hudkins P., et al: The inflammatory effects of nucleus

[14] Parke W., Watanabe R.: Adhesions of the ventral lumbar dura: an adjunct source of

[15] Viesca C., Racz G., Day M.: Special techniques in pain management: lysis of adhesions.

[16] Songer M., Ghosh L., Spencer D.: Effects of sodium hyaluronate on peridural fibrosis

[17] Key J., Ford L.: Experimental intervertebral disc lesions. *J Bone Joint Surg Am* 1948;

[18] Olmarker K., Rydevik B.: Pathophysiology of sciatica. *Orthop Clin North Am* 1991;

[19] Ross J., Robertson J., Frederickson R., et al: Association between peridural scar and

[20] Gilbert K., Brismee J., Collins D., et al: Lumbosacral nerve roots displacements and

[21] Heavner JE, Chokhavatia S, Kizelshteyn G: Percutaneous evaluation of the epidural and subarachnoid space with a flexible fiberscope, *Reg Anesth* 1991;15:85. [22] Bosscher HA, Heavner JE: Incidence and severity of epidural fibrosis after back surgery:

[23] Hatten Jr H.: Lumbar epidurography with metrizamide. *Radiology* 1980; 137:129-136. [24] Stewart H., Quinnell R., Dann N.: Epidurography in the management of sciatica. *Br J* 

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[33] Racz G., Day M., Heavner J., et al: Hyaluronidase: a review of approved formulations,

[25] Devulder J., Bogaert L., Castille F., et al: Relevance of epidurography and epidural adhesiolysis in chronic failed back surgery patients. *Clin J Pain* 1995; 11:147-150. [26] Manchikanti L., Bakhit C., Pampati V.: Role of epidurography in caudal neuroplasty.

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periradicular fibrosis and vascular abnormalities occur without inflammatory cell

pulposus; a possible element in the pathogenesis of low back pain. *Spine* 1987;


**18** 

*Australia* 

Kathryn Nicholson Perry *University of Western Sydney,* 

**Chronic Pain in People with Physically Disabling Conditions: A Review of the Application of Biopsychosocial Models** 

There are a wide range of conditions which can result in physical disabilities, affecting more than a billion people or approximately 15% of the population worldwide (World Health Organisation, 2011). Disability is an umbrella term for the restrictions and impairments arising from the interaction between an individual with a health condition and the environment (World Health Organisation, 2011). The physical conditions from which disability arises are diverse and heterogeneous, but include both diseases, such as multiple sclerosis, as well as traumatic and non-traumatic injuries, including spinal cord injury and brain injuries. Research concerning the occurrence of chronic pain (defined as pain persisting beyond the period of healing, usually operationalized as three or six months) among people with physical disabilities, and the impact upon those individuals affected, is relatively limited compared to that focusing on primary pain conditions, such as low back pain. Within the available literature the focus is largely biomedical, with the majority of available research exploring biological factors and medical interventions. A great deal has been gained in the management of primary pain conditions through investigating psychological and social factors, and developing interventions such as cognitive behavioural pain management programs to target these factors. This chapter will describe the current understanding of the role of psychological and social factors in understanding the experience of chronic pain in the context of a physically disabling condition, and the use of interventions addressing these factors in this population.

**2. The nature of chronic pain in people with physically disabling conditions**  What is known about the nature of chronic pain among those with physically disabling conditions varies depending on the condition of interest. An examination of those publishing in the area suggests that often there are only a small number of groups involved in this research. Most of these research groups only work with one specific condition, with only a very small number working across a range of physically disabling conditions. As a result of these research silos, there are many inconsistencies in the approaches taken in investigating pain in the different conditions. Interpreting the findings of this body of work, particularly attempting to make comparisons across conditions, should therefore be done with caution keeping in mind some important caveats. First, there are variations across studies concerning the nature of the pain conditions which are the subject of investigation,

**1. Introduction** 


### **Chronic Pain in People with Physically Disabling Conditions: A Review of the Application of Biopsychosocial Models**

Kathryn Nicholson Perry *University of Western Sydney, Australia* 

#### **1. Introduction**

370 Pain Management – Current Issues and Opinions

[51] Gerdesmeyer L., Lampe R., Veihelmann A., et al: Chronic radiculopathy: use of

[52] Gerdesmeyer L., Rechl H., Wagenpfeil S., et al: Minimally invasive epidural neurolysis

*Schmerz* 2005; 19:285-295.

*Orhopade* 2003; 32:869-876.

minimally invasive percutaneous epidural neurolysis according to Racz. *Der* 

in chronic radiculopathy: a prospective controlled study to prove effectiveness. *Der* 

There are a wide range of conditions which can result in physical disabilities, affecting more than a billion people or approximately 15% of the population worldwide (World Health Organisation, 2011). Disability is an umbrella term for the restrictions and impairments arising from the interaction between an individual with a health condition and the environment (World Health Organisation, 2011). The physical conditions from which disability arises are diverse and heterogeneous, but include both diseases, such as multiple sclerosis, as well as traumatic and non-traumatic injuries, including spinal cord injury and brain injuries. Research concerning the occurrence of chronic pain (defined as pain persisting beyond the period of healing, usually operationalized as three or six months) among people with physical disabilities, and the impact upon those individuals affected, is relatively limited compared to that focusing on primary pain conditions, such as low back pain. Within the available literature the focus is largely biomedical, with the majority of available research exploring biological factors and medical interventions. A great deal has been gained in the management of primary pain conditions through investigating psychological and social factors, and developing interventions such as cognitive behavioural pain management programs to target these factors. This chapter will describe the current understanding of the role of psychological and social factors in understanding the experience of chronic pain in the context of a physically disabling condition, and the use of interventions addressing these factors in this population.

#### **2. The nature of chronic pain in people with physically disabling conditions**

What is known about the nature of chronic pain among those with physically disabling conditions varies depending on the condition of interest. An examination of those publishing in the area suggests that often there are only a small number of groups involved in this research. Most of these research groups only work with one specific condition, with only a very small number working across a range of physically disabling conditions. As a result of these research silos, there are many inconsistencies in the approaches taken in investigating pain in the different conditions. Interpreting the findings of this body of work, particularly attempting to make comparisons across conditions, should therefore be done with caution keeping in mind some important caveats. First, there are variations across studies concerning the nature of the pain conditions which are the subject of investigation,

Chronic Pain in People with Physically Disabling

**2.1.3 Amputation** 

Schley, et al., 2008).

**2.1.4 Cerebral palsy** 

Conditions: A Review of the Application of Biopsychosocial Models 373

spinal cord injury has been undertaken by a number of groups, with more concordance among the groups in relation to some pain types than others, such as neuropathic pains (Cardenas, Felix, Cardenas, & Felix, 2009; Finnerup, Baastrup, & Jensen, 2009; Siddall, Yezierski, & Loeser, 2000). A recent systematic review of the prevalence of chronic pain of all causes among those with traumatic spinal cord injury have identified more than forty high quality studies from across the world, but the authors note that despite this there are many contradictions and unanswered questions about the nature of chronic pain in this group (Dijkers, Bryce, & Zanca, 2009). Prevalence rates of the studies included ranged from 26 to 98 percent, but the authors cautioned that the heterogeneity of the studies involved precluded calculation of an overall prevalence rate. It should be noted that co-morbid traumatic brain injury are not uncommon among this group, often within the mild range (Bradbury, et al., 2008). While spinal cord injury has been included in the section on traumatic injuries, some spinal cord injuries develop as a result of disease activity, such as cancer, which may mean the individual experiences other chronic pain conditions. As with many other physically disabling conditions, pain is only one of many troublesome complications. However, a recent study found that relative to others it is the most common and is closely associated with functioning (Jensen, Kuehn, Amtmann, & Cardenas, 2007).

Studies of pain post-amputation are largely related to either upper or lower limb amputations. Most studies report on traumatically acquired amputations, although those related to vascular or other conditions are also relatively common. The most common type of pain problems reported in these studies is phantom limb pain and residual (or stump) pain, although it is also possible for people to develop musculoskeletal pain following amputation, for example in the back (Hammarlund, Carlström, Melchior, & Persson, 2011; Kooijman, Dijkstra, Geertzen, Elzinga, & van der Schans, 2000). Prevalence estimates suggest that phantom limb pain occurs in approximately 45 to 80% of people postamputation, depending partly upon whether those with upper or lower limb amputations are considered, with rates of residual pain similarly high but varying (Behr, et al., 2009; Desmond & Maclachlan, 2010; Dijkstra, et al., 2002; Ehde, et al., 2000; Kooijman, et al., 2000;

In contrast to many of the other physically disabling conditions upon which this chapter focuses, research on cerebral palsy related pain is not confined to studies of adults. The common use of registries in a number of countries also means that the populations from which samples are drawn are more complete than in many other conditions. A French study of adults with cerebral palsy found that 75% reported pain of any sort (Gallien, et al., 2007). Musculoskeletal pain has been the subject of most investigation among this population. Prevalence estimates range from approximately one third to two thirds, with the pattern of distribution across the body different depending on the type of cerebral palsy (Engel, Jensen, Hoffman, & Kartin, 2003; Jahnsen, Villien, Aamodt, Stanghelle, & Holm, 2004; Schwartz, Engel, & Jensen, 1999; Vogtle, 2009). Although studies of children are more common in this group, they are limited by a number of factors regarding the measurement of pain and often rely on parental report. However, the available studies suggest 50 to 75 % of children are affected by pain, with approximately one third experiencing moderate to severe pain (Parkinson, Gibson, Dickinson, & Colver, 2010; Russo, Miller, Haan, Cameron, & Crotty, 2008).

including the duration of the pain condition being explored. Some studies focus on chronic pain (with various criterion applied, commonly either three or six months duration), where others report on episodic, procedural or acute pain or do not specify which type of pain participants are experiencing. Second, some studies restrict their attention to pain thought to be specific to the physically disabling condition in question (such as headaches in those with traumatic brain injury), putting aside those deemed to be general (such as low back pain) which may be overlooked by teams specialising in a specific disabling condition rather than pain itself (Ivanhoe & Hartman, 2004). Finally, studies draw samples from a number of different populations including community samples, membership organisations for people with the physically disabling condition in question, and clinical services, including tertiary services for either pain or a specific physically disabling condition. There are also the usual methodological issues associated with the use of cross-sectional designs and the inevitable reliance upon self-report measures which is a hallmark of this area of research. Despite these issues, there is increasing evidence of a significant prevalence of chronic pain among those with physically disabling conditions.

#### **2.1 Injury related conditions**

Injury related conditions for which there is data regarding the nature of chronic pain includes those with a traumatic onset, such as traumatic brain injury and spinal cord injury, and those with a non-traumatic onset, such as cerebral palsy which is thought to be due to an injury to the developing brain. The kinds of traumatic events from which these injuries arise, such as motor vehicle accidents and sporting injuries, may mean that the individual has acquired multiple injuries which may complicate the assessment of the relationship between specific pain conditions and the physically disabling condition of interest.

#### **2.1.1 Traumatic brain injury**

Specific pain conditions of interest among those with traumatic brain injury include headaches of various types, but others noted include complex regional pain syndrome (CRPS), heterotopic ossification, and pain due to spasticity (Ivanhoe & Hartman, 2004; Nampiaparampil, 2008). A recent systematic review of chronic pain among those with traumatic brain injury identified 23 studies meeting their criteria, from which they estimated the overall prevalence of chronic pain in people with traumatic brain injury at 51.5% among civilians, with 57.8% reporting chronic headache (Nampiaparampil, 2008). An interesting aspect of findings among this group is that prevalence of chronic headaches differs depending on the severity of the traumatic brain injury (Lahz & Bryant, 1996; Nampiaparampil, 2008), with higher prevalence reported among those with mild traumatic brain injury. It has been observed that those with traumatic brain injury may have other traumatic injuries, and studies regarding the pain conditions in this poly-trauma group are very limited (Dobscha, et al., 2009). The assessment of pain in those with traumatic brain injury, particularly those with severe enough injuries to result in significant impairments to cognition, language or behaviour, may be challenging and so result in less accurate estimates than in some other groups with physically disabling conditions.

#### **2.1.2 Spinal cord injury**

Relative to other conditions, there have been a larger number of studies examining chronic pain among those with spinal cord injury. Classifying the pain conditions associated with spinal cord injury has been undertaken by a number of groups, with more concordance among the groups in relation to some pain types than others, such as neuropathic pains (Cardenas, Felix, Cardenas, & Felix, 2009; Finnerup, Baastrup, & Jensen, 2009; Siddall, Yezierski, & Loeser, 2000). A recent systematic review of the prevalence of chronic pain of all causes among those with traumatic spinal cord injury have identified more than forty high quality studies from across the world, but the authors note that despite this there are many contradictions and unanswered questions about the nature of chronic pain in this group (Dijkers, Bryce, & Zanca, 2009). Prevalence rates of the studies included ranged from 26 to 98 percent, but the authors cautioned that the heterogeneity of the studies involved precluded calculation of an overall prevalence rate. It should be noted that co-morbid traumatic brain injury are not uncommon among this group, often within the mild range (Bradbury, et al., 2008). While spinal cord injury has been included in the section on traumatic injuries, some spinal cord injuries develop as a result of disease activity, such as cancer, which may mean the individual experiences other chronic pain conditions. As with many other physically disabling conditions, pain is only one of many troublesome complications. However, a recent study found that relative to others it is the most common and is closely associated with functioning (Jensen, Kuehn, Amtmann, & Cardenas, 2007).

#### **2.1.3 Amputation**

372 Pain Management – Current Issues and Opinions

including the duration of the pain condition being explored. Some studies focus on chronic pain (with various criterion applied, commonly either three or six months duration), where others report on episodic, procedural or acute pain or do not specify which type of pain participants are experiencing. Second, some studies restrict their attention to pain thought to be specific to the physically disabling condition in question (such as headaches in those with traumatic brain injury), putting aside those deemed to be general (such as low back pain) which may be overlooked by teams specialising in a specific disabling condition rather than pain itself (Ivanhoe & Hartman, 2004). Finally, studies draw samples from a number of different populations including community samples, membership organisations for people with the physically disabling condition in question, and clinical services, including tertiary services for either pain or a specific physically disabling condition. There are also the usual methodological issues associated with the use of cross-sectional designs and the inevitable reliance upon self-report measures which is a hallmark of this area of research. Despite these issues, there is increasing evidence of a significant prevalence of chronic pain among those

Injury related conditions for which there is data regarding the nature of chronic pain includes those with a traumatic onset, such as traumatic brain injury and spinal cord injury, and those with a non-traumatic onset, such as cerebral palsy which is thought to be due to an injury to the developing brain. The kinds of traumatic events from which these injuries arise, such as motor vehicle accidents and sporting injuries, may mean that the individual has acquired multiple injuries which may complicate the assessment of the relationship

Specific pain conditions of interest among those with traumatic brain injury include headaches of various types, but others noted include complex regional pain syndrome (CRPS), heterotopic ossification, and pain due to spasticity (Ivanhoe & Hartman, 2004; Nampiaparampil, 2008). A recent systematic review of chronic pain among those with traumatic brain injury identified 23 studies meeting their criteria, from which they estimated the overall prevalence of chronic pain in people with traumatic brain injury at 51.5% among civilians, with 57.8% reporting chronic headache (Nampiaparampil, 2008). An interesting aspect of findings among this group is that prevalence of chronic headaches differs depending on the severity of the traumatic brain injury (Lahz & Bryant, 1996; Nampiaparampil, 2008), with higher prevalence reported among those with mild traumatic brain injury. It has been observed that those with traumatic brain injury may have other traumatic injuries, and studies regarding the pain conditions in this poly-trauma group are very limited (Dobscha, et al., 2009). The assessment of pain in those with traumatic brain injury, particularly those with severe enough injuries to result in significant impairments to cognition, language or behaviour, may be challenging and so result in less accurate

Relative to other conditions, there have been a larger number of studies examining chronic pain among those with spinal cord injury. Classifying the pain conditions associated with

between specific pain conditions and the physically disabling condition of interest.

estimates than in some other groups with physically disabling conditions.

with physically disabling conditions.

**2.1 Injury related conditions** 

**2.1.1 Traumatic brain injury** 

**2.1.2 Spinal cord injury** 

Studies of pain post-amputation are largely related to either upper or lower limb amputations. Most studies report on traumatically acquired amputations, although those related to vascular or other conditions are also relatively common. The most common type of pain problems reported in these studies is phantom limb pain and residual (or stump) pain, although it is also possible for people to develop musculoskeletal pain following amputation, for example in the back (Hammarlund, Carlström, Melchior, & Persson, 2011; Kooijman, Dijkstra, Geertzen, Elzinga, & van der Schans, 2000). Prevalence estimates suggest that phantom limb pain occurs in approximately 45 to 80% of people postamputation, depending partly upon whether those with upper or lower limb amputations are considered, with rates of residual pain similarly high but varying (Behr, et al., 2009; Desmond & Maclachlan, 2010; Dijkstra, et al., 2002; Ehde, et al., 2000; Kooijman, et al., 2000; Schley, et al., 2008).

#### **2.1.4 Cerebral palsy**

In contrast to many of the other physically disabling conditions upon which this chapter focuses, research on cerebral palsy related pain is not confined to studies of adults. The common use of registries in a number of countries also means that the populations from which samples are drawn are more complete than in many other conditions. A French study of adults with cerebral palsy found that 75% reported pain of any sort (Gallien, et al., 2007). Musculoskeletal pain has been the subject of most investigation among this population. Prevalence estimates range from approximately one third to two thirds, with the pattern of distribution across the body different depending on the type of cerebral palsy (Engel, Jensen, Hoffman, & Kartin, 2003; Jahnsen, Villien, Aamodt, Stanghelle, & Holm, 2004; Schwartz, Engel, & Jensen, 1999; Vogtle, 2009). Although studies of children are more common in this group, they are limited by a number of factors regarding the measurement of pain and often rely on parental report. However, the available studies suggest 50 to 75 % of children are affected by pain, with approximately one third experiencing moderate to severe pain (Parkinson, Gibson, Dickinson, & Colver, 2010; Russo, Miller, Haan, Cameron, & Crotty, 2008).

Chronic Pain in People with Physically Disabling

reported to be involved.

**2.3 Summary** 

Conditions: A Review of the Application of Biopsychosocial Models 375

pain (Engel, Kartin, Carter, Jensen, & Jaffe, 2009; Jensen, Abresch, Carter, & McDonald, 2005; Jensen, et al., 2008; Miro, et al., 2009) although there are limited studies with these groups. More than half of the respondents in these studies reported the presence of chronic pain, with pain in the back and legs most commonly reported but with a large number of sites

Although not a comprehensive review of all of those physically disabling conditions which may result in the experience of chronic pain, the above summary suggests that chronic pain is a relatively common but perhaps neglected consequence of physically disabling conditions (Osterberg, et al., 2005). The specific causes and the nature of chronic pain experienced may differ between physically disabling conditions, but its high prevalence indicates that it is a legitimate concern for health practitioners and researchers. Awareness of the likelihood of pain is a necessary, although not sufficient, condition for the effective management of such pain. There is evidence that there are misconceptions among health professionals about the likely occurrence of pain in those with physically disabling conditions (Piwko, et al., 2007). Indeed, studies of people with pain associated with various conditions, including spinal cord injury, cerebral palsy, and multiple sclerosis, indicate that those affected perceive the available treatments and access to them to be inadequate (Cardenas, et al., 2009; Henwood & Ellis, 2004; Kennedy, Lude, & Taylor, 2006; Pollmann, Feneberg, & Erasmus, 2004; Wartan, Hamann, Wedley, & McColl, 1997). In addition, the economic costs of pain among those with physically disabling conditions appears to be large, with a Canadian study estimating that the cost of pain among people multiple

sclerosis over a 6 month period was Can\$80 million (Piwko, et al., 2007).

**physically disabling conditions** 

**3. Psychological and social factors in chronic pain among those with** 

functional disability experienced by those with persisting pain (Blyth, et al., 2001).

Within the broad category of biopsychosocial models, those informed by cognitive behavioural theories are most common. These models particularly address the role of cognitions and behaviours in the development and maintenance of pain, as well as associated pain-related distress and disability. A wide range of cognitive and behavioural constructs have been investigated to determine their relationship with the experience of pain and associated disability and distress (Vlaeyen & Linton, 2000). There is some support for many of these constructs in individual studies. However, among these constructs, pain

Biopsychosocial models of pain, which are characterized by a focus on the interaction between biological, psychological and social variables in the pain experience, dominate the contemporary understanding of primary pain conditions, such as headache and low back pain (Gatchel, Peng, Peters, Fuchs, & Turk, 2007). The use of biopsychosocial models has also been promoted as the most appropriate framework for the understanding and management of disability of all types (World Health Organisation, 2011).The importance of these models is that they broaden the focus of health professionals to consider psychological and social factors which affect the course of a chronic pain condition. Crucially, where many chronic pain conditions were resistant to the available medical interventions, resulting in a significant proportion of the population living with chronic pain, biopsychosocial models offered a new treatment target focused on reducing the psychological distress and

#### **2.2 Disease related conditions**

Chronic pain has been investigated in the context of a range of diseases which are associated with physical disability. Some of the central pains, such as central post-stroke pain, associated with these conditions have only been recognized relatively recently, and have been subject to intense investigation.

#### **2.2.1 Multiple sclerosis**

A range of pain conditions, both general and specific, have been reported in people with multiple sclerosis. These include those related to spasm, neuropathic pains of various types (including trigeminal neuralgia and L'hermitte's sign), back pain and headaches. A recent systematic review of pain among people with multiple sclerosis found twenty-one studies reporting pain prevalence, with an overall range of 29 to 86%, and with few consistent findings related to the relationship between the report of pain and multiple sclerosis characteristics (O'Connor, Schwid, Herrmann, Markman, & Dworkin, 2008). Further, this study reported that between 11 and 23% of people reported pain as a symptom at the onset of their multiple sclerosis. Central pain, including trigeminal neuralgia, has been reported in approximately one third of people with MS (Osterberg, Boivie, & Thuomas, 2005).

#### **2.2.2 Stroke**

A number of chronic pain conditions are observed in people who have had a stroke, including shoulder pain, spasticity related pain and headaches, and central post-stroke pain is a uncommon condition particular to stroke. Estimates of the prevalence of chronic pain between studies are variable. Approximately 11 to 21% of people following a first stroke have been reported to have a stroke related pain condition up to 16 months following the stroke (Appelros, 2006; Jonsson, Lindgren, Hallstrom, Norrving, & Lindgren, 2006; Lundstrom, Smits, Terent, & Borg, 2009), whereas 42% of people following stroke attending an out-patient rehabilitation clinic had chronic musculoskeletal pain (Kong, Woon, & Yang, 2004). Neuropathic and central pain conditions occur at a significant level among those who have had a stroke, including estimates of complex regional pain syndrome in 15% of those undergoing inpatient post-stroke rehabilitation and 7% with central poststroke pain (Kitisomprayoonkul, Sungkapo, Taveemanoon, & Chaiwanichsiri, 2010; Klit, Finnerup, Andersen, & Jensen, 2011).

#### **2.2.3 Parkinson's Disease**

Relatively little is known about the prevalence and nature of pain in people with Parkinson's Disease, although clinically it is reported to be observed frequently (Beiske & Loge, 2009). Ford (2010) has classified pain problems associated with Parkinson's Disease in five categories: musculoskeletal pain; radicular or neuropathic pain; dystonia-related pain; akathitic discomfort; and central or primary pain. Overall estimates of the prevalence of pain in this group range between and 40 and 83% (Beiske & Loge, 2009; Ford, 2010). Pain has been reported to be the first reported symptom of Parkinson's Disease among a significant minority of those who initially present with non-motor symptoms (O'Sullivan, et al., 2008).

#### **2.2.4 Muscular dystrophy**

Duchenne muscular dystrophy, myotonic muscular dystrophy, type I and facioscapulohumeral muscular dystrophy have all been found to be associated with chronic pain (Engel, Kartin, Carter, Jensen, & Jaffe, 2009; Jensen, Abresch, Carter, & McDonald, 2005; Jensen, et al., 2008; Miro, et al., 2009) although there are limited studies with these groups. More than half of the respondents in these studies reported the presence of chronic pain, with pain in the back and legs most commonly reported but with a large number of sites reported to be involved.

#### **2.3 Summary**

374 Pain Management – Current Issues and Opinions

Chronic pain has been investigated in the context of a range of diseases which are associated with physical disability. Some of the central pains, such as central post-stroke pain, associated with these conditions have only been recognized relatively recently, and have

A range of pain conditions, both general and specific, have been reported in people with multiple sclerosis. These include those related to spasm, neuropathic pains of various types (including trigeminal neuralgia and L'hermitte's sign), back pain and headaches. A recent systematic review of pain among people with multiple sclerosis found twenty-one studies reporting pain prevalence, with an overall range of 29 to 86%, and with few consistent findings related to the relationship between the report of pain and multiple sclerosis characteristics (O'Connor, Schwid, Herrmann, Markman, & Dworkin, 2008). Further, this study reported that between 11 and 23% of people reported pain as a symptom at the onset of their multiple sclerosis. Central pain, including trigeminal neuralgia, has been reported in

A number of chronic pain conditions are observed in people who have had a stroke, including shoulder pain, spasticity related pain and headaches, and central post-stroke pain is a uncommon condition particular to stroke. Estimates of the prevalence of chronic pain between studies are variable. Approximately 11 to 21% of people following a first stroke have been reported to have a stroke related pain condition up to 16 months following the stroke (Appelros, 2006; Jonsson, Lindgren, Hallstrom, Norrving, & Lindgren, 2006; Lundstrom, Smits, Terent, & Borg, 2009), whereas 42% of people following stroke attending an out-patient rehabilitation clinic had chronic musculoskeletal pain (Kong, Woon, & Yang, 2004). Neuropathic and central pain conditions occur at a significant level among those who have had a stroke, including estimates of complex regional pain syndrome in 15% of those undergoing inpatient post-stroke rehabilitation and 7% with central poststroke pain (Kitisomprayoonkul, Sungkapo, Taveemanoon, & Chaiwanichsiri, 2010; Klit, Finnerup,

Relatively little is known about the prevalence and nature of pain in people with Parkinson's Disease, although clinically it is reported to be observed frequently (Beiske & Loge, 2009). Ford (2010) has classified pain problems associated with Parkinson's Disease in five categories: musculoskeletal pain; radicular or neuropathic pain; dystonia-related pain; akathitic discomfort; and central or primary pain. Overall estimates of the prevalence of pain in this group range between and 40 and 83% (Beiske & Loge, 2009; Ford, 2010). Pain has been reported to be the first reported symptom of Parkinson's Disease among a significant minority

Duchenne muscular dystrophy, myotonic muscular dystrophy, type I and facioscapulohumeral muscular dystrophy have all been found to be associated with chronic

of those who initially present with non-motor symptoms (O'Sullivan, et al., 2008).

approximately one third of people with MS (Osterberg, Boivie, & Thuomas, 2005).

**2.2 Disease related conditions** 

been subject to intense investigation.

**2.2.1 Multiple sclerosis** 

**2.2.2 Stroke** 

Andersen, & Jensen, 2011).

**2.2.3 Parkinson's Disease** 

**2.2.4 Muscular dystrophy** 

Although not a comprehensive review of all of those physically disabling conditions which may result in the experience of chronic pain, the above summary suggests that chronic pain is a relatively common but perhaps neglected consequence of physically disabling conditions (Osterberg, et al., 2005). The specific causes and the nature of chronic pain experienced may differ between physically disabling conditions, but its high prevalence indicates that it is a legitimate concern for health practitioners and researchers. Awareness of the likelihood of pain is a necessary, although not sufficient, condition for the effective management of such pain. There is evidence that there are misconceptions among health professionals about the likely occurrence of pain in those with physically disabling conditions (Piwko, et al., 2007). Indeed, studies of people with pain associated with various conditions, including spinal cord injury, cerebral palsy, and multiple sclerosis, indicate that those affected perceive the available treatments and access to them to be inadequate (Cardenas, et al., 2009; Henwood & Ellis, 2004; Kennedy, Lude, & Taylor, 2006; Pollmann, Feneberg, & Erasmus, 2004; Wartan, Hamann, Wedley, & McColl, 1997). In addition, the economic costs of pain among those with physically disabling conditions appears to be large, with a Canadian study estimating that the cost of pain among people multiple sclerosis over a 6 month period was Can\$80 million (Piwko, et al., 2007).

#### **3. Psychological and social factors in chronic pain among those with physically disabling conditions**

Biopsychosocial models of pain, which are characterized by a focus on the interaction between biological, psychological and social variables in the pain experience, dominate the contemporary understanding of primary pain conditions, such as headache and low back pain (Gatchel, Peng, Peters, Fuchs, & Turk, 2007). The use of biopsychosocial models has also been promoted as the most appropriate framework for the understanding and management of disability of all types (World Health Organisation, 2011).The importance of these models is that they broaden the focus of health professionals to consider psychological and social factors which affect the course of a chronic pain condition. Crucially, where many chronic pain conditions were resistant to the available medical interventions, resulting in a significant proportion of the population living with chronic pain, biopsychosocial models offered a new treatment target focused on reducing the psychological distress and functional disability experienced by those with persisting pain (Blyth, et al., 2001).

Within the broad category of biopsychosocial models, those informed by cognitive behavioural theories are most common. These models particularly address the role of cognitions and behaviours in the development and maintenance of pain, as well as associated pain-related distress and disability. A wide range of cognitive and behavioural constructs have been investigated to determine their relationship with the experience of pain and associated disability and distress (Vlaeyen & Linton, 2000). There is some support for many of these constructs in individual studies. However, among these constructs, pain

Chronic Pain in People with Physically Disabling

**3.1 Psychological factors** 

conditions under consideration.

**3.1.1 Mood and mental health** 

Arnett, 2007).

Conditions: A Review of the Application of Biopsychosocial Models 377

Under the category psychological factors, the main variables to consider are mood and mental health, cognitive responses to pain, and behavioural responses to pain. The extent of the literature in these three areas varies markedly across the various physically disabling

The association between chronic pain and changes in mood and mental health, including symptoms of depression and anxiety, is perhaps the most frequently explored aspect of biopsychosocial models among those with physically disabling conditions. In some physically disabling conditions, a clear relationship between chronic pain and psychological distress has been consistently demonstrated, whereas in others the findings are more mixed. Pain has been found to be associated with psychological distress in most of the studies identified in cerebral palsy, traumatic brain injury, multiple sclerosis, amputation, spinal cord injury, and muscular dystrophy (Engel, et al., 2003; Engel, Schwartz, Jensen, & Johnson, 2000; Hoffman, et al., 2007; Kalia & O'Connor, 2005; Kratz, et al., 2010; Middleton, Tran, & Craig, 2007; Miro, et al., 2009; Motl, McAuley, Snook, & Gliottoni, 2009; Nicholson Perry, Nicholas, & Middleton, 2009; Nicholson Perry, Nicholas, Middleton, & Siddall, 2009; Norrbrink Budh, Hultling, & Lundeberg, 2005; Stormer, et al., 1997; Turner, Jensen, Warms, & Cardenas, 2002), although the strength of the relationship has varied across studies and conditions. In addition, studies in people with spinal cord injury pain found that continuous pain, as opposed to intermittent pain, was associated with higher levels of depression and anxiety, and conversely more stress among women with spinal cord injuries was associated with consistent reports of pain over a ten year period (Norrbrink Budh & Osteraker, 2007; Rintala, Hart, & Priebe, 2004). Negative mood has also been reported to be a trigger to exacerbations in chronic pain among people with spinal cord injury (Widerstrom-Noga & Turk, 2004). Some studies have presented exceptions to this general rule in the case of cerebral palsy, multiple sclerosis and stroke (Hirsh, Gallegos, Gertz, Engel, & Jensen, 2010; Kong, et al., 2004; Newland, Naismith, & Ullione, 2009; Newland, Wipke-Tevis, Williams, Rantz, & Petroski, 2005). Moderators of this relationship include gender, with the relationship not being found in males with multiple sclerosis in one study, and aetiology (traumatic versus non-traumatic) for amputation in one study moderating the relationship at early time points (Kalia & O'Connor, 2005; Kratz, et al., 2010). Physically disabling conditions in which findings are mixed in this regard include those with phantom limb pain and stump pain following amputation (Fisher & Hanspal, 1998). While most of these studies have been conducted with adults with physically disabling conditions, a study with a large sample of older children with cerebral palsy suggests that children with moderate or severe pain are significantly more likely to have higher levels emotional and behavioural problems (Parkes, et al., 2008). One study in people with multiple sclerosis found that affective memory biases, a measure of vulnerability to depression, may mediate the relationship between chronic pain and depressive symptoms in this group (Bruce, Polen, &

Most studies of the relationship between pain and depression in physically disabling conditions solely report on cross-sectional associations. In some studies, however, they specifically examine pain as a predictor of depression, or in other cases the reverse. Determining the direction of the relationship have proved problematic, although there is some evidence among people with spinal cord injury to support the hypothesis than persisting pain

catastrophizing, pain self-efficacy, and avoidance have all been found to be consistently related to the experience of pain and associated disability or distress across different populations and methodologies. In addition, the presence of altered mood, such as symptoms of depression and anxiety, or the co-existence of psychiatric disorders such as post-traumatic stress disorder, all seem to be important in influencing the course of a chronic pain condition.

The application of biopsychosocial models to chronic pain among those with physically disabling conditions has lagged significantly behind its use among primary pain conditions, where it has long been acknowledged that presence of pain or the intensity of pain does not fully explain pain-related disability or distress (Heneweer, et al., 2007). Among the physically disabling conditions outlined above with documented, significant rates of associated chronic pain there were no peer-reviewed publications available addressing psychosocial variables in the case of Parkinson's Disease. In addition, the investigation of variables has been patchy across the different conditions, and there are few specific models proposed for those with chronic pain in the context of physically disabling conditions. Some of the reasons for this are unclear, although it may be suggested that the obvious presence of pathology among those with physically disabling conditions results in a tendency to discount the possible role of other factors in causing pain-related disability or distress. This is despite repeated findings across a number of diagnoses that condition-related variables, such as severity of injury or illness, are frequently not at all or only weakly related to pain intensity and related disability or distress (Hoffman, et al., 2007).

It is notable that while biopsychosocial models do not dictate that only negative or adverse outcomes are possible following development of pain, much of the available research focuses on factors associated with poor outcomes. In contrast, a study of people with spinal cord injuries or multiple traumas examined factors which differentiated different adjustment trajectories and identified three: the resilience trajectory, characterized by low levels of mental health symptoms at both early and late stage of admission following injury, the recovery trajectory where the individual shows an improving pattern of mental health symptoms, and the distress trajectory, where higher levels of mental health symptoms at the early stage are sustained in the longer term (Quale & Schanke, 2010). The study reports that the latter accounted for only one fifth of the participants in their study, and that maximum pain at admission differentiated those in the resilience vs the distress trajectory.

Studies investigating the relationship between psychosocial factors and chronic pain in people with physically disabling conditions fall into two main categories. First, psychosocial factors are examined as predictors of chronic pain or pain-related disability, for example does a particular way of thinking about pain have an impact on how much pain is experienced. Second, chronic pain is examined as a contributor to adjustment following onset of a physically disabling condition, for example do those with chronic pain as a result of a physically disabling condition have higher levels of depressive symptomatology. The rapid development of theory and research related to biopsychosocial models of chronic pain has led to some overlap of concepts. A good example of this being that pain catastrophizing first appeared as one of many unhelpful coping strategies, but has now been reframed as a belief alongside others such as self-efficacy or helplessness. It is therefore somewhat difficult to categorize the current literature into particular themes. The purpose of this section is to describe the current evidence regarding the relationship between psychological and social factors and chronic pain in people with physically disabling conditions, and to identify gaps in the current literature which require further investigation.

#### **3.1 Psychological factors**

376 Pain Management – Current Issues and Opinions

catastrophizing, pain self-efficacy, and avoidance have all been found to be consistently related to the experience of pain and associated disability or distress across different populations and methodologies. In addition, the presence of altered mood, such as symptoms of depression and anxiety, or the co-existence of psychiatric disorders such as post-traumatic stress disorder, all seem to be important in influencing the course of a

The application of biopsychosocial models to chronic pain among those with physically disabling conditions has lagged significantly behind its use among primary pain conditions, where it has long been acknowledged that presence of pain or the intensity of pain does not fully explain pain-related disability or distress (Heneweer, et al., 2007). Among the physically disabling conditions outlined above with documented, significant rates of associated chronic pain there were no peer-reviewed publications available addressing psychosocial variables in the case of Parkinson's Disease. In addition, the investigation of variables has been patchy across the different conditions, and there are few specific models proposed for those with chronic pain in the context of physically disabling conditions. Some of the reasons for this are unclear, although it may be suggested that the obvious presence of pathology among those with physically disabling conditions results in a tendency to discount the possible role of other factors in causing pain-related disability or distress. This is despite repeated findings across a number of diagnoses that condition-related variables, such as severity of injury or illness, are frequently not at all or only weakly related to pain

It is notable that while biopsychosocial models do not dictate that only negative or adverse outcomes are possible following development of pain, much of the available research focuses on factors associated with poor outcomes. In contrast, a study of people with spinal cord injuries or multiple traumas examined factors which differentiated different adjustment trajectories and identified three: the resilience trajectory, characterized by low levels of mental health symptoms at both early and late stage of admission following injury, the recovery trajectory where the individual shows an improving pattern of mental health symptoms, and the distress trajectory, where higher levels of mental health symptoms at the early stage are sustained in the longer term (Quale & Schanke, 2010). The study reports that the latter accounted for only one fifth of the participants in their study, and that maximum

Studies investigating the relationship between psychosocial factors and chronic pain in people with physically disabling conditions fall into two main categories. First, psychosocial factors are examined as predictors of chronic pain or pain-related disability, for example does a particular way of thinking about pain have an impact on how much pain is experienced. Second, chronic pain is examined as a contributor to adjustment following onset of a physically disabling condition, for example do those with chronic pain as a result of a physically disabling condition have higher levels of depressive symptomatology. The rapid development of theory and research related to biopsychosocial models of chronic pain has led to some overlap of concepts. A good example of this being that pain catastrophizing first appeared as one of many unhelpful coping strategies, but has now been reframed as a belief alongside others such as self-efficacy or helplessness. It is therefore somewhat difficult to categorize the current literature into particular themes. The purpose of this section is to describe the current evidence regarding the relationship between psychological and social factors and chronic pain in people with physically disabling conditions, and to identify gaps

pain at admission differentiated those in the resilience vs the distress trajectory.

intensity and related disability or distress (Hoffman, et al., 2007).

in the current literature which require further investigation.

chronic pain condition.

Under the category psychological factors, the main variables to consider are mood and mental health, cognitive responses to pain, and behavioural responses to pain. The extent of the literature in these three areas varies markedly across the various physically disabling conditions under consideration.

#### **3.1.1 Mood and mental health**

The association between chronic pain and changes in mood and mental health, including symptoms of depression and anxiety, is perhaps the most frequently explored aspect of biopsychosocial models among those with physically disabling conditions. In some physically disabling conditions, a clear relationship between chronic pain and psychological distress has been consistently demonstrated, whereas in others the findings are more mixed. Pain has been found to be associated with psychological distress in most of the studies identified in cerebral palsy, traumatic brain injury, multiple sclerosis, amputation, spinal cord injury, and muscular dystrophy (Engel, et al., 2003; Engel, Schwartz, Jensen, & Johnson, 2000; Hoffman, et al., 2007; Kalia & O'Connor, 2005; Kratz, et al., 2010; Middleton, Tran, & Craig, 2007; Miro, et al., 2009; Motl, McAuley, Snook, & Gliottoni, 2009; Nicholson Perry, Nicholas, & Middleton, 2009; Nicholson Perry, Nicholas, Middleton, & Siddall, 2009; Norrbrink Budh, Hultling, & Lundeberg, 2005; Stormer, et al., 1997; Turner, Jensen, Warms, & Cardenas, 2002), although the strength of the relationship has varied across studies and conditions. In addition, studies in people with spinal cord injury pain found that continuous pain, as opposed to intermittent pain, was associated with higher levels of depression and anxiety, and conversely more stress among women with spinal cord injuries was associated with consistent reports of pain over a ten year period (Norrbrink Budh & Osteraker, 2007; Rintala, Hart, & Priebe, 2004). Negative mood has also been reported to be a trigger to exacerbations in chronic pain among people with spinal cord injury (Widerstrom-Noga & Turk, 2004). Some studies have presented exceptions to this general rule in the case of cerebral palsy, multiple sclerosis and stroke (Hirsh, Gallegos, Gertz, Engel, & Jensen, 2010; Kong, et al., 2004; Newland, Naismith, & Ullione, 2009; Newland, Wipke-Tevis, Williams, Rantz, & Petroski, 2005). Moderators of this relationship include gender, with the relationship not being found in males with multiple sclerosis in one study, and aetiology (traumatic versus non-traumatic) for amputation in one study moderating the relationship at early time points (Kalia & O'Connor, 2005; Kratz, et al., 2010). Physically disabling conditions in which findings are mixed in this regard include those with phantom limb pain and stump pain following amputation (Fisher & Hanspal, 1998). While most of these studies have been conducted with adults with physically disabling conditions, a study with a large sample of older children with cerebral palsy suggests that children with moderate or severe pain are significantly more likely to have higher levels emotional and behavioural problems (Parkes, et al., 2008). One study in people with multiple sclerosis found that affective memory biases, a measure of vulnerability to depression, may mediate the relationship between chronic pain and depressive symptoms in this group (Bruce, Polen, & Arnett, 2007).

Most studies of the relationship between pain and depression in physically disabling conditions solely report on cross-sectional associations. In some studies, however, they specifically examine pain as a predictor of depression, or in other cases the reverse. Determining the direction of the relationship have proved problematic, although there is some evidence among people with spinal cord injury to support the hypothesis than persisting pain

Chronic Pain in People with Physically Disabling

depression were controlled for (Vase, et al., 2011)

(Ullrich, Jensen, Loeser, Cardenas, & Weaver, 2008).

chronic pain, who are the subject of most other studies on the subject.

related disability (Hanley, et al., 2004; Hill, et al., 1995).

Conditions: A Review of the Application of Biopsychosocial Models 379

Ehde, Hanley, & Kraft, 2007; Turner, et al., 2002; Vase, et al., 2011; Wollaars, Post, van Asbeck, & Brand, 2007). In a study of people with phantom limb pain, pain catastrophizing was also shown to significantly contribute to wind-up-like pain when anxiety and

Pain catastrophizing has been found to be positively associated with pain-related disability among those with spinal cord injury, cerebral palsy, phantom limb pain, muscular dystrophy and multiple sclerosis (Borsbo, et al., 2009; Douglas, Wollin, & Windsor, 2008; Engel, et al., 2000; Hill, et al., 1995; Miro, et al., 2009; Molton, et al., 2009; Nicholson Perry, Nicholas, & Middleton, 2009; Nicholson Perry, Nicholas, Middleton, et al., 2009; Osborne, et al., 2007). Psychological functioning among people with spinal cord injury, multiple sclerosis, phantom limb pain, muscular dystrophy and cerebral palsy has been found to be negatively associated with pain catastrophizing (Douglas, et al., 2008; Engel, Jensen, & Schwartz, 2006; Engel, et al., 2000; Hanley, et al., 2004; Hill, et al., 1995; Miro, et al., 2009; Molton, et al., 2009; Nicholson Perry, Nicholas, & Middleton, 2009; Nicholson Perry, Nicholas, Middleton, et al., 2009; Osborne, et al., 2007; Smedema, Catalano, & Ebener, 2011; Ullrich, Jensen, Loeser, & Cardenas, 2007; Wollaars, et al., 2007). Pain catastrophizing has also been shown to mediate the relationship between pain severity and psychological distress and pain-related disability among people with spinal cord injury (Ullrich, et al., 2007). It has been suggested that pain catastrophizing may, in fact, be a function of disturbed mood. This suggestion is brought into question by findings in both phantom limb pain and spinal cord injury related chronic pain which shows that pain catastrophizing is associated with pain intensity when mood is controlled for (Ullrich, et al., 2007; Vase, et al., 2011). Among the many studies of individuals with spinal cord injury pain, veterans with the condition appear to have higher levels of pain catastrophizing than non-veterans

While most of these studies are cross-sectional in nature, a prospective study of people with spinal cord injury with chronic pain found that over a six month period decreases in pain catastrophizing were associated with decreased pain interference and improved psychological functioning (Hanley, Raichle, Jensen, & Cardenas, 2008). Conversely, a similar study in phantom limb pain found that pain catastrophizing at one month following amputation (that is, before chronic pain had developed) was predictive of decreased depressive symptoms and pain-related interference at both 12 and 24 months (Hanley, et al., 2004). While this may appear counter-intuitive, the authors suggest that the function of pain catastrophizing soon after amputation may be different to that in those with established

Perceived control over pain has also been investigated, and there is less extensive evidence to support its role in relation to psychological functioning and disability in those with chronic pain secondary to physically disabling conditions. A study of people with spinal cord injury related chronic pain found that increases in perceived control over pain in a six month period was related to decreased pain intensity and pain interference, as well as increased psychological functioning, although the former was a non-significant finding (Hanley, et al., 2008). External locus of control in relation to pain as also been positively associated with depression among people with spinal cord injury related pain (Wollaars, et al., 2007). In addition, two studies of people with phantom limb pain, including a prospective study of people with phantom limb pain from one to 24 months, demonstrated some weak evidence for its influence on pain intensity, psychological functioning, and pain-

is a driver of depression rather than the converse (Cairns, Adkins, & Scott, 1996; Putzke, Richards, Hicken, & DeVivo, 2002).The presence of depression at one time point has been reported to be a risk factor for pain at a later time point among those with multiple sclerosis and spinal cord injury (Buchanan, Wang, Tai-Seale, & Ju, 2003; Putzke, et al., 2002).

Depression is associated with pain-related interference in a number of physically disabling conditions, including amputation, multiple sclerosis and spinal cord injury (Kratz, et al., 2010; Nicholson Perry, Nicholas, & Middleton, 2009; Nicholson Perry, Nicholas, Middleton, et al., 2009; Norrbrink Budh, et al., 2005; Norrbrink Budh & Osteraker, 2007; Osborne, et al., 2006; Turner, et al., 2002). There is evidence of a similar moderating effect of depression upon the relationship between pain and disability among those with spinal cord injury as is seen in other chronic pain populations (Borsbo, Peolsson, & Gerdle, 2009), and a similar but less clear interaction between these variables in those with traumatic brain injury (Hoffman, et al., 2007). The impairment to quality of life attributable to chronic pain has been reported to be related to depressive symptoms among individuals with spinal cord injury (Cruz-Almeida, Alameda, & Widerstrom-Noga, 2009). In addition, negative moods, boredom and stress reported in a large sample of older children with cerebral palsy was found to be significantly predicted by the presence of pain, although only to contribute a relatively small proportion of variation in this aspects of quality of life and interestingly overall quality of life was found to be consistent with other children without cerebral palsy (Dickinson, et al., 2007).

Studies of the relationship between chronic pain and anxiety among people with physically disabling conditions are less common. However, in studies of people with multiple sclerosis, anxiety has been found to be positively associated with pain severity, particularly among women (Kalia & O'Connor, 2005; Motl, et al., 2009). Studies among people with spinal cord injury have also shown a significant relationship between anxiety and pain severity (Nicholson Perry, Nicholas, & Middleton, 2009; Nicholson Perry, Nicholas, Middleton, et al., 2009; Norrbrink Budh, et al., 2005; Norrbrink Budh & Osteraker, 2007). There are a few studies examining the relationship between pain and post-traumatic stress disorder (PTSD). In a study of people with both traumatic and non-traumatic amputation, pain and painrelated interference was positively correlated with PTSD symptoms in both groups (Kratz, et al., 2010). Pain-related anxiety, often measured as a combination of cognitions, behaviours and emotion, has also been found to moderate the relationship between chronic pain and disability among those with spinal cord injury, with those reporting higher levels of pain related anxiety experiencing greater disability (Borsbo, et al., 2009). Anger has been less well investigated, although it has been shown to moderate the perception of pain in people with spinal cord injury (Conant, 1998; Summers, Rapoff, Varghese, Porter, & Palmer, 1991).

#### **3.1.2 Cognitive responses to pain**

The relationship between cognitive responses to pain, or beliefs, and pain-related disability and distress has been explored in those with a number of the physically disabling conditions of interest. Pain catastrophizing, characterized by a tendency to negative and unrealistic beliefs in response to pain, and is the cognitive factor with the greatest body of evidence supporting its role. While pain catastrophizing has often been measured in questionnaires designed to measure coping strategies, it is best considered alongside other beliefs, and so will be reported on in this section.

Pain catastrophizing has been found to be associated with pain intensity among people with chronic phantom limb pain post-amputation, multiple sclerosis and spinal cord injury (Hill, Niven, & Knussen, 1995; Nicholson Perry, Nicholas, & Middleton, 2009; Osborne, Jensen,

is a driver of depression rather than the converse (Cairns, Adkins, & Scott, 1996; Putzke, Richards, Hicken, & DeVivo, 2002).The presence of depression at one time point has been reported to be a risk factor for pain at a later time point among those with multiple sclerosis

Depression is associated with pain-related interference in a number of physically disabling conditions, including amputation, multiple sclerosis and spinal cord injury (Kratz, et al., 2010; Nicholson Perry, Nicholas, & Middleton, 2009; Nicholson Perry, Nicholas, Middleton, et al., 2009; Norrbrink Budh, et al., 2005; Norrbrink Budh & Osteraker, 2007; Osborne, et al., 2006; Turner, et al., 2002). There is evidence of a similar moderating effect of depression upon the relationship between pain and disability among those with spinal cord injury as is seen in other chronic pain populations (Borsbo, Peolsson, & Gerdle, 2009), and a similar but less clear interaction between these variables in those with traumatic brain injury (Hoffman, et al., 2007). The impairment to quality of life attributable to chronic pain has been reported to be related to depressive symptoms among individuals with spinal cord injury (Cruz-Almeida, Alameda, & Widerstrom-Noga, 2009). In addition, negative moods, boredom and stress reported in a large sample of older children with cerebral palsy was found to be significantly predicted by the presence of pain, although only to contribute a relatively small proportion of variation in this aspects of quality of life and interestingly overall quality of life was found to be consistent with

Studies of the relationship between chronic pain and anxiety among people with physically disabling conditions are less common. However, in studies of people with multiple sclerosis, anxiety has been found to be positively associated with pain severity, particularly among women (Kalia & O'Connor, 2005; Motl, et al., 2009). Studies among people with spinal cord injury have also shown a significant relationship between anxiety and pain severity (Nicholson Perry, Nicholas, & Middleton, 2009; Nicholson Perry, Nicholas, Middleton, et al., 2009; Norrbrink Budh, et al., 2005; Norrbrink Budh & Osteraker, 2007). There are a few studies examining the relationship between pain and post-traumatic stress disorder (PTSD). In a study of people with both traumatic and non-traumatic amputation, pain and painrelated interference was positively correlated with PTSD symptoms in both groups (Kratz, et al., 2010). Pain-related anxiety, often measured as a combination of cognitions, behaviours and emotion, has also been found to moderate the relationship between chronic pain and disability among those with spinal cord injury, with those reporting higher levels of pain related anxiety experiencing greater disability (Borsbo, et al., 2009). Anger has been less well investigated, although it has been shown to moderate the perception of pain in people with spinal cord injury (Conant, 1998; Summers, Rapoff, Varghese, Porter, & Palmer, 1991).

The relationship between cognitive responses to pain, or beliefs, and pain-related disability and distress has been explored in those with a number of the physically disabling conditions of interest. Pain catastrophizing, characterized by a tendency to negative and unrealistic beliefs in response to pain, and is the cognitive factor with the greatest body of evidence supporting its role. While pain catastrophizing has often been measured in questionnaires designed to measure coping strategies, it is best considered alongside other beliefs, and so

Pain catastrophizing has been found to be associated with pain intensity among people with chronic phantom limb pain post-amputation, multiple sclerosis and spinal cord injury (Hill, Niven, & Knussen, 1995; Nicholson Perry, Nicholas, & Middleton, 2009; Osborne, Jensen,

and spinal cord injury (Buchanan, Wang, Tai-Seale, & Ju, 2003; Putzke, et al., 2002).

other children without cerebral palsy (Dickinson, et al., 2007).

**3.1.2 Cognitive responses to pain** 

will be reported on in this section.

Ehde, Hanley, & Kraft, 2007; Turner, et al., 2002; Vase, et al., 2011; Wollaars, Post, van Asbeck, & Brand, 2007). In a study of people with phantom limb pain, pain catastrophizing was also shown to significantly contribute to wind-up-like pain when anxiety and depression were controlled for (Vase, et al., 2011)

Pain catastrophizing has been found to be positively associated with pain-related disability among those with spinal cord injury, cerebral palsy, phantom limb pain, muscular dystrophy and multiple sclerosis (Borsbo, et al., 2009; Douglas, Wollin, & Windsor, 2008; Engel, et al., 2000; Hill, et al., 1995; Miro, et al., 2009; Molton, et al., 2009; Nicholson Perry, Nicholas, & Middleton, 2009; Nicholson Perry, Nicholas, Middleton, et al., 2009; Osborne, et al., 2007). Psychological functioning among people with spinal cord injury, multiple sclerosis, phantom limb pain, muscular dystrophy and cerebral palsy has been found to be negatively associated with pain catastrophizing (Douglas, et al., 2008; Engel, Jensen, & Schwartz, 2006; Engel, et al., 2000; Hanley, et al., 2004; Hill, et al., 1995; Miro, et al., 2009; Molton, et al., 2009; Nicholson Perry, Nicholas, & Middleton, 2009; Nicholson Perry, Nicholas, Middleton, et al., 2009; Osborne, et al., 2007; Smedema, Catalano, & Ebener, 2011; Ullrich, Jensen, Loeser, & Cardenas, 2007; Wollaars, et al., 2007). Pain catastrophizing has also been shown to mediate the relationship between pain severity and psychological distress and pain-related disability among people with spinal cord injury (Ullrich, et al., 2007). It has been suggested that pain catastrophizing may, in fact, be a function of disturbed mood. This suggestion is brought into question by findings in both phantom limb pain and spinal cord injury related chronic pain which shows that pain catastrophizing is associated with pain intensity when mood is controlled for (Ullrich, et al., 2007; Vase, et al., 2011). Among the many studies of individuals with spinal cord injury pain, veterans with the condition appear to have higher levels of pain catastrophizing than non-veterans (Ullrich, Jensen, Loeser, Cardenas, & Weaver, 2008).

While most of these studies are cross-sectional in nature, a prospective study of people with spinal cord injury with chronic pain found that over a six month period decreases in pain catastrophizing were associated with decreased pain interference and improved psychological functioning (Hanley, Raichle, Jensen, & Cardenas, 2008). Conversely, a similar study in phantom limb pain found that pain catastrophizing at one month following amputation (that is, before chronic pain had developed) was predictive of decreased depressive symptoms and pain-related interference at both 12 and 24 months (Hanley, et al., 2004). While this may appear counter-intuitive, the authors suggest that the function of pain catastrophizing soon after amputation may be different to that in those with established chronic pain, who are the subject of most other studies on the subject.

Perceived control over pain has also been investigated, and there is less extensive evidence to support its role in relation to psychological functioning and disability in those with chronic pain secondary to physically disabling conditions. A study of people with spinal cord injury related chronic pain found that increases in perceived control over pain in a six month period was related to decreased pain intensity and pain interference, as well as increased psychological functioning, although the former was a non-significant finding (Hanley, et al., 2008). External locus of control in relation to pain as also been positively associated with depression among people with spinal cord injury related pain (Wollaars, et al., 2007). In addition, two studies of people with phantom limb pain, including a prospective study of people with phantom limb pain from one to 24 months, demonstrated some weak evidence for its influence on pain intensity, psychological functioning, and painrelated disability (Hanley, et al., 2004; Hill, et al., 1995).

Chronic Pain in People with Physically Disabling

**3.2 Social factors** 

**3.2.1 Social support** 

life of the study (Rintala, et al., 2004)

behaviours.

Conditions: A Review of the Application of Biopsychosocial Models 381

Although clearly identified as part of the various biopsychosocial models of pain proposed, social factors have been relatively less well represented in the literature. Studies examining social factors most often report on perceived social support and partner responses to pain

Studies examining the associations between social support and pain are available in people

Social support was found to be negatively associated with pain in studies among people with traumatic limb loss, whereas no relationship was found in people with spinal cord injury pain (Kratz, et al., 2010; Stroud, Turner, Jensen, & Cardenas, 2006). Studies of people with multiple sclerosis have resulted in mixed findings, with negative associations with pain in one study and no association in the other (Motl, et al., 2009; Osborne, et al., 2007). A study designed to identify factors which were predictive of consistency of pain over ten years among people with spinal cord injury found that among male respondents, receiving less social support during the first phase of the study was predictive of continuing pain over the

Associations between lower levels of social support and greater pain-related disability has been found in people with non-traumatic limb loss, multiple sclerosis and muscular dystrophy, but not in people with spinal cord injury (Kratz, et al., 2010; Miro, et al., 2009; Motl, et al., 2009; Osborne, et al., 2007; Stroud, et al., 2006). In one study, greater social support at one month post amputation was predictive of greater reduction in pain interference at 12 and 24 months (Hanley, et al., 2004). In addition, increased social support has been found to be associated with lower levels of anxiety and depression in people with multiple sclerosis and with depression in people with spinal cord injury (Motl, et al., 2009; Stroud, et al., 2006). Among people with muscular dystrophy, social support was associated positively with psychological functioning (Miro, et al., 2009). Hanley et al. (2004) also looked at the relationship between social constraint, which is the need to hide one's feelings about the amputation from others, and pain and pain-related interference. Increased need for social constraint was associated with pain intensity and interference in both those with

The most common maladaptive form of partner response to pain behaviours reported in the general chronic pain literature is that of solicitous responding, which is a key mechanism in operant models of pain, hypothesized to increase pain-related disability. A study in people with spinal cord injury chronic pain found perceived solicitous responding from partners were unrelated to pain intensity, pain-related disability, or depression (Stroud, et al., 2006). One study in people with limb loss found that less frequent solicitous responding at one month post amputation was predictive of greater reductions in pain interference at 12 and 24 months (Hanley, et al., 2004). Other forms of partner responses to pain behaviour measured in people with spinal cord injury related chronic pain are negative and distracting responses (Stroud, et al., 2006). Negative responses, such as criticism, and distracting responses were both associated with higher depression, but not pain intensity or pain related disability. Most studies which report upon partner responses to pain behaviours in the context of physically disabling conditions provide information about participants

with limb loss, spinal cord injury, multiple sclerosis and muscular dystrophy.

traumatic and non-traumatic limb loss in the 6 to 12 month period.

**3.2.2 Partner responses to pain behaviours** 

Other findings related to pain-related beliefs have also been noted but with much less consistency. A belief that pain is constant or enduring has been found to significantly predict both pain intensity and interference to activities due to pain among those with multiple sclerosis (Douglas, et al., 2008). The lower endorsement of the belief that others should be solicitous in response to pain behaviours was associated with better psychological functioning among people with muscular dystrophy (Miro, et al., 2009)

#### **3.1.3 Behavioural responses to pain**

Comparison of the use of behavioural responses to pain, also commonly referred to as coping strategies, among people with chronic pain secondary to physically disabling conditions to those with chronic primary pain conditions has revealed both similarities and differences. In people with cerebral palsy, use of behavioural coping strategies such as guarding and rest was reported to be less common and task persistence more common (Engel, et al., 2000). Conversely, cognitive coping strategies, such as diverting attention, reinterpreting sensations, and praying and hoping, were reportedly used more commonly. The authors suggest that some of these differences may be attributable to different background levels of the use of behavioural strategies such as resting and guarding, which may already be employed for non-pain related reasons among those with physically disabling conditions, and increased reliance on cognitive strategies over which they may be hypothesized to have more control.

The association of particular coping strategies with pain intensity or associated psychological distress or disability has been explored in a number of physically disabling conditions, including spinal cord injury, but with few significant relationships detected (Hanley, et al., 2008; Turner, et al., 2002). In some other studies, however, significant relationships have been found. In a study of people with phantom limb pain, behavioural activity was found to be associated with higher levels of pain, in contrast with findings in those with chronic primary pain conditions (Hill, et al., 1995). Passive coping strategies, including guarding, resting, asking for assistance, seeking social support and pacing, were found to be predictive of pain interference but not psychological functioning among people with spinal cord injury and muscular dystrophy (Miro, et al., 2009; Molton, et al., 2009). Reduction of activity, through resting or avoidance, has been associated with positively associated with pain interference in people with cerebral palsy and muscular dystrophy, and with symptoms of depression in people with cerebral palsy (Engel, et al., 2000; Miro, et al., 2009).

Seeking social support has been found to be positively associated with pain-related disability among people with cerebral palsy and muscular dystrophy (Engel, et al., 2006; Miro, et al., 2009), a finding that may initially appear counter-intuitive. The authors of the cerebral palsy study identified the fact that the items on the scale potentially reflect both adaptive and maladaptive aspects of social support seeking (Engel, et al., 2006). However, operant models of chronic pain suggest that pain contingent social support would result in increased disability, which may also provide a parsimonious explanation of the findings.

The extent to which respondents with multiple sclerosis believed they were able to control or decrease their pain through use of their coping strategies has been found to be associated with decreased pain intensity, however no specific coping strategy was predictive (Douglas, et al., 2008). Further, in the same study no coping strategy was found to be predictive of life interference due to pain and only coping by increasing activities was found to be associated with improved psychological functioning.

#### **3.2 Social factors**

380 Pain Management – Current Issues and Opinions

Other findings related to pain-related beliefs have also been noted but with much less consistency. A belief that pain is constant or enduring has been found to significantly predict both pain intensity and interference to activities due to pain among those with multiple sclerosis (Douglas, et al., 2008). The lower endorsement of the belief that others should be solicitous in response to pain behaviours was associated with better psychological

Comparison of the use of behavioural responses to pain, also commonly referred to as coping strategies, among people with chronic pain secondary to physically disabling conditions to those with chronic primary pain conditions has revealed both similarities and differences. In people with cerebral palsy, use of behavioural coping strategies such as guarding and rest was reported to be less common and task persistence more common (Engel, et al., 2000). Conversely, cognitive coping strategies, such as diverting attention, reinterpreting sensations, and praying and hoping, were reportedly used more commonly. The authors suggest that some of these differences may be attributable to different background levels of the use of behavioural strategies such as resting and guarding, which may already be employed for non-pain related reasons among those with physically disabling conditions, and increased reliance on cognitive strategies over which they may be

The association of particular coping strategies with pain intensity or associated psychological distress or disability has been explored in a number of physically disabling conditions, including spinal cord injury, but with few significant relationships detected (Hanley, et al., 2008; Turner, et al., 2002). In some other studies, however, significant relationships have been found. In a study of people with phantom limb pain, behavioural activity was found to be associated with higher levels of pain, in contrast with findings in those with chronic primary pain conditions (Hill, et al., 1995). Passive coping strategies, including guarding, resting, asking for assistance, seeking social support and pacing, were found to be predictive of pain interference but not psychological functioning among people with spinal cord injury and muscular dystrophy (Miro, et al., 2009; Molton, et al., 2009). Reduction of activity, through resting or avoidance, has been associated with positively associated with pain interference in people with cerebral palsy and muscular dystrophy, and with symptoms of depression in people with cerebral palsy (Engel, et al., 2000; Miro, et

Seeking social support has been found to be positively associated with pain-related disability among people with cerebral palsy and muscular dystrophy (Engel, et al., 2006; Miro, et al., 2009), a finding that may initially appear counter-intuitive. The authors of the cerebral palsy study identified the fact that the items on the scale potentially reflect both adaptive and maladaptive aspects of social support seeking (Engel, et al., 2006). However, operant models of chronic pain suggest that pain contingent social support would result in increased disability, which may also provide a parsimonious explanation of the findings. The extent to which respondents with multiple sclerosis believed they were able to control or decrease their pain through use of their coping strategies has been found to be associated with decreased pain intensity, however no specific coping strategy was predictive (Douglas, et al., 2008). Further, in the same study no coping strategy was found to be predictive of life interference due to pain and only coping by increasing activities was found to be associated

functioning among people with muscular dystrophy (Miro, et al., 2009)

**3.1.3 Behavioural responses to pain** 

hypothesized to have more control.

with improved psychological functioning.

al., 2009).

Although clearly identified as part of the various biopsychosocial models of pain proposed, social factors have been relatively less well represented in the literature. Studies examining social factors most often report on perceived social support and partner responses to pain behaviours.

#### **3.2.1 Social support**

Studies examining the associations between social support and pain are available in people with limb loss, spinal cord injury, multiple sclerosis and muscular dystrophy.

Social support was found to be negatively associated with pain in studies among people with traumatic limb loss, whereas no relationship was found in people with spinal cord injury pain (Kratz, et al., 2010; Stroud, Turner, Jensen, & Cardenas, 2006). Studies of people with multiple sclerosis have resulted in mixed findings, with negative associations with pain in one study and no association in the other (Motl, et al., 2009; Osborne, et al., 2007). A study designed to identify factors which were predictive of consistency of pain over ten years among people with spinal cord injury found that among male respondents, receiving less social support during the first phase of the study was predictive of continuing pain over the life of the study (Rintala, et al., 2004)

Associations between lower levels of social support and greater pain-related disability has been found in people with non-traumatic limb loss, multiple sclerosis and muscular dystrophy, but not in people with spinal cord injury (Kratz, et al., 2010; Miro, et al., 2009; Motl, et al., 2009; Osborne, et al., 2007; Stroud, et al., 2006). In one study, greater social support at one month post amputation was predictive of greater reduction in pain interference at 12 and 24 months (Hanley, et al., 2004). In addition, increased social support has been found to be associated with lower levels of anxiety and depression in people with multiple sclerosis and with depression in people with spinal cord injury (Motl, et al., 2009; Stroud, et al., 2006). Among people with muscular dystrophy, social support was associated positively with psychological functioning (Miro, et al., 2009). Hanley et al. (2004) also looked at the relationship between social constraint, which is the need to hide one's feelings about the amputation from others, and pain and pain-related interference. Increased need for social constraint was associated with pain intensity and interference in both those with traumatic and non-traumatic limb loss in the 6 to 12 month period.

#### **3.2.2 Partner responses to pain behaviours**

The most common maladaptive form of partner response to pain behaviours reported in the general chronic pain literature is that of solicitous responding, which is a key mechanism in operant models of pain, hypothesized to increase pain-related disability. A study in people with spinal cord injury chronic pain found perceived solicitous responding from partners were unrelated to pain intensity, pain-related disability, or depression (Stroud, et al., 2006). One study in people with limb loss found that less frequent solicitous responding at one month post amputation was predictive of greater reductions in pain interference at 12 and 24 months (Hanley, et al., 2004). Other forms of partner responses to pain behaviour measured in people with spinal cord injury related chronic pain are negative and distracting responses (Stroud, et al., 2006). Negative responses, such as criticism, and distracting responses were both associated with higher depression, but not pain intensity or pain related disability. Most studies which report upon partner responses to pain behaviours in the context of physically disabling conditions provide information about participants

Chronic Pain in People with Physically Disabling

related pain.

Conditions: A Review of the Application of Biopsychosocial Models 383

of these have involved group-based cognitive behavioural pain management programs, but they also include cognitive restructuring and hypnosis. The potential use of such interventions in people with spinal cord injury was identified in the early 1990's (Umlauf, 1992), but a review of the literature concerning the application and evaluation of these programs among any group with a physically disabling condition reveals a disappointingly

A study undertaken in the US specifically examined the issue of the feasibility and acceptability of psychosocial interventions, with a mixed sample of individuals with chronic pain of more than six months duration occurring secondary to multiple sclerosis, amputations, spinal cord injury and cerebral palsy (Ehde & Jensen, 2004). The study found that both the cognitive restructuring intervention, and the control condition which was an educational intervention, were both rated positively by the participants. A study of a cognitive behavioural pain management program for people with spinal cord injury neuropathic pain reported that attendance at the group was high and participants reported that they were very satisfied with the program (Norrbrink Budh, Kowalski, & Lundeberg, 2006). Authors of another study, examining the effectiveness of a cognitive behavioural pain management program for people with spinal cord injury, provide an analysis of the issues encountered in the implementation of the program (Nicholson Perry, Nicholas, & Middleton, 2010; Nicholson Perry, Nicholas, & Middleton, 2011). These findings suggest that these interventions are potentially acceptable, at least to people with spinal cord injury

Psychosocial interventions for pain either described for use with or evaluated with people with physically disabling conditions are extremely few. They are mainly cognitive behavioural, group-based pain management programs, but examples of the use of cognitive

Four group-based, cognitive behavioural pain management program of various sorts are described in the literature (Cundiff, Blair, & Puckett, 1995; Gironda, 2004; Nicholson Perry, et al., 2010; Norrbrink Budh, et al., 2006). The main components of such interventions are represented in Table 1. The earliest reports in the literature of cognitive behavioural pain management programs in physically disabling conditions were for spinal cord injury pain and were descriptive. Cundiff and colleagues (1995) described the development of a groupbased cognitive behavioural pain management program for people with spinal cord injury pain of all types. This involved many of the common components of pain management programs for primary pain diagnoses, including: the explanation of the self-management model, relaxation (including diaphragmatic breathing, guided imagery), the role of self-talk, and pain behaviours and their impact. Gironda (2004) reported on an intervention which was characterized as an interdisciplinary pain management program for spinal cord injury shoulder pain. It was described as a functional preservation approach aimed at enabling individuals to maintain and improve functional capacities where injuries had already been sustained. The program was provided during a two week in-patient stay and comprised of:

small number of studies and little translation into standard practice.

**4.2 Feasibility and acceptability of psychosocial interventions** 

**4.3 Use and effectiveness of psychosocial interventions** 

**4.3.1 Cognitive behavioural group-based pain management programs** 

restructuring alone and hypnosis are also reported.

perception of their significant others solicitous responses to their pain behaviours. One study in people with spinal cord injury reported on partner's ratings of their own responses to pain behaviour, and it was notable that these were unrelated to pain intensity, depression or pain-related disability in their partner (Stroud, et al., 2006).

#### **3.3 Summary**

Reviewing the evidence presented here, a number of issues are apparent. First, that there is a great deal of variation across physically disabling conditions in the extent to which biopsychosocial factors have been investigated. Second, that over all the conditions considered, social factors are relatively less well explored and this remains a significant omission in the literature. Despite this, and the variation in the patterns in each specific physically disabling condition, across the majority of the conditions for which data is available it is clear that there is evidence to suggest that psychological and social factors are broadly related to pain intensity, as well as associated disability and distress. Across all the factors which have been investigated thus far, it appears that the findings related to pain catastrophizing and its association with pain intensity and related disability and distress are the most consistent. This suggests that pain catastrophizing should be explored as part of assessment protocols for people with chronic pain associated with physically disabling conditions. Further research in the area is clearly needed, particularly prospective studies that begin prior to the development of chronic pain, and which are sufficiently large to permit demographic and medical factors to be controlled for in the analyses.

#### **4. Interventions focused on psychological and social factors**

There are two major reasons why psychosocial interventions for pain might be considered for people with chronic pain secondary to physically disabling conditions. The first, that psychosocial variables are important contributors to variance in pain itself, as well as pain related distress or disability, and the second, that existing interventions based on biomedical models of pain are insufficient. The evidence presented in the previous section suggests that, while there are gaps in the literature, there is sufficient reason to think that psychosocial variables do make a significant contribution to pain and associated distress and disability. In addition, there is evidence that people with chronic pain secondary to a range of physically disabling conditions, including cerebral palsy, stroke and multiple sclerosis, are unlikely to be receiving treatment for their pain, are dissatisfied with the pain treatment available to them or report limited improvement in pain despite treatment (Engel, et al., 2003; Hirsh, et al., 2010; Kalia & O'Connor, 2005; Kong, et al., 2004).

Psychosocial interventions for people with chronic pain, predominantly behavioural and cognitive behavioural in origin, are well-established and supported by an extensive evidence base (Meldrum, 2007). A series of systematic reviews and meta-analyses attest to the efficacy of these programs among child and adults with primary chronic pain conditions, as well as early interventions designed to reduce the development of pain-related disability (Eccleston, Morley, Williams, Yorke, & Mastroyannopoulou, 2002; Eccleston, Yorke, Morley, Williams, & Mastroyannopoulou, 2003; Linton & Nordin, 2006; Morley, Eccleston, & Williams, 1999).

#### **4.1 The nature of psychosocial interventions**

A very small number of studies have been published that specifically report on the use of psychosocial interventions among people with physically disabling conditions. The majority

perception of their significant others solicitous responses to their pain behaviours. One study in people with spinal cord injury reported on partner's ratings of their own responses to pain behaviour, and it was notable that these were unrelated to pain intensity, depression

Reviewing the evidence presented here, a number of issues are apparent. First, that there is a great deal of variation across physically disabling conditions in the extent to which biopsychosocial factors have been investigated. Second, that over all the conditions considered, social factors are relatively less well explored and this remains a significant omission in the literature. Despite this, and the variation in the patterns in each specific physically disabling condition, across the majority of the conditions for which data is available it is clear that there is evidence to suggest that psychological and social factors are broadly related to pain intensity, as well as associated disability and distress. Across all the factors which have been investigated thus far, it appears that the findings related to pain catastrophizing and its association with pain intensity and related disability and distress are the most consistent. This suggests that pain catastrophizing should be explored as part of assessment protocols for people with chronic pain associated with physically disabling conditions. Further research in the area is clearly needed, particularly prospective studies that begin prior to the development of chronic pain, and which are sufficiently large to

There are two major reasons why psychosocial interventions for pain might be considered for people with chronic pain secondary to physically disabling conditions. The first, that psychosocial variables are important contributors to variance in pain itself, as well as pain related distress or disability, and the second, that existing interventions based on biomedical models of pain are insufficient. The evidence presented in the previous section suggests that, while there are gaps in the literature, there is sufficient reason to think that psychosocial variables do make a significant contribution to pain and associated distress and disability. In addition, there is evidence that people with chronic pain secondary to a range of physically disabling conditions, including cerebral palsy, stroke and multiple sclerosis, are unlikely to be receiving treatment for their pain, are dissatisfied with the pain treatment available to them or report limited improvement in pain despite treatment (Engel,

Psychosocial interventions for people with chronic pain, predominantly behavioural and cognitive behavioural in origin, are well-established and supported by an extensive evidence base (Meldrum, 2007). A series of systematic reviews and meta-analyses attest to the efficacy of these programs among child and adults with primary chronic pain conditions, as well as early interventions designed to reduce the development of pain-related disability (Eccleston, Morley, Williams, Yorke, & Mastroyannopoulou, 2002; Eccleston, Yorke, Morley, Williams, & Mastroyannopoulou, 2003; Linton & Nordin, 2006; Morley, Eccleston, & Williams, 1999).

A very small number of studies have been published that specifically report on the use of psychosocial interventions among people with physically disabling conditions. The majority

permit demographic and medical factors to be controlled for in the analyses.

**4. Interventions focused on psychological and social factors** 

et al., 2003; Hirsh, et al., 2010; Kalia & O'Connor, 2005; Kong, et al., 2004).

**4.1 The nature of psychosocial interventions** 

or pain-related disability in their partner (Stroud, et al., 2006).

**3.3 Summary** 

of these have involved group-based cognitive behavioural pain management programs, but they also include cognitive restructuring and hypnosis. The potential use of such interventions in people with spinal cord injury was identified in the early 1990's (Umlauf, 1992), but a review of the literature concerning the application and evaluation of these programs among any group with a physically disabling condition reveals a disappointingly small number of studies and little translation into standard practice.

#### **4.2 Feasibility and acceptability of psychosocial interventions**

A study undertaken in the US specifically examined the issue of the feasibility and acceptability of psychosocial interventions, with a mixed sample of individuals with chronic pain of more than six months duration occurring secondary to multiple sclerosis, amputations, spinal cord injury and cerebral palsy (Ehde & Jensen, 2004). The study found that both the cognitive restructuring intervention, and the control condition which was an educational intervention, were both rated positively by the participants. A study of a cognitive behavioural pain management program for people with spinal cord injury neuropathic pain reported that attendance at the group was high and participants reported that they were very satisfied with the program (Norrbrink Budh, Kowalski, & Lundeberg, 2006). Authors of another study, examining the effectiveness of a cognitive behavioural pain management program for people with spinal cord injury, provide an analysis of the issues encountered in the implementation of the program (Nicholson Perry, Nicholas, & Middleton, 2010; Nicholson Perry, Nicholas, & Middleton, 2011). These findings suggest that these interventions are potentially acceptable, at least to people with spinal cord injury related pain.

#### **4.3 Use and effectiveness of psychosocial interventions**

Psychosocial interventions for pain either described for use with or evaluated with people with physically disabling conditions are extremely few. They are mainly cognitive behavioural, group-based pain management programs, but examples of the use of cognitive restructuring alone and hypnosis are also reported.

#### **4.3.1 Cognitive behavioural group-based pain management programs**

Four group-based, cognitive behavioural pain management program of various sorts are described in the literature (Cundiff, Blair, & Puckett, 1995; Gironda, 2004; Nicholson Perry, et al., 2010; Norrbrink Budh, et al., 2006). The main components of such interventions are represented in Table 1. The earliest reports in the literature of cognitive behavioural pain management programs in physically disabling conditions were for spinal cord injury pain and were descriptive. Cundiff and colleagues (1995) described the development of a groupbased cognitive behavioural pain management program for people with spinal cord injury pain of all types. This involved many of the common components of pain management programs for primary pain diagnoses, including: the explanation of the self-management model, relaxation (including diaphragmatic breathing, guided imagery), the role of self-talk, and pain behaviours and their impact. Gironda (2004) reported on an intervention which was characterized as an interdisciplinary pain management program for spinal cord injury shoulder pain. It was described as a functional preservation approach aimed at enabling individuals to maintain and improve functional capacities where injuries had already been sustained. The program was provided during a two week in-patient stay and comprised of:

Chronic Pain in People with Physically Disabling

context of refractive spinal cord injury pain.

**4.3.2 Cognitive restructuring** 

Conditions: A Review of the Application of Biopsychosocial Models 385

measures (including pain intensity and unpleasantness, health-related quality of life and life satisfaction). An Australian study compared a cognitive behavioural pain management program with standard care in a tertiary pain management service in Australia. The program was a modification of an existing program, the design and implementation of which is reported in depth elsewhere, which was approximately half of the usual number of contact hours (Nicholson Perry, et al., 2011). The group attending the pain management program showed an overall improved in mood and pain-related disability at the end of the program compared with the controlled group. This was associated with significant decreases in pain catastrophizing and anxiety in the pain management program group. Three-quarters of people completing the pain management program reported a clinically significant improvement, in contrast to less than a third in the usual care comparison group, however long-term follow up data in this group suggested that benefits were not maintained at six months. Both programs were approximately half of the optimal dose (100 hours) recommended for the management of patients with heterogeneous, disabling chronic pain in a pain management program (Guzman, et al., 2001). While it may appear at first sight that there is a degree of inconsistency in providing an intervention incorporating pacing, where other evidence suggests pacing is an unhelpful strategy among those with chronic pain due to physically disabling conditions, this may be a matter of definition; pacing as taught in cognitive behavioural pain management programs takes a systematic approach to continuing to build up quotas of activity which it may be hypothesized is absent in what respondents would endorse as pacing in surveys of pain-related coping strategies. However, the findings from the evaluation of the programs suggested that there was merit in pursuing the use of cognitive behavioural pain management programs in the

A pilot program exploring the use of a cognitive restructuring intervention targeting catastrophizing for a heterogeneous group of people with disability related chronic pain has recently been reported (Ehde & Jensen, 2004). The authors compared eight 90-minute sessions of cognitive restructuring with an education control intervention among 18 people with disability-related chronic pain (including those with amputations, spinal cord injury, cerebral palsy and multiple sclerosis). The cognitive restructuring intervention included: the role of negative cognitions; how to identify maladaptive thinking; thought-stopping and cognitive restructuring techniques; and use of reassuring self-statements. The education control intervention included pain education (underlying mechanisms and theories of pain), sleep problems in pain and common pain treatments. The authors report that nine of those who attended the first session did not return, but of the eighteen who did continue with their treatment all reported benefiting from the intervention regardless of the group attended. The preliminary results reported by the authors, describing mean pain intensity on a range of 0 to 10 before and after attendance, suggested that whereas pain intensity was unchanged in those attending the education group there was a reduction of approximately 0.2 of a standard deviation among those participating in the cognitive intervention. The authors conclude that a properly powered controlled trial would be required to establish the effectiveness of this approach, but that it was certainly feasible to provide and regarded as acceptable by at least half the patients. Although the literature on the use of psychosocial interventions in people with physically disabling conditions is limited, there is some evidence of similar therapeutic mechanisms operating in these populations as in chronic primary pain conditions (Burns,

medication adjustment; an exercise regimen designed to increase range of motion, endurance and stretch in upper limbs; biomechanical education; a psychoeducational component designed to enhance understanding of the self-management approach, promote problem-solving and implementation of strategies at home, raise awareness of compensatory responses that may be impacting upon psychological or physical well-being; and recreation therapy to encourage return to social and leisure interests. Preliminary data from eight participants in the program suggested improvements across a range of domains, including mood, sleep and pain intensity during shoulder range of motion testing.


Table 1. Common components of cognitive behavioural pain management programs

Two controlled studies have been published which have examined the effectiveness of cognitive behavioural group pain management programs for people with physically disabling conditions, both in those with spinal cord injury (Nicholson Perry, et al., 2010; Norrbrink Budh, et al., 2006). The first controlled study in the literature described a cognitive behavioural pain management program for people with neuropathic pain arising from a spinal cord injury (Norrbrink Budh et al., 2006). The program developed was very like the pain management programs described for people with primary pain diagnoses in content, although of shorter duration (totalling 50 hours over ten weeks). Compared with those in the no-treatment control group, those participating in the program showed significant improvements in depression and sense of coherence (a concept comprising comprehensibility, manageability and meaningfulness of the injury) over 12 months. While there were no other significant differences between the groups, the treatment group showed improvements in anxiety symptoms, emotional reaction and sleep from baseline to the 12 month evaluation, but no significant changes over time were observed in the other outcome

medication adjustment; an exercise regimen designed to increase range of motion, endurance and stretch in upper limbs; biomechanical education; a psychoeducational component designed to enhance understanding of the self-management approach, promote problem-solving and implementation of strategies at home, raise awareness of compensatory responses that may be impacting upon psychological or physical well-being; and recreation therapy to encourage return to social and leisure interests. Preliminary data from eight participants in the program suggested improvements across a range of domains,

> Information is presented about the underlying pain mechanisms relevant to chronic pain, including central sensitization, as well as

Collaborative goal-setting related to a variety of goals across a wide spread of domains, including physical activities or mood, emphasizing the identification of short-term goals building towards long-term goals that are challenging but achievable in

Development of a plan to manage temporary increases in pain

(flare ups) or other situations likely to trigger relapse.

the limitations of medical treatment for chronic pain.

including mood, sleep and pain intensity during shoulder range of motion testing.

order to increase a sense of mastery. Activity pacing Adoption of quota or time based activities, systematically upgraded over time and linked to goals. Relaxation Applied relaxation to reduce muscle tension and improve sleep. Functional exercise Whole body reconditioning exercise programme related functional

Cognitive therapy Identification and modification of unhelpful thoughts regarding

Medication reduction Gradual reduction of inappropriate or excessive pain medications

Two controlled studies have been published which have examined the effectiveness of cognitive behavioural group pain management programs for people with physically disabling conditions, both in those with spinal cord injury (Nicholson Perry, et al., 2010; Norrbrink Budh, et al., 2006). The first controlled study in the literature described a cognitive behavioural pain management program for people with neuropathic pain arising from a spinal cord injury (Norrbrink Budh et al., 2006). The program developed was very like the pain management programs described for people with primary pain diagnoses in content, although of shorter duration (totalling 50 hours over ten weeks). Compared with those in the no-treatment control group, those participating in the program showed significant improvements in depression and sense of coherence (a concept comprising comprehensibility, manageability and meaningfulness of the injury) over 12 months. While there were no other significant differences between the groups, the treatment group showed improvements in anxiety symptoms, emotional reaction and sleep from baseline to the 12 month evaluation, but no significant changes over time were observed in the other outcome

Table 1. Common components of cognitive behavioural pain management programs

pain, such as catastrophizing.

using an agreed schedule.

Component Description

physical goals. Stretch Whole body daily stretch programme.

Education regarding

Flare-up management & relapse prevention

pain

Goal-setting

measures (including pain intensity and unpleasantness, health-related quality of life and life satisfaction). An Australian study compared a cognitive behavioural pain management program with standard care in a tertiary pain management service in Australia. The program was a modification of an existing program, the design and implementation of which is reported in depth elsewhere, which was approximately half of the usual number of contact hours (Nicholson Perry, et al., 2011). The group attending the pain management program showed an overall improved in mood and pain-related disability at the end of the program compared with the controlled group. This was associated with significant decreases in pain catastrophizing and anxiety in the pain management program group. Three-quarters of people completing the pain management program reported a clinically significant improvement, in contrast to less than a third in the usual care comparison group, however long-term follow up data in this group suggested that benefits were not maintained at six months. Both programs were approximately half of the optimal dose (100 hours) recommended for the management of patients with heterogeneous, disabling chronic pain in a pain management program (Guzman, et al., 2001). While it may appear at first sight that there is a degree of inconsistency in providing an intervention incorporating pacing, where other evidence suggests pacing is an unhelpful strategy among those with chronic pain due to physically disabling conditions, this may be a matter of definition; pacing as taught in cognitive behavioural pain management programs takes a systematic approach to continuing to build up quotas of activity which it may be hypothesized is absent in what respondents would endorse as pacing in surveys of pain-related coping strategies. However, the findings from the evaluation of the programs suggested that there was merit in pursuing the use of cognitive behavioural pain management programs in the context of refractive spinal cord injury pain.

#### **4.3.2 Cognitive restructuring**

A pilot program exploring the use of a cognitive restructuring intervention targeting catastrophizing for a heterogeneous group of people with disability related chronic pain has recently been reported (Ehde & Jensen, 2004). The authors compared eight 90-minute sessions of cognitive restructuring with an education control intervention among 18 people with disability-related chronic pain (including those with amputations, spinal cord injury, cerebral palsy and multiple sclerosis). The cognitive restructuring intervention included: the role of negative cognitions; how to identify maladaptive thinking; thought-stopping and cognitive restructuring techniques; and use of reassuring self-statements. The education control intervention included pain education (underlying mechanisms and theories of pain), sleep problems in pain and common pain treatments. The authors report that nine of those who attended the first session did not return, but of the eighteen who did continue with their treatment all reported benefiting from the intervention regardless of the group attended. The preliminary results reported by the authors, describing mean pain intensity on a range of 0 to 10 before and after attendance, suggested that whereas pain intensity was unchanged in those attending the education group there was a reduction of approximately 0.2 of a standard deviation among those participating in the cognitive intervention. The authors conclude that a properly powered controlled trial would be required to establish the effectiveness of this approach, but that it was certainly feasible to provide and regarded as acceptable by at least half the patients. Although the literature on the use of psychosocial interventions in people with physically disabling conditions is limited, there is some evidence of similar therapeutic mechanisms operating in these populations as in chronic primary pain conditions (Burns,

Chronic Pain in People with Physically Disabling

physically disabling conditions.

**4.5 Summary** 

**5. Conclusion** 

psychosocial interventions.

**6. Acknowledgement** 

Conditions: A Review of the Application of Biopsychosocial Models 387

Service delivery models which are able to overcome some of these barriers are yet to be designed, and many of the interventions with a research pedigree to support them have not generalized to routine care due to the lack of support to assist with translation into routine clinical practice. The increased availability of high speed internet may permit the use of online interventions to provide at least some access to some of the components of effective psychosocial interventions for chronic pain, either for use alone or with the support of a health professional, and this may be of particular benefit to those with pain secondary to

Despite the limited evidence available about the effective of psychosocial interventions in people with physically disabling conditions, the findings suggest that there is merit in further research to evaluate their usefulness in a broader range of conditions. Intervention studies in this area are notoriously difficult, due to the many barriers to participation and retention in trials. National and international collaborations are likely to be necessary to ensure a sufficient sample size for such studies to be adequately powered. Provision of these services is impeded by a number of practical barriers, some of which might at least partially addressed by making more effective use of information technology (World Health Organisation, 2011). While there is currently insufficient evidence to support a wholesale recommendation to use these interventions in all physically disabling conditions, in light of the dissatisfaction with pain treatment among many with chronic pain secondary to physically disabling conditions they may be considered for use on an individual basis.

It can be concluded based upon the data presented that the application of biopsychosocial models to the understanding, assessment and management of chronic pain associated with physically disabling conditions is at an early stage of development. There is a well-established body of research in some conditions, such as spinal cord injury, whereas almost nothing is known about the application of these models to other conditions, notably Parkinson's Disease. Many of the patterns observed in primary pain conditions are replicated in these conditions, but the exceptions noted underscore the importance of caution in generalising findings from one condition to another. Relatively, research concerning the use of psychosocial interventions is less well-developed that research examining the relationships between psychosocial and pain variables in physically disabling conditions. Despite this, the findings generally are suggestive of an important role of including psychosocial variables in our conceptualization of individual differences in the experience of chronic pain and its consequences in people with physically disabling conditions, and the possibility of improved outcomes through the use of

Much of what I have learned about this area has resulted from the conversations I have been privileged to have with people with physically disabling conditions, and I thank them for their willingness to educate me. I am continually grateful for the opportunity to work with many wise colleagues who have taught me a great deal about pain and some of the physically disabling conditions which have formed the subject of this chapter. In particular, I would like to thank Associate Professor Michael Nicholas, Associate Professor James

Kubilus, Bruehl, Harden, & Lofland, 2003). In particular, the observation of the association between decreased pain catastrophising and improvements in mood and disability in those who participate in the interventions is consistent with findings in other chronic pain populations (Jensen, et al., 2011; Nicholson Perry, et al., 2010). This cognitive restructuring intervention therefore has particular promise as it targets pain catastrophizing, but requires implementation of a smaller range of treatment strategies than traditional cognitive behavioural pain management programs as described above.

#### **4.3.3 Hypnosis**

Hypnosis has also been applied to spinal cord injury related pain in a series of studies (Ehde & Jensen, 2007) using individual hypnosis treatments with 10 sessions over four weeks and daily practice. The suggestions used were reported to include imagery, changing sensations and ignoring pain, with associated post-hypnotic suggestions that a relaxed state and the ability to ignore pain will become increasingly easy. The case studies found that a sub-group of individuals with disability-related pain were able to obtain decreases in pain severity, with associated improvements in mood, sleep and general well-being in individual cases. However, in the absence of randomized controlled trials, no firm conclusions can be drawn about the effectiveness of hypnosis in this context.

In a variation of the more common cognitive behavioural interventions reported in the literature, a cognitive restructuring approach combined with self-hypnosis training was reported in people with multiple sclerosis (Jensen, et al., 2011). This intervention was intended to target pain catastrophising as well as pain intensity. When compared with either cognitive restructuring or hypnosis alone, or the control condition, the combined approach resulted in a decrease in the frequency of pain catastrophising and increase in the frequency of reassuring cognitions, as well as improved average and worst pain intensity.

#### **4.4 Barriers to the use of psychosocial interventions**

While access to specialist pain management services of any type is problematic, there are some additional reasons to think that access to psychosocial pain interventions will be particularly difficult for those with physically disabling conditions. Broadly, these include the demands of providing such services and accessibility of such services. Health professionals specialising in the provision of psychosocial interventions for chronic pain, such as clinical psychologists, tend to be limited in supply and concentrated in specialist services in major cities. The skills and expertise required to provide psychosocial pain management interventions to those with physically disabling conditions requires expertise in both pain and some of the specific aspects of the physically disabling condition which may impact upon the delivery of the intervention. This includes having an understanding of the physically disabling conditions and its associated symptoms, such as motor function or fatigue, and how these may impact upon the relevance or implementation of the strategies taught. The additional challenges to mobility from having a physically disabling conditions, as well as chronic pain, in combination with environmental barriers which must be overcome to attend a specialist pain management service reduces the chances that an individual with a chronic pain problem due to a physically disabling condition will be able to attend. The costs of living with a physically disabling condition may result in limited financial resources available to fund travel or accommodation in locations where specialist pain management services are available.

Service delivery models which are able to overcome some of these barriers are yet to be designed, and many of the interventions with a research pedigree to support them have not generalized to routine care due to the lack of support to assist with translation into routine clinical practice. The increased availability of high speed internet may permit the use of online interventions to provide at least some access to some of the components of effective psychosocial interventions for chronic pain, either for use alone or with the support of a health professional, and this may be of particular benefit to those with pain secondary to physically disabling conditions.

#### **4.5 Summary**

386 Pain Management – Current Issues and Opinions

Kubilus, Bruehl, Harden, & Lofland, 2003). In particular, the observation of the association between decreased pain catastrophising and improvements in mood and disability in those who participate in the interventions is consistent with findings in other chronic pain populations (Jensen, et al., 2011; Nicholson Perry, et al., 2010). This cognitive restructuring intervention therefore has particular promise as it targets pain catastrophizing, but requires implementation of a smaller range of treatment strategies than traditional cognitive

Hypnosis has also been applied to spinal cord injury related pain in a series of studies (Ehde & Jensen, 2007) using individual hypnosis treatments with 10 sessions over four weeks and daily practice. The suggestions used were reported to include imagery, changing sensations and ignoring pain, with associated post-hypnotic suggestions that a relaxed state and the ability to ignore pain will become increasingly easy. The case studies found that a sub-group of individuals with disability-related pain were able to obtain decreases in pain severity, with associated improvements in mood, sleep and general well-being in individual cases. However, in the absence of randomized controlled trials, no firm conclusions can be drawn

In a variation of the more common cognitive behavioural interventions reported in the literature, a cognitive restructuring approach combined with self-hypnosis training was reported in people with multiple sclerosis (Jensen, et al., 2011). This intervention was intended to target pain catastrophising as well as pain intensity. When compared with either cognitive restructuring or hypnosis alone, or the control condition, the combined approach resulted in a decrease in the frequency of pain catastrophising and increase in the frequency of reassuring cognitions, as well as improved average and worst pain

While access to specialist pain management services of any type is problematic, there are some additional reasons to think that access to psychosocial pain interventions will be particularly difficult for those with physically disabling conditions. Broadly, these include the demands of providing such services and accessibility of such services. Health professionals specialising in the provision of psychosocial interventions for chronic pain, such as clinical psychologists, tend to be limited in supply and concentrated in specialist services in major cities. The skills and expertise required to provide psychosocial pain management interventions to those with physically disabling conditions requires expertise in both pain and some of the specific aspects of the physically disabling condition which may impact upon the delivery of the intervention. This includes having an understanding of the physically disabling conditions and its associated symptoms, such as motor function or fatigue, and how these may impact upon the relevance or implementation of the strategies taught. The additional challenges to mobility from having a physically disabling conditions, as well as chronic pain, in combination with environmental barriers which must be overcome to attend a specialist pain management service reduces the chances that an individual with a chronic pain problem due to a physically disabling condition will be able to attend. The costs of living with a physically disabling condition may result in limited financial resources available to fund travel or accommodation in locations where specialist

behavioural pain management programs as described above.

about the effectiveness of hypnosis in this context.

**4.4 Barriers to the use of psychosocial interventions** 

pain management services are available.

**4.3.3 Hypnosis** 

intensity.

Despite the limited evidence available about the effective of psychosocial interventions in people with physically disabling conditions, the findings suggest that there is merit in further research to evaluate their usefulness in a broader range of conditions. Intervention studies in this area are notoriously difficult, due to the many barriers to participation and retention in trials. National and international collaborations are likely to be necessary to ensure a sufficient sample size for such studies to be adequately powered. Provision of these services is impeded by a number of practical barriers, some of which might at least partially addressed by making more effective use of information technology (World Health Organisation, 2011). While there is currently insufficient evidence to support a wholesale recommendation to use these interventions in all physically disabling conditions, in light of the dissatisfaction with pain treatment among many with chronic pain secondary to physically disabling conditions they may be considered for use on an individual basis.

#### **5. Conclusion**

It can be concluded based upon the data presented that the application of biopsychosocial models to the understanding, assessment and management of chronic pain associated with physically disabling conditions is at an early stage of development. There is a well-established body of research in some conditions, such as spinal cord injury, whereas almost nothing is known about the application of these models to other conditions, notably Parkinson's Disease. Many of the patterns observed in primary pain conditions are replicated in these conditions, but the exceptions noted underscore the importance of caution in generalising findings from one condition to another. Relatively, research concerning the use of psychosocial interventions is less well-developed that research examining the relationships between psychosocial and pain variables in physically disabling conditions. Despite this, the findings generally are suggestive of an important role of including psychosocial variables in our conceptualization of individual differences in the experience of chronic pain and its consequences in people with physically disabling conditions, and the possibility of improved outcomes through the use of psychosocial interventions.

#### **6. Acknowledgement**

Much of what I have learned about this area has resulted from the conversations I have been privileged to have with people with physically disabling conditions, and I thank them for their willingness to educate me. I am continually grateful for the opportunity to work with many wise colleagues who have taught me a great deal about pain and some of the physically disabling conditions which have formed the subject of this chapter. In particular, I would like to thank Associate Professor Michael Nicholas, Associate Professor James

Chronic Pain in People with Physically Disabling

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**19** 

 *Canada* 

**The Role of Peripheral Nerve Blocks in the Interdisciplinary** 

Gillian R. Lauder1 and Nicholas West2

**Care of Children with Chronic Pain:** 

**A Case Series and Review of the Literature** 

Chronic pain of childhood is an extremely complex condition which can lead to damaging effects on physical and social wellbeing. Some children with severe chronic pain embark on a downward spiral of decreased physical, psychological and social functioning. This includes loss of mobility and inability to participate in physical and sporting activities, poor sleep, difficulty concentrating on school work, school absenteeism, social isolation and family stress. As chronic pain persists the child can experience increased pain intensity, distress, anxiety and depression. When enmeshed in this disordered lifestyle the child and their family require coordinated integrated care. The interdisciplinary team management approach, based on pharmacology, physiotherapy and psychology, is now well established to be the standard of care for children with chronic pain. Treatment goals are targeted to individual children after careful consideration of the history and examination. In appropriately selected children peripheral nerve blocks can provide immediate and effective pain relief. This chapter will present a referenced review of the literature on interdisciplinary paediatric chronic pain management whilst highlighting the role of peripheral nerve blocks. The case histories of eight paediatric patients with chronic pain

who gained significant relief from peripheral nerve blocks will be presented.

The International Association for the Study of Pain (IASP) defines pain as "an unpleasant sensory or emotional experience associated with actual or potential tissue damage, or described in terms of such damage" (1986). One defining characteristic of pain is its duration. Acute pain is relatively short-term pain that typically lasts until the underlying cause has been identified and treated. On the other hand, chronic pain is understood to mean prolonged pain or "pain that extends beyond the expected period of healing" (Turk & Okifuji, 2001) and while defined time frames that determine a diagnosis of chronic pain vary, the definition adopted by most studies, including those cited here, is pain lasting

Chronic pain can have its roots in one or a combination of types of pain mechanism. Types of pain include nociceptive, inflammatory, neuropathic or psychogenic pain (DSM-IV "Pain Disorder"). Extreme caution is required before labelling a patient with a diagnosis of

**1. Introduction** 

longer than three months.

*1Department of Anesthesia, British Columbia Children's Hospital (BCCH), 2Pediatric Anesthesia Research Team, University of British Columbia (UBC),* 


### **The Role of Peripheral Nerve Blocks in the Interdisciplinary Care of Children with Chronic Pain: A Case Series and Review of the Literature**

Gillian R. Lauder1 and Nicholas West2

*1Department of Anesthesia, British Columbia Children's Hospital (BCCH), 2Pediatric Anesthesia Research Team, University of British Columbia (UBC), Canada* 

#### **1. Introduction**

394 Pain Management – Current Issues and Opinions

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injury pain: the influence of psychologic factors and impact on quality of life.

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injury. *Clinical Journal of Pain, 8*, 111-118.

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Organisation.

phantom limb pain patients. *Pain, 152*(1), 157-162.

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cord injury. *Journal of Neurotrauma, 21*(10), 1384-1395.

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associated with pain intensity, psychological distress, and pain-related disability among individuals with chronic pain after spinal cord injury. *Pain, 98*(1-2), 127-134.

associations between pain severity, psychological distress, and functional disability among persons with spinal cord injury. *Rehabilitation Psychology, 52*(4), 390-398. Ullrich, P. M., Jensen, M. P., Loeser, J. D., Cardenas, D. D., & Weaver, F. M. (2008). Pain

among veterans with spinal cord injury. *Journal of Rehabilitation Research and* 

al. (2011). Cognitive-emotional sensitization contributes to wind-up-like pain in

Chronic pain of childhood is an extremely complex condition which can lead to damaging effects on physical and social wellbeing. Some children with severe chronic pain embark on a downward spiral of decreased physical, psychological and social functioning. This includes loss of mobility and inability to participate in physical and sporting activities, poor sleep, difficulty concentrating on school work, school absenteeism, social isolation and family stress. As chronic pain persists the child can experience increased pain intensity, distress, anxiety and depression. When enmeshed in this disordered lifestyle the child and their family require coordinated integrated care. The interdisciplinary team management approach, based on pharmacology, physiotherapy and psychology, is now well established to be the standard of care for children with chronic pain. Treatment goals are targeted to individual children after careful consideration of the history and examination. In appropriately selected children peripheral nerve blocks can provide immediate and effective pain relief. This chapter will present a referenced review of the literature on interdisciplinary paediatric chronic pain management whilst highlighting the role of peripheral nerve blocks. The case histories of eight paediatric patients with chronic pain who gained significant relief from peripheral nerve blocks will be presented.

The International Association for the Study of Pain (IASP) defines pain as "an unpleasant sensory or emotional experience associated with actual or potential tissue damage, or described in terms of such damage" (1986). One defining characteristic of pain is its duration. Acute pain is relatively short-term pain that typically lasts until the underlying cause has been identified and treated. On the other hand, chronic pain is understood to mean prolonged pain or "pain that extends beyond the expected period of healing" (Turk & Okifuji, 2001) and while defined time frames that determine a diagnosis of chronic pain vary, the definition adopted by most studies, including those cited here, is pain lasting longer than three months.

Chronic pain can have its roots in one or a combination of types of pain mechanism. Types of pain include nociceptive, inflammatory, neuropathic or psychogenic pain (DSM-IV "Pain Disorder"). Extreme caution is required before labelling a patient with a diagnosis of

The Role of Peripheral Nerve Blocks in the Interdisciplinary

Gagnon et al, 2007).

conflict.

Care of Children with Chronic Pain: A Case Series and Review of the Literature 397

Previous pain experiences, cognitive, emotional and behavioural factors, family background, environment, peer group and culture have an influence on the impact, perception and biopsychosocial outcomes of chronic pain. Children living in lower educated, lower income families have been found to be at a greater risk of suffering recurrent pain, which is consistent with adult studies (Grøholt et al, 2003). Children suffering chronic pain themselves are quite likely to be living with another chronic pain sufferer, whether parent or sibling, and further investigation suggests that pre-existing chronic pain in the family environment is a predictor of both physical and psychological effects on the child (Lynch et al, 2006). Ethnicity and area of residence also appear to affect prevalence rates. For example, in Canada, the incidence of chronic pain is higher among Aboriginal people and, for males, is higher in rural areas (Ramage-Morin & Gilmour, 2010). There may also be cultural differences in the perception and reporting of pain (Mailis-

While chronic pain is clearly not confined to the developed world, most published studies provide figures for European or North American children, which may not be generalisable to different environments. A US study found that 13% of 12-13 year-olds and 17% of 15-16 year-olds experience abdominal pain every week (Hyams et al, 1996), while Dutta et al (1999) reported a considerably higher incidence (74%) in India. However, with gastrointestinal infections more widespread than the inflammatory bowel disease seen in developing countries, these figures probably represent the outcome of different disease processes (Ganesh et al, 2010). Abu-Saad Huijer (2010) considers the effects of war and traumatic events. Despite an absence of research in this area, he argues that chronic pain has been linked with post-traumatic stress disorders and that, as a consequence, we may expect to see a different profile of chronic pain among children affected by armed

In developed countries, headache, abdominal and musculoskeletal pain form the primary foci of chronic and recurrent pain among the paediatric population. In their study of Canadian 9-13 year olds, van Dijk et al (2006) received reports of recurrent headaches (32%), growing pains (21%), stomach pains (19%) and muscle aches (2%). Perquin et al (2000) had published similar findings from their survey of Dutch schoolchildren, in which they also analysed reports of pain at multiple locations. They found that the single location pain was most often reported. The combination of headache and abdominal pain was the most commonly reported multiple pain, found in 25% of all children. This greater than one pain

Recent figures from a Statistics Canada health report identify chronic pain among 2.4% of males and 5.9% of females aged 12 to 17 years (Ramage-Morin & Gilmour, 2010). It has been reported that girls are as much as three times more likely to report chronic pain than boys (Martin et al, 2007). Perquin et al (2000) also showed a significant increase in the prevalence of chronic pain in girls. These girls were aged between 12 and 14 which may well be linked with the onset of menstruation. In general, abdominal pain is significantly more likely to be reported by girls and limb pain (or growing pains/muscle aches) is significantly more likely to be reported by boys (Perquin et al, 2000; van Dijk et al, 2006). A review on gender and pain suggests potential mechanisms within social and psychological processes, such as coping processes and catastrophising, are likely to contribute to the repeatedly observed sex

Aetiology and predisposition to chronic pain in children is largely unknown and depends on the type of pain. Factors associated with the development of chronic pain include

profile was significantly more prevalent in adolescent girls.

differences in pain (Fillingim et al, 2009).

psychogenic pain, functional pain or somatisation disorder as the true prevalence of these conditions is extremely low. Most patients with chronic pain will have psychosocial elements to their suffering, but this does not mean that the pain is "psychogenic".

Nociceptive pain is felt in response to noxious stimuli, such as the trauma associated with injury, oncological and other disease processes as well as following surgery. This pain functions as a protective and interpretable symptom: 'it hurts here' means 'here is the damage' and can be a straightforward guide to what needs to be treated or allowed to heal. *Inflammatory pain* occurs as a result of inflammatory mediators in many disease processes or associated with healing following acute trauma or surgery. If either nociceptive or inflammatory pains are left unrecognised or undertreated they can lead to ongoing and then chronic pain. *Neuropathic pain* signifies some dysfunction in the nervous system itself and is a major cause of chronic suffering, occurring in about 6-7% of the population (Vinik, 2010).

Neuropathic pain may derive from some identifiable damage to the nerves, resulting from a disease process, inflammation or accidental damage during trauma or surgery, or may result from a failure of integration and function of the peripheral and central nervous systems. Many conditions previously labelled as functional pain are now known to have peripheral and central nervous elements, which would re-class them as neuropathic pain. Complex regional pain syndrome (CRPS) is an immuno-neurological disorder (Fechir et al, 2008). It may be associated with no nerve lesion (type I) or may be related to some identifiable nerve lesion (type II). Chronic conditions like functional abdominal pain syndrome (FAPS) and CRPS have been under-recognised by physicians, but are experienced by a significant number of adolescents (Clouse et al, 2006; Kachko et al, 2008). In summary, a combination of pain mechanisms may be involved in the development of chronic pain conditions.

#### **1.1 The epidemiology of paediatric chronic pain**

The epidemiology of chronic pain in children is less well understood than it is in adults, but some useful studies have been published in the last decade that help us to understand the overall scale of the problem and to elicit some socio-demographic particulars of the affected population. A survey of over 5,000 children aged 0 – 18 years in the Netherlands reported that 25% had experienced some form of chronic or recurrent pain (Perquin et al, 2000). A Spanish study, of 561 schoolchildren aged 8 – 16 years, reported an incidence of 37%, but concluded that only 5% suffer moderate or severe chronic pain (Huguet & Miró, 2008). In a Canadian study of 495 schoolchildren aged 9 - 13, more than half reported having experienced at least one recurrent pain, typically characterised as a headache, stomach pain or 'growing pain'. Although 46% reported a 'long-lasting' pain, the researchers judged that in many cases this represented a recurrent pain condition; nonetheless, 6% of children were classified as having possible, probable or definite chronic pain (van Dijk et al, 2006).

While these studies highlight the methodological difficulties in distinguishing acute, recurrent and chronic pain from children's responses to questionnaire and interview questions, these statistics clearly also demonstrate that childhood chronic pain is a significant problem: slightly more than one child in every twenty is a chronic pain sufferer; that is, at least one child in every average-sized classroom in every school. Perquin et al (2000) conclude that childhood chronic pain is 'a common experience' and that the incidence of severe chronic pain amongst adolescents should provoke both concern and further research from the healthcare community.

psychogenic pain, functional pain or somatisation disorder as the true prevalence of these conditions is extremely low. Most patients with chronic pain will have psychosocial

Nociceptive pain is felt in response to noxious stimuli, such as the trauma associated with injury, oncological and other disease processes as well as following surgery. This pain functions as a protective and interpretable symptom: 'it hurts here' means 'here is the damage' and can be a straightforward guide to what needs to be treated or allowed to heal. *Inflammatory pain* occurs as a result of inflammatory mediators in many disease processes or associated with healing following acute trauma or surgery. If either nociceptive or inflammatory pains are left unrecognised or undertreated they can lead to ongoing and then chronic pain. *Neuropathic pain* signifies some dysfunction in the nervous system itself and is a major cause of chronic suffering, occurring in about 6-7% of the

Neuropathic pain may derive from some identifiable damage to the nerves, resulting from a disease process, inflammation or accidental damage during trauma or surgery, or may result from a failure of integration and function of the peripheral and central nervous systems. Many conditions previously labelled as functional pain are now known to have peripheral and central nervous elements, which would re-class them as neuropathic pain. Complex regional pain syndrome (CRPS) is an immuno-neurological disorder (Fechir et al, 2008). It may be associated with no nerve lesion (type I) or may be related to some identifiable nerve lesion (type II). Chronic conditions like functional abdominal pain syndrome (FAPS) and CRPS have been under-recognised by physicians, but are experienced by a significant number of adolescents (Clouse et al, 2006; Kachko et al, 2008). In summary, a combination of pain

The epidemiology of chronic pain in children is less well understood than it is in adults, but some useful studies have been published in the last decade that help us to understand the overall scale of the problem and to elicit some socio-demographic particulars of the affected population. A survey of over 5,000 children aged 0 – 18 years in the Netherlands reported that 25% had experienced some form of chronic or recurrent pain (Perquin et al, 2000). A Spanish study, of 561 schoolchildren aged 8 – 16 years, reported an incidence of 37%, but concluded that only 5% suffer moderate or severe chronic pain (Huguet & Miró, 2008). In a Canadian study of 495 schoolchildren aged 9 - 13, more than half reported having experienced at least one recurrent pain, typically characterised as a headache, stomach pain or 'growing pain'. Although 46% reported a 'long-lasting' pain, the researchers judged that in many cases this represented a recurrent pain condition; nonetheless, 6% of children were classified as having possible, probable or definite

While these studies highlight the methodological difficulties in distinguishing acute, recurrent and chronic pain from children's responses to questionnaire and interview questions, these statistics clearly also demonstrate that childhood chronic pain is a significant problem: slightly more than one child in every twenty is a chronic pain sufferer; that is, at least one child in every average-sized classroom in every school. Perquin et al (2000) conclude that childhood chronic pain is 'a common experience' and that the incidence of severe chronic pain amongst adolescents should provoke both concern and further

mechanisms may be involved in the development of chronic pain conditions.

**1.1 The epidemiology of paediatric chronic pain** 

chronic pain (van Dijk et al, 2006).

research from the healthcare community.

elements to their suffering, but this does not mean that the pain is "psychogenic".

population (Vinik, 2010).

Previous pain experiences, cognitive, emotional and behavioural factors, family background, environment, peer group and culture have an influence on the impact, perception and biopsychosocial outcomes of chronic pain. Children living in lower educated, lower income families have been found to be at a greater risk of suffering recurrent pain, which is consistent with adult studies (Grøholt et al, 2003). Children suffering chronic pain themselves are quite likely to be living with another chronic pain sufferer, whether parent or sibling, and further investigation suggests that pre-existing chronic pain in the family environment is a predictor of both physical and psychological effects on the child (Lynch et al, 2006). Ethnicity and area of residence also appear to affect prevalence rates. For example, in Canada, the incidence of chronic pain is higher among Aboriginal people and, for males, is higher in rural areas (Ramage-Morin & Gilmour, 2010). There may also be cultural differences in the perception and reporting of pain (Mailis-Gagnon et al, 2007).

While chronic pain is clearly not confined to the developed world, most published studies provide figures for European or North American children, which may not be generalisable to different environments. A US study found that 13% of 12-13 year-olds and 17% of 15-16 year-olds experience abdominal pain every week (Hyams et al, 1996), while Dutta et al (1999) reported a considerably higher incidence (74%) in India. However, with gastrointestinal infections more widespread than the inflammatory bowel disease seen in developing countries, these figures probably represent the outcome of different disease processes (Ganesh et al, 2010). Abu-Saad Huijer (2010) considers the effects of war and traumatic events. Despite an absence of research in this area, he argues that chronic pain has been linked with post-traumatic stress disorders and that, as a consequence, we may expect to see a different profile of chronic pain among children affected by armed conflict.

In developed countries, headache, abdominal and musculoskeletal pain form the primary foci of chronic and recurrent pain among the paediatric population. In their study of Canadian 9-13 year olds, van Dijk et al (2006) received reports of recurrent headaches (32%), growing pains (21%), stomach pains (19%) and muscle aches (2%). Perquin et al (2000) had published similar findings from their survey of Dutch schoolchildren, in which they also analysed reports of pain at multiple locations. They found that the single location pain was most often reported. The combination of headache and abdominal pain was the most commonly reported multiple pain, found in 25% of all children. This greater than one pain profile was significantly more prevalent in adolescent girls.

Recent figures from a Statistics Canada health report identify chronic pain among 2.4% of males and 5.9% of females aged 12 to 17 years (Ramage-Morin & Gilmour, 2010). It has been reported that girls are as much as three times more likely to report chronic pain than boys (Martin et al, 2007). Perquin et al (2000) also showed a significant increase in the prevalence of chronic pain in girls. These girls were aged between 12 and 14 which may well be linked with the onset of menstruation. In general, abdominal pain is significantly more likely to be reported by girls and limb pain (or growing pains/muscle aches) is significantly more likely to be reported by boys (Perquin et al, 2000; van Dijk et al, 2006). A review on gender and pain suggests potential mechanisms within social and psychological processes, such as coping processes and catastrophising, are likely to contribute to the repeatedly observed sex differences in pain (Fillingim et al, 2009).

Aetiology and predisposition to chronic pain in children is largely unknown and depends on the type of pain. Factors associated with the development of chronic pain include

The Role of Peripheral Nerve Blocks in the Interdisciplinary

a child's quality of life are wide-ranging and profound.

not properly understood or tolerated.

There are a number of reasons for this difficulty.

prompted poorer function regardless of the level of pain.

amounts of school.

Care of Children with Chronic Pain: A Case Series and Review of the Literature 399

2–21 years, attending a chronic pain clinic found that the HRQoL scores of these patients were not only considerably lower than scores obtained from normal healthy children, but were significantly lower than scores observed in children with rheumatological or cancer disease (Vetter, 2008). Another US study found that the mean PedsQL score for a cohort of 69 children and adolescents (aged 8 – 18 years) seeking outpatient pain management services, fell below the 'at-risk cut-off score' for all dimensions except social functioning, suggesting that the majority of these children were experiencing significant disruption in their day-to-day lives. The message from these studies is clear: the effects of chronic pain on

School functioning has received perhaps the most attention (Palermo, 2000). It demonstrates the most marked detriment of all the psychosocial dimensions of the PedsQL scale (Vetter, 2008; Gold et al, 2009) and clearly illustrates the complex effects of chronic pain on quality of life. A child with chronic pain may experience a range of problems which impact on their schooling: fatigue and/or poor sleep profile prevents early morning waking; pain inhibits physical ability to get to school, to sit in a classroom for long periods or to participate in physical activities; fear of pain by accidentally being knocked during recess times inhibits social interaction and imparts a sense of isolation, difference and not being involved with peers; poor memory and concentration affects schoolwork; as school work becomes missed or incomplete these unfinished projects become a barrier to return to school if workload is not controlled; and the school may represent an environment where their pain condition is

For all these reasons school absences are common. In a survey of adolescent chronic pain sufferers aged 12-17 in Boston USA, 44% missed more than one-quarter of school days and 20% had missed more than half (Logan et al, 2008). Of course, schools typically offer only a limited degree of health-related support. In the Boston study, two-thirds of participants had received some form of accommodation from their school, such as being sent to the nurse's office, being sent home in pain, reduction in workload, extension on an assignment, and so on. Nonetheless, 44.3% of parents reported their child's grades had suffered (Logan et al, 2008) and missing school can clearly have negative consequences that extend beyond academic performance to a child's physical, emotional and social development. Six of the eight cases presented in this chapter had missed significant

Assessing the impact of chronic pain on a child's life is an important but problematic task.

Firstly, the specific effects of chronic pain are not easily isolated from one another. For example, fatigue may be a mediating factor between pain and school functioning (Gold et al, 2009). Anxiety also plays a complex role in moderating the relationship between pain and function. Tsao et al (2007) studied anxiety sensitivity, or the fear of anxiety sensations, in 87 children aged 10-18 presenting at a US chronic pain clinic. Anxiety sensitivity was found to be linked with academic and/or social limitations, where those limitations arose from emotional rather than physical difficulties. Greater anxiety sensitivity was associated with lower self-esteem and perceived general and mental health, and with more behavioural problems and family disruption, but did not appear to affect physical functioning (Tsao et al, 2007). In a similar study of 222 adolescents aged 11 to 19 years attending two chronic pain clinics in the UK, Cohen et al (2010) found that in children with low anxiety, level of pain was a good predictor of physical and social function, but that high levels of anxiety

surgery, trauma, emotional distress and chronic disease. In many cases, a definitive aetiology is difficult to establish. Even chronic post-surgical pain (CPSP) can be difficult to diagnose and consequently remains under-recognised. However, it represents a significant clinical problem. A 2006 review suggests that CPSP occurs after 10-50% of operations and results in severe chronic pain in 2-10% of these patients (Kehlet et al, 2006). This may, in fact, represent a significant portion of chronic pain sufferers. A UK study found that 22.5% of chronic pain patients developed their condition after surgery (Crombie et al, 1998). CPSP will often be neuropathic, resulting from nerve damage during surgery, though it could also be an ongoing inflammatory/nociceptive mechanism. The incidence of CPSP in the adult population is found to depend on a number of perioperative factors which include: genetic predisposition, degree of pre-operative anxiety, depression, pre-operative pain status, the surgical pain model, surgical technique, length of surgery and the quality of acute postoperative pain management (Kehlet et al, 2006; Macrae, 2008). The probability of an adult developing chronic pain after mastectomy or hernia surgery is decreased with increased age (Poleshuck et al, 2006; Poobalan et al, 2003). How this relationship to age translates to children and adolescents is not known as there is no published literature on CPSP in children. Six out of the eight paediatric cases presented in this chapter developed chronic pain following surgery.

Untangling factors to establish clear causality for the development of paediatric chronic pain is a challenge. Whether initiated by surgery or injury or other cause, it is a complex multifactorial process. Understanding this mechanism requires not only a search for a cause, but also a clearer understanding of the effects of chronic pain. It is established that some paediatric chronic pain conditions have been under-diagnosed. Better recognition and early treatment of these conditions requires that healthcare providers understand the effects of chronic pain on a child and their family.

#### **1.2 The impact of chronic pain on children and their families**

Childhood chronic pain has a negative impact on physical, psychological and social function. It can prevent a child participating in sporting activities and other forms of exercise. It can cause sleep disruption and fatigue. It can contribute to depression and anxiety. It can affect school work through fatigue, poor memory and concentration and result in reduced school attendance. Friendships and family relationships are disrupted which may lead to varying degrees of social isolation. An Australian study of 207 children and adolescents attending a paediatric pain management clinic found that 95% had missed school, 90% had been unable to participate in some sporting activity and 71% had suffered some sleep disruption (Chalkiadis, 2001). Roth-Isigkeit et al (2005) found that 30-40% of children/adolescents with pain reported effects of their pain on school attendance, hobbies, social contacts, appetite, sleep, as well as increased utilization of health services because of their pain. An understanding of the range and interaction of all these different effects is crucial to the effective recognition and treatment of chronic pain in children.

These impacts on daily living can be bundled into the notion of Health-Related Quality of Life (HRQoL), which may be defined as *"an individual's subjective assessment of his or her functioning and emotional state"* (Gold et al, 2009) and can be used for comparative purposes. One such measurement instrument is the Pediatric Quality of Life Inventory (PedsQL), which contains items relating specifically to both physical and psychosocial function (the latter comprising emotional, social and school function) and can be completed by self-report or parent-proxy (Varni et al, 2001). Using this instrument, a US study of 100 patients, aged

surgery, trauma, emotional distress and chronic disease. In many cases, a definitive aetiology is difficult to establish. Even chronic post-surgical pain (CPSP) can be difficult to diagnose and consequently remains under-recognised. However, it represents a significant clinical problem. A 2006 review suggests that CPSP occurs after 10-50% of operations and results in severe chronic pain in 2-10% of these patients (Kehlet et al, 2006). This may, in fact, represent a significant portion of chronic pain sufferers. A UK study found that 22.5% of chronic pain patients developed their condition after surgery (Crombie et al, 1998). CPSP will often be neuropathic, resulting from nerve damage during surgery, though it could also be an ongoing inflammatory/nociceptive mechanism. The incidence of CPSP in the adult population is found to depend on a number of perioperative factors which include: genetic predisposition, degree of pre-operative anxiety, depression, pre-operative pain status, the surgical pain model, surgical technique, length of surgery and the quality of acute postoperative pain management (Kehlet et al, 2006; Macrae, 2008). The probability of an adult developing chronic pain after mastectomy or hernia surgery is decreased with increased age (Poleshuck et al, 2006; Poobalan et al, 2003). How this relationship to age translates to children and adolescents is not known as there is no published literature on CPSP in children. Six out of the eight paediatric cases presented in this chapter developed

Untangling factors to establish clear causality for the development of paediatric chronic pain is a challenge. Whether initiated by surgery or injury or other cause, it is a complex multifactorial process. Understanding this mechanism requires not only a search for a cause, but also a clearer understanding of the effects of chronic pain. It is established that some paediatric chronic pain conditions have been under-diagnosed. Better recognition and early treatment of these conditions requires that healthcare providers understand the effects of

Childhood chronic pain has a negative impact on physical, psychological and social function. It can prevent a child participating in sporting activities and other forms of exercise. It can cause sleep disruption and fatigue. It can contribute to depression and anxiety. It can affect school work through fatigue, poor memory and concentration and result in reduced school attendance. Friendships and family relationships are disrupted which may lead to varying degrees of social isolation. An Australian study of 207 children and adolescents attending a paediatric pain management clinic found that 95% had missed school, 90% had been unable to participate in some sporting activity and 71% had suffered some sleep disruption (Chalkiadis, 2001). Roth-Isigkeit et al (2005) found that 30-40% of children/adolescents with pain reported effects of their pain on school attendance, hobbies, social contacts, appetite, sleep, as well as increased utilization of health services because of their pain. An understanding of the range and interaction of all these different effects is

These impacts on daily living can be bundled into the notion of Health-Related Quality of Life (HRQoL), which may be defined as *"an individual's subjective assessment of his or her functioning and emotional state"* (Gold et al, 2009) and can be used for comparative purposes. One such measurement instrument is the Pediatric Quality of Life Inventory (PedsQL), which contains items relating specifically to both physical and psychosocial function (the latter comprising emotional, social and school function) and can be completed by self-report or parent-proxy (Varni et al, 2001). Using this instrument, a US study of 100 patients, aged

chronic pain following surgery.

chronic pain on a child and their family.

**1.2 The impact of chronic pain on children and their families** 

crucial to the effective recognition and treatment of chronic pain in children.

2–21 years, attending a chronic pain clinic found that the HRQoL scores of these patients were not only considerably lower than scores obtained from normal healthy children, but were significantly lower than scores observed in children with rheumatological or cancer disease (Vetter, 2008). Another US study found that the mean PedsQL score for a cohort of 69 children and adolescents (aged 8 – 18 years) seeking outpatient pain management services, fell below the 'at-risk cut-off score' for all dimensions except social functioning, suggesting that the majority of these children were experiencing significant disruption in their day-to-day lives. The message from these studies is clear: the effects of chronic pain on a child's quality of life are wide-ranging and profound.

School functioning has received perhaps the most attention (Palermo, 2000). It demonstrates the most marked detriment of all the psychosocial dimensions of the PedsQL scale (Vetter, 2008; Gold et al, 2009) and clearly illustrates the complex effects of chronic pain on quality of life. A child with chronic pain may experience a range of problems which impact on their schooling: fatigue and/or poor sleep profile prevents early morning waking; pain inhibits physical ability to get to school, to sit in a classroom for long periods or to participate in physical activities; fear of pain by accidentally being knocked during recess times inhibits social interaction and imparts a sense of isolation, difference and not being involved with peers; poor memory and concentration affects schoolwork; as school work becomes missed or incomplete these unfinished projects become a barrier to return to school if workload is not controlled; and the school may represent an environment where their pain condition is not properly understood or tolerated.

For all these reasons school absences are common. In a survey of adolescent chronic pain sufferers aged 12-17 in Boston USA, 44% missed more than one-quarter of school days and 20% had missed more than half (Logan et al, 2008). Of course, schools typically offer only a limited degree of health-related support. In the Boston study, two-thirds of participants had received some form of accommodation from their school, such as being sent to the nurse's office, being sent home in pain, reduction in workload, extension on an assignment, and so on. Nonetheless, 44.3% of parents reported their child's grades had suffered (Logan et al, 2008) and missing school can clearly have negative consequences that extend beyond academic performance to a child's physical, emotional and social development. Six of the eight cases presented in this chapter had missed significant amounts of school.

Assessing the impact of chronic pain on a child's life is an important but problematic task. There are a number of reasons for this difficulty.

Firstly, the specific effects of chronic pain are not easily isolated from one another. For example, fatigue may be a mediating factor between pain and school functioning (Gold et al, 2009). Anxiety also plays a complex role in moderating the relationship between pain and function. Tsao et al (2007) studied anxiety sensitivity, or the fear of anxiety sensations, in 87 children aged 10-18 presenting at a US chronic pain clinic. Anxiety sensitivity was found to be linked with academic and/or social limitations, where those limitations arose from emotional rather than physical difficulties. Greater anxiety sensitivity was associated with lower self-esteem and perceived general and mental health, and with more behavioural problems and family disruption, but did not appear to affect physical functioning (Tsao et al, 2007). In a similar study of 222 adolescents aged 11 to 19 years attending two chronic pain clinics in the UK, Cohen et al (2010) found that in children with low anxiety, level of pain was a good predictor of physical and social function, but that high levels of anxiety prompted poorer function regardless of the level of pain.

The Role of Peripheral Nerve Blocks in the Interdisciplinary

treatment strategies for children with chronic pain.

biopsychosocial aspects of the child's life.

pharmacological treatment of paediatric chronic pain.

**Drug Dose Comments** 

10-15 mg/kg/dose PO Q4H PRN (max 75 mg/kg/day)

8H (max 40 mg/kg/day)

5-7 mg/kg/dose PO/PR

**>3 months of age to adolescents:**

Ibuprofen 5-10 mg/kg/dose PO Q6-

Naprosyn **Children >2 years:** 

Q8-12H

**1.3.1 Pharmacology** 

Acetaminophen

Care of Children with Chronic Pain: A Case Series and Review of the Literature 401

clinician should consider including interventions that address these factors in their

Management of children and adolescents with severe suffering and extensive pain-related disability as a result of chronic pain requires an interdisciplinary approach (Eccleston et al, 2003). This includes the treatment modalities of pharmacology, physiotherapy and psychology running in parallel or, more importantly, enmeshed with one another. How these elements are balanced is dependant on each individual child and takes into consideration the type and duration of pain, as well as the impact of pain on particular

The pharmacological approach to management of a child with chronic pain requires consideration of the type of pain, the impact of the pain on the child's biopsychosocial functions and the potential side effects of the medications. Medications need to be individualised to each child and continually re-assessed for efficacy and side effects. If medications are having no impact at therapeutic dosage they need to be discontinued and the child re-evaluated for consideration of other appropriate agents. Close liaison with psychiatry is advised prior to and following up on prescription of mood stabilising medications. It is important to emphasise that pharmacological interventions are only one part of an interdisciplinary approach to improve function in children/adolescents with chronic pain. Table 1 provides a summary of the medications that may be considered in the

mechanism

malnutrition

compromise)

constipation

or renal insufficiency

concomitantly with other NSAIDs

concomitantly with other NSAIDs

Central analgesic action via cannabinoid or prostaglandin

Hepatotoxic in acute overdose or with chronic long term use; risk factors for toxicity include fever, prolonged fasting (>48 hrs), concomitant interacting drugs, obesity, poorly controlled diabetes, liver disease, viral infections and

Doses apply to normal healthy children (i.e. no hepatic or renal

Non steroidal anti-inflammatory agent; should not be used

Use caution in patients with aspirin hypersensitivity, hepatic

Non steroidal anti-inflammatory agent; should not be used

Contraindicated with active GI bleeding and ulcer disease; administer with food or milk to avoid GI upset; common GI side effects include abdominal pain, appetite loss, stomatitis or

May cause photosensitive vesicular rash (pseudoporphyria)

Administer with food or milk to lessen GI upset; contraindicated with active GI bleeding and ulcer disease

**1.3 Interdisciplinary team management of children with chronic pain** 

Secondly, the impact of chronic pain on health and quality of life often extends beyond any immediate effects. For example, more than 50% of adolescents with chronic pain report some symptoms of insomnia (compared with less than 20% of healthy adolescents), and while these may initially be related directly to the experience of pain, behavioural patterns can transform this disruption into a primary sleep disorder (Palermo et al, 2010). Furthermore, chronic pain in childhood appears to increase the risk of developing further chronic conditions in adulthood. Adults, who have suffered recurrent headaches as children, are at an increased risk not only of headaches, but other physical and psychiatric symptoms (Fearon & Hotopf, 2001). Similarly, a longitudinal cohort study of paediatric FAPS patients, aged 6 to 18 at enrolment, found that, 15 years later, those with unresolved FAPS experienced higher levels of non-abdominal chronic pain (including migraine, tension-type headaches, and pelvic, back and limb pain) than those with resolved FAPS or normal controls (Walker et al, 2010).

Thirdly, the effects of chronic pain are felt not just by the child, but become a burden for the whole family. The child may no longer participate in shared physical activities, limiting family excursions and fun. Relationships with parents, siblings and other family members are put under strain resulting in anxiety and depression (Eccleston et al, 2004). A number of studies report associations between family functioning and the level of a child's pain-related disability, generally finding that the worse the disability, the greater the family dysfunction (Lewandowski et al, 2010). While it is difficult to interpret the causal relationship underpinning this association with confidence, it is likely that causation runs in both directions: a child's chronic pain has an adverse effect on family life; family problems make it more difficult for the child to cope and so worsen the experience of pain. The impact of chronic pain on the family matches the adverse impact experienced by families caring for children at home with severe cerebral palsy or birth defects (Vetter, 2008).

Daily care arrangements for the child/adolescent with chronic pain require additional support, which may cost money or require a parent to give up a job. The direct and indirect costs of caring for a child with chronic pain have been estimated. A UK study calculated, from a sample of 52 families, that the total annual cost, to a family living with a child in chronic pain, was as much as £14,160 or, approximately, \$25,000 (Sleed et al, 2005). This figure included direct healthcare costs for the child and other family members and indirect costs such as loss of earnings, adaptations to housing, over-the-counter medications and care assistance. This is a potentially ruinous sum for low-income families.

Fourthly, physical and social effects of chronic pain carry another associated economic burden, which may be less easily identified and difficult to quantify. Diminished school function and educational achievement will have potential long-term career and economic cost for both the child and for society.

Finally, the immediate effects of chronic pain have the potential to feed back negatively on the physical and psychosocial health of children and their families. This further reduces their capacity to cope. Unremitting pain can cause sleep disruption and fatigue. Missing school leads to social isolation. The extra burden of stress and financial hardship on families makes them less able to provide the required care. The physical, psychological and social effects of chronic pain can lead the child and their family into a downward spiral, from which it is difficult to emerge without inter-disciplinary support. It is crucial that physicians not only identify the wider psychosocial effects of chronic pain, but recognise that these effects are contributory factors which play an important role in the ongoing pain and functioning of their patient (Jensen, 2011). With the goal of optimal patient care in mind, a clinician should consider including interventions that address these factors in their treatment strategies for children with chronic pain.

#### **1.3 Interdisciplinary team management of children with chronic pain**

Management of children and adolescents with severe suffering and extensive pain-related disability as a result of chronic pain requires an interdisciplinary approach (Eccleston et al, 2003). This includes the treatment modalities of pharmacology, physiotherapy and psychology running in parallel or, more importantly, enmeshed with one another. How these elements are balanced is dependant on each individual child and takes into consideration the type and duration of pain, as well as the impact of pain on particular biopsychosocial aspects of the child's life.

#### **1.3.1 Pharmacology**

400 Pain Management – Current Issues and Opinions

Secondly, the impact of chronic pain on health and quality of life often extends beyond any immediate effects. For example, more than 50% of adolescents with chronic pain report some symptoms of insomnia (compared with less than 20% of healthy adolescents), and while these may initially be related directly to the experience of pain, behavioural patterns can transform this disruption into a primary sleep disorder (Palermo et al, 2010). Furthermore, chronic pain in childhood appears to increase the risk of developing further chronic conditions in adulthood. Adults, who have suffered recurrent headaches as children, are at an increased risk not only of headaches, but other physical and psychiatric symptoms (Fearon & Hotopf, 2001). Similarly, a longitudinal cohort study of paediatric FAPS patients, aged 6 to 18 at enrolment, found that, 15 years later, those with unresolved FAPS experienced higher levels of non-abdominal chronic pain (including migraine, tension-type headaches, and pelvic, back and limb pain) than those with resolved FAPS or

Thirdly, the effects of chronic pain are felt not just by the child, but become a burden for the whole family. The child may no longer participate in shared physical activities, limiting family excursions and fun. Relationships with parents, siblings and other family members are put under strain resulting in anxiety and depression (Eccleston et al, 2004). A number of studies report associations between family functioning and the level of a child's pain-related disability, generally finding that the worse the disability, the greater the family dysfunction (Lewandowski et al, 2010). While it is difficult to interpret the causal relationship underpinning this association with confidence, it is likely that causation runs in both directions: a child's chronic pain has an adverse effect on family life; family problems make it more difficult for the child to cope and so worsen the experience of pain. The impact of chronic pain on the family matches the adverse impact experienced by families caring for

Daily care arrangements for the child/adolescent with chronic pain require additional support, which may cost money or require a parent to give up a job. The direct and indirect costs of caring for a child with chronic pain have been estimated. A UK study calculated, from a sample of 52 families, that the total annual cost, to a family living with a child in chronic pain, was as much as £14,160 or, approximately, \$25,000 (Sleed et al, 2005). This figure included direct healthcare costs for the child and other family members and indirect costs such as loss of earnings, adaptations to housing, over-the-counter medications and

Fourthly, physical and social effects of chronic pain carry another associated economic burden, which may be less easily identified and difficult to quantify. Diminished school function and educational achievement will have potential long-term career and economic

Finally, the immediate effects of chronic pain have the potential to feed back negatively on the physical and psychosocial health of children and their families. This further reduces their capacity to cope. Unremitting pain can cause sleep disruption and fatigue. Missing school leads to social isolation. The extra burden of stress and financial hardship on families makes them less able to provide the required care. The physical, psychological and social effects of chronic pain can lead the child and their family into a downward spiral, from which it is difficult to emerge without inter-disciplinary support. It is crucial that physicians not only identify the wider psychosocial effects of chronic pain, but recognise that these effects are contributory factors which play an important role in the ongoing pain and functioning of their patient (Jensen, 2011). With the goal of optimal patient care in mind, a

children at home with severe cerebral palsy or birth defects (Vetter, 2008).

care assistance. This is a potentially ruinous sum for low-income families.

normal controls (Walker et al, 2010).

cost for both the child and for society.

The pharmacological approach to management of a child with chronic pain requires consideration of the type of pain, the impact of the pain on the child's biopsychosocial functions and the potential side effects of the medications. Medications need to be individualised to each child and continually re-assessed for efficacy and side effects. If medications are having no impact at therapeutic dosage they need to be discontinued and the child re-evaluated for consideration of other appropriate agents. Close liaison with psychiatry is advised prior to and following up on prescription of mood stabilising medications. It is important to emphasise that pharmacological interventions are only one part of an interdisciplinary approach to improve function in children/adolescents with chronic pain. Table 1 provides a summary of the medications that may be considered in the pharmacological treatment of paediatric chronic pain.


The Role of Peripheral Nerve Blocks in the Interdisciplinary

**Drug Dose Comments** 

Initial: 25 mg PO daily Titrate upward to effect to 2.5 mg/kg PO BID or max

agents see Compendium of Pharmaceuticals and

37.5 – 75 mg PO Once

37.5-75 mg every 4-7 days **Usual Dose Range:**  75-225 mg/day

Pregabalin **Children > 10 years:** 

300 mg/day

Opioids For dosing of different

Specialties

DAILY **Increment:** 

**Clonidine** 1-4 micrograms/kg/dose PO Q4-6H

pain management

Venlafaxine **Initial Dose:**

Care of Children with Chronic Pain: A Case Series and Review of the Literature 403

neuron hyperexcited.

behaviour change.

mu-opioid agonist

Similar in mechanism to gabapentin

week.

week.

alcohol

addiction

oral doses are associated with decreased bioavailability; do not administer with antacids; primarily excreted unchanged in the urine, therefore need to adjust dose in renal impairment Maximum dose often not be needed for maximum effect; do not suddenly stop long-term treatment; wean dose by 25% per

Calcium channel α 2-δ ligand; calcium channel blocker when

Gradual dose increase helps to minimize sedation; increased oral doses are associated with increased bioavailability; do not administer with antacids; primarily excreted unchanged in the urine, therefore need to adjust dose in renal impairment. Maximum dose often not be needed for maximum effect; do not suddenly stop long-term treatment; wean dose by 25% per

Side effects may include somnolence, ataxia, fatigue and

Additive sedative effects with other medications and/or

Serotonin/norepinephrine reuptake inhibitor (SNRI) Effective in the treatment of Depression, Generalized Anxiety Disorder, Social Anxiety Disorder, Panic Disorder. Also used to treat ADHD, Post-Traumatic Stress Disorder and

sweating, tremor and impaired sexual function

Side effects include: headache, nausea, increased heart rate and blood pressure (more prominent at higher doses), anorexia/weight loss, drowsiness, dizziness, dry mouth,

Administer with food or milk to decrease GI upset; full beneficial effects may not be seen until 4 weeks of therapy

*Warnings issued by Health Canada regarding use of* 

An alpha adrenergic receptor antagonist; metabolism is hepatic and renal (roughly 50:50); drug interactions with beta

Sedative, anxiolytic and analgesic effects; a useful adjunct used to minimise other analgesic drug doses such as opioids Side effects include sedation, dry mouth, hypotension Do not suddenly stop long-term treatment; wean dose by 25%

Obsessive-Compulsive Disorder.

*antidepressants in pediatric patients.*

blockers, tricyclic anti-depressants

per week to prevent rebound hypertension

(adolescents/adults).

completed.

Table 1. Modalities of medications that may be considered in outpatient paediatric chronic

Side effects include sedation, nausea, vomiting, constipation, pruritis, tolerance dependance opioid induced hyperalgesia,

Long-term use rarely indicated in children; addiction potential should be assessed prior to commencement of opioids; opioid prescription should follow national guidelines for safe practice


efficacy

per week

nerves.

serotonergic drugs

improved by gradual dose titration. Caution in renal and/or hepatic impairment

An opioid analgesic with norepinephrine and serotonin effects Side effects include nausea and vomiting; tolerability is

Serotonin syndrome reported with concurrent use of

Seizures reported with concurrent TCAs, SSRIs, and opioids or

Withdrawal symptoms may develop if abruptly discontinued; do not suddenly stop long-term treatment; wean dose by 25%

Blockade of upregulated sodium channel receptors in injured

Tricyclic antidepressant agent (TCA) used in low dose for chronic neuropathic pain; prevents the re-uptake of serotonin

Pretreatment ECG required to exclude arrhythmia potential.

Side effects include: sedation, confusion, weakness, fatigue, tremor, sweating, headache, anticholinergic effects, cardiovascular effects (including orthostatic hypotension, tachycardia, prolonged QTc and arrhythmias at higher plasma

Sedative side effect used to help with improved sleep profile If one TCA not helpful due to intolerable side effects try another with a different SE profile before abandoning this modality of pharmacological therapy (Nortriptyline is less

A withdrawal syndrome is documented for Tricyclics (flu-like symptoms, dizziness, mood changes). Assess patient carefully and limit prescribed quantities to minimum effective dose; do not suddenly stop long-term treatment; wean dose by 25% per

Calcium channel α 2-δ ligand; calcium channel blocker when

Analgesic, anticonvulsant, anxiolytic, and sleep-modulating

Gradual dose increase helps to minimize sedation; increased

Side effects may include somnolence, ataxia, fatigue and

Tramadol is metabolized to active form (i.e. a prodrug) Inter-individual pharmacogenomic variations affect

with conditions that lower seizure threshold

Extended release product given ONCE daily.

Minimal side effects (mild skin reactions)

Drug interactions via cytochrome p450 system; contraindicated if MAO inhibitors used within 14 days; tricyclics have limited efficacy for treatment of depression in

Useful for very localised pain

and norepinephrine.

children and adolescents

commencement.

neuron hyperexcited

behaviour change.

week.

activities.

levels), decreased seizure threshold.

sedating, doxepin less anticholinergic).

Analgesic effect may not occur for 2 weeks from

**Drug Dose Comments** 

50-100 mg Q4-6H PRN (max: 400 mg/day)

**Extended-release form: Adolescents:** Initial: 100 mg PO daily; titrate by 100 mg increments every 2-3 days PRN (max: 300

**Adolescents:** 

mg/day).

Amitriptyline Initial: 0.1 mg/kg/dose

Gabapentin **Children:** titrate to effect

over a few days, starting at 2 mg/kg once or twice daily, then increase to TID dosing to a maximum of 35 mg/kg/24hr (max 3600 mg/day)

Topical: 5% under occlusive

dressing for 12 hours (once per day)

PO HS; increase as needed and tolerated over 2-3 wks to 0.5-2 mg/kg/dose HS

**Immediate-release form: Children:** 1-2 mg/kg Q4- 6H PRN (max: 400 mg/day or 8 mg/kg/day)

Tramadol (Ultram, Ralivia)

Topical Lidocaine


Table 1. Modalities of medications that may be considered in outpatient paediatric chronic pain management

The Role of Peripheral Nerve Blocks in the Interdisciplinary

of the individual patient.

(Peng & Castano, 2005).

meningitis (Gaul et al, 2005).

benefit from interventional treatments.

**1.3.4 Interventional therapies** 

Care of Children with Chronic Pain: A Case Series and Review of the Literature 405

teachers become more aware of the condition and its impact on schoolwork. The psychologist helps to negotiate or advocate for any accommodations needed in order to help the child succeed at school. Psychologists help the child and their family identify and resolve stresses such as anxiety or depression that could be preventing return to function. A Cochrane Review determined that there is strong evidence for psychological therapies being effective in the treatment of headaches in children and some evidence for their efficacy in the treatment of musculoskeletal and recurrent abdominal pain (Eccleston et al, 2009). Psychological interventions are often, and ideally, delivered as part of an interdisciplinary approach and consequently there are few randomized-controlled-trial (RCT) studies providing definite evidence for individual therapies (McGrath & Holahan, 2003). Nonetheless, psychological techniques are a vital component of the interdisciplinary approach and experienced therapists will select particular techniques according to the needs

Interventional procedures offered at Canadian paediatric *multidisciplinary pain treatment facilities* (MPTFs) include continuous epidural infusions, single epidural injections, facet injections, stellate ganglion nerve blocks, peripheral nerve blocks, trigger point injections, sympathetic blocks with local anaesthetic, Botox injections, intravenous regional anaesthesia, paravertebral nerve blocks and radiofrequency lesioning (Peng et al, 2007). Nerve blocks are used widely among Canadian anaesthesiologists who specifically practice chronic pain management: of those, 84% perform nerve blocks, compared with 60% who use pharmacotherapy, and a majority of them estimated that more than 40% of their patients require some form of nerve block as part of their treatment programme

However, there is very little evidence to demonstrate that interventions benefit a patient more than would be seen from a placebo response. The literature is comprised of case reports and small case series, along with a few randomized, placebo-controlled trials (RCTs). For example, therapeutic lumbar facet joint nerve blocks can provide effective pain relief and functional improvement (Manchikanti et al, 2010). However, epidural corticosteroid injections for sciatica appear to offer only transient benefit (Arden et al, 2005). Results of RCTs are not always consistent, however. For example, one RCT has shown that radiofrequency lesioning of the dorsal root ganglion for treatment of chronic lumbosacral radicular pain appears not to be more effective than control treatment with local anaesthetic (Geurts et al, 2003); on the the other hand, another RCT has shown that it is both safe and effective (Simopoulos et al, 2008). For some techniques, such as myofascial trigger point injections, it has not even been possible to establish a consensus on methods for diagnosis or treatment (Tough et al, 2007). Furthermore, any RCTs that have been done mainly comprise adult studies. The evidence of efficacy in children/adolescents is even more limited and more research is required. There are also rare but significant iatrogenic risks associated with some of these interventions. Injection therapies for lower back pain carry the risk of paraspinal, spinal end epidural abscesses or

Despite this negative portrayal of interventional medicine for chronic pain "absence of evidence is not evidence of absence" (Altman & Bland, 1995) and there are many pain physicians and patients, including those in this case series, who have derived enormous

#### **1.3.2 Physiotherapy**

Chronic pain sufferers often experience some level of physical incapacity and many adopt activity patterns that can make their pain worse, such as alternating episodes of overactivity and under-activity (Birkholtz et al, 2004). Physiotherapy plays an important role in the interdisciplinary treatment of chronic pain in children and adolescents. Eccleston & Eccleston (2004) divide it into the following four components:


Other reports of physiotherapy interventions in the treatment of chronic pain stress the importance of the interdisciplinary approach. For example, a combination of physical therapy and CBT has been shown to be effective in treating CRPS in children (Lee et al, 2002). Harding et al (1998) also highlight the need to integrate behavioural and cognitive components in activity training to minimise distress and unhelpful beliefs.

#### **1.3.3 Psychology**

There are a number of psychological factors, which are directly involved in the perception, reporting and self-management of pain. These include fear, vigilance to the feeling and threat of pain, catastrophising, avoidance of pain-inducing activity, sadness, depression, anger and self-denigration. Psychological factors are also important in coping mechanisms, taking action, and being able to predict or make sense of pain and its consequences (Eccleston, 2001). Psychologists provide continual education/reassurance on the pathophysiology of the chronic pain condition and teach mind-body techniques like breathing, muscle relaxation exercises, self-hypnosis, imagery, and cognitive strategies. These techniques help reduce the impact of pain on daily living and mood.

Cognitive behaviour therapy (CBT) is central to the notion of interdisciplinary care. CBT refers to an *"integration of treatments aimed at reducing or extinguishing the influence of the factors that maintain patients' maladaptive behaviours, beliefs and patterns of thought... and is delivered by a team of pain therapists, including anaesthetists, clinical psychologists and physiotherapists"* (Eccleston, 2001). Interdisciplinary CBT programmes aimed at adolescents with chronic musculoskeletal pain have been found to improve physical function, reduce emotional distress, increase attendance at school and reduce medicine consumption (Eccleston et al, 2003; de Blécourt et al, 2008). Furthermore, there is evidence to suggest that an interdisciplinary framework is beneficial for the family members involved. Schurman & Friesen (2010) report that an 'integrative care' approach in a paediatric Abdominal Pain Clinic (that is, service delivered by a gastroenterologist and a psychologist) was acceptable to families, produced higher satisfaction scores and, crucially, improved receptivity to treatment recommendations.

Relaxation strategies and plans to improve sleep hygiene are a vital part of the psychologist's role. When schooling has been impacted by pain, the psychologist helps teachers become more aware of the condition and its impact on schoolwork. The psychologist helps to negotiate or advocate for any accommodations needed in order to help the child succeed at school. Psychologists help the child and their family identify and resolve stresses such as anxiety or depression that could be preventing return to function.

A Cochrane Review determined that there is strong evidence for psychological therapies being effective in the treatment of headaches in children and some evidence for their efficacy in the treatment of musculoskeletal and recurrent abdominal pain (Eccleston et al, 2009). Psychological interventions are often, and ideally, delivered as part of an interdisciplinary approach and consequently there are few randomized-controlled-trial (RCT) studies providing definite evidence for individual therapies (McGrath & Holahan, 2003). Nonetheless, psychological techniques are a vital component of the interdisciplinary approach and experienced therapists will select particular techniques according to the needs of the individual patient.

#### **1.3.4 Interventional therapies**

404 Pain Management – Current Issues and Opinions

Chronic pain sufferers often experience some level of physical incapacity and many adopt activity patterns that can make their pain worse, such as alternating episodes of overactivity and under-activity (Birkholtz et al, 2004). Physiotherapy plays an important role in the interdisciplinary treatment of chronic pain in children and adolescents. Eccleston &

*Exercise* – this is used to increase aerobic endurance, flexibility, strength and overall

 *Education* – this helps the patient relate their pain to their anatomy, physiology and activity levels and to address issues such as fear of movement and the potential for re-

 *Behavioural management* – this may involve physical retraining and activity pacing, aiming for a gradual increase in the range and extent of movement, including a steady return to any activities abandoned since the onset of pain (see also Harding et al, 1998); *Performance assessment* – there is a clear link between reduced pain and improved physical function; the physiotherapist is well-placed to assess treatment progress. Other reports of physiotherapy interventions in the treatment of chronic pain stress the importance of the interdisciplinary approach. For example, a combination of physical therapy and CBT has been shown to be effective in treating CRPS in children (Lee et al, 2002). Harding et al (1998) also highlight the need to integrate behavioural and cognitive

There are a number of psychological factors, which are directly involved in the perception, reporting and self-management of pain. These include fear, vigilance to the feeling and threat of pain, catastrophising, avoidance of pain-inducing activity, sadness, depression, anger and self-denigration. Psychological factors are also important in coping mechanisms, taking action, and being able to predict or make sense of pain and its consequences (Eccleston, 2001). Psychologists provide continual education/reassurance on the pathophysiology of the chronic pain condition and teach mind-body techniques like breathing, muscle relaxation exercises, self-hypnosis, imagery, and cognitive strategies.

Cognitive behaviour therapy (CBT) is central to the notion of interdisciplinary care. CBT refers to an *"integration of treatments aimed at reducing or extinguishing the influence of the factors that maintain patients' maladaptive behaviours, beliefs and patterns of thought... and is delivered by a team of pain therapists, including anaesthetists, clinical psychologists and physiotherapists"* (Eccleston, 2001). Interdisciplinary CBT programmes aimed at adolescents with chronic musculoskeletal pain have been found to improve physical function, reduce emotional distress, increase attendance at school and reduce medicine consumption (Eccleston et al, 2003; de Blécourt et al, 2008). Furthermore, there is evidence to suggest that an interdisciplinary framework is beneficial for the family members involved. Schurman & Friesen (2010) report that an 'integrative care' approach in a paediatric Abdominal Pain Clinic (that is, service delivered by a gastroenterologist and a psychologist) was acceptable to families, produced higher satisfaction scores and, crucially, improved receptivity to

Relaxation strategies and plans to improve sleep hygiene are a vital part of the psychologist's role. When schooling has been impacted by pain, the psychologist helps

Eccleston (2004) divide it into the following four components:

fitness, which all have potential benefits for pain reduction;

components in activity training to minimise distress and unhelpful beliefs.

These techniques help reduce the impact of pain on daily living and mood.

**1.3.2 Physiotherapy** 

injury;

**1.3.3 Psychology** 

treatment recommendations.

Interventional procedures offered at Canadian paediatric *multidisciplinary pain treatment facilities* (MPTFs) include continuous epidural infusions, single epidural injections, facet injections, stellate ganglion nerve blocks, peripheral nerve blocks, trigger point injections, sympathetic blocks with local anaesthetic, Botox injections, intravenous regional anaesthesia, paravertebral nerve blocks and radiofrequency lesioning (Peng et al, 2007). Nerve blocks are used widely among Canadian anaesthesiologists who specifically practice chronic pain management: of those, 84% perform nerve blocks, compared with 60% who use pharmacotherapy, and a majority of them estimated that more than 40% of their patients require some form of nerve block as part of their treatment programme (Peng & Castano, 2005).

However, there is very little evidence to demonstrate that interventions benefit a patient more than would be seen from a placebo response. The literature is comprised of case reports and small case series, along with a few randomized, placebo-controlled trials (RCTs). For example, therapeutic lumbar facet joint nerve blocks can provide effective pain relief and functional improvement (Manchikanti et al, 2010). However, epidural corticosteroid injections for sciatica appear to offer only transient benefit (Arden et al, 2005). Results of RCTs are not always consistent, however. For example, one RCT has shown that radiofrequency lesioning of the dorsal root ganglion for treatment of chronic lumbosacral radicular pain appears not to be more effective than control treatment with local anaesthetic (Geurts et al, 2003); on the the other hand, another RCT has shown that it is both safe and effective (Simopoulos et al, 2008). For some techniques, such as myofascial trigger point injections, it has not even been possible to establish a consensus on methods for diagnosis or treatment (Tough et al, 2007). Furthermore, any RCTs that have been done mainly comprise adult studies. The evidence of efficacy in children/adolescents is even more limited and more research is required. There are also rare but significant iatrogenic risks associated with some of these interventions. Injection therapies for lower back pain carry the risk of paraspinal, spinal end epidural abscesses or meningitis (Gaul et al, 2005).

Despite this negative portrayal of interventional medicine for chronic pain "absence of evidence is not evidence of absence" (Altman & Bland, 1995) and there are many pain physicians and patients, including those in this case series, who have derived enormous benefit from interventional treatments.

The Role of Peripheral Nerve Blocks in the Interdisciplinary

patient to return to his previous physical activities.

**2.2 Case 2: A 14-year-old male with abdominal pain** 

acetaminophen or homeopathic remedies.

He did not require repeat therapeutic blocks.

pain 2-3 times per day, which lasted several hours.

term, he returned to school and reported no subsequent absences.

**2.3 Case 3: An 18-year-old with groin pain after hydrocele repair** 

chronic abdominal wall pain.

by acetaminophen.

Care of Children with Chronic Pain: A Case Series and Review of the Literature 407

junctions, and left side of chest were unremarkable and pain free. His chest X-ray (CXR) revealed that his Nuss bar had not moved, with no bony reaction or wire migration. The

A diagnostic intercostal nerve block was performed, which provided effective short-term symptomatic relief so a follow-up therapeutic block was done 10 days later. For the therapeutic block, 5mls of 0.25% bupivicaine with 1/200,000 epinephrine and 10mg triamcinolone was injected at four sites: at the affected rib, one above, one below and at the right sided Nuss bar insertion scar site. This provided complete pain relief to allow the

He required repeat therapeutic blocks at 3 months and 1 year from the initial block for resurgence of pain, but had no further pain up to and after the removal of the Nuss bar.

A 56kg 14-year-old male presented with a 9 month history of abdominal pain. There was no apparent precipitating event. He was referred to the Pain Service after multiple referrals and investigations had excluded a remedial cause for his pain but drawn a blank on a diagnosis. The pain was described as a dull, aching pain, present all the time, but worse with exercise and on palpation. There was no pattern to his pain or any relation to his diet. There were no other symptoms related to the abdominal system. The pain was not relieved by ibuprofen,

This young man had been extremely fit and well. However his pain was such that he had to stop all his sporting activities, experienced difficulty getting to sleep, was depressed and grumpy with his family and had been absent from school for the preceding 6 months. On examination, his abdomen was slim and soft, with normal bowel sounds, no masses and no organomegaly. There was tenderness in the midline above the umbilicus, which was worse on abdominal wall tensing (Carnett's test positive). The presumed diagnosis was

A diagnostic bilateral rectus sheath block was performed above the umbilicus under ultrasound control which provided effective short-term symptomatic relief so a follow-up therapeutic block was done two weeks later. For the therapeutic block 10mls of 0.25% bupivicaine with 1/200,000 epinephrine and 20mg triamcinolone was injected at each site.

Two weeks after his therapeutic block, he slowly returned to his normal activity levels, sleeping and eating patterns and resumed his previous happy demeanour. The following

A 60kg 18-year-old male presented with a 1 year history of a shooting pain in his groin, which was present all the time and radiated down the medial aspect of his thigh to his knee. There was no apparent precipitating event; however, he was a competitive fencer and had undergone a left hydrocele repair 6 months prior to the onset of pain. The pain was worse in morning, walking up stairs and mobilizing from lying down. He had episodes of severe

He was referred to the Pain Service after multiple referrals and investigations had excluded a remedial cause for his pain, but drawn a blank on a diagnosis. The pain was not relieved

CXR was otherwise normal. The presumed diagnosis was intercostal neuralgia.

### **2. Case reports**


The cases are described below and summarised in table 2.

Table 2. Summary of cases

#### **2.1 Case 1: A 16-year-old adolescent with chest pain related to a Nuss bar**

A 60kg 16-year-old male presented with a 5 month history of right sided chest wall pain. He had undergone a Nuss procedure for cosmetic repair of pectus excavatum one year prior to presentation and had received satisfactory acute pain management with epidural analgesia. He was referred to the Pain Service by his surgeon. His pain was precipitated by a sudden lateral movement, but aggravated by activity, laughter and bending down. The pain was described as "shooting". The pain was not relieved by ibuprofen and/or acetaminophen.

This young man, an active kick-boxer, was extremely fit and well. However, his pain was so unremitting that he had to stop all sporting activities and was completely sedentary. His sleep was not disrupted, nor was his school attendance or academic performance. However, he was very frustrated that his pain prevented him pursuing his kick-boxing and his ability to perform simple physical tasks. He was able to maintain friendships, but could not engage in some of the more physical social activities.

On examination, his pain was found to radiate laterally from the site of his Nuss bar on the right side, in one dermatomal level at the level of the 7th rib from midaxillary line to sternum. There was no pain on palpation or deep inspiration/expiration. There was no numbness, allodynia or skin changes. Palpation of the thoracic spines, costochondral

**(months) Diagnosis Block(s) performed** 

Intercostal nerve blocks (1

Bilateral rectus abdominis sheath blocks (diagnostic and therapeutic)

Ilioinguinal nerve blocks (1

Intercostal nerve block; rectus sheath block.

Rectus abdominis sheath

intercostal nerve blocks (diagnostic and therapeutic)

Bilateral rectus abdominis sheath blocks (diagnostic and therapeutic)

Intercostal nerve blocks (diagnostic and therapeutic)

diagnostic and 3 therapeutic)

diagnostic and 3 therapeutic )

block

related to Nuss bar

Ilioinguinal neuralgia following hydrocele

incisional hernia

Genitofemoral or ilioinguinal neuralgia following orchidopexy

post-surgery

Abdominal wall pain following laparascopic appendectomy

repair

**Duration**

The cases are described below and summarised in table 2.

**of pain** 

1 Male 16 60kg Chest 5 Intercostal neuralgia

2 Male 14 56kg Abdomen 9 Abdominal wall pain

4 Male 15 66kg Abdomen <sup>3</sup>Neuropathic pain, *not*

6 Female 15 45kg Rib 8 Intercostal neuralgia,

8 Female 17 66kg Rib 7 Intercostal neuralgia

**2.1 Case 1: A 16-year-old adolescent with chest pain related to a Nuss bar** 

A 60kg 16-year-old male presented with a 5 month history of right sided chest wall pain. He had undergone a Nuss procedure for cosmetic repair of pectus excavatum one year prior to presentation and had received satisfactory acute pain management with epidural analgesia. He was referred to the Pain Service by his surgeon. His pain was precipitated by a sudden lateral movement, but aggravated by activity, laughter and bending down. The pain was described as "shooting". The pain was not relieved by ibuprofen and/or

This young man, an active kick-boxer, was extremely fit and well. However, his pain was so unremitting that he had to stop all sporting activities and was completely sedentary. His sleep was not disrupted, nor was his school attendance or academic performance. However, he was very frustrated that his pain prevented him pursuing his kick-boxing and his ability to perform simple physical tasks. He was able to maintain friendships, but could not engage

On examination, his pain was found to radiate laterally from the site of his Nuss bar on the right side, in one dermatomal level at the level of the 7th rib from midaxillary line to sternum. There was no pain on palpation or deep inspiration/expiration. There was no numbness, allodynia or skin changes. Palpation of the thoracic spines, costochondral

**2. Case reports** 

**No Gender Age Weight Site** 

3 Male 18 60kg Groin 12

5 Male 9 25kg Groin 4

7 Female 9 33kg Abdomen 2

in some of the more physical social activities.

Table 2. Summary of cases

acetaminophen.

junctions, and left side of chest were unremarkable and pain free. His chest X-ray (CXR) revealed that his Nuss bar had not moved, with no bony reaction or wire migration. The CXR was otherwise normal. The presumed diagnosis was intercostal neuralgia.

A diagnostic intercostal nerve block was performed, which provided effective short-term symptomatic relief so a follow-up therapeutic block was done 10 days later. For the therapeutic block, 5mls of 0.25% bupivicaine with 1/200,000 epinephrine and 10mg triamcinolone was injected at four sites: at the affected rib, one above, one below and at the right sided Nuss bar insertion scar site. This provided complete pain relief to allow the patient to return to his previous physical activities.

He required repeat therapeutic blocks at 3 months and 1 year from the initial block for resurgence of pain, but had no further pain up to and after the removal of the Nuss bar.

#### **2.2 Case 2: A 14-year-old male with abdominal pain**

A 56kg 14-year-old male presented with a 9 month history of abdominal pain. There was no apparent precipitating event. He was referred to the Pain Service after multiple referrals and investigations had excluded a remedial cause for his pain but drawn a blank on a diagnosis. The pain was described as a dull, aching pain, present all the time, but worse with exercise and on palpation. There was no pattern to his pain or any relation to his diet. There were no other symptoms related to the abdominal system. The pain was not relieved by ibuprofen, acetaminophen or homeopathic remedies.

This young man had been extremely fit and well. However his pain was such that he had to stop all his sporting activities, experienced difficulty getting to sleep, was depressed and grumpy with his family and had been absent from school for the preceding 6 months.

On examination, his abdomen was slim and soft, with normal bowel sounds, no masses and no organomegaly. There was tenderness in the midline above the umbilicus, which was worse on abdominal wall tensing (Carnett's test positive). The presumed diagnosis was chronic abdominal wall pain.

A diagnostic bilateral rectus sheath block was performed above the umbilicus under ultrasound control which provided effective short-term symptomatic relief so a follow-up therapeutic block was done two weeks later. For the therapeutic block 10mls of 0.25% bupivicaine with 1/200,000 epinephrine and 20mg triamcinolone was injected at each site. He did not require repeat therapeutic blocks.

Two weeks after his therapeutic block, he slowly returned to his normal activity levels, sleeping and eating patterns and resumed his previous happy demeanour. The following term, he returned to school and reported no subsequent absences.

#### **2.3 Case 3: An 18-year-old with groin pain after hydrocele repair**

A 60kg 18-year-old male presented with a 1 year history of a shooting pain in his groin, which was present all the time and radiated down the medial aspect of his thigh to his knee. There was no apparent precipitating event; however, he was a competitive fencer and had undergone a left hydrocele repair 6 months prior to the onset of pain. The pain was worse in morning, walking up stairs and mobilizing from lying down. He had episodes of severe pain 2-3 times per day, which lasted several hours.

He was referred to the Pain Service after multiple referrals and investigations had excluded a remedial cause for his pain, but drawn a blank on a diagnosis. The pain was not relieved by acetaminophen.

The Role of Peripheral Nerve Blocks in the Interdisciplinary

normal. He did not require repeat therapeutic blocks.

**2.5 Case 5: A 9-year-old with post-orchidopexy pain** 

often woken with pain and cramps and cried as a result of his pain.

positive. The presumed diagnosis was genitofemoral or ilioinguinal neuralgia.

by his surgeon.

patient reported the pain was gone.

and with sitting or physical activity.

Care of Children with Chronic Pain: A Case Series and Review of the Literature 409

and was sleeping normally. Within 2 months he had started gym. He quickly caught up with most of his schoolwork and was now motivated to do additional study during the summer vacation. He resumed contact with friends and his family were able to return to

A 25kg 9-year-old male presented with a 4 month history of left sided groin pain. He had been experiencing this pain for three years on and off, but it had been worse since his orchidopexy surgery 4 months prior to the consultation. He was referred to the Pain Service

He continued to attend school, but had to visit the nurse twice a day and lie down to recover his strength. Often the school requested that he be collected and taken home early. He found it difficult to engage in physical or social activities and had to give up Tae Kwon Do. He was

The pain was described as "stabbing". It was not relieved by ibuprofen and/or acetaminophen. On examination, there was no numbness, allodynia or skin changes and Carnett's test was

A diagnostic rectus abdominis sheath block was performed, under ultrasound control: 15ml 0.25% bupivicaine, 1/200,000 epinephrine was injected into the rectus sheath and between the transverse abdominis and internal oblique; 10ml was injected at his flank at the anterior superior iliac spine; and some was injected at his orchidopexy scar site. On awakening, the

A therapeutic block was not done in this case. He was able to resume a normal sleeping pattern within 2 weeks, was much happier and once again able to spend time with friends.

It was 8 months since her surgery. She had missed some school, had stopped gymnastics classes and soccer training completely and had to limit her social activities. She was grumpy with friends and family. Physiotherapy had not helped, but ketorolac (10mg twice a day as needed), psychology, TENS and laser therapy were judged to have provided some benefit. She was examined by the interdisciplinary team. Physical examination revealed that her pain was localised to the right anterolateral aspect of her 10th rib, close to the exostosis excision; there was no associated numbness, no allodynia and no skin colour change. The physiotherapist noted that her right waist crease and elevated iliac crest suggested a protective response, but that she had a full range of motion in spine and extremities. The psychologist determined that she was not overly anxious or depressed, despite some

He made a gradual return to Tae Kwon Do and normal schooling with no absences.

**2.6 Case 6: A 15-year-old female with chest pain following removal of exostosis**  A 45 kg 15-year-old female presented at the Complex Pain Clinic with post-surgical chest pain. Successful removal of an exostosis from her right rib cage was followed by the gradual emergence of a new, sharp pain, which was present every day. It worsened during the day

ongoing family conflicts. A preliminary diagnosis of intercostal neuralgia was made.

with 1/200,000 epinephrine & 1mg/ml triamcinolone injected under the scar site.

A diagnostic intercostal nerve block was performed. This provided effective short-term symptomatic relief so a follow-up therapeutic block was done 3 weeks later. The therapeutic block comprised: 5ml 0.25% bupivicaine with 1/200,000 epinephrine & 2mg/ml triamcinolone injected at 3 sites above & below the affected rib; and 4ml 0.25% bupivicaine

This young man had been extremely fit and well. However his pain was such that his appetite was reduced, he was losing weight and he had to stop all his physical activities to the point that his future competitive aspirations were severely compromised. He continued to attend school, but was under pressure to compete in the fencing team. His mood during this period was described as 'testy'.

On examination, he had pain on palpation of the hydrocele repair scar, but no pain on palpation underneath inguinal ligament. He had a full range of non-painful movements of his lumbar spine, hips and knees with normal bulk, tone & power in his lower limbs, and brisk but equal knee and ankle jerk reflexes. He exhibited a downgoing plantar reflex and bilateral abdominal reflexes. His abdomen was slim and soft, with normal bowel sounds, no masses and no organomegaly. There was no apparent numbness to light touch of his scar or thigh and no allodynia, skin or hair changes. There was no pain to palpation in his scrotum or penis. The presumed diagnosis was ilioinguinal neuralgia.

A diagnostic ilioinguinal nerve block was performing under ultrasound control which provided effective short-term symptomatic relief so a follow-up therapeutic block was done one week later. For the therapeutic block 20mls of 0.25% bupivacaine with 1/200,000 epinephrine and 20mg triamcinolone was injected between the internal oblique and transverse abdominis muscles; some was also injected under the scar site from his hydrocele repair. This provided complete pain relief.

His mood and eating pattern improved within the first month, but he did require repeat therapeutic blocks at 5 months and 11 months following the initial block. These provided good pain relief to allow the patient to make a graded return to competitive fencing.

#### **2.4 Case 4: A 15-year-old male with a suspected incisional hernia**

A 66kg 15-year-old male presented with a 3 month history of left upper quadrant pain associated with a bulge just lateral & inferior to the incision from a congenital diaphragmatic hernia repair when he was 14 months old. The pain was described as a burning, stabbing sensation. He exhibited no symptoms related to the respiratory, cardiovascular or abdominal systems.

He had been extremely fit and well. However his pain was such that he could not stand up straight, suffered pain with all activity and was unable to sleep soundly because he could not get comfortable. He had completely lost his appetite and had lost 10kg in weight. He became depressed and ceased to interact with friends. His suffering affected his family deeply: his parents' relationship suffered, his sister became depressed. He could not sit or concentrate and consequently missed 5 months of school.

An upper gastrointestinal endoscopy was normal. Surgical repair of the suspected incisional hernia revealed no hernia of the abdominal wall. Pain occurred in the immediate postoperative period. This pain did not respond to simple analgesics or hydromorphone. He was referred to the Pain Service and a diagnosis of neuropathic pain was made.

Intercostal nerve blocks were administered to the left sided 9th, 10th, and 11th ribs. This provided effective short-term symptomatic relief, so a follow-up therapeutic block was done a week later. For the therapeutic block, 5ml of 0.25% bupivacaine with 1/200,000 epinephrine & 10mg triamcinolone was injected at the same 3 intercostal spaces; in addition, the same amount was administered as a left rectus sheath block under ultrasound control, adjacent to the site of surgery. On awakening, the patient reported that his pain had gone.

This treatment provided immediate pain relief, which allowed the patient to return to his normal self. His appetite returned the next day. Within a few days, he was laughing again and was sleeping normally. Within 2 months he had started gym. He quickly caught up with most of his schoolwork and was now motivated to do additional study during the summer vacation. He resumed contact with friends and his family were able to return to normal. He did not require repeat therapeutic blocks.

#### **2.5 Case 5: A 9-year-old with post-orchidopexy pain**

408 Pain Management – Current Issues and Opinions

This young man had been extremely fit and well. However his pain was such that his appetite was reduced, he was losing weight and he had to stop all his physical activities to the point that his future competitive aspirations were severely compromised. He continued to attend school, but was under pressure to compete in the fencing team. His mood during

On examination, he had pain on palpation of the hydrocele repair scar, but no pain on palpation underneath inguinal ligament. He had a full range of non-painful movements of his lumbar spine, hips and knees with normal bulk, tone & power in his lower limbs, and brisk but equal knee and ankle jerk reflexes. He exhibited a downgoing plantar reflex and bilateral abdominal reflexes. His abdomen was slim and soft, with normal bowel sounds, no masses and no organomegaly. There was no apparent numbness to light touch of his scar or thigh and no allodynia, skin or hair changes. There was no pain to palpation in his scrotum

A diagnostic ilioinguinal nerve block was performing under ultrasound control which provided effective short-term symptomatic relief so a follow-up therapeutic block was done one week later. For the therapeutic block 20mls of 0.25% bupivacaine with 1/200,000 epinephrine and 20mg triamcinolone was injected between the internal oblique and transverse abdominis muscles; some was also injected under the scar site from his hydrocele

His mood and eating pattern improved within the first month, but he did require repeat therapeutic blocks at 5 months and 11 months following the initial block. These provided

A 66kg 15-year-old male presented with a 3 month history of left upper quadrant pain associated with a bulge just lateral & inferior to the incision from a congenital diaphragmatic hernia repair when he was 14 months old. The pain was described as a burning, stabbing sensation. He exhibited no symptoms related to the respiratory,

He had been extremely fit and well. However his pain was such that he could not stand up straight, suffered pain with all activity and was unable to sleep soundly because he could not get comfortable. He had completely lost his appetite and had lost 10kg in weight. He became depressed and ceased to interact with friends. His suffering affected his family deeply: his parents' relationship suffered, his sister became depressed. He could not sit or

An upper gastrointestinal endoscopy was normal. Surgical repair of the suspected incisional hernia revealed no hernia of the abdominal wall. Pain occurred in the immediate postoperative period. This pain did not respond to simple analgesics or hydromorphone. He

Intercostal nerve blocks were administered to the left sided 9th, 10th, and 11th ribs. This provided effective short-term symptomatic relief, so a follow-up therapeutic block was done a week later. For the therapeutic block, 5ml of 0.25% bupivacaine with 1/200,000 epinephrine & 10mg triamcinolone was injected at the same 3 intercostal spaces; in addition, the same amount was administered as a left rectus sheath block under ultrasound control, adjacent to the site of surgery. On awakening, the patient reported that his pain had gone. This treatment provided immediate pain relief, which allowed the patient to return to his normal self. His appetite returned the next day. Within a few days, he was laughing again

was referred to the Pain Service and a diagnosis of neuropathic pain was made.

good pain relief to allow the patient to make a graded return to competitive fencing.

**2.4 Case 4: A 15-year-old male with a suspected incisional hernia** 

concentrate and consequently missed 5 months of school.

this period was described as 'testy'.

repair. This provided complete pain relief.

cardiovascular or abdominal systems.

or penis. The presumed diagnosis was ilioinguinal neuralgia.

A 25kg 9-year-old male presented with a 4 month history of left sided groin pain. He had been experiencing this pain for three years on and off, but it had been worse since his orchidopexy surgery 4 months prior to the consultation. He was referred to the Pain Service by his surgeon.

He continued to attend school, but had to visit the nurse twice a day and lie down to recover his strength. Often the school requested that he be collected and taken home early. He found it difficult to engage in physical or social activities and had to give up Tae Kwon Do. He was often woken with pain and cramps and cried as a result of his pain.

The pain was described as "stabbing". It was not relieved by ibuprofen and/or acetaminophen. On examination, there was no numbness, allodynia or skin changes and Carnett's test was positive. The presumed diagnosis was genitofemoral or ilioinguinal neuralgia.

A diagnostic rectus abdominis sheath block was performed, under ultrasound control: 15ml 0.25% bupivicaine, 1/200,000 epinephrine was injected into the rectus sheath and between the transverse abdominis and internal oblique; 10ml was injected at his flank at the anterior superior iliac spine; and some was injected at his orchidopexy scar site. On awakening, the patient reported the pain was gone.

A therapeutic block was not done in this case. He was able to resume a normal sleeping pattern within 2 weeks, was much happier and once again able to spend time with friends. He made a gradual return to Tae Kwon Do and normal schooling with no absences.

#### **2.6 Case 6: A 15-year-old female with chest pain following removal of exostosis**

A 45 kg 15-year-old female presented at the Complex Pain Clinic with post-surgical chest pain. Successful removal of an exostosis from her right rib cage was followed by the gradual emergence of a new, sharp pain, which was present every day. It worsened during the day and with sitting or physical activity.

It was 8 months since her surgery. She had missed some school, had stopped gymnastics classes and soccer training completely and had to limit her social activities. She was grumpy with friends and family. Physiotherapy had not helped, but ketorolac (10mg twice a day as needed), psychology, TENS and laser therapy were judged to have provided some benefit.

She was examined by the interdisciplinary team. Physical examination revealed that her pain was localised to the right anterolateral aspect of her 10th rib, close to the exostosis excision; there was no associated numbness, no allodynia and no skin colour change. The physiotherapist noted that her right waist crease and elevated iliac crest suggested a protective response, but that she had a full range of motion in spine and extremities. The psychologist determined that she was not overly anxious or depressed, despite some ongoing family conflicts. A preliminary diagnosis of intercostal neuralgia was made.

A diagnostic intercostal nerve block was performed. This provided effective short-term symptomatic relief so a follow-up therapeutic block was done 3 weeks later. The therapeutic block comprised: 5ml 0.25% bupivicaine with 1/200,000 epinephrine & 2mg/ml triamcinolone injected at 3 sites above & below the affected rib; and 4ml 0.25% bupivicaine with 1/200,000 epinephrine & 1mg/ml triamcinolone injected under the scar site.

The Role of Peripheral Nerve Blocks in the Interdisciplinary

diagnosis was intercostal neuralgia.

**3. Discussion** 

Care of Children with Chronic Pain: A Case Series and Review of the Literature 411

A variety of therapies had been tried, including psychology, physiotherapy, acupuncture, TENS and two sessions with a chiropractor, but these had afforded only partial pain relief. Acetaminophen and non-steroidal anti-inflammatory agents were not effective. She obtained some relief from morphine, consuming up to 50mg each day. The presumed

A diagnostic intercostal nerve block was performed, which provided effective short term symptomatic relief so a follow-up therapeutic block was done three weeks later. For the therapeutic block, a total of 12ml 0.25% bupivicaine with 1/200,000 epinephrine was injected at 3 sites; one above & below and at the site of the affected rib on the right side. This treatment allowed her to make a gradual return to normal. She began exercising again after 2 weeks, started sleeping deeper and longer and was generally in much better mood. She was able to sit and concentrate once again and resumed social activities with friends.

The cases described in this chapter demonstrate that, in properly selected children and adolescents, a peripheral nerve block can be an extremely beneficial component of interdisciplinary care. The case histories demonstrate the effective use of targeted nerve blocks for specific pain conditions such as ilioinguinal block for ilioinguinal neuralgia. The children and adolescents affected are often extremely physically active prior to the first reports of pain. They are usually previously fit and well with no previous pain or medical problems. There is typically an inciting event. The pain is characteristically neuropathic in description with sharp shooting elements and allodynia. The pain distribution is often dermatomal but not necessarily associated with numbness. The pain is not responsive or resolved with simple medications. The impact of the pain is considerable in its effects on

Peripheral nerve blockade in paediatric chronic pain has previously been described specifically for chronic abdominal wall pain (Skinner & Lauder, 2007). Due to the lack of evidence to guide therapy, the following recommendations are the opinion of the author (GL). Peripheral nerve blocks are done under sedation or general anesthesia to minimise further stress and pain to children and adolescents. Strict sterile procedure is followed. Plain local anaesthetic is used for the initial block to ensure that the diagnosis is correct prior to installation of steroids. Peripheral nerve blocks are done whenever possible under ultrasound control to maximise the chance of an effective block by ensuring the local anaesthetic is deposited in the correct plane or near the correct nerve. A diagnostic peripheral nerve block is considered to have worked if the local anaesthetic provided numbness in the dermatomal region to be blocked and also resulted in a clinically significant reduction in pain (>50% reduction). A therapeutic block is only performed after a positive diagnostic block. To achieve a therapeutic peripheral nerve block the same block is performed under ultrasound control with local anaesthetic and steroid (1-2mg/ml of trimcinolone to a maximum dose of 40mg). Peripheral nerve blocks are only offered if children and adolescents are willing to participate in the whole team approach with adherence to paced activity and integration with psychology. The duration of effect of a therapeutic block is extremely varied and may be related to time from diagnosis as well as

**3.1 Diagnosis and selection criteria for the use of peripheral nerve blocks** 

physical function, schooling, mood and family dynamics.

**3.2 Effective techniques in the use of peripheral nerve blocks** 

Though she did not return to gymnastics, her tiredness was resolved and she was able to begin soccer refereeing a week later. She was more energetic, happier and able to spend time with friends again. Her concentration and focus improved which enabled her to achieve better grades at school.

#### **2.7 Case 7: A 9-year-old female with persistent pain following appendectomy**

A 33kg 9-year-old female presented with right-sided abdominal pain, which had begun 3 days after a laparoscopic appendectomy two months previously. The pain, present all the time, but varying in intensity, was described as 'stabbing'. It was worse with activity and at the end of the day.

She had experienced disturbed sleep and was often woken by pain. She had only attended school for only three or four days since her surgery and was completely unable to attend her rhythmic gymnastics classes. Her appetite was reduced and her pain was worse after eating. She became anxious and this period of uncertainty was a tremendously stressful time for her whole family. Tramadol, ibuprofen and acetaminophen had not helped her pain.

A physical examination revealed a positive Carnett's test and normal bowel sounds. Her femoral pulses were present and equal. There was no lymphadenopathy in the inguinal region or neck and no organomegaly. There was no allodynia, no numbness and no skin colour change at the site of her pain. Pain was increased by squatting, walking, use of upper extremities and right leg raises. Right hip flexor function and ability to do sit-ups were limited by pain. She was diagnosed with abdominal wall pain secondary to surgery for laparoscopic appendectomy.

A diagnostic abdominal wall block was performed, which provided effective short-term symptomatic relief so a follow-up therapeutic block was performed two weeks later. The therapeutic block was administered on the right side using ultrasound control, with a 22 gauge IV cannula. A total of 10ml 0.25% bupivicaine with 2mg/ml triamcinolone was injected: 4ml into rectus sheath and 6ml between the transverse abdominus and internal oblique muscles.

On awakening she reported her right side was numb. She experienced an achy bruising pain for 36 hours, which settled down. She was soon able to return to normal sleeping, eating and activity levels. She returned to gymnastics within 3 weeks and was back to her previous level of activity within 2 months. She was significantly happier and quickly re-established her relationships with friends. She returned to school within 2 weeks and was back to a full timetable within a month.

#### **2.8 Case 8: A 17-year-old female with rib pain**

A 66kg 17-year-old female presented with a 6 month history of right-sided lower rib pain. It may have been caused by an injury incurred playing volleyball. She described it as a 'stabbing', burning pain that sometimes radiated to the back or the epigastrum. She had no pain-free days. The pain was worse at night, with deep-breathing and with sitting for long periods of time.

She experienced considerable difficulty maintaining a normal sleep balance: she had trouble getting to sleep and was woken at least once a night in pain, often for long periods. As a consequence, she was often very fatigued, which she felt made her pain worse. She had a reduced appetite in the morning and had stopped all sporting activities. She showed some signs of depression and isolated herself from friends and family. She struggled to concentrate and missed approximately 40% of school.

A variety of therapies had been tried, including psychology, physiotherapy, acupuncture, TENS and two sessions with a chiropractor, but these had afforded only partial pain relief. Acetaminophen and non-steroidal anti-inflammatory agents were not effective. She obtained some relief from morphine, consuming up to 50mg each day. The presumed diagnosis was intercostal neuralgia.

A diagnostic intercostal nerve block was performed, which provided effective short term symptomatic relief so a follow-up therapeutic block was done three weeks later. For the therapeutic block, a total of 12ml 0.25% bupivicaine with 1/200,000 epinephrine was injected at 3 sites; one above & below and at the site of the affected rib on the right side.

This treatment allowed her to make a gradual return to normal. She began exercising again after 2 weeks, started sleeping deeper and longer and was generally in much better mood. She was able to sit and concentrate once again and resumed social activities with friends.

#### **3. Discussion**

410 Pain Management – Current Issues and Opinions

Though she did not return to gymnastics, her tiredness was resolved and she was able to begin soccer refereeing a week later. She was more energetic, happier and able to spend time with friends again. Her concentration and focus improved which enabled her to achieve

A 33kg 9-year-old female presented with right-sided abdominal pain, which had begun 3 days after a laparoscopic appendectomy two months previously. The pain, present all the time, but varying in intensity, was described as 'stabbing'. It was worse with activity and at

She had experienced disturbed sleep and was often woken by pain. She had only attended school for only three or four days since her surgery and was completely unable to attend her rhythmic gymnastics classes. Her appetite was reduced and her pain was worse after eating. She became anxious and this period of uncertainty was a tremendously stressful time for her

A physical examination revealed a positive Carnett's test and normal bowel sounds. Her femoral pulses were present and equal. There was no lymphadenopathy in the inguinal region or neck and no organomegaly. There was no allodynia, no numbness and no skin colour change at the site of her pain. Pain was increased by squatting, walking, use of upper extremities and right leg raises. Right hip flexor function and ability to do sit-ups were limited by pain. She was diagnosed with abdominal wall pain secondary to surgery for

A diagnostic abdominal wall block was performed, which provided effective short-term symptomatic relief so a follow-up therapeutic block was performed two weeks later. The therapeutic block was administered on the right side using ultrasound control, with a 22 gauge IV cannula. A total of 10ml 0.25% bupivicaine with 2mg/ml triamcinolone was injected: 4ml into rectus sheath and 6ml between the transverse abdominus and internal

On awakening she reported her right side was numb. She experienced an achy bruising pain for 36 hours, which settled down. She was soon able to return to normal sleeping, eating and activity levels. She returned to gymnastics within 3 weeks and was back to her previous level of activity within 2 months. She was significantly happier and quickly re-established her relationships with friends. She returned to school within 2 weeks and was back to a full

A 66kg 17-year-old female presented with a 6 month history of right-sided lower rib pain. It may have been caused by an injury incurred playing volleyball. She described it as a 'stabbing', burning pain that sometimes radiated to the back or the epigastrum. She had no pain-free days. The pain was worse at night, with deep-breathing and with sitting for long

She experienced considerable difficulty maintaining a normal sleep balance: she had trouble getting to sleep and was woken at least once a night in pain, often for long periods. As a consequence, she was often very fatigued, which she felt made her pain worse. She had a reduced appetite in the morning and had stopped all sporting activities. She showed some signs of depression and isolated herself from friends and family. She struggled to

**2.7 Case 7: A 9-year-old female with persistent pain following appendectomy** 

whole family. Tramadol, ibuprofen and acetaminophen had not helped her pain.

better grades at school.

the end of the day.

laparoscopic appendectomy.

oblique muscles.

periods of time.

timetable within a month.

**2.8 Case 8: A 17-year-old female with rib pain** 

concentrate and missed approximately 40% of school.

#### **3.1 Diagnosis and selection criteria for the use of peripheral nerve blocks**

The cases described in this chapter demonstrate that, in properly selected children and adolescents, a peripheral nerve block can be an extremely beneficial component of interdisciplinary care. The case histories demonstrate the effective use of targeted nerve blocks for specific pain conditions such as ilioinguinal block for ilioinguinal neuralgia. The children and adolescents affected are often extremely physically active prior to the first reports of pain. They are usually previously fit and well with no previous pain or medical problems. There is typically an inciting event. The pain is characteristically neuropathic in description with sharp shooting elements and allodynia. The pain distribution is often dermatomal but not necessarily associated with numbness. The pain is not responsive or resolved with simple medications. The impact of the pain is considerable in its effects on physical function, schooling, mood and family dynamics.

#### **3.2 Effective techniques in the use of peripheral nerve blocks**

Peripheral nerve blockade in paediatric chronic pain has previously been described specifically for chronic abdominal wall pain (Skinner & Lauder, 2007). Due to the lack of evidence to guide therapy, the following recommendations are the opinion of the author (GL). Peripheral nerve blocks are done under sedation or general anesthesia to minimise further stress and pain to children and adolescents. Strict sterile procedure is followed. Plain local anaesthetic is used for the initial block to ensure that the diagnosis is correct prior to installation of steroids. Peripheral nerve blocks are done whenever possible under ultrasound control to maximise the chance of an effective block by ensuring the local anaesthetic is deposited in the correct plane or near the correct nerve. A diagnostic peripheral nerve block is considered to have worked if the local anaesthetic provided numbness in the dermatomal region to be blocked and also resulted in a clinically significant reduction in pain (>50% reduction). A therapeutic block is only performed after a positive diagnostic block. To achieve a therapeutic peripheral nerve block the same block is performed under ultrasound control with local anaesthetic and steroid (1-2mg/ml of trimcinolone to a maximum dose of 40mg). Peripheral nerve blocks are only offered if children and adolescents are willing to participate in the whole team approach with adherence to paced activity and integration with psychology. The duration of effect of a therapeutic block is extremely varied and may be related to time from diagnosis as well as

The Role of Peripheral Nerve Blocks in the Interdisciplinary

workable goal-directed and achievable management plan.

to placebo analgesic treatments (Finniss et al, 2009).

**4. Conclusion** 

**3.3.2 Placebo response to peripheral nerve block intervention** 

Benedetti, 2008; Scott et al, 2008; Eippert et al, 2009; Finniss et al, 2009).

Care of Children with Chronic Pain: A Case Series and Review of the Literature 413

Verheul et al, 2010). Meaningful two-way communication between healthcare provider and patient is crucial. However, a patient-centred dialogue may depend on circumstances, as physicians appear to adopt a more patient-centred style of communication with patients who participate actively in the discussion (Cegala & Post, 2009). In paediatric care, the communication is, typically, three-way between provider, patient and parent or caregiver which makes adopting a patient-centred approach will often be more challenging. Effective communication, in this context, means using appropriate terminology and actively listening to both patient and parent as well as giving attention to their body language. Factors which have to be considered include: identifying patient and parental expectations, i.e. goal directed therapy; devoting enough time to acquire the whole pain-related history; interpreting non-responsiveness; identifying hidden messages conveyed in what's being said and not said; understanding family beliefs, hopes and fears; asking potentially embarrassing questions separately and in confidence; conveying empathy; introducing appropriate humour into the dialogue; conveying expertise and credibility in pain management; establishing trust; not causing more pain on examination; providing an agreed

Without the evidence of a randomized double blind placebo controlled trial, it is not easy to stipulate that the interventional blocks are the overriding therapeutic modality in this case series. Many would argue that this represents a placebo response. A placebo response refers to the psychobiological response seen after administration of a placebo (a non therapeutic modality) in an individual or groups of patients. Placebo treatments have known effects on the endogenous pharmacology, cognitive and conditioning systems in humans (Fields & Levine, 1981; de la Fuente-Fernandez et al, 2001; Meissner et al, 2007; Wager et al, 2007;

Expectations have the strongest evidence for contributing to the placebo response, especially placebo analgesia. Within the neuro-pharmacological aspect of an analgesic placebo response, there is evidence for the role of endogenous endorphins as some placebo analgesic responses are reversed with naloxone. The respiratory centres, serotonin secretion, hormone secretion, immune responses and heart function are also involved in the biological response

Whatever the mechanism of therapeutic benefit, placebo responses are potentially embedded in every intervention for pain relief (Robinson, 2009). The key message from our case series is that plain local anaesthetic nerve block provided only temporary relief for 7 out of 8 cases. Only when local anaesthetic and steroid was used, in conjunction with their ongoing interdisciplinary care, did these children and adolescents turn their lives around to their pre-pain level of functioning. If only a placebo response, it would be expected to last 1- 3 months only. Only 2 of the cases required repeat therapeutic blocks which were performed greater than three months after the initial therapeutic block. This all points to a mainly

Chronic pain of childhood is an extremely complex condition which can have devastating effects on physical, psychological and social functioning. The interdisciplinary team management approach, based on pharmacology, physiotherapy and psychology, is the

therapeutic effect, but would have to be supported by a properly conducted study.

to the degree in which paced return to activity is adhered to following successful block. Subsequent therapeutic blocks tend to last longer than the previous.

#### **3.2.1 Pharmacology**

The steroid element of the therapeutic peripheral nerve block is considered to either reduce inflammation or result in thinning of the connective tissue around painful nerves (Suleiman & Johnston, 2001). There is no consensus on the correct dose of steroid that should be used for peripheral nerve blocks in children. Steroids have local and systemic side effects. The local effect of fascial thinning may have detrimental effects with repeat injections (Suleiman & Johnston, 2001). Side effects of ongoing or chronic systemic steroids include carbohydrate intolerance, hypothalamic-pituitary-adrenal suppression, growth failure (Hochberg, 2002) and others such as immunosuppression, cataracts, pseudomotor cerebri, pancreatitis steroid psychosis, and steroid myopathy (Rimsza, 1978). The incidence of major systemic side effects to infrequent intermittent steroid injections is not known.

#### **3.3 The mechanism and effects of the treatment**

The specific effects of peripheral nerve blocks rely on the action of pharmacological agents such as local anaesthetics and triamcinolone. However, broader elements of care are also significant. In the context of an ongoing treatment regime, it is particularly important to consider the psychosocial dynamics of the diagnosis and treatment processes, including development of trust in the healthcare team and springboard effects from the realization of interim treatment goals. It is presumed that the combination of these effects creates/initiates a break or change in the pain cycle and reverses the changes that occurred within the peripheral and central nervous system to cause chronic pain.

#### **3.3.1 Nonspecific treatment effects**

We may like to think that when a patient gets better, it is the direct and intentional result of medical intervention, but it may not be quite so straightforward. Jamison (2011) identifies three mechanisms, which may contribute to any improvement in a patient's pain or functioning – (i) the specific or intended effects of any treatment, (ii) natural history and (iii) nonspecific effects of treatment – and there may be some interaction between these elements. Nonspecific treatment effects are the outcomes of patient encounters with healthcare providers. These include attention, stimulation of the desire to get better, reduced anxiety, increased understanding, trust, hope, optimism and improved ability to cope (Jamison, 2011). One important nonspecific treatment effect with children and adolescents is for others, including healthcare providers, to believe that they have pain. These non-specific treatment effects represent a complex array of psychosocial variables that, when utilized correctly, can bestow huge benefit to the patient's sense of wellbeing and outcomes.

The team's attention to the broader effects of pain on daily functioning and quality of life is crucial. What does the child's pain mean to them? What does it mean to their family? What are the patient goals of therapy and are they achievable? As discussed, psychosocial effects of pain such as sadness, frustration, anxiety or depression can become contributory factors to the continuation or worsening of pain in a vicious circle that is hard to escape without effective support. If they remain unrecognized and untreated, these factors may hinder the progress of any management plan.

It has been established that the style of communication adopted by a physician can have a dramatic effect on patient patient's health outcomes (Di Blasi et al, 2001; Griffin et al, 2004; Verheul et al, 2010). Meaningful two-way communication between healthcare provider and patient is crucial. However, a patient-centred dialogue may depend on circumstances, as physicians appear to adopt a more patient-centred style of communication with patients who participate actively in the discussion (Cegala & Post, 2009). In paediatric care, the communication is, typically, three-way between provider, patient and parent or caregiver which makes adopting a patient-centred approach will often be more challenging. Effective communication, in this context, means using appropriate terminology and actively listening to both patient and parent as well as giving attention to their body language. Factors which have to be considered include: identifying patient and parental expectations, i.e. goal directed therapy; devoting enough time to acquire the whole pain-related history; interpreting non-responsiveness; identifying hidden messages conveyed in what's being said and not said; understanding family beliefs, hopes and fears; asking potentially embarrassing questions separately and in confidence; conveying empathy; introducing appropriate humour into the dialogue; conveying expertise and credibility in pain management; establishing trust; not causing more pain on examination; providing an agreed workable goal-directed and achievable management plan.

#### **3.3.2 Placebo response to peripheral nerve block intervention**

Without the evidence of a randomized double blind placebo controlled trial, it is not easy to stipulate that the interventional blocks are the overriding therapeutic modality in this case series. Many would argue that this represents a placebo response. A placebo response refers to the psychobiological response seen after administration of a placebo (a non therapeutic modality) in an individual or groups of patients. Placebo treatments have known effects on the endogenous pharmacology, cognitive and conditioning systems in humans (Fields & Levine, 1981; de la Fuente-Fernandez et al, 2001; Meissner et al, 2007; Wager et al, 2007; Benedetti, 2008; Scott et al, 2008; Eippert et al, 2009; Finniss et al, 2009).

Expectations have the strongest evidence for contributing to the placebo response, especially placebo analgesia. Within the neuro-pharmacological aspect of an analgesic placebo response, there is evidence for the role of endogenous endorphins as some placebo analgesic responses are reversed with naloxone. The respiratory centres, serotonin secretion, hormone secretion, immune responses and heart function are also involved in the biological response to placebo analgesic treatments (Finniss et al, 2009).

Whatever the mechanism of therapeutic benefit, placebo responses are potentially embedded in every intervention for pain relief (Robinson, 2009). The key message from our case series is that plain local anaesthetic nerve block provided only temporary relief for 7 out of 8 cases. Only when local anaesthetic and steroid was used, in conjunction with their ongoing interdisciplinary care, did these children and adolescents turn their lives around to their pre-pain level of functioning. If only a placebo response, it would be expected to last 1- 3 months only. Only 2 of the cases required repeat therapeutic blocks which were performed greater than three months after the initial therapeutic block. This all points to a mainly therapeutic effect, but would have to be supported by a properly conducted study.

#### **4. Conclusion**

412 Pain Management – Current Issues and Opinions

to the degree in which paced return to activity is adhered to following successful block.

The steroid element of the therapeutic peripheral nerve block is considered to either reduce inflammation or result in thinning of the connective tissue around painful nerves (Suleiman & Johnston, 2001). There is no consensus on the correct dose of steroid that should be used for peripheral nerve blocks in children. Steroids have local and systemic side effects. The local effect of fascial thinning may have detrimental effects with repeat injections (Suleiman & Johnston, 2001). Side effects of ongoing or chronic systemic steroids include carbohydrate intolerance, hypothalamic-pituitary-adrenal suppression, growth failure (Hochberg, 2002) and others such as immunosuppression, cataracts, pseudomotor cerebri, pancreatitis steroid psychosis, and steroid myopathy (Rimsza, 1978). The incidence of major systemic side

The specific effects of peripheral nerve blocks rely on the action of pharmacological agents such as local anaesthetics and triamcinolone. However, broader elements of care are also significant. In the context of an ongoing treatment regime, it is particularly important to consider the psychosocial dynamics of the diagnosis and treatment processes, including development of trust in the healthcare team and springboard effects from the realization of interim treatment goals. It is presumed that the combination of these effects creates/initiates a break or change in the pain cycle and reverses the changes that occurred within the

We may like to think that when a patient gets better, it is the direct and intentional result of medical intervention, but it may not be quite so straightforward. Jamison (2011) identifies three mechanisms, which may contribute to any improvement in a patient's pain or functioning – (i) the specific or intended effects of any treatment, (ii) natural history and (iii) nonspecific effects of treatment – and there may be some interaction between these elements. Nonspecific treatment effects are the outcomes of patient encounters with healthcare providers. These include attention, stimulation of the desire to get better, reduced anxiety, increased understanding, trust, hope, optimism and improved ability to cope (Jamison, 2011). One important nonspecific treatment effect with children and adolescents is for others, including healthcare providers, to believe that they have pain. These non-specific treatment effects represent a complex array of psychosocial variables that, when utilized

correctly, can bestow huge benefit to the patient's sense of wellbeing and outcomes.

The team's attention to the broader effects of pain on daily functioning and quality of life is crucial. What does the child's pain mean to them? What does it mean to their family? What are the patient goals of therapy and are they achievable? As discussed, psychosocial effects of pain such as sadness, frustration, anxiety or depression can become contributory factors to the continuation or worsening of pain in a vicious circle that is hard to escape without effective support. If they remain unrecognized and untreated, these factors may hinder the

It has been established that the style of communication adopted by a physician can have a dramatic effect on patient patient's health outcomes (Di Blasi et al, 2001; Griffin et al, 2004;

Subsequent therapeutic blocks tend to last longer than the previous.

effects to infrequent intermittent steroid injections is not known.

peripheral and central nervous system to cause chronic pain.

**3.3 The mechanism and effects of the treatment** 

**3.3.1 Nonspecific treatment effects** 

progress of any management plan.

**3.2.1 Pharmacology** 

Chronic pain of childhood is an extremely complex condition which can have devastating effects on physical, psychological and social functioning. The interdisciplinary team management approach, based on pharmacology, physiotherapy and psychology, is the

The Role of Peripheral Nerve Blocks in the Interdisciplinary

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standard of care for children with severe or ongoing chronic pain. However, in a small proportion of appropriately selected children peripheral nerve blocks can provide immediate, effective and long-term pain relief. The case histories outlined in this chapter demonstrate the enormous impact that pain can have on a child, their functioning and their families. The significant relief received from peripheral nerve blockade indicates that this is a modality that must be considered when the history and examination findings match those presented. However, formal studies are required to definitively evaluate the effectiveness of the peripheral nerve block intervention.

#### **5. Acknowledgement**

The authors would like to thank UBC's *Pediatric Anesthesia Research Team* and the children and adolescents reported in this chapter for allowing us to detail their pain journey.

#### **6. References**


standard of care for children with severe or ongoing chronic pain. However, in a small proportion of appropriately selected children peripheral nerve blocks can provide immediate, effective and long-term pain relief. The case histories outlined in this chapter demonstrate the enormous impact that pain can have on a child, their functioning and their families. The significant relief received from peripheral nerve blockade indicates that this is a modality that must be considered when the history and examination findings match those presented. However, formal studies are required to definitively evaluate the effectiveness of

The authors would like to thank UBC's *Pediatric Anesthesia Research Team* and the children

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**5. Acknowledgement** 

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**20** 

*Italy* 

**Risk Factors in Opioid** 

**Treatment of Chronic Non-Cancer** 

Renata Ferrari, Michela Capraro and Marco Visentin

**Pain: A Multidisciplinary Assessment** 

*Hospital Psychology Service, Pain Relief and Palliative Care Unit, Vicenza Hospital,* 

When pain becomes chronic it assumes an almost absolute central role in the disease experience: it characterises and qualifies it, and constantly interferes with the daily life of the patient (Bonica, 1992). It could be said that chronic pain becomes a disease in itself in the patient's perception; daily activities, interpersonal relationships, feelings, are profoundly

While modern medicine has made notable progress in understanding, diagnosing and treating chronic pain, it continues to be a very widespread problem that significantly compromises the professional, social and family life of the patient, and is often not

The problem of inadequately managed pain is still a considerable one (Breivik et al., 2006), although the World Health Organization [WHO] (1990) has stated that to be pain free should be considered a right of every patient. The consequences of inadequately treated pain not only have an impact in terms of the physical and psychological suffering of the patient and his family, they also have an enormous economic impact on society as a whole

Options for the treatment of chronic pain include both pharmacological treatments (e.g. non steroidal anti-inflammatory drugs, opioids) and non-pharmacological treatments (e.g. physical therapies, acupuncture, cognitive-behavioural therapy, surgical procedures). Choice of treatment should be guided by a complex initial assessment of the patient, which includes the collection of historical information (e.g. pain history and treatments tried, surgical procedures, psychosocial and family history), a physical examination and

Opioids are considered one of the most efficacious groups of drugs in treating mediumsevere pain (Portenoy, 2000), and their use can result in a significant improvement in the patient's quality of life (Dillie et al., 2008); while there is unanimous agreement on their use in acute and cancer pain, their long-term use for non-cancer chronic pain remains controversial (Dews & Mekhail, 2004; Manchikanti et al., 2010; Rosenblum et al., 2008). The discovery of the properties of these substances, and their use as analgesics, is lost in the mists of time: the Sumerians were starting to cultivate poppies as early as 3400 B.C. (Booth, 1986, as cited in Dews & Mekhail, 2004). In 1803, Friedrich Serturner, a German pharmacist,

**1. Introduction** 

disturbed by living with pain (Loeser, 2000).

adequately managed (Manchikanti et al., 2010).

(Brennan et al., 2007; van Leeuwen et al., 2006).

appropriate diagnostic tests (Passik, 2009).


### **Risk Factors in Opioid Treatment of Chronic Non-Cancer Pain: A Multidisciplinary Assessment**

Renata Ferrari, Michela Capraro and Marco Visentin *Hospital Psychology Service, Pain Relief and Palliative Care Unit, Vicenza Hospital, Italy* 

#### **1. Introduction**

418 Pain Management – Current Issues and Opinions

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0021-972X

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Quality of Life Inventory version 4.0 generic core scales in healthy and patient

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pain', *Proceedings of the National Academy of Sciences of the USA*, Vol. 104, No. 26,

childhood and adolescence increases risk for chronic pain in adulthood', *Pain*, Vol.

When pain becomes chronic it assumes an almost absolute central role in the disease experience: it characterises and qualifies it, and constantly interferes with the daily life of the patient (Bonica, 1992). It could be said that chronic pain becomes a disease in itself in the patient's perception; daily activities, interpersonal relationships, feelings, are profoundly disturbed by living with pain (Loeser, 2000).

While modern medicine has made notable progress in understanding, diagnosing and treating chronic pain, it continues to be a very widespread problem that significantly compromises the professional, social and family life of the patient, and is often not adequately managed (Manchikanti et al., 2010).

The problem of inadequately managed pain is still a considerable one (Breivik et al., 2006), although the World Health Organization [WHO] (1990) has stated that to be pain free should be considered a right of every patient. The consequences of inadequately treated pain not only have an impact in terms of the physical and psychological suffering of the patient and his family, they also have an enormous economic impact on society as a whole (Brennan et al., 2007; van Leeuwen et al., 2006).

Options for the treatment of chronic pain include both pharmacological treatments (e.g. non steroidal anti-inflammatory drugs, opioids) and non-pharmacological treatments (e.g. physical therapies, acupuncture, cognitive-behavioural therapy, surgical procedures). Choice of treatment should be guided by a complex initial assessment of the patient, which includes the collection of historical information (e.g. pain history and treatments tried, surgical procedures, psychosocial and family history), a physical examination and appropriate diagnostic tests (Passik, 2009).

Opioids are considered one of the most efficacious groups of drugs in treating mediumsevere pain (Portenoy, 2000), and their use can result in a significant improvement in the patient's quality of life (Dillie et al., 2008); while there is unanimous agreement on their use in acute and cancer pain, their long-term use for non-cancer chronic pain remains controversial (Dews & Mekhail, 2004; Manchikanti et al., 2010; Rosenblum et al., 2008). The discovery of the properties of these substances, and their use as analgesics, is lost in the mists of time: the Sumerians were starting to cultivate poppies as early as 3400 B.C. (Booth, 1986, as cited in Dews & Mekhail, 2004). In 1803, Friedrich Serturner, a German pharmacist,

Risk Factors in Opioid Treatment of Chronic Non-Cancer Pain: A Multidisciplinary Assessment 421

**Opioid for moderate to severe pain +/- Non opioid +/- Adjuvant** 

**1**

**2**

**3**

Physicians may not prescribe opioids at adequate doses because they do not know how to use them effectively, because they do not assess the pain or effects of treatment systematically, because of fear of sanctions by medical commissions. But some data lead one to believe that the overestimation of the risk of addiction is a significant problem (Dews & Mekhail, 2004); in this respect, the term *opiophobia* has been coined, to refer to the practice of under-prescription of opioid medication due to the fear of inducing addiction in patients (Collett, 1998). By interviewing over 248 US physicians, Bhamb et al. (2006) recently reported that just over half of those interviewed (55.9%), had specific clinical protocols for the prolonged use of opioids in patients with chronic non-cancer pain. 35.1% believed they prescribed opioids less frequently than their colleagues; while the most frequent concerns about starting treatment with opioids were the fear of abuse (84.2%) and addiction (74.9%). Concerns of patients should also be considered: they may not communicate their pain symptoms to their physicians, or may not take the drugs as instructed for fear of becoming dependent on "narcotics" (Dews & Mekhail, 2004). Furthermore, both physicians and patients may develop unjustified anxiety about the side effects of opioid use, believing that these drugs must therefore be reserved for cancer pain (Brennan et al., 2007). Finally, a further barrier to the use of these drugs may be due to overly restrictive national control laws and regulations. Because of this, the WHO has issued guidelines on legislative policies that enable Governments to check if their national laws ensure the availability of opioid

**Opioid for mild to moderate pain +/- Adjuvant** 

*Pain persisting or increasing* 

**Non opioid +/- Adjuvant** 

*Pain persisting or increasing* 

Given the importance of these drugs in pain management, as well as the concerns about their use, a series of investigations were carried out in the last twenty years to identify the risk factors that promote or exacerbate opioid misuse. In fact, for physicians, determining the patient's risk of addiction to opioids is of fundamental importance, so that a series of measures can be taken to limit the negative consequences of this (such as constantly monitoring the patient during treatment, planning interdisciplinary treatment or scheduling

The intention of this chapter is to examine the principal risk factors for opioid misuse in patients with chronic non-cancer pain. It will also describe the principal tools for selecting patients who are candidates for opioid treatment and for stratifying the risk of misuse. This will be followed by a presentation of the preliminary results of our experience using a

Fig. 1. The WHO pain analgesia scale

analgesics to treat severe pain (WHO, 2002).

regular urine toxicology screening).

isolated an alkaloid from opium that he named morphine, and in 1853 Scottish physician Alexander Wood introduced the hypodermic needle and successfully used injections of morphine to treat neuralgia. As Way (1982, as cited in Dews & Mekhail, 2004) highlighted, morphine was the "mainstay" of medical treatment in the United States throughout the nineteenth century, used to treat pain, anxiety and respiratory problems as well as "consumption" and "women's ailments". Opium cultivation was legal in some states, and opium-based products could be bought over the counter (Dews & Mekhail, 2004). Between 1875 and 1877, German physician Eduard Levinstein published a series of articles calling attention to the problem of morphine dependence: his was one of the first studies on the risk of dependence on narcotics, which he estimated to be 75% (White et al., 2001a). In 1914 Kennedy Foster wrote, in New York Medical Journal, *"...morphinism is a disease, in the majority of cases, initiated, sustained and left uncured by members of the medical profession"* (White et al., 2001b); in the same year the US Congress approved the Harrison Anti-Narcotic Act, the first federal law to limit the sale of any drug. Opioids and cocaine were included in the list of drugs that could only be obtained from a physician or authorised pharmacist. Physicians were authorised to prescribe these substances, but not to patients with dependence problem; given the likelihood of arrest or prosecution, physicians became increasingly cautious in prescribing opioids even for chronic pain (Dews & Mekhail, 2004). In 1969, the WHO abandoned the belief that the medical use of morphine led inevitably to dependence; the WHO clarified that tolerance and physical dependence did not in itself constitute "drug dependence", a diagnosis characterised by typical behaviours, including difficulty in controlling the assumption of drugs, compulsive use of the substance and inappropriate social behaviours (WHO, 1986). In 1970 the Harrison Anti-Narcotic Act and the other federal laws on drugs were replaced by the Comprehensive Drug Abuse and Control Act, which divided substances into six categories, according to their risk of addiction: category I includes heroin and marijuana, category II includes cocaine, opium and morphine, category III includes codeine, category IV includes diazepam and alprazolam, category V includes drugs with small quantities of codeine and category VI includes penicillin and ibuprofen (Dews & Mekhail, 2004). This law established that there were no impediments to prescribing drugs in categories II, III or IV provided there were indications for their use, including chronic non-cancer pain. There was a further development when the WHO Expert Committee on Essential Drugs recognised morphine, codeine and other opioids as "essential drugs," defining them as: "*those that satisfy the health care needs of the majority of the population; they should therefore be available at all times in adequate amounts and in the appropriate dosage forms...*" (WHO, 1998). The WHO also introduced the "pain analgesia scale" (figure 1) which distinguishes between strong and weak opioids, and establishes their clear roles in pain relief. In Italy, which is one of the countries with the lowest morphine consumption in Europe, several measures have been developed to eliminate the bureaucratic obstacles to the use of opioid analgesics, starting with Law no. 12 of 2001. With Law no. 38 of 2010, opioids may finally be prescribed for pain relief in the same way as other prescription-only drugs.

As illustrated, the use of opioids has historically been subject to cycles of liberalisation and prohibition in clinical practice that account for their still-limited use today (WHO, 1998).

The potential barriers to treatment with opioids may be due to inadequate beliefs of both medical personnel and the patients themselves (Garcia & Altman, 1997).

Fig. 1. The WHO pain analgesia scale

isolated an alkaloid from opium that he named morphine, and in 1853 Scottish physician Alexander Wood introduced the hypodermic needle and successfully used injections of morphine to treat neuralgia. As Way (1982, as cited in Dews & Mekhail, 2004) highlighted, morphine was the "mainstay" of medical treatment in the United States throughout the nineteenth century, used to treat pain, anxiety and respiratory problems as well as "consumption" and "women's ailments". Opium cultivation was legal in some states, and opium-based products could be bought over the counter (Dews & Mekhail, 2004). Between 1875 and 1877, German physician Eduard Levinstein published a series of articles calling attention to the problem of morphine dependence: his was one of the first studies on the risk of dependence on narcotics, which he estimated to be 75% (White et al., 2001a). In 1914 Kennedy Foster wrote, in New York Medical Journal, *"...morphinism is a disease, in the majority of cases, initiated, sustained and left uncured by members of the medical profession"* (White et al., 2001b); in the same year the US Congress approved the Harrison Anti-Narcotic Act, the first federal law to limit the sale of any drug. Opioids and cocaine were included in the list of drugs that could only be obtained from a physician or authorised pharmacist. Physicians were authorised to prescribe these substances, but not to patients with dependence problem; given the likelihood of arrest or prosecution, physicians became increasingly cautious in prescribing opioids even for chronic pain (Dews & Mekhail, 2004). In 1969, the WHO abandoned the belief that the medical use of morphine led inevitably to dependence; the WHO clarified that tolerance and physical dependence did not in itself constitute "drug dependence", a diagnosis characterised by typical behaviours, including difficulty in controlling the assumption of drugs, compulsive use of the substance and inappropriate social behaviours (WHO, 1986). In 1970 the Harrison Anti-Narcotic Act and the other federal laws on drugs were replaced by the Comprehensive Drug Abuse and Control Act, which divided substances into six categories, according to their risk of addiction: category I includes heroin and marijuana, category II includes cocaine, opium and morphine, category III includes codeine, category IV includes diazepam and alprazolam, category V includes drugs with small quantities of codeine and category VI includes penicillin and ibuprofen (Dews & Mekhail, 2004). This law established that there were no impediments to prescribing drugs in categories II, III or IV provided there were indications for their use, including chronic non-cancer pain. There was a further development when the WHO Expert Committee on Essential Drugs recognised morphine, codeine and other opioids as "essential drugs," defining them as: "*those that satisfy the health care needs of the majority of the population; they should therefore be available at all times in adequate amounts and in the appropriate dosage forms...*" (WHO, 1998). The WHO also introduced the "pain analgesia scale" (figure 1) which distinguishes between strong and weak opioids, and establishes their clear roles in pain relief. In Italy, which is one of the countries with the lowest morphine consumption in Europe, several measures have been developed to eliminate the bureaucratic obstacles to the use of opioid analgesics, starting with Law no. 12 of 2001. With Law no. 38 of 2010, opioids may finally be prescribed for pain relief in the

As illustrated, the use of opioids has historically been subject to cycles of liberalisation and prohibition in clinical practice that account for their still-limited use today (WHO,

The potential barriers to treatment with opioids may be due to inadequate beliefs of both

medical personnel and the patients themselves (Garcia & Altman, 1997).

same way as other prescription-only drugs.

1998).

Physicians may not prescribe opioids at adequate doses because they do not know how to use them effectively, because they do not assess the pain or effects of treatment systematically, because of fear of sanctions by medical commissions. But some data lead one to believe that the overestimation of the risk of addiction is a significant problem (Dews & Mekhail, 2004); in this respect, the term *opiophobia* has been coined, to refer to the practice of under-prescription of opioid medication due to the fear of inducing addiction in patients (Collett, 1998). By interviewing over 248 US physicians, Bhamb et al. (2006) recently reported that just over half of those interviewed (55.9%), had specific clinical protocols for the prolonged use of opioids in patients with chronic non-cancer pain. 35.1% believed they prescribed opioids less frequently than their colleagues; while the most frequent concerns about starting treatment with opioids were the fear of abuse (84.2%) and addiction (74.9%). Concerns of patients should also be considered: they may not communicate their pain symptoms to their physicians, or may not take the drugs as instructed for fear of becoming dependent on "narcotics" (Dews & Mekhail, 2004). Furthermore, both physicians and patients may develop unjustified anxiety about the side effects of opioid use, believing that these drugs must therefore be reserved for cancer pain (Brennan et al., 2007). Finally, a further barrier to the use of these drugs may be due to overly restrictive national control laws and regulations. Because of this, the WHO has issued guidelines on legislative policies that enable Governments to check if their national laws ensure the availability of opioid analgesics to treat severe pain (WHO, 2002).

Given the importance of these drugs in pain management, as well as the concerns about their use, a series of investigations were carried out in the last twenty years to identify the risk factors that promote or exacerbate opioid misuse. In fact, for physicians, determining the patient's risk of addiction to opioids is of fundamental importance, so that a series of measures can be taken to limit the negative consequences of this (such as constantly monitoring the patient during treatment, planning interdisciplinary treatment or scheduling regular urine toxicology screening).

The intention of this chapter is to examine the principal risk factors for opioid misuse in patients with chronic non-cancer pain. It will also describe the principal tools for selecting patients who are candidates for opioid treatment and for stratifying the risk of misuse. This will be followed by a presentation of the preliminary results of our experience using a

Risk Factors in Opioid Treatment of Chronic Non-Cancer Pain: A Multidisciplinary Assessment 423

explains neither the presence nor the intensity of the pain (Bonica, 1992). Disputes remain about the interval of time that needs to have elapsed since the trauma for pain to be defined as chronic; in clinical practice, a pain is generally described as chronic when it persists for more than 3-6 months (Bonica, 1991; Loeser & Melzack, 1999; Merskey, 1986b; Merskey &

From a pathogenic perspective, pain may be classified as nociceptive, neuropathic or mixed. Nociceptive pain (somatic or visceral pain) is determined by the activation of nociceptors located in the somatic and visceral structures. It may be further classified as superficial or deep, according to the structure involved, and is due to a tissue lesion that is often evident. Neuropathic pain is typically caused by a change or alteration in the transmission of impulses along the somato-sensorial pathways and is indicative of damage to the conduction systems or to the integration and transmission systems of the central or peripheral nervous system; often it is not accompanied by tissue damage. Finally, when these two types of pain (nociceptive and neuropathic) are both present, this is referred to as

Pain is physiological, i.e. it is a vital sign, and a defence system when it constitutes an alarm signal for tissue damage. It becomes pathological when it maintains itself, losing its initial

Chronic pain is a common and persistent problem in society, with a relatively high incidence and a low remission rate (Elliott et al., 2002). Verhaak et al. (1998), after reviewing 15 epidemiological studies on chronic pain in the adult population, concluded that its prevalence varied from 2% to 40%, with a mean value of 15%. Back pain is one of the most frequent forms of chronic pain, with a prevalence rate of approximately 48% (Gureje et al., 1998). Based on interviews of 2305 subjects aged between 35 and 45, Linton et al. (1998) showed that the prevalence of back pain is 66% with slightly higher incidence in women; in particular, 56% of the subjects complained of low back pain, 44% complained of neck pain,

A recent epidemiological study about the prevalence of chronic pain in European countries involving 46,394 subjects found that approximately 19% of adults suffer continuous pain of medium-high intensity that seriously compromises quality of their emotional, social and working life. The prevalence of chronic pain varies from 12% to 20%, and is highest in Norway, Poland and Spain. In Italy, people who suffer from chronic pain syndromes

meaning and becoming an illness in itself (pain syndrome) (Mannion & Woolf, 2000). In biopsychosocial terms, the experience of pain and its impact on the individual are due to the complex interaction of somatic inputs (nociception), psychological processes (e.g. thoughts, coping strategies and emotions) and social contingencies (e.g. social context, significant others, roles and expectations) (Turk & Okifuji, 2002). In persistent pain syndromes, the weight of these three factors can change at different moments of the illness, and none alone can explain the pain situation as a whole. The biological factors can origin, maintain and modulate the physical disorder, the psychological factors influence perception and evaluation of body signals and the social factors give form to the patients' behavioural responses and their perception of their physical condition. Given this complexity, an adequate approach to chronic pain requires multidisciplinary intervention; the treatment aims in these patients are not only pharmacological treatment but also reduction of affective/emotional discomfort, functional recovery, return to work and improvement in

**2.1.1 The prevalence of chronic pain and its socio-economic impact** 

Bogduk, 1994).

mixed pain (Mannion & Woolf, 2000).

family and social relationships.

and 15% complained of pain in the thoracic spine.

diagnostic protocol for patients undergoing long-term treatment with opioids in a multidisciplinary pain relief unit.

#### **2. Risk factors in opioid treatment of patients with chronic pain: Theoretical and research aspects**

Over the last twenty years, opioids have been used increasingly to treat chronic non-cancer pain (Ballantyne & Shin, 2008). A broad US investigation fund that, between 1980 and 2000, prescriptions of opioids for musculoskeletal pain doubled from 8% to 16%. Over the same two decades, the use of more powerful opioids for chronic pain (hydrocodone, oxycodone, morphine) increased from 2% to 9% (Caudill-Slosberg et al., 2004). However, if some patients benefit from such treatment in terms of reduction of pain and improvement in quality of life (Dillie et al., 2008), others do not (Ballantyne, 2007; Trescot et al., 2008). Side effects, the absence of any improvement in physical function, the excessive use of opioids, abuse and addiction are common problems that may present during the administration of opioid analgesics (Manchikanti et al., 2010). So in recent years experts and researchers have sought to answer many questions regarding risk factor for opioid misuse, selection of patients, efficacy of treatment particularly over time, whether opioids are able to improve physical function and quality of life. The clear and urgent need to answer these questions is reflected in the considerable increase in studies on this topic in the last decade (Ballantyne & Shin, 2008). Moreover, many guidelines for the use of opioids in patients with chronic noncancer pain have been produced, which recommend their use for those patients who have not benefited from other pharmacological and non-pharmacological treatments (Chou, 2009; Chou et al, 2009a; Chou et al, 2009b; Chou et al, 2009c; Kalso et al., 2003; Trescot et al., 2006; Trescot at al., 2008).

The following section will provide some notes on pain, on the recommendations contained in the guidelines for the prolonged use of opioids and on the terminology used. The intention is to offer adequate context for the subsequent discussion of the risk factors related to abuse of opioids and the tools that have been developed to select patients to treat with these drugs.

Finally, the preliminary data of our experience using two of these tools, the *Pain Medication Questionnaire* (PMQ; Adams et al., 2004) and the *Diagnosis Intractability Risk and Efficacy Score* (DIRE; Belgrade et al., 2006) in the Italian population are presented.

#### **2.1 The definition and classification of pain**

Pain is an extremely complex and subjective phenomenon, defined by the International Association for the Study of Pain [IASP] as *"an unpleasant sensory and emotional experience, associated with real or potential tissue damage or described in terms of such damage"* (Merskey, 1986a). Whether acute or chronic, pain is above all a subjective and multidimensional experience, influenced by biological, psychological and socio-environmental factors.

Pain may be distinguished as acute or chronic based on its duration in time and underlying pathology. Acute pain is produced by lesions to body tissues and the activation of the nociceptive transducers at the site of the tissue damage. It may be consequent on a trauma, a surgical procedure or an inflammatory process, and generally lasts for a relatively short period of time (hours, days or weeks) and stops when the underlying pathology is resolved. Chronic pain lasts for a long period of time (continuously or recurring at intervals of months or years), and is generally accompanies by a low level of underlying pathology which fully

diagnostic protocol for patients undergoing long-term treatment with opioids in a

**2. Risk factors in opioid treatment of patients with chronic pain: Theoretical** 

Over the last twenty years, opioids have been used increasingly to treat chronic non-cancer pain (Ballantyne & Shin, 2008). A broad US investigation fund that, between 1980 and 2000, prescriptions of opioids for musculoskeletal pain doubled from 8% to 16%. Over the same two decades, the use of more powerful opioids for chronic pain (hydrocodone, oxycodone, morphine) increased from 2% to 9% (Caudill-Slosberg et al., 2004). However, if some patients benefit from such treatment in terms of reduction of pain and improvement in quality of life (Dillie et al., 2008), others do not (Ballantyne, 2007; Trescot et al., 2008). Side effects, the absence of any improvement in physical function, the excessive use of opioids, abuse and addiction are common problems that may present during the administration of opioid analgesics (Manchikanti et al., 2010). So in recent years experts and researchers have sought to answer many questions regarding risk factor for opioid misuse, selection of patients, efficacy of treatment particularly over time, whether opioids are able to improve physical function and quality of life. The clear and urgent need to answer these questions is reflected in the considerable increase in studies on this topic in the last decade (Ballantyne & Shin, 2008). Moreover, many guidelines for the use of opioids in patients with chronic noncancer pain have been produced, which recommend their use for those patients who have not benefited from other pharmacological and non-pharmacological treatments (Chou, 2009; Chou et al, 2009a; Chou et al, 2009b; Chou et al, 2009c; Kalso et al., 2003; Trescot et al., 2006;

The following section will provide some notes on pain, on the recommendations contained in the guidelines for the prolonged use of opioids and on the terminology used. The intention is to offer adequate context for the subsequent discussion of the risk factors related to abuse of opioids and the tools that have been developed to select patients to treat with

Finally, the preliminary data of our experience using two of these tools, the *Pain Medication Questionnaire* (PMQ; Adams et al., 2004) and the *Diagnosis Intractability Risk and Efficacy Score*

Pain is an extremely complex and subjective phenomenon, defined by the International Association for the Study of Pain [IASP] as *"an unpleasant sensory and emotional experience, associated with real or potential tissue damage or described in terms of such damage"* (Merskey, 1986a). Whether acute or chronic, pain is above all a subjective and multidimensional

Pain may be distinguished as acute or chronic based on its duration in time and underlying pathology. Acute pain is produced by lesions to body tissues and the activation of the nociceptive transducers at the site of the tissue damage. It may be consequent on a trauma, a surgical procedure or an inflammatory process, and generally lasts for a relatively short period of time (hours, days or weeks) and stops when the underlying pathology is resolved. Chronic pain lasts for a long period of time (continuously or recurring at intervals of months or years), and is generally accompanies by a low level of underlying pathology which fully

experience, influenced by biological, psychological and socio-environmental factors.

(DIRE; Belgrade et al., 2006) in the Italian population are presented.

**2.1 The definition and classification of pain** 

multidisciplinary pain relief unit.

**and research aspects** 

Trescot at al., 2008).

these drugs.

explains neither the presence nor the intensity of the pain (Bonica, 1992). Disputes remain about the interval of time that needs to have elapsed since the trauma for pain to be defined as chronic; in clinical practice, a pain is generally described as chronic when it persists for more than 3-6 months (Bonica, 1991; Loeser & Melzack, 1999; Merskey, 1986b; Merskey & Bogduk, 1994).

From a pathogenic perspective, pain may be classified as nociceptive, neuropathic or mixed. Nociceptive pain (somatic or visceral pain) is determined by the activation of nociceptors located in the somatic and visceral structures. It may be further classified as superficial or deep, according to the structure involved, and is due to a tissue lesion that is often evident. Neuropathic pain is typically caused by a change or alteration in the transmission of impulses along the somato-sensorial pathways and is indicative of damage to the conduction systems or to the integration and transmission systems of the central or peripheral nervous system; often it is not accompanied by tissue damage. Finally, when these two types of pain (nociceptive and neuropathic) are both present, this is referred to as mixed pain (Mannion & Woolf, 2000).

Pain is physiological, i.e. it is a vital sign, and a defence system when it constitutes an alarm signal for tissue damage. It becomes pathological when it maintains itself, losing its initial meaning and becoming an illness in itself (pain syndrome) (Mannion & Woolf, 2000).

In biopsychosocial terms, the experience of pain and its impact on the individual are due to the complex interaction of somatic inputs (nociception), psychological processes (e.g. thoughts, coping strategies and emotions) and social contingencies (e.g. social context, significant others, roles and expectations) (Turk & Okifuji, 2002). In persistent pain syndromes, the weight of these three factors can change at different moments of the illness, and none alone can explain the pain situation as a whole. The biological factors can origin, maintain and modulate the physical disorder, the psychological factors influence perception and evaluation of body signals and the social factors give form to the patients' behavioural responses and their perception of their physical condition. Given this complexity, an adequate approach to chronic pain requires multidisciplinary intervention; the treatment aims in these patients are not only pharmacological treatment but also reduction of affective/emotional discomfort, functional recovery, return to work and improvement in family and social relationships.

#### **2.1.1 The prevalence of chronic pain and its socio-economic impact**

Chronic pain is a common and persistent problem in society, with a relatively high incidence and a low remission rate (Elliott et al., 2002). Verhaak et al. (1998), after reviewing 15 epidemiological studies on chronic pain in the adult population, concluded that its prevalence varied from 2% to 40%, with a mean value of 15%. Back pain is one of the most frequent forms of chronic pain, with a prevalence rate of approximately 48% (Gureje et al., 1998). Based on interviews of 2305 subjects aged between 35 and 45, Linton et al. (1998) showed that the prevalence of back pain is 66% with slightly higher incidence in women; in particular, 56% of the subjects complained of low back pain, 44% complained of neck pain, and 15% complained of pain in the thoracic spine.

A recent epidemiological study about the prevalence of chronic pain in European countries involving 46,394 subjects found that approximately 19% of adults suffer continuous pain of medium-high intensity that seriously compromises quality of their emotional, social and working life. The prevalence of chronic pain varies from 12% to 20%, and is highest in Norway, Poland and Spain. In Italy, people who suffer from chronic pain syndromes

Risk Factors in Opioid Treatment of Chronic Non-Cancer Pain: A Multidisciplinary Assessment 425

abuse, informed consent to treatment with opioids, initiation and titration of chronic opioid therapy, the use of methadone, patient monitoring, the use of opioids in high risk patients, the assessment of the effectiveness of the drug and the aberrant drug-related behaviours, dose escalation and high dose therapy, opioid rotation, indications for discontinuation of therapy, prevention and management of opioid-related side effects and issues about driving and work safety during treatment with such drugs (Chou, 2009; Chou et al, 2009a; Chou et al, 2009b; Chou et al, 2009c). The recommendations of the American Pain Society and the

> Prior to initiating chronic opioid therapy, clinicians should conduct a history, physical examination and appropriate testing, including an assessment of risk of substance abuse, misuse, or addiction (strong recommendation, low-quality

A benefit-to-harm evaluation including a history, physical examination, and appropriate diagnostic testing, should be performed and documented prior to and on an ongoing basis during chronic opioid therapy (strong recommendation,

When starting chronic opioid therapy, informed consent should be obtained. A continuing discussion with the patient regarding chronic opioid therapy should include goals, expectations, potential risks, and alternatives to chronic opioid

Clinicians may consider using a written chronic opioid therapy management plan to document patient and clinician responsibilities and expectations and assist in

Clinicians and patients should regard initial treatment with opioids as a therapeutic

Opioid selection, initial dosing, and titration should be individualized according to the patient's health status, previous exposure to opioids, attainment of therapeutic goals, and predicted or observed harms (strong recommendation, low-quality evidence). There is insufficient evidence to recommend short-acting versus long-acting opioids, or as-needed versus around-the-clock dosing of opioids.

Methadone is characterized by complicated and variable pharmacokinetics and pharmacodynamics and should be initiated and titrated cautiously, by clinicians familiar with its use and risks (strong recommendation, moderate-quality evidence).

Clinicians should reassess patients on chronic opioid therapy periodically and as warranted by changing circumstances. Monitoring should include documentation of pain intensity and level of functioning, assessments of progress towards achieving therapeutic goals, presence of adverse events, and adherence to prescribed therapies

In patients on chronic opioid therapy who are at high risk or who have engaged in aberrant drug-related behaviours, clinicians should periodically obtain urine drug screens or other information to confirm adherence to the chronic opioid therapy

periodically obtaining urine drug screens or other information to confirm adherence to the chronic opioid therapy plan of care (weak recommendation, low-quality

In patients on chronic opioid therapy not at high risk and not known to have engaged in aberrant drug-related behaviors, clinicians should consider

potential harms (strong recommendation, low-quality evidence).

therapy (strong recommendation, low-quality evidence).

recommendation, low-quality evidence).

(strong recommendation, low-quality evidence).

plan of care (strong recommendation, low-quality evidence).

patient education (weak recommendation, low-quality evidence).

trial to determine whether chronic opioid therapy is appropriate (strong

Clinicians may consider a trial of chronic opioid therapy as an option if chronic noncancer pain is moderate or severe, pain is having an adverse impact on function or quality of life, and potential therapeutic benefits outweigh or are likely to outweigh

American Academy of Pain Medicine are shown in table 1.

low-quality evidence).

evidence).

evidence).

**TOPIC AREA RECOMENDATIONS** 

Patient selection and risk stratification

Informed consent and opioid management

Initiation and titration of chronic opioid therapy

Methadone

Monitoring

plans

account for approximately 27% of the population. It also emerged that: 59% of those interviewed had been experiencing pain for at least 2-15 years, 21% had been diagnosed with depression consequent on pain, 61% reported great difficulty or incapacity in working outside home, 19% had lost their job and 13% had been forced to change jobs because of the pain. Just 2% of patients reported they were being treated by pain specialists, and about half of these were receiving inadequate treatment (Breivik et al., 2006).

Therefore chronic pain has serious negative effects on the quality of life of the millions of people who experience it, and on the quality of life of their families. In the absence of adequate treatments, patients with chronic pain are often unable to work or even to carry out their normal daily activities.

As well as causing unspeakable suffering to millions of people all over the world, chronic pain has high social cost too. Analysing data from the 1997 Medical Expenditures Panel Survey, which involved 14,147 families, Yelin et al.(2004) found that expenditure by patients with rheumatic disorders was US \$ 4,865 per head, for a total of US \$ 186.9 million. In 1998, US healthcare expenditure on lower back pain was US \$ 90.7 billions (Luo et. al., 2004). A similar investigation found that in 2003 overall spending in the US on care for arthritis and other rheumatic disorders was approximately US \$ 128 billion, equivalent to 1.2% of the US gross domestic product in 2003 (Centers for Disease Control and Prevention, 2007).

So far as Europe is concerned, a study of the socio-economic costs of pain syndromes in the United Kingdom estimated that the cost of direct healthcare was £ 1.6 billion in 1998. But this direct cost is insignificant compared to the indirect costs (e.g. days of work lost and loss of productivity) associated with back pain, totalling 10.7 billion (Maniadakis & Gray, 2000). Winkelmann et al. (2011) estimated the annual costs per fibromyalgia patient for 2008 as € 7,900 in France (of which €960 direct costs, €6,990 indirect costs), and € 7,256 in Germany (€ 1,756 direct costs, € 5,491 indirect costs).

#### **2.2 Opioid treatment of chronic non-cancer pain**

In recent years, many guidelines for the use of opioids in patients with chronic non-cancer pain have been drawn up. In general the objectives of such documents are: to bring consistency in opioid prescribing to the many diverse groups involved; to provide analysis of evidence to treat a chronic pain patient with opioids, thus, maintaining reasonable patient access while reducing the risk of drug diversion; to provide practical prescribing guidelines for physicians to reduce the risk of legal and regulatory sanctions; and to emphasize the need for systematic evaluation and ongoing care of patients with chronic or persistent pain (Trescot et al., 2006). The perceived benefits of these guidelines include: increased physician awareness about the current issues involving opioids and non-cancer pain; improved patient access; reduced level of opioid abuse; improved ability to manage patient expectations; reduced diversion; improved understanding by law enforcement about proper prescribing patterns; improved cooperation among patients, providers, and regulatory agencies; improved understanding by patients regarding their rights as well as their responsibilities when taking opioid medications (Trescot et al., 2008). These guidelines should be applied flexibly: every physician must establish a treatment plan that takes account of the specific medical conditions of the patient and his personal preferences and needs, and of the physician's own professional experience (Trescot et al., 2006; 2008). Based on a systematic review of the efficacy of treatment with opioids in chronic non-cancer pain by a multidisciplinary group of experts, the American Academy of Pain Medicine formulated a series of recommendations for: patient selection and the stratification of risk of

account for approximately 27% of the population. It also emerged that: 59% of those interviewed had been experiencing pain for at least 2-15 years, 21% had been diagnosed with depression consequent on pain, 61% reported great difficulty or incapacity in working outside home, 19% had lost their job and 13% had been forced to change jobs because of the pain. Just 2% of patients reported they were being treated by pain specialists, and about half

Therefore chronic pain has serious negative effects on the quality of life of the millions of people who experience it, and on the quality of life of their families. In the absence of adequate treatments, patients with chronic pain are often unable to work or even to carry

As well as causing unspeakable suffering to millions of people all over the world, chronic pain has high social cost too. Analysing data from the 1997 Medical Expenditures Panel Survey, which involved 14,147 families, Yelin et al.(2004) found that expenditure by patients with rheumatic disorders was US \$ 4,865 per head, for a total of US \$ 186.9 million. In 1998, US healthcare expenditure on lower back pain was US \$ 90.7 billions (Luo et. al., 2004). A similar investigation found that in 2003 overall spending in the US on care for arthritis and other rheumatic disorders was approximately US \$ 128 billion, equivalent to 1.2% of the US

So far as Europe is concerned, a study of the socio-economic costs of pain syndromes in the United Kingdom estimated that the cost of direct healthcare was £ 1.6 billion in 1998. But this direct cost is insignificant compared to the indirect costs (e.g. days of work lost and loss of productivity) associated with back pain, totalling 10.7 billion (Maniadakis & Gray, 2000). Winkelmann et al. (2011) estimated the annual costs per fibromyalgia patient for 2008 as € 7,900 in France (of which €960 direct costs, €6,990 indirect costs), and € 7,256 in Germany (€

In recent years, many guidelines for the use of opioids in patients with chronic non-cancer pain have been drawn up. In general the objectives of such documents are: to bring consistency in opioid prescribing to the many diverse groups involved; to provide analysis of evidence to treat a chronic pain patient with opioids, thus, maintaining reasonable patient access while reducing the risk of drug diversion; to provide practical prescribing guidelines for physicians to reduce the risk of legal and regulatory sanctions; and to emphasize the need for systematic evaluation and ongoing care of patients with chronic or persistent pain (Trescot et al., 2006). The perceived benefits of these guidelines include: increased physician awareness about the current issues involving opioids and non-cancer pain; improved patient access; reduced level of opioid abuse; improved ability to manage patient expectations; reduced diversion; improved understanding by law enforcement about proper prescribing patterns; improved cooperation among patients, providers, and regulatory agencies; improved understanding by patients regarding their rights as well as their responsibilities when taking opioid medications (Trescot et al., 2008). These guidelines should be applied flexibly: every physician must establish a treatment plan that takes account of the specific medical conditions of the patient and his personal preferences and needs, and of the physician's own professional experience (Trescot et al., 2006; 2008). Based on a systematic review of the efficacy of treatment with opioids in chronic non-cancer pain by a multidisciplinary group of experts, the American Academy of Pain Medicine formulated a series of recommendations for: patient selection and the stratification of risk of

gross domestic product in 2003 (Centers for Disease Control and Prevention, 2007).

of these were receiving inadequate treatment (Breivik et al., 2006).

out their normal daily activities.

1,756 direct costs, € 5,491 indirect costs).

**2.2 Opioid treatment of chronic non-cancer pain** 

abuse, informed consent to treatment with opioids, initiation and titration of chronic opioid therapy, the use of methadone, patient monitoring, the use of opioids in high risk patients, the assessment of the effectiveness of the drug and the aberrant drug-related behaviours, dose escalation and high dose therapy, opioid rotation, indications for discontinuation of therapy, prevention and management of opioid-related side effects and issues about driving and work safety during treatment with such drugs (Chou, 2009; Chou et al, 2009a; Chou et al, 2009b; Chou et al, 2009c). The recommendations of the American Pain Society and the American Academy of Pain Medicine are shown in table 1.


Risk Factors in Opioid Treatment of Chronic Non-Cancer Pain: A Multidisciplinary Assessment 427

Trescot et al. (2006, 2008) confirmed the importance of an overall patient assessment (physical and psychological) before initiating long-term opioid therapy; this assessment must include an appropriate assessment of treatment efficacy at regular intervals (in terms of both pain reduction and recovery of physical function), the identification and treatment of side effects and the monitoring of any abuse or misuse of the drug. The authors proposed a ten step algorithm that physicians could use for this purpose during

To ensure effective communication between physicians, researchers and legislators, a clear common terminology is needed. Many drugs, including opioids, play an important role in the treatment of pain. However, as shown earlier, the use of opioids is often limited by concerns about abuse, dependence and their possible use for non-medical reasons. Addiction, tolerance and physical dependence are distinct and different phenomena that are often used in a confused way. Since their clinical implications and management are clearly different, it is important to establish uniform definitions based on current scientific and clinical knowledge, to improve the care of patients with chronic pain and encourage appropriate policies for the regulation and control of drugs. For this purpose, the American Academy of Pain Medicine, the American Pain Society and the American Society of Addiction Medicine (American Society of Addiction Medicine, 2001) have recognised the

*Addiction* is a primary, chronic, neurobiologic disease, with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviours that include one or more of the following: impaired control over drug use,

*Physical dependence* is a state of adaptation that is manifested by a drug class specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction,

*Tolerance* is a state of adaptation in which exposure to a drug induces changes that result in a

*Pseudoaddiction* is a term that has been used to describe behaviour that can occur when the pain is undertreated. Patients with inadequately managed pain may in fact become excessively focused on obtaining drugs. In their intent to obtain relief, patients may also resort to trickery and the use of unlawful substances. Pseudoaddiction may be distinguished from true addiction by the fact that the behaviour disappears when the pain is treated

*Misuse* is defined as the use of any psychoactive substance in a way other than that for which it has been indicated or prescribed (Wasan et al., 2007). In practical terms, opioid misuse means: inadequate pain management, ineffective treatment, excessive focus on the drug and its effects which does not allow the patient to use other strategies efficaciously to cope with the pain, and finally, worsening of quality of life and altered social, working and

The term *aberrant drug-related behaviours* has been used to indicate the broad array of problematic nonadherence behaviours (Passik et al., 2006), the nature of which is uncertain until a diagnosis can be developed based on astute clinical assessment (Rosenblum et al., 2008). Portenoy (1996; 2004) has listed a series of behaviours that should engender suspicion of addiction in patients with pain being treated with opioids (table 2). Moreover, Savage

decreasing blood level of the drug, and/or administration of an antagonist.

**2.2.1 Terminology of opioid abuse: Dependence, tolerance, addiction** 

following definitions, and recommend their use:

compulsive use, continued use despite harm, and craving.

diminution of one or more of the drug's effects over time.

treatment with opioids.

efficaciously.

psychological functioning.


Table 1. Guidelines recommended by the American Pain Society and the American Academy of Pain Medicine for the long-term treatment with opioids of patients with chronic non-cancer pain (adapted from Chou, 2009).

Trescot et al. (2006, 2008) confirmed the importance of an overall patient assessment (physical and psychological) before initiating long-term opioid therapy; this assessment must include an appropriate assessment of treatment efficacy at regular intervals (in terms of both pain reduction and recovery of physical function), the identification and treatment of side effects and the monitoring of any abuse or misuse of the drug. The authors proposed a ten step algorithm that physicians could use for this purpose during treatment with opioids.

#### **2.2.1 Terminology of opioid abuse: Dependence, tolerance, addiction**

426 Pain Management – Current Issues and Opinions

(strong recommendation, low-quality evidence).

(strong recommendation, low-quality evidence).

(weak recommendation, low-quality evidence).

recommendation, low-quality evidence).

Table 1. Guidelines recommended by the American Pain Society and the American

Academy of Pain Medicine for the long-term treatment with opioids of patients with chronic

low-quality evidence).

evidence).

non-cancer pain (adapted from Chou, 2009).

moderate-quality evidence).

effects (strong recommendation, low-quality evidence).

effects (strong recommendation, moderate-quality evidence).

Clinicians may consider chronic opioid therapy for patients with chronic non-cancer pain and history of drug abuse, psychiatric issues, or serious aberrant drug-related behaviours only if they are able to implement more frequent and stringent monitoring parameters. In such situations, clinicians should strongly consider consultation with a mental health or addiction specialist (strong recommendation,

Clinicians should evaluate patients engaging in aberrant drug-related behaviours for appropriateness of chronic opioid therapy or need for restructuring of therapy, referral for assistance in management, or discontinuation of chronic opioid therapy

When repeated dose escalations occur in patients on chronic opioid therapy, clinicians should evaluate potential causes and re-assess benefits relative to harms

In patients who require relatively high doses of chronic opioid therapy clinicians should evaluate for unique opioid-related adverse effects, changes in health status, and adherence to the chronic opioid therapy treatment plan on an ongoing basis, and consider more frequent follow-up visits (strong recommendation, low-quality

Clinicians should consider opioid rotation when patients on chronic opioid therapy experience intolerable adverse effects or inadequate benefit despite dose increases

Clinicians should taper or wean patients off of chronic opioid therapy who engage in repeated aberrant drug-related behaviours or drug abuse/diversion, experience no progress towards meeting therapeutic goals, or experience intolerable adverse

Clinicians should anticipate, identify, and treat common opioid-associated adverse

As chronic noncancer pain is often a complex biopsychosocial condition, clinicians who prescribe chronic opioid therapy should routinely integrate psychotherapeutic interventions, functional restoration, interdisciplinary therapy, and other adjunctive non-opioid therapies (strong recommendation, moderate-quality evidence).

Clinicians should counsel patients on chronic opioid therapy about transient or lasting cognitive impairment that may affect driving and work safety. Patients should be counselled not to drive or engage in potentially dangerous activities when

Patients on chronic opioid therapy should identify a clinician who accepts primary responsibility for their overall medical care. This clinician may or may not prescribe chronic opioid therapy, but should coordinate consultation and communication among all clinicians involved in the patient's care (strong recommendation,

In patients on around-the-clock chronic opioid therapy with breakthrough pain, clinicians may consider as-needed opioids based upon an initial and ongoing analysis of therapeutic benefit versus risk (weak recommendation, low-quality

impaired or if they describe or demonstrate signs of impairment (strong

Clinicians should pursue consultation, including interdisciplinary pain management, when patients with chronic non-cancer pain may benefit from additional skills or resources that they cannot provide (strong recommendation,

**TOPIC AREA RECOMENDATIONS** 

low-quality evidence).

evidence).

High-risk patients

Aberrant drug-related

Dose escalations and high-dose therapy

Opioid rotation

Indications for discontinuation of

Opioid-related adverse

Driving and work safety

Identifying a medical home and when to obtain consultation

Breakthrough pain

psychotherapeutic co-interventions

therapy

effects

Use of

behaviours

To ensure effective communication between physicians, researchers and legislators, a clear common terminology is needed. Many drugs, including opioids, play an important role in the treatment of pain. However, as shown earlier, the use of opioids is often limited by concerns about abuse, dependence and their possible use for non-medical reasons. Addiction, tolerance and physical dependence are distinct and different phenomena that are often used in a confused way. Since their clinical implications and management are clearly different, it is important to establish uniform definitions based on current scientific and clinical knowledge, to improve the care of patients with chronic pain and encourage appropriate policies for the regulation and control of drugs. For this purpose, the American Academy of Pain Medicine, the American Pain Society and the American Society of Addiction Medicine (American Society of Addiction Medicine, 2001) have recognised the following definitions, and recommend their use:

*Addiction* is a primary, chronic, neurobiologic disease, with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviours that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving.

*Physical dependence* is a state of adaptation that is manifested by a drug class specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist.

*Tolerance* is a state of adaptation in which exposure to a drug induces changes that result in a diminution of one or more of the drug's effects over time.

*Pseudoaddiction* is a term that has been used to describe behaviour that can occur when the pain is undertreated. Patients with inadequately managed pain may in fact become excessively focused on obtaining drugs. In their intent to obtain relief, patients may also resort to trickery and the use of unlawful substances. Pseudoaddiction may be distinguished from true addiction by the fact that the behaviour disappears when the pain is treated efficaciously.

*Misuse* is defined as the use of any psychoactive substance in a way other than that for which it has been indicated or prescribed (Wasan et al., 2007). In practical terms, opioid misuse means: inadequate pain management, ineffective treatment, excessive focus on the drug and its effects which does not allow the patient to use other strategies efficaciously to cope with the pain, and finally, worsening of quality of life and altered social, working and psychological functioning.

The term *aberrant drug-related behaviours* has been used to indicate the broad array of problematic nonadherence behaviours (Passik et al., 2006), the nature of which is uncertain until a diagnosis can be developed based on astute clinical assessment (Rosenblum et al., 2008). Portenoy (1996; 2004) has listed a series of behaviours that should engender suspicion of addiction in patients with pain being treated with opioids (table 2). Moreover, Savage

Risk Factors in Opioid Treatment of Chronic Non-Cancer Pain: A Multidisciplinary Assessment 429

Many studies have been carried out about the prevalence of opioid addiction in patients with chronic pain, but one of the limitations in interpreting their results is the fact that the researchers have used different criteria to establish problematic opioid use; some studies are based on behavioural observations, others on the results of urine toxicology screening, others again on the criteria Diagnostic and Statistical Manual of mental disorders – III or IV [DSM-III-IV] and yet other studies are based on definitions established by the authors

Based on an extensive literature review, Højsted & Sjøgren (2007) estimated that the prevalence of addiction in the population with chronic non-cancer pain varies from 0% to 50%. In particular, in the studies based on urine toxicology screening the prevalence varies from 17.2% to 39%; in the studies using the DSM-III or DSM-IV criteria it varied from 1.9% to 37%; and, finally, in the studies based on the various behavioural indicators, the prevalence varied from 0% to 50%. In a study of 100 patients with chronic pain in treatment with opioids, Manchikanti et al. (2001) found a prevalence of drug abuse, defined as the occurrence of obtaining a prescription of a controlled substance at least once a month from another physician without approval of the pain physician signing the controlled substance contract, of 24%. Fleming et al. (2007), considering 801 patients with non-cancer pain in chronic treatment with opioids, reported that 9.7% of the sample met the DSM-IV diagnostic criteria for opioid use disorder; the prevalence found by the authors was four times the

Finally, a recent review of the prolonged use of opioids in patients with non-cancer pain estimated the prevalence of addiction indicators as 0.27% of the total number of patients examined (Noble et al., 2010); the authors also observed that minor unwanted effects (e.g. nausea, headache) are frequent during treatment with opioids, but more serious adverse

The hypothesis that short acting drugs such as hydrocodone may make patients more liable to ineffective pain management and misuse or abuse of the drugs than long acting drugs such as methadone was investigated by Manchikanti et al. (2005), who analysed 200 patients with chronic pain, half being treated with hydrocodone and the remainder with methadone. The study found no significant differences in the use of illegal substances and/or opioid

So addiction is a well documented problem in pain patients, although it is difficult to estimate its exact prevalence. It is therefore important that clinicians consider the risk of opioid addiction without this prejudicing their use where indicated. In fact, those who use opioids constitute a heterogeneous category that includes extreme cases of patients who abuse medical and non-medical substances, and patients who adhere to treatment (Passik, 2009). For adequate management and treatment of pain, physicians must balance the costs and benefits of opioid treatment; to maximise the benefits they can use different strategies, such as risk assessment and stratification, using specific tools, constant monitoring of treatment and any aberrant drug behaviours, regular urine screening and the possible

Risk factors for opioid abuse and addiction may be divided into three categories: psychosocial factors, substance-related factors and genetic factors (figure 2). The risk of addiction is highest when the various categories of risk factor are combined. Pain patients without a genetic predisposition, without psychiatric comorbidity who take a stable dose of

themselves.

prevalence in the general population.

events, such as addiction, are rare.

**2.3 Risk factors for opioid abuse** 

abuse in patients treated with short- or long-acting drugs.

involvement of another specialist (e.g. psychotherapist, addiction expert).

(1993), suggested that the following aspects should also be considered: frequent cancellation of appointments; asking for medicines at the end of every appointment; a history of nonresponsiveness to treatment, apart from opioids; a history of negative relationships with many physicians; many "drug allergies" that limit treatment options; finally, a degree of disability that is disproportionate to the basic disorder.

As described above, the use of opioids has raised many concerns; in fact, the use of analgesics without medical prescription, or just to test their effects ("non medical use") represents the second most frequent form of illicit substance use in the United States, after marijuana use (Office of Applied Studies, Substance Abuse and Mental Health Services Administration [SAMHSA], 2008). The National Survey on Drug Use and Health (Office of Applied Studies, SAMHSA, 2009) report on the use of opioids for non-medical purposes in the United States from 2002 to 2007 showed that: in 2007 approximately 5.2 million people of 12 years of age or more had used prescription-only analgesics for non-medical purposes in the previous month; from 2002 to 2007 the use of opioids for non-therapeutic purposes decreased among young people between 12 and 17 years of age (from 3.2% to 2.7%) , while it increased in young adults between 18 and 25 years of age (4.1% to 4.6%) and in adults over 26 (from 1.3% to 1.6%).

#### *Behaviours probably more predictive of addiction*

Selling prescriptions drugs Prescription forgery Stealing or "borrowing" drugs from others Injection oral formulations Obtaining prescription drugs from non-medical sources Concurrent abuse of alcohol or illicit drugs Multiple dose escalation or other non-compliance with therapy despite warnings Multiple episodes of prescription "loss" Repeatedly seeking prescription from other clinicians or from emergency rooms without informing prescriber or after warning to desist Evidence of deterioration in the ability to function in work, in the family, or socially that appear to be related to the drug use Repeated resistance to changes in therapy despite clear evidence of adverse physical or psychological effect from the drug *Behaviours probably less predictive of addiction*  Aggressive complaining about the need for more drug Drug hoarding during periods of reduced symptoms Requesting specific drugs Openly acquiring similar drugs from other medical sources Unsanctioned dose escalation or other non-compliance with therapy on one or two occasions Reporting psychic effects not intended by the clinician

Resistance to change in therapy associated with "tolerable" adverse effects with expression of anxiety related to the return of severe symptoms

Table 2. Behaviours predictive of addiction (adapted from Portenoy 1996, 2004).

Many studies have been carried out about the prevalence of opioid addiction in patients with chronic pain, but one of the limitations in interpreting their results is the fact that the researchers have used different criteria to establish problematic opioid use; some studies are based on behavioural observations, others on the results of urine toxicology screening, others again on the criteria Diagnostic and Statistical Manual of mental disorders – III or IV [DSM-III-IV] and yet other studies are based on definitions established by the authors themselves.

Based on an extensive literature review, Højsted & Sjøgren (2007) estimated that the prevalence of addiction in the population with chronic non-cancer pain varies from 0% to 50%. In particular, in the studies based on urine toxicology screening the prevalence varies from 17.2% to 39%; in the studies using the DSM-III or DSM-IV criteria it varied from 1.9% to 37%; and, finally, in the studies based on the various behavioural indicators, the prevalence varied from 0% to 50%. In a study of 100 patients with chronic pain in treatment with opioids, Manchikanti et al. (2001) found a prevalence of drug abuse, defined as the occurrence of obtaining a prescription of a controlled substance at least once a month from another physician without approval of the pain physician signing the controlled substance contract, of 24%. Fleming et al. (2007), considering 801 patients with non-cancer pain in chronic treatment with opioids, reported that 9.7% of the sample met the DSM-IV diagnostic criteria for opioid use disorder; the prevalence found by the authors was four times the prevalence in the general population.

Finally, a recent review of the prolonged use of opioids in patients with non-cancer pain estimated the prevalence of addiction indicators as 0.27% of the total number of patients examined (Noble et al., 2010); the authors also observed that minor unwanted effects (e.g. nausea, headache) are frequent during treatment with opioids, but more serious adverse events, such as addiction, are rare.

The hypothesis that short acting drugs such as hydrocodone may make patients more liable to ineffective pain management and misuse or abuse of the drugs than long acting drugs such as methadone was investigated by Manchikanti et al. (2005), who analysed 200 patients with chronic pain, half being treated with hydrocodone and the remainder with methadone. The study found no significant differences in the use of illegal substances and/or opioid abuse in patients treated with short- or long-acting drugs.

So addiction is a well documented problem in pain patients, although it is difficult to estimate its exact prevalence. It is therefore important that clinicians consider the risk of opioid addiction without this prejudicing their use where indicated. In fact, those who use opioids constitute a heterogeneous category that includes extreme cases of patients who abuse medical and non-medical substances, and patients who adhere to treatment (Passik, 2009). For adequate management and treatment of pain, physicians must balance the costs and benefits of opioid treatment; to maximise the benefits they can use different strategies, such as risk assessment and stratification, using specific tools, constant monitoring of treatment and any aberrant drug behaviours, regular urine screening and the possible involvement of another specialist (e.g. psychotherapist, addiction expert).

#### **2.3 Risk factors for opioid abuse**

428 Pain Management – Current Issues and Opinions

(1993), suggested that the following aspects should also be considered: frequent cancellation of appointments; asking for medicines at the end of every appointment; a history of nonresponsiveness to treatment, apart from opioids; a history of negative relationships with many physicians; many "drug allergies" that limit treatment options; finally, a degree of

As described above, the use of opioids has raised many concerns; in fact, the use of analgesics without medical prescription, or just to test their effects ("non medical use") represents the second most frequent form of illicit substance use in the United States, after marijuana use (Office of Applied Studies, Substance Abuse and Mental Health Services Administration [SAMHSA], 2008). The National Survey on Drug Use and Health (Office of Applied Studies, SAMHSA, 2009) report on the use of opioids for non-medical purposes in the United States from 2002 to 2007 showed that: in 2007 approximately 5.2 million people of 12 years of age or more had used prescription-only analgesics for non-medical purposes in the previous month; from 2002 to 2007 the use of opioids for non-therapeutic purposes decreased among young people between 12 and 17 years of age (from 3.2% to 2.7%) , while it increased in young adults between 18 and 25 years of age (4.1% to 4.6%) and in adults

disability that is disproportionate to the basic disorder.

*Behaviours probably more predictive of addiction* 

Obtaining prescription drugs from non-medical sources

Multiple dose escalation or other non-compliance with therapy despite warnings

Repeatedly seeking prescription from other clinicians or from emergency rooms without

Evidence of deterioration in the ability to function in work, in the family, or socially that

Repeated resistance to changes in therapy despite clear evidence of adverse physical or

Unsanctioned dose escalation or other non-compliance with therapy on one or two

Table 2. Behaviours predictive of addiction (adapted from Portenoy 1996, 2004).

Resistance to change in therapy associated with "tolerable" adverse effects with expression

Stealing or "borrowing" drugs from others

Concurrent abuse of alcohol or illicit drugs

informing prescriber or after warning to desist

*Behaviours probably less predictive of addiction*  Aggressive complaining about the need for more drug Drug hoarding during periods of reduced symptoms

Openly acquiring similar drugs from other medical sources

Reporting psychic effects not intended by the clinician

of anxiety related to the return of severe symptoms

Multiple episodes of prescription "loss"

appear to be related to the drug use

psychological effect from the drug

Requesting specific drugs

occasions

over 26 (from 1.3% to 1.6%).

Selling prescriptions drugs Prescription forgery

Injection oral formulations

Risk factors for opioid abuse and addiction may be divided into three categories: psychosocial factors, substance-related factors and genetic factors (figure 2). The risk of addiction is highest when the various categories of risk factor are combined. Pain patients without a genetic predisposition, without psychiatric comorbidity who take a stable dose of

Risk Factors in Opioid Treatment of Chronic Non-Cancer Pain: A Multidisciplinary Assessment 431

Using logistic regression, the authors showed that panic attacks, high trait anxiety and the presence of a personality disorder are able to explain the 38% variance in potential abuse of prescribed opioids. To investigate the role of psychological adjustment and psychiatric symptoms in aberrant drug behaviours in pain patients, Wasan et al. (2007) divided the 228 patients enrolled into high-psychiatric and low-psychiatric morbidity, based on the responses to the psychiatric subscale of the Prescription Drug Use Questionnaire (PDUQ; Compton et al., 2008; see § 2.4.). Patients with high psychiatric comorbidity were significantly younger, with a longer mean opioid assumption time (p<0.05); altered urine toxicology screening results were also more frequent among these patients (p<0.01), and

Edlund et al. (2007) conducted a broad prospective study of the risk factors for opioid abuse and addiction using the South Central Veterans Affairs Health Care Network databank. The sample included 15.160 chronic users of opioids in 2002; 45.3% of the sample had a psychiatric diagnosis and 7.6% had a non-opioid substance abuse diagnosis. The results show that prior abuse of non-opioid substances is a strong predictor of abuse/addiction to opioid drugs, while mental disorders are moderately strong predictors. The authors also found that the risk of abuse decreases uniformly with age. Other risk factors for opioid abuse/addiction were male gender, being divorced/separated or single and, finally, being in treatment with opioids for longer. A broad retrospective cohort study that involved 704 patients with chronic pain being treated with opioids was carried out by Banta-Green et al. (2009a) to further comprehend the complex interaction between pain, mental health and addiction. The patients were initially assessed using a structured interview based on DSM-IV criteria for abuse and dependence on opioids, misuse of opioids, anxiety and depression. By regression analysis, the authors identified three distinct categories of patients which they called: a) Typical group (characterised by moderate pain symptoms and limited psychiatric problems); b) Addictive Behaviours group (high psychiatric symptoms, misuse of opioids and moderate pain symptoms); c) Pain Dysfunction group (high intensity and interference of pain, high psychiatric symptoms and consistent misuse of opioids). The patients in the last two groups took an average daily dose of opioids that was three times that of the typical group. The authors suggest that the use of high doses of drugs could constitute a simple indicator to identify those patients that might benefit from further medical or psychiatric

To determine the incidence of opioid addiction, and the factors predictive for abuse, Ives et al. (2006) carried out a prospective cohort study of 196 patients with chronic pain being treated with opioids. Patients were monitored at regular intervals for an entire year. Opioid abuse was defined based on the presence of: negative urine toxicology screening for prescribed opioids; positive urine toxicology screening for non-prescribed drugs or opioids; supplies of opioids obtained from more than one provider; diversion of opioids, prescription forgery and positive urine toxicology screening for narcotics (cocaine or amphetamines). Opioid abuse was observed in 32% of patients; the most common form of misuse was the detection of cocaine or amphetamine in urine (40.3% of misusers). Abusers were found to be significantly younger (p<0.001); male (p= 0.023); with a history of abuse of alcohol (p= 0.004) and cocaine (p<0.001) than non-abusers. Ethnicity, income, education, levels of depression or disability and pain intensity were not found to be associated with drug misuse. Manchikanti et al. (2006) carried out a prospective longitudinal study of 500 patients with chronic pain to evaluate and correlate multiple variables with the abuse of opioids and illegal substances. Patients who obtained opioid

they often displayed aberrant drug-related behaviours.

assessment, or assessment of drug misuse behaviours.

opioids for the treatment of severe pain in a controlled clinical setting are most unlikely to develop addiction. In contrast, patients with a personal or family history of substance abuse, and with one or more psychosocial issues are at greater risk of developing addiction, especially if the treatment is not carefully structured (Ballantyne, 2007).

Fig. 2. Genetic, psychosocial and drug-related factors associated with the development of addiction. Adapted from Ballantyne (2007).

The psychosocial factors considered to be most predictive of opioid abuse are the presence of psychiatric disorders (Compton et al., 1998; Sullivan et al., 2006) and a personal and/or family history of substance abuse or drug abuse (Dunbar & Katz, 1996; Schieffer et al., 2005). A significant correlation has been found between chronic pain, mood disorders and aberrant drug use: patients with chronic pain report higher levels of anxiety and depression than patients with other medical conditions, and the incidence of mood disorders has been shown to be higher in patients at high risk of opioid misuse or dependence (Bair et al., 2003; Dersh et al., 2002; Fishbain, 1999).

opioids for the treatment of severe pain in a controlled clinical setting are most unlikely to develop addiction. In contrast, patients with a personal or family history of substance abuse, and with one or more psychosocial issues are at greater risk of developing addiction,

> **PSYCHOSOCIAL Psychological**  (Genetic factors) Depression Anxiety Somatoform disorder Personality disorder Atypical stress responsivity **Social and Environmental**  Circumstances of drug use Poverty Childhood abuse Unemployment Peer pressure

> > **GENETIC Vulnerability**  Family history of addiction Personality disorder Gene variants associated with risk taking and impulsivity (initiation phase) **Drug Disposition**  Pharmakokinetic genes affecting drug metabolism and transport Pharmacodynamic genes affecting pain and analgesic responses, dependence and addiction

Fig. 2. Genetic, psychosocial and drug-related factors associated with the development of

The psychosocial factors considered to be most predictive of opioid abuse are the presence of psychiatric disorders (Compton et al., 1998; Sullivan et al., 2006) and a personal and/or family history of substance abuse or drug abuse (Dunbar & Katz, 1996; Schieffer et al., 2005). A significant correlation has been found between chronic pain, mood disorders and aberrant drug use: patients with chronic pain report higher levels of anxiety and depression than patients with other medical conditions, and the incidence of mood disorders has been shown to be higher in patients at high risk of opioid misuse or dependence (Bair et al., 2003;

addiction. Adapted from Ballantyne (2007).

**DRUG Initiation**  Stimulates mesocorticolimbic reward circuitry Mode of administration/formulation enhances euphoria (eg. IV, snorted) **Maintenance**  Produces tolerance and dependence (negative reinforcement) Produces enduring neuroadaptations associated with lifelong craving **Withdrawal and Abstinence**  Anhedonic state Negative reinforcement

Dersh et al., 2002; Fishbain, 1999).

especially if the treatment is not carefully structured (Ballantyne, 2007).

Using logistic regression, the authors showed that panic attacks, high trait anxiety and the presence of a personality disorder are able to explain the 38% variance in potential abuse of prescribed opioids. To investigate the role of psychological adjustment and psychiatric symptoms in aberrant drug behaviours in pain patients, Wasan et al. (2007) divided the 228 patients enrolled into high-psychiatric and low-psychiatric morbidity, based on the responses to the psychiatric subscale of the Prescription Drug Use Questionnaire (PDUQ; Compton et al., 2008; see § 2.4.). Patients with high psychiatric comorbidity were significantly younger, with a longer mean opioid assumption time (p<0.05); altered urine toxicology screening results were also more frequent among these patients (p<0.01), and they often displayed aberrant drug-related behaviours.

Edlund et al. (2007) conducted a broad prospective study of the risk factors for opioid abuse and addiction using the South Central Veterans Affairs Health Care Network databank. The sample included 15.160 chronic users of opioids in 2002; 45.3% of the sample had a psychiatric diagnosis and 7.6% had a non-opioid substance abuse diagnosis. The results show that prior abuse of non-opioid substances is a strong predictor of abuse/addiction to opioid drugs, while mental disorders are moderately strong predictors. The authors also found that the risk of abuse decreases uniformly with age. Other risk factors for opioid abuse/addiction were male gender, being divorced/separated or single and, finally, being in treatment with opioids for longer. A broad retrospective cohort study that involved 704 patients with chronic pain being treated with opioids was carried out by Banta-Green et al. (2009a) to further comprehend the complex interaction between pain, mental health and addiction. The patients were initially assessed using a structured interview based on DSM-IV criteria for abuse and dependence on opioids, misuse of opioids, anxiety and depression. By regression analysis, the authors identified three distinct categories of patients which they called: a) Typical group (characterised by moderate pain symptoms and limited psychiatric problems); b) Addictive Behaviours group (high psychiatric symptoms, misuse of opioids and moderate pain symptoms); c) Pain Dysfunction group (high intensity and interference of pain, high psychiatric symptoms and consistent misuse of opioids). The patients in the last two groups took an average daily dose of opioids that was three times that of the typical group. The authors suggest that the use of high doses of drugs could constitute a simple indicator to identify those patients that might benefit from further medical or psychiatric assessment, or assessment of drug misuse behaviours.

To determine the incidence of opioid addiction, and the factors predictive for abuse, Ives et al. (2006) carried out a prospective cohort study of 196 patients with chronic pain being treated with opioids. Patients were monitored at regular intervals for an entire year. Opioid abuse was defined based on the presence of: negative urine toxicology screening for prescribed opioids; positive urine toxicology screening for non-prescribed drugs or opioids; supplies of opioids obtained from more than one provider; diversion of opioids, prescription forgery and positive urine toxicology screening for narcotics (cocaine or amphetamines). Opioid abuse was observed in 32% of patients; the most common form of misuse was the detection of cocaine or amphetamine in urine (40.3% of misusers). Abusers were found to be significantly younger (p<0.001); male (p= 0.023); with a history of abuse of alcohol (p= 0.004) and cocaine (p<0.001) than non-abusers. Ethnicity, income, education, levels of depression or disability and pain intensity were not found to be associated with drug misuse. Manchikanti et al. (2006) carried out a prospective longitudinal study of 500 patients with chronic pain to evaluate and correlate multiple variables with the abuse of opioids and illegal substances. Patients who obtained opioid

Risk Factors in Opioid Treatment of Chronic Non-Cancer Pain: A Multidisciplinary Assessment 433

Compton et al.

*Risk* STAR Friedman et al. 2003 Self-administered 14

*Questionnaire* PMQ Adams et al. 2004 Self-administered 26

Butler et al.

f *Opioid Risk Tool* ORT Webster et al. 2005 Self-administered 5

*Checklist* ABC Wu et al. 2006 Interview 20

*and Efficacy Score* DIRE Belgrade et al. 2006 Team assessment 7 i *Drug Abuse Screening Test* DAST Yudko et al 2007 Self-administered 28 Table 3. Principal tools for the stratification of the risk of opioid addiction and abuse.

a. The *CAGE questions Adapted to Include Drugs* (CAGE-AID; Brown & Rounds, 1995) is an adaptation of the CAGE questionnaire, used for a short screening for alcohol abuse, which also includes substance use. The name CAGE is derived from 4 key words: "cut", "annoyed", "guilty" and "eye-opener". The questionnaire consists of the following 4 questions, to which the subject must reply "yes" or "no": 1) Have you felt you ought to cut down your drinking or drug use?; 2) Have people annoyed you by criticizing your drinking or drug use?; 3) Have you felt bad or guilty about your drinking or drug use?; 4) Have you ever had a drink or used drugs first thing in the morning to steady your nerves or to get rid of a hangover (eye-opener)?. The addiction screening is positive with at least 2 affirmative responses. The CAGE-AID has been validated on a sample of 124 pain patients, demonstrating high values of sensitivity

b1. *Prescription Drug Use Questionnaire* (PDUQ, Compton et al., 1998) is a tool, consisting of 42 items to be administered in the form of an interview, that assesses the degree of abuse / misuse of the drug in patients with chronic pain. Care staff trained in the use of the tool take about twenty minutes to complete the interview. The patient must answer yes/no to questions that investigate: pain condition (e.g. "Has the patient explored and/or tried non-opioid or non-pharmacological pain management techniques?"), the ways in which they use drugs (e.g. "Does the patient have more than one prescription

d name Authors Year Method of

AID Brown & Rounds 1995 Self-administered 4

PDUQp 2008 Self-administered 31

2004

SOAPP-R 2008 24

administration

1998 Interview 42

Self-administered

Number of items

14

Name Abbreviate

*Questionnaire* PDUQ

CAGE-

SOAPP

<sup>a</sup>*CAGE- questions Adapted to Include Drugs* 

> *Prescription Drug Use Questionnaire – patient*

<sup>c</sup>*Screening Tool for Addiction* 

*Screener and Opioid Assessment for Patients with* 

*Screener and Opioid Assessment for Patients with* 

*Addiction Behaviour* 

<sup>h</sup>*Diagnosis Intractability Risk* 

(0.70) and specificity (0.85).

*Pain – Revised* 

b1 *Prescription Drug Use* 

*version* 

<sup>d</sup>*Pain Medication* 

*Pain* 

b2

e1

e2

g

drugs from sources other than the physicians at the clinic where the study was carried out were considered abusers; use of narcotics was ascertained through urine toxicology screening. Opioid abuse was observed in 9% of patients, while the use of illegal substances (e.g. cocaine, marijuana, metamphetamines) was detected in 16% of the sample. Opioid abuse was found to be more frequent in patients with pain due to road traffic accidents, pain in more than one region of the body and subjects with prior substance abuse. The use of illegal substances was more frequent among women and in patients under 45 years of age. The onset of pain after a road traffic accident and the presence of pain in more than one part of the body were also risk factors for narcotic substance abuse. To investigate the effect of gender on aberrant drug-related behaviours, Back et al. (2009) carried out a study on 121 patients (49 make and 72 female), who had to complete a set of tests designed to collect personal and clinical information and data on aberrant drug behaviours (e.g. prescription fraud, using other drug administration routes) and the use of nicotine, alcohol, marijuana, cocaine and hallucinogens. The results show that men were taking the prescribed drug significantly more regularly than women (91.7% v 77.8%, p<0.05), while women tend to keep unused drugs (67.6% v 47.7%; p=0.04) and to use other drugs (e.g. sedatives) to enhance the efficacy of analgesics (38.8% v 20%; p=0.04) more than men. Men tend to use other drug administration routes (e.g. crushing and snorting pills) than women, although this difference was not statistically significant. For men, there was an association between alcohol abuse, use of oxycodone or morphine and aberrant drug behaviours, while in women the aberrant drug behaviours were associated with the use of hydrocodone.

In conclusion, the presence of psychiatric disorders and a personal and/or family history of substance abuse seem to be the most predictive factors of risk of opioid misuse in patients with chronic pain. Other variables such as gender, age and marital status may influence the risk of abuse, although the relationship is less clear, and further investigation is required (Savage, 2002).

#### **2.4 Tools to assess the risk of addiction and dependence**

Guidelines suggest that the use of opioids in patients with chronic non-cancer pain must be preceded by an initial stratification of the risk of drug misuse; this evaluation should include even a psychological and psychiatric assessment (Chou, 2009; Chou et al, 2009a; Chou et al, 2009b; Chou et al, 2009c; Kalso et al., 2003; Trescot et al., 2006; Trescot at al., 2008). In recent years, many tools have been developed and examined for this purpose; most investigate the presence of a family and/or personal history of addiction and other factors correlated with opioid misuse, such as age, history of childhood sexual abuse and the presence of mental distress. Some of these tools, were created specifically for use in a population of patients with chronic pain, while others assess the addiction risk factors in general. Table 3 summarises the tools that will then be described in greater detail; however, it is important to bear in mind that none is able to produce an accurate diagnosis about the presence of addiction, abuse or dependence. Besides, many of these are self-assessment tools, and therefore potentially at risk of falsification by the respondent. It is therefore advisable to supplement the information obtained with such tools with data obtained from direct observation of the patient during medical appointments. Anyhow, for patients who are found to be at high risk of misuse of the drug from the initial assessment with one of these scales, it is advisable to provide for constant monitoring of treatment, with regular urine toxicology screening.

drugs from sources other than the physicians at the clinic where the study was carried out were considered abusers; use of narcotics was ascertained through urine toxicology screening. Opioid abuse was observed in 9% of patients, while the use of illegal substances (e.g. cocaine, marijuana, metamphetamines) was detected in 16% of the sample. Opioid abuse was found to be more frequent in patients with pain due to road traffic accidents, pain in more than one region of the body and subjects with prior substance abuse. The use of illegal substances was more frequent among women and in patients under 45 years of age. The onset of pain after a road traffic accident and the presence of pain in more than one part of the body were also risk factors for narcotic substance abuse. To investigate the effect of gender on aberrant drug-related behaviours, Back et al. (2009) carried out a study on 121 patients (49 make and 72 female), who had to complete a set of tests designed to collect personal and clinical information and data on aberrant drug behaviours (e.g. prescription fraud, using other drug administration routes) and the use of nicotine, alcohol, marijuana, cocaine and hallucinogens. The results show that men were taking the prescribed drug significantly more regularly than women (91.7% v 77.8%, p<0.05), while women tend to keep unused drugs (67.6% v 47.7%; p=0.04) and to use other drugs (e.g. sedatives) to enhance the efficacy of analgesics (38.8% v 20%; p=0.04) more than men. Men tend to use other drug administration routes (e.g. crushing and snorting pills) than women, although this difference was not statistically significant. For men, there was an association between alcohol abuse, use of oxycodone or morphine and aberrant drug behaviours, while in women the aberrant drug behaviours were associated

In conclusion, the presence of psychiatric disorders and a personal and/or family history of substance abuse seem to be the most predictive factors of risk of opioid misuse in patients with chronic pain. Other variables such as gender, age and marital status may influence the risk of abuse, although the relationship is less clear, and further investigation is required

Guidelines suggest that the use of opioids in patients with chronic non-cancer pain must be preceded by an initial stratification of the risk of drug misuse; this evaluation should include even a psychological and psychiatric assessment (Chou, 2009; Chou et al, 2009a; Chou et al, 2009b; Chou et al, 2009c; Kalso et al., 2003; Trescot et al., 2006; Trescot at al., 2008). In recent years, many tools have been developed and examined for this purpose; most investigate the presence of a family and/or personal history of addiction and other factors correlated with opioid misuse, such as age, history of childhood sexual abuse and the presence of mental distress. Some of these tools, were created specifically for use in a population of patients with chronic pain, while others assess the addiction risk factors in general. Table 3 summarises the tools that will then be described in greater detail; however, it is important to bear in mind that none is able to produce an accurate diagnosis about the presence of addiction, abuse or dependence. Besides, many of these are self-assessment tools, and therefore potentially at risk of falsification by the respondent. It is therefore advisable to supplement the information obtained with such tools with data obtained from direct observation of the patient during medical appointments. Anyhow, for patients who are found to be at high risk of misuse of the drug from the initial assessment with one of these scales, it is advisable to provide for constant monitoring of treatment, with regular urine

**2.4 Tools to assess the risk of addiction and dependence** 

with the use of hydrocodone.

(Savage, 2002).

toxicology screening.


Table 3. Principal tools for the stratification of the risk of opioid addiction and abuse.


Risk Factors in Opioid Treatment of Chronic Non-Cancer Pain: A Multidisciplinary Assessment 435

scores of those assessed (age, history of alcohol and/or substance abuse).

distress and prior substance abuse, the sensitivity increased to 0.90.

e2. *The Screener and Opioid Assessment for Patients with Pain – Revised* (SOAPP-R) is a 24-item version developed by Butler et al. (2008) in order to overcome some limitations of the original SOAPP. The new version, tested on a sample of 283 patients, proved to have

e1. The Screener and Opioid Assessment for Patients with Pain (SOAPP, Butler et al., 2004) is a self-administered tool with 14 items that investigate potential risk factors for opioid misuse (e.g. "How often do you take more medications than you are supposed to?"; "How often have others expressed concerns over your use of medication?"). These items were proposed and voted on by a team of experts; the patient must indicate the frequency of each behaviour on a 5 point Likert scale (0 = "never"; 4 = "very often"). The tool was administered to 175 patients with chronic pain and readministered 6 months later to 95 of these patients, to test its reliability over time. The SOAPP proved to have adequate internal consistency (Cronbach's α= 0.74) and good test-retest reliability six months after its first administration (r = 0.71). Scores of 8 or more are indicative of high risk of abuse (sensitivity: 0.91; specificity: 0.69). In a study investigating the psychometric characteristics and clinical utility of the SOAPP in 397 patients, Akbik et al. (2006) found patients classified at high risk were significantly younger, with altered urine screening results (p<0.05) than low risk patients. The factor analysis also revealed the presence of 5 factors, called: 1) History of substance abuse; 2) Legal problems; 3) Craving medications; 4) Heavy smoking and 5) Mood swings. Moore et al. (2009), in a study to examine the efficacy of the SOAPP and other tools in predicting the risk of opioid misuse, found good sensitivity for the tool (0.72); combining the data from the SOAPP with those from a semi-structured clinical interview designed to investigate prior treatments used, the presence of emotional

scores of the single items gives a total score, which can vary from a minimum of 0 to a maximum of 104. High scores are correlated with a high risk of opioid misuse. In particular, scores of 25 or more are indicative of opioid misuse, while scores of 30 or more suggest that the patient should be constantly monitored during treatment (Dowling et al., 2007). The validity of the tool was investigated by Adams et al. (2004) on 184 patients with chronic pain, comparing the results obtained with the PMQ with a series of assessment of substance abuse, degree of psychosocial distress, and some indicators of psychological and physical functioning; the test-retest reliability coefficient is 0.85 and the internal consistency is acceptable (Cronbach's α = 0.73). A further study to examine the psychometric characteristics of the PMQ in greater depth was carried out by Buelow et al. (2009). One of the aims was to examine the accuracy of the short form of the PMQ (from which items 5, 10 and 23 had been eliminated, since they had the lowest correlation coefficients) in predicting opioid misuse. Examining 4.182 subjects, of whom 1.813 were involved in an interdisciplinary treatment programme (that included physical, pharmacological and psychological therapy) the authors confirmed the adequate internal consistency of the abbreviated form (Cronbach's α = 0.70) e and of test-retest reliability (r= 0.77). Significant differences also emerged in the mean PMQ score of patients with a history of substance abuse (mean = 24.39) and of patients without a history of abuse (mean = 21.95). Moreover, those patients who interrupted the treatment had mean scores that were significantly higher than those of patients who displayed good compliance. By logistic regression, the authors showed that early request of opioids is the only factor able to predict high or low questionnaire

provider?"), social/family factors (e.g. "Have family members expressed concerns that the patient is addicted?"), family history of chronic pain and/or addiction (e.g. "Is there a positive history of chronic pain in the patient's mother, father, sibling or blood relative?"), personal history of substance abuse (e.g. "Has the patient ever been diagnosed with addiction to any drug or alcohol") and psychiatric history (e.g. "Has the patient ever been diagnosed with a psychiatric disorder?"). The tool has good internal consistency (Cronbach's α = 0.79). To identify a cut-off, the 52 patients with chronic pain who participated in the pilot study to validate the PDUQ were initially classified as addicted or non-addicted based on criteria developed by the American Society of Addiction Medicine (see § 2.2.2.). Patients with scores of less than 11 did not meet the criteria for a substance abuse disorder, while patients with scores of 15 or more reflected the criteria for a substance abuse disorder. So those who achieved scores of less than 11 use the drug in a suitable way. Moreover, positive answers to 3 specific items of the tool (notably "patient believes he/she is addicted"; "increases analgesic dose/frequency"; "specific drug or route of administration preference") have been identified as more predictive of addiction, with a 92.9% of correct classification. Banta-Green et al. (2009b) carried out a study of 704 patients who had been prescribed longterm treatment with opioids, aimed to examine the factorial structure of the PDUQ. The results show that the items may be grouped into three distinct types of factor "addictive behaviours", "addiction concerns" and "pain treatment problems". The limits of the PDUQ concern the fact that it relies solely on the sincerity of the patient and is difficult to use in an overloaded clinical context.


b2. The *Prescription Drug Use Questionnaire* – *patient version* (PDUQp) was created by Compton et al. (2008) to obviate the difficulty mentioned above. The PDUQp is a selfadministered instrument which consists of 31 items and the total score can vary from 0 to 30. Analysis of the psychometric properties of the new self-administered version was carried out on 135 patients with chronic pain being treated with opioids, monitored for 12 months. The PDUQp proved to have good concurrent validity, calculated by comparing the scores obtained with the scores obtained with the PDUQ (r = 0.64). The tool also proved to have good test-retest reliability, assessed at 4, 8 and 12 months after its first administration (r = 0.67, r = 0.61 and r = 0.40 respectively). A cut-off of 10 is

c. The *Screening Tool for Addiction Risk* (STAR, Friedman et al., 2003) consists of 14 questions with true/false responses that investigate potential risk factors for drug. The items were developed based on a literature review carried out by a team of specialists in pain and addiction. Validation of the questionnaire was carried out on 48 patients with chronic pain, 14 of whom had a diagnosis of addiction based on the DSM-IV criteria. The authors found a close correlation between addiction and prior treatment in a rehabilitation unit for alcohol or drug dependence, smoking, and intensity of nicotine craving. In particular, the item on prior experience of alcohol and/or substance detoxification was able to identify

d. The Pain Medication Questionnaire (PMQ, Adams et al., 2004) is a self-administered questionnaire that describes a series of dysfunctional behaviours and characteristics that underlie the use of drugs for the treatment of pain. The tool consists of 26 items, for each of which the subject must indicate his degree of agreement or disagreement on a 5 point Likert scale, and a score is attributed to the selected response (disagree = 0, somewhat disagree = 1, neutral = 3, somewhat agree = 4, agree = 5). The sum of the

to use in an overloaded clinical context.

suggested as indicative of drug misuse.

correctly 93% of the patients who met the addiction criteria.

provider?"), social/family factors (e.g. "Have family members expressed concerns that the patient is addicted?"), family history of chronic pain and/or addiction (e.g. "Is there a positive history of chronic pain in the patient's mother, father, sibling or blood relative?"), personal history of substance abuse (e.g. "Has the patient ever been diagnosed with addiction to any drug or alcohol") and psychiatric history (e.g. "Has the patient ever been diagnosed with a psychiatric disorder?"). The tool has good internal consistency (Cronbach's α = 0.79). To identify a cut-off, the 52 patients with chronic pain who participated in the pilot study to validate the PDUQ were initially classified as addicted or non-addicted based on criteria developed by the American Society of Addiction Medicine (see § 2.2.2.). Patients with scores of less than 11 did not meet the criteria for a substance abuse disorder, while patients with scores of 15 or more reflected the criteria for a substance abuse disorder. So those who achieved scores of less than 11 use the drug in a suitable way. Moreover, positive answers to 3 specific items of the tool (notably "patient believes he/she is addicted"; "increases analgesic dose/frequency"; "specific drug or route of administration preference") have been identified as more predictive of addiction, with a 92.9% of correct classification. Banta-Green et al. (2009b) carried out a study of 704 patients who had been prescribed longterm treatment with opioids, aimed to examine the factorial structure of the PDUQ. The results show that the items may be grouped into three distinct types of factor "addictive behaviours", "addiction concerns" and "pain treatment problems". The limits of the PDUQ concern the fact that it relies solely on the sincerity of the patient and is difficult scores of the single items gives a total score, which can vary from a minimum of 0 to a maximum of 104. High scores are correlated with a high risk of opioid misuse. In particular, scores of 25 or more are indicative of opioid misuse, while scores of 30 or more suggest that the patient should be constantly monitored during treatment (Dowling et al., 2007). The validity of the tool was investigated by Adams et al. (2004) on 184 patients with chronic pain, comparing the results obtained with the PMQ with a series of assessment of substance abuse, degree of psychosocial distress, and some indicators of psychological and physical functioning; the test-retest reliability coefficient is 0.85 and the internal consistency is acceptable (Cronbach's α = 0.73). A further study to examine the psychometric characteristics of the PMQ in greater depth was carried out by Buelow et al. (2009). One of the aims was to examine the accuracy of the short form of the PMQ (from which items 5, 10 and 23 had been eliminated, since they had the lowest correlation coefficients) in predicting opioid misuse. Examining 4.182 subjects, of whom 1.813 were involved in an interdisciplinary treatment programme (that included physical, pharmacological and psychological therapy) the authors confirmed the adequate internal consistency of the abbreviated form (Cronbach's α = 0.70) e and of test-retest reliability (r= 0.77). Significant differences also emerged in the mean PMQ score of patients with a history of substance abuse (mean = 24.39) and of patients without a history of abuse (mean = 21.95). Moreover, those patients who interrupted the treatment had mean scores that were significantly higher than those of patients who displayed good compliance. By logistic regression, the authors showed that early request of opioids is the only factor able to predict high or low questionnaire scores of those assessed (age, history of alcohol and/or substance abuse).


Risk Factors in Opioid Treatment of Chronic Non-Cancer Pain: A Multidisciplinary Assessment 437

i. The Drug Abuse Screening Test (DAST, Yudko et al., 2007) is a self-administered questionnaire consisting of 28 items with binary (yes/no) answers. Scores of 6 or more indicate the presence of substance dependence or abuse. In addition to the complete version of the questionnaire, which can be too time-consuming in some clinical contexts, there are various short versions of the DAST, based on 10 items instead of 28. The 28-item DAST has proved to have high test-retest reliability (r = 0.85) and good internal consistency (Cronbach's α 0.92-0.94). The tool has shown good sensitivity, between 81% and 96%, and good specificity (from 71% to 94%). One limitation of the tool is the fact that it is susceptible to falsification and may therefore not identify those people who, while abusing the drug, intentionally give false answers. Moreover, the tool is predictive of

substance abuse but does not specifically examine the aberrant drug behaviours.

A number of different tools have been created for clinicians to monitor opioid treatment and as checklists for the systemic observation of aberrant drug behaviours. The tools most

The *Prescription Opioid Therapy Questionnaire* (POTQ; Michna et al., 2004) is a tool with 11 items to which the clinician must answer yes or no to assess opioid misuse. The items reflect the behaviours suggested by Chabal et al. (1997) as indicative of substance abuse. These behaviours include multiple unauthorised dosage increases, episodes of lost or stolen prescriptions, frequent unplanned visits to the clinic or emergency room, excessive telephone calls and inflexibility about treatment options. Patients who were positively rated

The *Pain Assessment and Documentation Tool* (PADT; Passik et al., 2004; Passik et al., 2005) is a brief (takes between 10 to 20 minutes to complete) clinician-directed interview. The clinician asks the patients questions that are organized in four primary areas called the "Four A's" and are notably: Analgesia - focuses on pain intensity (numeric rating scales) and pain relief; Activities of Daily Living - focuses on whether the patient's functioning since the last

alpha coefficient of 0.80 and an inter-rater validity of 0.95.

widely mentioned in the literature are described briefly below.

on two or more of the items met criteria for prescription opioid misuse.

**2.4.1 Ways of monitoring treatment** 

and how he or she is involved in the treatment, i.e. if they play a passive or an active role in managing their pain. The Risk factor was created to estimate the extent to which the patient would adhere to the instructions of the clinician during treatment. As stated above, it comprises four categories: Psychological health assesses the psychiatric and psychological status of the patient; Chemical health assesses the patient's relationship with substances with potential risk of abuse; Reliability assesses compliance with treatment in the past, whether or not the patient attends appointments and following the physician's recommendations fully; Social support assesses the patient's support network and his or her ability to function in life roles, such as work, school, parenting, etc. Efficacy assesses the analgesic effectiveness of opioids, based on physical functionality and patient's pain self-report. When efficacy cannot be assessed because the patient has not yet started to take opioids, or takes them in quantities that are too low (less than the equivalent of 30 mg/day of morphine) a score of 2 is attributed. All the scales and subscales of the Risk factor are firstly assessed individually and then added together to obtain the DIRE score. The total score can vary from a minimum of 7 to a maximum of 21; scores between 14 and 21 are indicative of a greater degree of patient compliance and, in general, greater treatment efficacy. The psychometric analyses of the original version, carried out on a group of 61 patients with chronic pain, shown an internal consistency

good internal consistency (Cronbach's α = 0.88); the cut-off of 18 shows adequate sensitivity (0.81) and specificity (0.68). Patients with low SOAPP-R scores appear to be at less risk of developing a substance abuse disorder.


and how he or she is involved in the treatment, i.e. if they play a passive or an active role in managing their pain. The Risk factor was created to estimate the extent to which the patient would adhere to the instructions of the clinician during treatment. As stated above, it comprises four categories: Psychological health assesses the psychiatric and psychological status of the patient; Chemical health assesses the patient's relationship with substances with potential risk of abuse; Reliability assesses compliance with treatment in the past, whether or not the patient attends appointments and following the physician's recommendations fully; Social support assesses the patient's support network and his or her ability to function in life roles, such as work, school, parenting, etc. Efficacy assesses the analgesic effectiveness of opioids, based on physical functionality and patient's pain self-report. When efficacy cannot be assessed because the patient has not yet started to take opioids, or takes them in quantities that are too low (less than the equivalent of 30 mg/day of morphine) a score of 2 is attributed. All the scales and subscales of the Risk factor are firstly assessed individually and then added together to obtain the DIRE score. The total score can vary from a minimum of 7 to a maximum of 21; scores between 14 and 21 are indicative of a greater degree of patient compliance and, in general, greater treatment efficacy. The psychometric analyses of the original version, carried out on a group of 61 patients with chronic pain, shown an internal consistency alpha coefficient of 0.80 and an inter-rater validity of 0.95.

i. The Drug Abuse Screening Test (DAST, Yudko et al., 2007) is a self-administered questionnaire consisting of 28 items with binary (yes/no) answers. Scores of 6 or more indicate the presence of substance dependence or abuse. In addition to the complete version of the questionnaire, which can be too time-consuming in some clinical contexts, there are various short versions of the DAST, based on 10 items instead of 28. The 28-item DAST has proved to have high test-retest reliability (r = 0.85) and good internal consistency (Cronbach's α 0.92-0.94). The tool has shown good sensitivity, between 81% and 96%, and good specificity (from 71% to 94%). One limitation of the tool is the fact that it is susceptible to falsification and may therefore not identify those people who, while abusing the drug, intentionally give false answers. Moreover, the tool is predictive of substance abuse but does not specifically examine the aberrant drug behaviours.

#### **2.4.1 Ways of monitoring treatment**

436 Pain Management – Current Issues and Opinions

f. The *Opioid Risk Tool* (ORT, Webster et al., 2005) is a self-administered tool developed to estimate the probability that the patient displays aberrant drug behaviours during longterm opioid treatment. The ORT consists of 5 items which investigate the following risk factors: family history of substance abuse (alcohol, drugs or prescribed medicines); personal history of substance abuse (alcohol, drugs or prescribed medicines); age (if between 16 and 45 years); history of childhood sexual abuse; presence of psychological distress (attention deficit disorder, obsessive-compulsive disorder, bipolar disorder, schizophrenia and depression). Each factor has a different weight in determining the potential risk of drug misuse, and so a specific numerical value is assigned to each, which also varies according to the sex of the respondent. There are three risk levels: scores from 0 to 3 are indicative of low risk; scores from 4 to 7 determine moderate risk; finally, scores of 8 or more are indicative of a high risk of misuse. This questionnaire was validated on 108 women and 77 men with chronic pain, followed for a period of 12 months from the initial appointment. 94% of the patients classified as low risk based on the total ORT score did not display aberrant drug behaviours in the year in which they were monitored, while 90.9% of the patients with scores of the cut-off value of 8 or more

g. The *Addiction Behaviour Checklist* (ABC, Wu et al., 2006) consists of 20 items to be administered in the form of an interview. The items are grouped in two principal categories: 1) addicted behaviours noted during visit (e.g. "patient running out of medications early"; "receiving narcotics from other providers"); 2) addictive behaviours observed within the visit (e.g. "patient appearing sedated"; "patient expressing concern about the future availability of narcotics"). Finally, there is a further question that can be used if family members of the patient are present during the medical appointment ("significant others express concern over patient's use of analgesic"). The answer system is binary (yes/no): each affirmative answer is assigned a point and the total score can vary from 0 to 20. To investigate its psychometric characteristics, the ABC was administered to 136 patients with chronic pain prescribed long-term opioid treatment. The tool proved to have high inter-rater validity (0.94 – 0.95) and significant concurrent validity: a significant correlation (r=0.40; p< .01) was found between the ABC score and the Prescription Drug Use Questionnaire (PDUQ, Compton et al., 1998) score. A cut-off value of 3 on this tool is able to provide a good estimate of appropriate/inappropriate use that the patient will make of the drug. For scores of 3 or more, the authors suggest that the patient should be

monitored frequently, including more frequent urine toxicology screening.

h. The *Diagnosis Intractability Risk and Efficacy Score* (DIRE, Belgrade et al., 2006) is a tool that is compiled by a multidisciplinary team of physicians and psychologists. It consists of 4 scales: Diagnosis, Intractability, Risk (4 subcategories) Efficacy. Each class requires assessment on a 3 point scale, where a score of 1 corresponds to characteristics and behaviours that are indicative of a negative prognosis, and a score of 3 is indicative of suitability for treatment with opioids. The Diagnosis factor requires the clinician to determine the extent to which the patient's diagnosis is sufficiently compelling or advanced to warrant an aggressive pharmacological approach. The Intractability factor requires a determination of how many appropriate treatments the patient has undergone

at less risk of developing a substance abuse disorder.

displayed aberrant drug behaviours.

good internal consistency (Cronbach's α = 0.88); the cut-off of 18 shows adequate sensitivity (0.81) and specificity (0.68). Patients with low SOAPP-R scores appear to be

> A number of different tools have been created for clinicians to monitor opioid treatment and as checklists for the systemic observation of aberrant drug behaviours. The tools most widely mentioned in the literature are described briefly below.

> The *Prescription Opioid Therapy Questionnaire* (POTQ; Michna et al., 2004) is a tool with 11 items to which the clinician must answer yes or no to assess opioid misuse. The items reflect the behaviours suggested by Chabal et al. (1997) as indicative of substance abuse. These behaviours include multiple unauthorised dosage increases, episodes of lost or stolen prescriptions, frequent unplanned visits to the clinic or emergency room, excessive telephone calls and inflexibility about treatment options. Patients who were positively rated on two or more of the items met criteria for prescription opioid misuse.

> The *Pain Assessment and Documentation Tool* (PADT; Passik et al., 2004; Passik et al., 2005) is a brief (takes between 10 to 20 minutes to complete) clinician-directed interview. The clinician asks the patients questions that are organized in four primary areas called the "Four A's" and are notably: Analgesia - focuses on pain intensity (numeric rating scales) and pain relief; Activities of Daily Living - focuses on whether the patient's functioning since the last

Risk Factors in Opioid Treatment of Chronic Non-Cancer Pain: A Multidisciplinary Assessment 439

preliminary step, the predictive validity of the Italian versions of the PMQ and the DIRE was investigated: until now the Italian versions of these instrument are not available. Besides, the capacity of the two tools to predict opioid misuse was compared to the subjective estimate made by the physician based on his or her clinical experience. Furthermore, the presence of possible relationships between aberrant drug behaviours and the presence of risk factors for treatment compliance was examined, as was any use of illegal substances established by urine drug tests. Finally, the efficacy of the treatment was analysed the patient's perceived quality of life and pain experience after 2 and 4 months

The preliminary data presented below refer to 25 patients treated in the Pain Relief and Palliative Care Unit. The inclusion criteria were: age between 18 and 70 years; presence of non-cancer pain for at least 6 months; pain intensity assessed on an 11 point Numerical Rating Scale of at least 4 in the last month; good knowledge/understanding of Italian; absence of cognitive deficit; use of fixed regime weak opioids insufficiently efficacious; other pharmacological and non-pharmacological treatments used for at least 3 months not sufficiently efficacious; no significant decrease in life expectancy; informed consent to

> 17 (68.0%) 8 (32.0%)

5 (20.0%) 10 (41%) 9 (35%) 1 (4%)

2 (8%) 13 (52%) 3 (11%) 7 (27%)

6 (24%) 7 (28%) 1 (4%) 11 (44%)

10 (40%) 5 (20%) 10 (40%)

**Descriptives (mean SD or % frequency)** 

after the start of treatment.

participation in the study obtained.


**Education (years)** 

**Marital status**  - Never married - Married - Divorced - Widowed

**Occupation**  - Employed - Housewife - Unemployed - Retired

**Type of pain**  - Nociceptive - Neuropathic - Mixed

Table 4. Socio-demographic characteristics.

**Sex** 


**Age** 56.2 (10.6)

**Duration of pain (months)** 88.2 (57.7)

**2.5.1 Subjects** 

assessment is better, same, or worse; Adverse Events - identifies whether the patient is experiencing side effects from current pain relievers, and if so, what they are; potentially Aberrant Drug-Related Behaviours - assesses 17 aberrant behaviours. The availability of this checklist is likely to improve the ability of clinicians to capture problematic behaviours and implement appropriate actions in response. In addition, there is a fifth section on "Assessment" which identifies a specific analgesic plan.

The *Current Opioid Misuse Measure* (COMM, Bultler at al., 2007) is a tool with 17 items, asking the patient how he or she currently uses pain medication. For each behaviour listed (e.g. "how often have you needed to take pain medications belonging to someone else?"), the patient must indicate the frequency of each behaviour on a 5 point Likert scale (0 = "never"; 4 = "very often"). The current 17-item version of COMM was created from the 40 item version produced from the concept mapping work carried out by 26 pain and addiction professionals. Validation of the tool was carried out on 227 patients with chronic pain. Scores of 9 or more (sensitivity=0.77; specificity=0.68) are considered to be indicative of high risk of drug abuse. The tool has excellent internal consistency (Cronbach's α= 0.86) and very good test-retest reliability one week after its first administration (r = 0.86).

As well as the tools mentioned above, urine drug screens and other laboratory tests can help the clinician to understand if the patient is using illegal substances or non-prescribed drugs. It is important to supplement the observation-based tools with laboratory tests. In fact, Katz et al. (2003) showed that even if a clinician has been very careful to detect aberrant drug behaviours, some signals may be missed: approximately 20% of patients considered compliant with the treatment prescribed by expert clinicians actually tested positive in urine toxicology screening. Urine screening is an economical and non-invasive monitoring strategy that enables most drugs to be identified between 1 and 3 days after they were taken (Heit & Gourley, 2004). In addition, urine screening may be very useful in preventing opioid abuse, detecting the presence of illegal substances, identifying those patients who are not taking the prescribed drugs, or those who are using non-prescribed opioids (Atluri & Sudarshan, 2003). However, the results of urine toxicology screening must be interpreted with caution, since they may not always be correct, and in some cases can produce false positives and false negatives. Moreover, some substances are not detected by standard urine screening, and so clinicians must result to more specific or costly urine tests (or to blood or hair analysis). For this reason the results of urine drug screen should be considered a further piece of the puzzle in assessing patients with problematic opioid use behaviours (Ballantyne, 2009).

#### **2.5 The research**

This section describes the preliminary results of a prospective longitudinal study to identify some procedures that allow the risk of opioid misuse to be determined in patients with chronic non-cancer pain. Specifically, the study examines the efficacy and clinical utility of the Pain Medication Questionnaire – PMQ (Adams et al. 2004) and the Diagnosis, Intractability, Risk and Efficacy – DIRE (Belgrade et al. 2006). The PMQ was selected because it is a selfadministered scale that can easily be integrated into clinical-care routine, and the DIRE because it is an assessment tool used in a multidisciplinary setting that requires a medical and psychological assessment of the patient. In addition, both tools have been shown to possess characteristics that make them suitable for use in clinical practice: good psychometric properties in their original version, easy to complete, and sufficiently short to administer and score.

The specific aim of the study is to identify and examine the efficacy of a clinical protocol for the systematic assessment of patients who are candidates for starting opioid treatment. As a preliminary step, the predictive validity of the Italian versions of the PMQ and the DIRE was investigated: until now the Italian versions of these instrument are not available. Besides, the capacity of the two tools to predict opioid misuse was compared to the subjective estimate made by the physician based on his or her clinical experience. Furthermore, the presence of possible relationships between aberrant drug behaviours and the presence of risk factors for treatment compliance was examined, as was any use of illegal substances established by urine drug tests. Finally, the efficacy of the treatment was analysed the patient's perceived quality of life and pain experience after 2 and 4 months after the start of treatment.

#### **2.5.1 Subjects**

438 Pain Management – Current Issues and Opinions

assessment is better, same, or worse; Adverse Events - identifies whether the patient is experiencing side effects from current pain relievers, and if so, what they are; potentially Aberrant Drug-Related Behaviours - assesses 17 aberrant behaviours. The availability of this checklist is likely to improve the ability of clinicians to capture problematic behaviours and implement appropriate actions in response. In addition, there is a fifth section on

The *Current Opioid Misuse Measure* (COMM, Bultler at al., 2007) is a tool with 17 items, asking the patient how he or she currently uses pain medication. For each behaviour listed (e.g. "how often have you needed to take pain medications belonging to someone else?"), the patient must indicate the frequency of each behaviour on a 5 point Likert scale (0 = "never"; 4 = "very often"). The current 17-item version of COMM was created from the 40 item version produced from the concept mapping work carried out by 26 pain and addiction professionals. Validation of the tool was carried out on 227 patients with chronic pain. Scores of 9 or more (sensitivity=0.77; specificity=0.68) are considered to be indicative of high risk of drug abuse. The tool has excellent internal consistency (Cronbach's α= 0.86) and

As well as the tools mentioned above, urine drug screens and other laboratory tests can help the clinician to understand if the patient is using illegal substances or non-prescribed drugs. It is important to supplement the observation-based tools with laboratory tests. In fact, Katz et al. (2003) showed that even if a clinician has been very careful to detect aberrant drug behaviours, some signals may be missed: approximately 20% of patients considered compliant with the treatment prescribed by expert clinicians actually tested positive in urine toxicology screening. Urine screening is an economical and non-invasive monitoring strategy that enables most drugs to be identified between 1 and 3 days after they were taken (Heit & Gourley, 2004). In addition, urine screening may be very useful in preventing opioid abuse, detecting the presence of illegal substances, identifying those patients who are not taking the prescribed drugs, or those who are using non-prescribed opioids (Atluri & Sudarshan, 2003). However, the results of urine toxicology screening must be interpreted with caution, since they may not always be correct, and in some cases can produce false positives and false negatives. Moreover, some substances are not detected by standard urine screening, and so clinicians must result to more specific or costly urine tests (or to blood or hair analysis). For this reason the results of urine drug screen should be considered a further piece of the puzzle in assessing

This section describes the preliminary results of a prospective longitudinal study to identify some procedures that allow the risk of opioid misuse to be determined in patients with chronic non-cancer pain. Specifically, the study examines the efficacy and clinical utility of the Pain Medication Questionnaire – PMQ (Adams et al. 2004) and the Diagnosis, Intractability, Risk and Efficacy – DIRE (Belgrade et al. 2006). The PMQ was selected because it is a selfadministered scale that can easily be integrated into clinical-care routine, and the DIRE because it is an assessment tool used in a multidisciplinary setting that requires a medical and psychological assessment of the patient. In addition, both tools have been shown to possess characteristics that make them suitable for use in clinical practice: good psychometric properties in their original version, easy to complete, and sufficiently short to administer and score. The specific aim of the study is to identify and examine the efficacy of a clinical protocol for the systematic assessment of patients who are candidates for starting opioid treatment. As a

very good test-retest reliability one week after its first administration (r = 0.86).

patients with problematic opioid use behaviours (Ballantyne, 2009).

**2.5 The research** 

"Assessment" which identifies a specific analgesic plan.

The preliminary data presented below refer to 25 patients treated in the Pain Relief and Palliative Care Unit. The inclusion criteria were: age between 18 and 70 years; presence of non-cancer pain for at least 6 months; pain intensity assessed on an 11 point Numerical Rating Scale of at least 4 in the last month; good knowledge/understanding of Italian; absence of cognitive deficit; use of fixed regime weak opioids insufficiently efficacious; other pharmacological and non-pharmacological treatments used for at least 3 months not sufficiently efficacious; no significant decrease in life expectancy; informed consent to participation in the study obtained.


Table 4. Socio-demographic characteristics.

Risk Factors in Opioid Treatment of Chronic Non-Cancer Pain: A Multidisciplinary Assessment 441

The *Visual Analogue Scale* (VAS) consists of a 10 cm long horizontal line, the start and end points of which are labelled "no pain" and "worst possible pain". The patient is asked to mark the precise points corresponding to his or her maximum, minimum and habitual pain

The *Minnesota Multiphasic Personality Inventory II* (MMPI-2; Hataway e McKinley, 1989; Italian adaptation by Pancheri et al., 1996) is a self-administered questionnaire used to assess personality characteristics. It consists of 567 items to be answered "true" or "false". Scores are obtained referred to three control scales and ten clinical scales (Hypochondria, Depression, Hysteria, Psychopathic Deviate, Masculinity – Femininity, Paranoia,

The *Beck Depression Inventory II* (BDI-II; Beck et al., 1996; Italian adaptation by Ghisi et al., 2006) is a 21-item self-administered questionnaire commonly used among chronic pain patients to determine their depressive reaction, assessing both the cognitive component (e.g. sadness, pessimism) and the somatic component (e.g. loss of appetite, sleep disorders). The *State Trait Anxiety Inventory-Y* (STAI-Y, Spielberger,1983; Italian adaptation by Pedrabissi and Santinello, 1989) is a 40-item questionnaire that assesses the level of patient anxiety. Two scores can be obtained, referring to two subscales that assess state anxiety (i.e. the anxiety experienced by the patient at the time they complete the questionnaire) and trait

The *Pain Related Self-Statement Scale* (PRSS; Flor and Turk, 1988; Italian adaptation by Ferrari et al., 2004) is a self-administered scale developed to assess the cognitions specifically triggered in the pain situation that might inhibit or promote coping responses. The tool consists of 18 items, from which two total scores can be obtained for the subscales called

The *Nottingham Health Profile* (NPH, Hunt et al., 1985; Italian adaptation by Bertin et al, 1992) was used to assess quality of life. It consists of 38 items covering 6 content areas: physical mobility, energy, sleep, pain, social isolation, emotional reactions. The scores are expressed on percentage scales and correspond to the level of compromise perceived by the subject in

The *Multidimensional Pain Inventory* (MPI, Kerns et al., 1985; Italian adaptation by Ferrari et al., 2000) is a 61-item self-administered questionnaire that allow a multidimensional assessment of the pain experience. The tool is divided into 3 parts: the first focuses on assessing the intensity of the pain, its interference in the life of the patient, the patient's perceived control of the pain and of events in his or her life (it consists of the following subscales: pain severity, interference, life-control, affective distress and support). The second part investigates the patient's perception of the responses of his or her significant others to his or her pain communications (negative/solicitous and distracting responses). The third part examines the frequency with which the patient carries out common daily activities (household chores, outdoor work, distant activities, social activities and general

Finally, the *McGill Pain Questionnaire* (MPQ, Melzack, 1983; Italian adaptation by Maiani and Sanavio, 1985) is a tool consisting of a list of 78 adjectives related to pain grouped into 20 subclasses of homogeneous content; within each subgroup the descriptors are arranged in order of increasing intensity. The subject is invited to choose the adjective that best describes his or her pain in each category. The tool allows the pain to be assessed as an experience with three major dimensions: sensory-discriminative, motivational-affective and cognitive-

Psychasthenia, Schizophrenia, Hypomania and Social Introversion).

anxiety (i.e. the anxiety that the patient habitually experiences).

in the last month.

Catastrophizing and Coping.

the quality of life area considered.

activity).

evaluative.

The socio-demographic and clinical characteristics of the group of subjects are represented in table 4. The mean age is 56.2 years (±10.6) and 68% are women. Most subjects were not working at the time of the study due to their pain condition. Regarding the characteristics of their pain symptoms, the most prevalent types were nociceptive (40%) or mixed (40%); the average duration of the pain condition was 88.2 months (±57.7). There were no statistically significant differences between men and women in any of the descriptive variables considered.

#### **2.5.2 Instruments**

The *Checklist for medical selection* is a tool constructed ad hoc that enabled physicians to collect information needed to check the suitability of the patient for inclusion in the study. It includes the collection of personal data (age, sex, nationality), clinical data (disorder causing the pain, characteristics of the pain, prior pharmacological and non-pharmacological treatments) and the assessment of pain intensity (in the last month) using the *11-point Numerical Rating Scale* (NRS-11). The doctor must also indicate the drug administration route (oral or transdermal) and the initial dosage.

The *11-point Numerical Rating Scale* (NRS-11) is a pain assessment scale in which the patient is asked to report the intensity of the pain, over a specific time interval, with a number from 0 to 10, where 0 indicates no pain and 10 the worst possible pain.

The risk opioid misuse was assessed using the Pain Medication Questionnaire- PMQ (Adams et al., 2004) and the Diagnosis Intractability Risk and Efficacy Score - DIRE; Belgrade et al. 2006): see § 2.4 for a detailed description of these tools. The Italian version of the tools elaborated for this study was authorised and approved by the original Authors.

The *Medical risk prediction* requires the physician to provide an estimate, based on his or her clinical experience, of the risk of opioid misuse, answering 3 questions on an 11 point numerical scale: compliance with medical treatment (0=no compliance; 10=maximum compliance), risk of abuse and/or underuse of the drug (0=no risk, 10=maximum risk) and expected efficacy of treatment (0=no efficacy, 10=maximum efficacy).

The *Medical control form* was designed to collect clinical information about the progress of the treatment, any side effects, and the intention to continue or suspend treatment. It contains also a list of aberrant drug behaviours, based on the reference literature; the physician must tick those behaviours displayed by the patient (e.g. The patient uses other opioids in addition to those prescribed, The patient displays little interest in managing himself and his rehabilitation).

*Urine toxicology screening* was performed with fast immunodosages that could be read visually, allowing the qualitative determination of the pharmacological substances and their metabolites present in the urine. For opiates, marijuana and buprenorfin, QuikStripTM OneStep immunodosages were used; QuikPac IITM OneStep were used to detect the presence of amphetamines, metamphetamines and cocaine.

Regarding the psychological assessment the following tools were used.

The *Initial pain interview* is a semi—structured interview designed to reconstruct the clinical history of the pain, and its progress over time. The interview is used to gather a wide range of personal information (e.g. marital status, level of education, employment status, etc.) and other information about the pain and its interference in daily activities. The habits and behaviours that, based on the literature, are considered risk factors for aberrant opioid use were also investigated (smoking, alcohol consumption patterns, use of drugs, family history of alcohol and/or drug abuse, sexual abuse).

The socio-demographic and clinical characteristics of the group of subjects are represented in table 4. The mean age is 56.2 years (±10.6) and 68% are women. Most subjects were not working at the time of the study due to their pain condition. Regarding the characteristics of their pain symptoms, the most prevalent types were nociceptive (40%) or mixed (40%); the average duration of the pain condition was 88.2 months (±57.7). There were no statistically significant differences between men and women in any of the descriptive variables

The *Checklist for medical selection* is a tool constructed ad hoc that enabled physicians to collect information needed to check the suitability of the patient for inclusion in the study. It includes the collection of personal data (age, sex, nationality), clinical data (disorder causing the pain, characteristics of the pain, prior pharmacological and non-pharmacological treatments) and the assessment of pain intensity (in the last month) using the *11-point Numerical Rating Scale* (NRS-11). The doctor must also indicate the drug administration route

The *11-point Numerical Rating Scale* (NRS-11) is a pain assessment scale in which the patient is asked to report the intensity of the pain, over a specific time interval, with a number from

The risk opioid misuse was assessed using the Pain Medication Questionnaire- PMQ (Adams et al., 2004) and the Diagnosis Intractability Risk and Efficacy Score - DIRE; Belgrade et al. 2006): see § 2.4 for a detailed description of these tools. The Italian version of the tools elaborated for this study was authorised and approved by the original Authors. The *Medical risk prediction* requires the physician to provide an estimate, based on his or her clinical experience, of the risk of opioid misuse, answering 3 questions on an 11 point numerical scale: compliance with medical treatment (0=no compliance; 10=maximum compliance), risk of abuse and/or underuse of the drug (0=no risk, 10=maximum risk) and

The *Medical control form* was designed to collect clinical information about the progress of the treatment, any side effects, and the intention to continue or suspend treatment. It contains also a list of aberrant drug behaviours, based on the reference literature; the physician must tick those behaviours displayed by the patient (e.g. The patient uses other opioids in addition to those prescribed, The patient displays little interest in managing

*Urine toxicology screening* was performed with fast immunodosages that could be read visually, allowing the qualitative determination of the pharmacological substances and their metabolites present in the urine. For opiates, marijuana and buprenorfin, QuikStripTM OneStep immunodosages were used; QuikPac IITM OneStep were used to detect the

The *Initial pain interview* is a semi—structured interview designed to reconstruct the clinical history of the pain, and its progress over time. The interview is used to gather a wide range of personal information (e.g. marital status, level of education, employment status, etc.) and other information about the pain and its interference in daily activities. The habits and behaviours that, based on the literature, are considered risk factors for aberrant opioid use were also investigated (smoking, alcohol consumption patterns, use of drugs, family history

considered.

**2.5.2 Instruments** 

(oral or transdermal) and the initial dosage.

himself and his rehabilitation).

0 to 10, where 0 indicates no pain and 10 the worst possible pain.

expected efficacy of treatment (0=no efficacy, 10=maximum efficacy).

presence of amphetamines, metamphetamines and cocaine.

of alcohol and/or drug abuse, sexual abuse).

Regarding the psychological assessment the following tools were used.

The *Visual Analogue Scale* (VAS) consists of a 10 cm long horizontal line, the start and end points of which are labelled "no pain" and "worst possible pain". The patient is asked to mark the precise points corresponding to his or her maximum, minimum and habitual pain in the last month.

The *Minnesota Multiphasic Personality Inventory II* (MMPI-2; Hataway e McKinley, 1989; Italian adaptation by Pancheri et al., 1996) is a self-administered questionnaire used to assess personality characteristics. It consists of 567 items to be answered "true" or "false". Scores are obtained referred to three control scales and ten clinical scales (Hypochondria, Depression, Hysteria, Psychopathic Deviate, Masculinity – Femininity, Paranoia, Psychasthenia, Schizophrenia, Hypomania and Social Introversion).

The *Beck Depression Inventory II* (BDI-II; Beck et al., 1996; Italian adaptation by Ghisi et al., 2006) is a 21-item self-administered questionnaire commonly used among chronic pain patients to determine their depressive reaction, assessing both the cognitive component (e.g. sadness, pessimism) and the somatic component (e.g. loss of appetite, sleep disorders).

The *State Trait Anxiety Inventory-Y* (STAI-Y, Spielberger,1983; Italian adaptation by Pedrabissi and Santinello, 1989) is a 40-item questionnaire that assesses the level of patient anxiety. Two scores can be obtained, referring to two subscales that assess state anxiety (i.e. the anxiety experienced by the patient at the time they complete the questionnaire) and trait anxiety (i.e. the anxiety that the patient habitually experiences).

The *Pain Related Self-Statement Scale* (PRSS; Flor and Turk, 1988; Italian adaptation by Ferrari et al., 2004) is a self-administered scale developed to assess the cognitions specifically triggered in the pain situation that might inhibit or promote coping responses. The tool consists of 18 items, from which two total scores can be obtained for the subscales called Catastrophizing and Coping.

The *Nottingham Health Profile* (NPH, Hunt et al., 1985; Italian adaptation by Bertin et al, 1992) was used to assess quality of life. It consists of 38 items covering 6 content areas: physical mobility, energy, sleep, pain, social isolation, emotional reactions. The scores are expressed on percentage scales and correspond to the level of compromise perceived by the subject in the quality of life area considered.

The *Multidimensional Pain Inventory* (MPI, Kerns et al., 1985; Italian adaptation by Ferrari et al., 2000) is a 61-item self-administered questionnaire that allow a multidimensional assessment of the pain experience. The tool is divided into 3 parts: the first focuses on assessing the intensity of the pain, its interference in the life of the patient, the patient's perceived control of the pain and of events in his or her life (it consists of the following subscales: pain severity, interference, life-control, affective distress and support). The second part investigates the patient's perception of the responses of his or her significant others to his or her pain communications (negative/solicitous and distracting responses). The third part examines the frequency with which the patient carries out common daily activities (household chores, outdoor work, distant activities, social activities and general activity).

Finally, the *McGill Pain Questionnaire* (MPQ, Melzack, 1983; Italian adaptation by Maiani and Sanavio, 1985) is a tool consisting of a list of 78 adjectives related to pain grouped into 20 subclasses of homogeneous content; within each subgroup the descriptors are arranged in order of increasing intensity. The subject is invited to choose the adjective that best describes his or her pain in each category. The tool allows the pain to be assessed as an experience with three major dimensions: sensory-discriminative, motivational-affective and cognitiveevaluative.

Risk Factors in Opioid Treatment of Chronic Non-Cancer Pain: A Multidisciplinary Assessment 443

Continuous variables are expressed with mean, standard deviation, minimum and maximum and centiles into which the variables fall, when possible. Discrete and nominal variables are reported in frequency tables with the related percentages. To examine the differences between continuous variables, Student's parametric t test was used, with Chi

The reliability of the PMQ was assessed using test-retest, and Cronbach's α, while the

Correspondence Analysis was used to examine the relationship between the PMQ and DIRE scores obtained by the patients in the pre-treatment phase and the number of aberrant drug behaviours detected in the patients at the medical follow-ups recorded in the "Medical control form", the duration of treatment and the presence of the drug in the urine. Analysis of variance and correlational analysis with Spearman's non-parametric coefficient were used to analyse the relationship between the PMQ scores and the DIRE and the clinical variables

All the patients reported continuous pain; table 5 shows the mean values for pain intensity (assessed using the VAS) and the data on pharmacological treatment in the three assessment phases. No significant gender differences were found in maximum, minimum or habitual pain intensity. However, there was a statistically significant reduction in maximum and minimum pain intensity from the pre-treatment to the 2 month follow-up (F1,24= 4.64; F1,24= 6.75 respectively; both for *p*<0.05); from pre-treatment to the 4 month follow-up the only difference was in maximum VAS (F1,24= 8.21; *p*<0.01). This variation was not influenced by

Analysing the type of pharmacological treatment, it may be noted that at both the start of the pharmacological treatment and at the subsequent follow-ups, the most frequently administered active substance was oxycodone. The administration route during the data collection phases remained primarily oral. The drug dosages were transformed into equivalent mg of morphine, and classified as mild/average/high based on the indications supplied by Bruera et al. (1995). Regarding the dosage, it showed a tendency to increase at

Approximately half (46%) of the patients reported the presence of at least one side effect at the follow-ups; the most frequently reported side effects were sleepiness (29%), constipation (29%) and nausea (21%). The drug administration route did not appear to have any effect on

With respect to the psychological indicators investigated in the pre-treatment assessment, it was found that, based on the personality profile obtained with the MMPI-2, 56.2% of women and 33.3% of men had clinically significant scores in at least one of the clinical scales with psychopathological content (Paranoia, Schizofrenia, Hypomania). As for the affectiveemotional variables, the mean total score at BDI-II in the initial treatment phase was 24.6 (SD= 13.40) in women and 18.2 (SD= 9.94) in men; the level of depression was clinically significant (scores higher than 95th percentile) in 61% of women and 50% of men. Considering trait anxiety, the mean score was 52.7 (SD= 11.97) in women and 46.2 (SD= 7.22) in men, with 27.7% clinically significant levels of anxiety only in women (scores higher than 95th percentile). Regarding PRSS, the subjects reported a mean score of 3.20 (range 0-5, SD= 1.15) on the

**2.5.4 Statistical analysis** 

**2.5.5 Results** 

the 4 month follow-up.

squared for the comparison of frequency distributions.

related to pain, psychological function and quality of life.

the number and type of side effects reported by the patients.

Catastrophizing scale and 2.76 on the Coping scale (range 0-5, SD= 0.88).

the active substance administration route.

internal consistency of the DIRE was determined from Cronbach's α.

#### **2.5.3 Procedure**

The study is observational prospective and longitudinal; patient selection, data collection and the subsequent follow-ups took place from December 2009 to March 2011 in the Pain Relief and Palliative Care Unit of Vicenza hospital. The study consisted of the following assessment phases: patient selection, collection of pre-treatment data, 2 and 4 month followups (figure 3).

The specialist physician selected patients according to the personal and clinical criteria indicated above, as well as by using the numerical scale to assess pain intensity. Patients who were candidates for opioid treatment were asked to undergo psycho-clinical assessment in accordance with the multidisciplinary care diagnostic protocol, for patients with chronic non-cancer pain referred for opioid treatment at our Centre.

Pre-treatment data were collected in the two week period following selection. It consisted of the compilation of the questionnaire to determine the risk of opioid misuse (PMQ) by the patient, and the compilation of the DIRE by the team of pain specialists. Questionnaires to assess the intensity and experience of pain (VAS, MPI, MPQ, PRSS) and affective/emotional state (STAI-Y, BDI-II), quality of life (NHP) and personality characteristics (MMPI-2) were also administered. Medical and psychological follow-ups were scheduled 2 and 4 months after the start of treatment. At 2 months, medical data such as the presence of any side effects, changes in dosage, presence of aberrant drug behaviours and any intention to stop treatment were collected for treatment monitoring. The PMQ was administered again, to assess its reliability over time, and the questionnaires assessing quality of life and pain experience (VAS, MPI and NHP) were also administered. The same medical and psychological data were collected at 4 months, apart from the PMQ. At both follow-up appointment urine drug test was proposed. The study protocol was approved by the competent Ethics Committee.


Fig. 3. Study procedures

#### **2.5.4 Statistical analysis**

442 Pain Management – Current Issues and Opinions

The study is observational prospective and longitudinal; patient selection, data collection and the subsequent follow-ups took place from December 2009 to March 2011 in the Pain Relief and Palliative Care Unit of Vicenza hospital. The study consisted of the following assessment phases: patient selection, collection of pre-treatment data, 2 and 4 month follow-

The specialist physician selected patients according to the personal and clinical criteria indicated above, as well as by using the numerical scale to assess pain intensity. Patients who were candidates for opioid treatment were asked to undergo psycho-clinical assessment in accordance with the multidisciplinary care diagnostic protocol, for patients

Pre-treatment data were collected in the two week period following selection. It consisted of the compilation of the questionnaire to determine the risk of opioid misuse (PMQ) by the patient, and the compilation of the DIRE by the team of pain specialists. Questionnaires to assess the intensity and experience of pain (VAS, MPI, MPQ, PRSS) and affective/emotional state (STAI-Y, BDI-II), quality of life (NHP) and personality characteristics (MMPI-2) were also administered. Medical and psychological follow-ups were scheduled 2 and 4 months after the start of treatment. At 2 months, medical data such as the presence of any side effects, changes in dosage, presence of aberrant drug behaviours and any intention to stop treatment were collected for treatment monitoring. The PMQ was administered again, to assess its reliability over time, and the questionnaires assessing quality of life and pain experience (VAS, MPI and NHP) were also administered. The same medical and psychological data were collected at 4 months, apart from the PMQ. At both follow-up appointment urine drug test was proposed. The study protocol was approved by the

**UP** 

*Medical assessment*  Medical control form Urine drug tests **4 MONTH FOLLOW-UP** 

*Medical assessment*  Medical control form Urine drug tests *Psychological assessment* Pain intensity (VAS) Experience of pain (MPI) Quality of life (NHP)

with chronic non-cancer pain referred for opioid treatment at our Centre.

**SELECTION PRE-TREATMENT 2 MONTH FOLLOW-**

*Medical assessment* 

(PMQ)

(MMPI-II)

 Medical risk prediction *Psychological assessment*  Risk of opioid misuse

 Initial pain interview Pain intensity (VAS) Personality characteristics

 Affective-emotional state (STAI-Y,BDI-2) Pain experience and coping strategies (MPI,MPQ,PRSS)

Quality of life (NHP)

Risk of opioid misuse

*Team assessment* 

(DIRE)

**2.5.3 Procedure** 

ups (figure 3).

competent Ethics Committee.

**PATIENT** 

Fig. 3. Study procedures

 Checklist for medical selection Intensity of pain in the last month ≥4/10 (NRS)

Continuous variables are expressed with mean, standard deviation, minimum and maximum and centiles into which the variables fall, when possible. Discrete and nominal variables are reported in frequency tables with the related percentages. To examine the differences between continuous variables, Student's parametric t test was used, with Chi squared for the comparison of frequency distributions.

The reliability of the PMQ was assessed using test-retest, and Cronbach's α, while the internal consistency of the DIRE was determined from Cronbach's α.

Correspondence Analysis was used to examine the relationship between the PMQ and DIRE scores obtained by the patients in the pre-treatment phase and the number of aberrant drug behaviours detected in the patients at the medical follow-ups recorded in the "Medical control form", the duration of treatment and the presence of the drug in the urine. Analysis of variance and correlational analysis with Spearman's non-parametric coefficient were used to analyse the relationship between the PMQ scores and the DIRE and the clinical variables related to pain, psychological function and quality of life.

#### **2.5.5 Results**

All the patients reported continuous pain; table 5 shows the mean values for pain intensity (assessed using the VAS) and the data on pharmacological treatment in the three assessment phases. No significant gender differences were found in maximum, minimum or habitual pain intensity. However, there was a statistically significant reduction in maximum and minimum pain intensity from the pre-treatment to the 2 month follow-up (F1,24= 4.64; F1,24= 6.75 respectively; both for *p*<0.05); from pre-treatment to the 4 month follow-up the only difference was in maximum VAS (F1,24= 8.21; *p*<0.01). This variation was not influenced by the active substance administration route.

Analysing the type of pharmacological treatment, it may be noted that at both the start of the pharmacological treatment and at the subsequent follow-ups, the most frequently administered active substance was oxycodone. The administration route during the data collection phases remained primarily oral. The drug dosages were transformed into equivalent mg of morphine, and classified as mild/average/high based on the indications supplied by Bruera et al. (1995). Regarding the dosage, it showed a tendency to increase at the 4 month follow-up.

Approximately half (46%) of the patients reported the presence of at least one side effect at the follow-ups; the most frequently reported side effects were sleepiness (29%), constipation (29%) and nausea (21%). The drug administration route did not appear to have any effect on the number and type of side effects reported by the patients.

With respect to the psychological indicators investigated in the pre-treatment assessment, it was found that, based on the personality profile obtained with the MMPI-2, 56.2% of women and 33.3% of men had clinically significant scores in at least one of the clinical scales with psychopathological content (Paranoia, Schizofrenia, Hypomania). As for the affectiveemotional variables, the mean total score at BDI-II in the initial treatment phase was 24.6 (SD= 13.40) in women and 18.2 (SD= 9.94) in men; the level of depression was clinically significant (scores higher than 95th percentile) in 61% of women and 50% of men. Considering trait anxiety, the mean score was 52.7 (SD= 11.97) in women and 46.2 (SD= 7.22) in men, with 27.7% clinically significant levels of anxiety only in women (scores higher than 95th percentile). Regarding PRSS, the subjects reported a mean score of 3.20 (range 0-5, SD= 1.15) on the Catastrophizing scale and 2.76 on the Coping scale (range 0-5, SD= 0.88).

Risk Factors in Opioid Treatment of Chronic Non-Cancer Pain: A Multidisciplinary Assessment 445

(Hypocondria) of the MMPI-2, in which the H-PMQ subjects had scores that were significantly higher than the L-PMQ subjects (means 21 and 16.5 respectively, t=23.60; p<0.05) and for the total depression score in the BDI-II (H-PMQ mean =27.36; L-PMQ mean

As for the predictive validity of the tool, a highly significant correlation was found between the total PMQ score (high risk of opioid misuse) and the number of aberrant drug-related behaviours noted by the physician at the 4 month follow-up (r=0.95; p<0.01). Significant correlations were also found between the PMQ score and the "HS" (Hypochondria) scale of the MMPI-2 (r=0.49; p<0.01), the total score in the BDI-II (r=0.43; p<0.05), the trait anxiety score of the STAI-Y (r=0.38; p<0.05) and the "emotional reaction" scale of the NHP (r=0.39; p<0.05). The mean time required by the patient to complete the tool was 12'02" (SD=6.35; range: 4- 30). Finally, analysis of internal consistency produced an alpha coefficient of 0.82, indicating that the tool has excellent internal coherence; the test-retest reliability at 2 months was very

In the DIRE, the mean score assigned by the multidisciplinary team was 15.35; in this case too there were no significant differences in the mean scores of men and women. Figure 5 shows the percentage of patients suitable or not suitable for treatment based on DIRE total Score according to the cut-offs established by Belgrade et al. (2006). Most women (81.2%) and men (87.5%) were found suitable to start chronic opioid treatment according to the DIRE score.

Fig. 4. Percentage of patients with low/moderate/high risk level for opioid misuse, based

The total DIRE score was not found to be significantly correlated with the number of aberrant drug behaviours recorded by the physician at 2 and 4 months; however, a significant negative correlation (r=0.83; p<0.05) was found between the scores in the "Risk" category of the DIRE (psychological risk, chemical health, reliability, social support) and the number of aberrant drug behaviours recorded by the physician at the 4 month follow-up. The total DIRE score correlates negatively with the total BDI-II score (r=0.46, p<0.01) and with many of the MMPI-2 scales, and specifically: "PD" (Psychopathic Deviate) (r= 0.44; p<0.05), "PA" (Paranoia) (r= 0.40; p<0.05), "D" (Depression) (r= 039; p<005); "FAM" (Family Problems) (r= 044; p<005), "WRK" (Work Interference) (r= 040; p<005) and "TRT"( Negative

=17.88; t=26.18, p<0.05).

high (r= 0.76; p<0.001).

on PMQ scores.

Treatment Indicators) (r= 0.39; p<0.05).


Table 5. Pain intensity, active medication taken, administration route and dosage in initial treatment and in subsequent follow-ups.

In the description of the pain characteristics at the MPQ, higher scores emerged in the evaluative and affective -evaluative dimensions (means 0.87 and 0.73, respectively) , while the lower scores referred to the affective and mixed-sensory dimensions (means 0.4 and 0.52, respectively).

In the MPI the subjects reported high mean on "Pain severity" (mean: 4.6; SD= 0.9), "Interference" (mean: 4.3; SD= 1.1) and "Affective distress" (mean: 3.6; SD= 1.1) in the pretreatment assessment. Quality of life, measured using the NHP, appears more compromised in the following areas: "Emotional reactions" (mean: 80; SD= 56), "Pain" (mean: 77; SD= 26.2) and "Energy" (mean: 64; SD= 40). There were no statistically significant variations in the mean scores at the start of treatment and at the subsequent follow-ups for either the MPI or the NHP.

As for the tools to assess the risk of opioid misuse, the mean score at the PMQ was 24.59 (SD=9.43); there were no significant gender differences in the PMQ scores. Figure 4 shows the three different levels of the PMQ scores that, according to the cut-offs established by Dowling et al. (2007), identify a low/moderate or high risk of drug misuse. Overall, 36% of the subjects were found to be at high risk of misuse, 20% at moderate risk, and the remaining 44% at low risk. The distribution in the three risk levels between men and women was comparable.

The group was subsequently divided into patients with high PMQ scores (H-PMQ; n=9) and patients with low PMQ scores (L-PMQ; n=11) in order to analyse the presence of any significant differences in the psychological variables considered in the study. The patients with H-PMQ had a mean score of 3.78 on the Catastrophizing scale of the PRSS, statistically higher than that of the L-PMQ patients (mean 2.61) (t=-3.16; p<0.01); while on the Coping scale the H-PMQ subjects had mean scores that were significantly lower than those of the L-PMQ group (t=-2.18; p<0.05). Further statistical differences were found for the "HS" scale

Mean (SD) 90.2 (12.9) 33.1 (22.4) 55.5 (20.6)

12 (48%) 10 (40%) 3 (12%) -

15 (60%) 10 (40%)

Frequency (%) 24 (96%) 1 (4%) -

Table 5. Pain intensity, active medication taken, administration route and dosage in initial

In the description of the pain characteristics at the MPQ, higher scores emerged in the evaluative and affective -evaluative dimensions (means 0.87 and 0.73, respectively) , while the lower scores referred to the affective and mixed-sensory dimensions (means 0.4 and 0.52,

In the MPI the subjects reported high mean on "Pain severity" (mean: 4.6; SD= 0.9), "Interference" (mean: 4.3; SD= 1.1) and "Affective distress" (mean: 3.6; SD= 1.1) in the pretreatment assessment. Quality of life, measured using the NHP, appears more compromised in the following areas: "Emotional reactions" (mean: 80; SD= 56), "Pain" (mean: 77; SD= 26.2) and "Energy" (mean: 64; SD= 40). There were no statistically significant variations in the mean scores at the start of treatment and at the subsequent follow-ups for either the MPI

As for the tools to assess the risk of opioid misuse, the mean score at the PMQ was 24.59 (SD=9.43); there were no significant gender differences in the PMQ scores. Figure 4 shows the three different levels of the PMQ scores that, according to the cut-offs established by Dowling et al. (2007), identify a low/moderate or high risk of drug misuse. Overall, 36% of the subjects were found to be at high risk of misuse, 20% at moderate risk, and the remaining 44% at low risk. The distribution in the three risk levels between men and women was comparable. The group was subsequently divided into patients with high PMQ scores (H-PMQ; n=9) and patients with low PMQ scores (L-PMQ; n=11) in order to analyse the presence of any significant differences in the psychological variables considered in the study. The patients with H-PMQ had a mean score of 3.78 on the Catastrophizing scale of the PRSS, statistically higher than that of the L-PMQ patients (mean 2.61) (t=-3.16; p<0.01); while on the Coping scale the H-PMQ subjects had mean scores that were significantly lower than those of the L-PMQ group (t=-2.18; p<0.05). Further statistical differences were found for the "HS" scale

**Pain intensity**  - maximum VAS - minimum VAS - habitual VAS

**Drug active substance**  - Oxycodone - Fentanyl



respectively).

or the NHP.


**Route of administration** 

**Dosage (mg morphine)**  - Mild (<60 mg) - Average (60-300mg) - High (>300 mg)

treatment and in subsequent follow-ups.

**Initial treatment 2 month follow-up 4 month follow-up**  Mean (SD) Mean (SD) Mean (SD)

> Mean (SD) 80.6 (16.4) 24.0 (18.7) 52.6 (13.8)

Frequency (%) Frequency (%) Frequency (%)

12 (48%) 6 (24%) 4 (16%) 3 (12%)

16 (64%) 9 (36%)

Frequency (%) 11 (44%) 14 (56%) -

Mean (SD) 78.7 (28.3) 31.8 (19.6) 56.1 (24.5)

15 (60%) 5 (20%) 5 (20%) -

20 (80%) 5 (20%)

Frequency (%) 6 (24%) 11 (44%) 8 (32%)

(Hypocondria) of the MMPI-2, in which the H-PMQ subjects had scores that were significantly higher than the L-PMQ subjects (means 21 and 16.5 respectively, t=23.60; p<0.05) and for the total depression score in the BDI-II (H-PMQ mean =27.36; L-PMQ mean =17.88; t=26.18, p<0.05).

As for the predictive validity of the tool, a highly significant correlation was found between the total PMQ score (high risk of opioid misuse) and the number of aberrant drug-related behaviours noted by the physician at the 4 month follow-up (r=0.95; p<0.01). Significant correlations were also found between the PMQ score and the "HS" (Hypochondria) scale of the MMPI-2 (r=0.49; p<0.01), the total score in the BDI-II (r=0.43; p<0.05), the trait anxiety score of the STAI-Y (r=0.38; p<0.05) and the "emotional reaction" scale of the NHP (r=0.39; p<0.05).

The mean time required by the patient to complete the tool was 12'02" (SD=6.35; range: 4- 30). Finally, analysis of internal consistency produced an alpha coefficient of 0.82, indicating that the tool has excellent internal coherence; the test-retest reliability at 2 months was very high (r= 0.76; p<0.001).

In the DIRE, the mean score assigned by the multidisciplinary team was 15.35; in this case too there were no significant differences in the mean scores of men and women. Figure 5 shows the percentage of patients suitable or not suitable for treatment based on DIRE total Score according to the cut-offs established by Belgrade et al. (2006). Most women (81.2%) and men (87.5%) were found suitable to start chronic opioid treatment according to the DIRE score.

Fig. 4. Percentage of patients with low/moderate/high risk level for opioid misuse, based on PMQ scores.

The total DIRE score was not found to be significantly correlated with the number of aberrant drug behaviours recorded by the physician at 2 and 4 months; however, a significant negative correlation (r=0.83; p<0.05) was found between the scores in the "Risk" category of the DIRE (psychological risk, chemical health, reliability, social support) and the number of aberrant drug behaviours recorded by the physician at the 4 month follow-up.

The total DIRE score correlates negatively with the total BDI-II score (r=0.46, p<0.01) and with many of the MMPI-2 scales, and specifically: "PD" (Psychopathic Deviate) (r= 0.44; p<0.05), "PA" (Paranoia) (r= 0.40; p<0.05), "D" (Depression) (r= 039; p<005); "FAM" (Family Problems) (r= 044; p<005), "WRK" (Work Interference) (r= 040; p<005) and "TRT"( Negative Treatment Indicators) (r= 0.39; p<0.05).

Risk Factors in Opioid Treatment of Chronic Non-Cancer Pain: A Multidisciplinary Assessment 447

The main purpose of this study was to identify clinical procedures that allow to estimate the risk of opioid misuse in patients with chronic non-cancer pain treated as outpatients in a pain relief centre. With this aim, two tools were selected and adapted in Italian – the Pain Medication Questionnaire (PMQ) and the Diagnosis, Intractability, Risk and Efficacy Score (DIRE). These tools examine the perspectives of the patient and the multispecialist team,

The preliminary results reported above show that the PMQ has a good capacity to predict the risk of drug misuse by the patient. A strong correlation was found between high PMQ scores and the number of aberrant drug behaviours reported by the physician 4 months

From the PMQ scores, 36% of the subjects were found to be at high risk of misuse, 20% at moderate risk, and the remaining 44% at low risk. High PMQ scores (high risk of misuse) were found to be associated with higher levels of anxiety, depression and persistent bodyrelated worries. Furthermore, those patients classified as high risk of misuse, based on the cut-offs suggested by Dowling et al. (2007), were found to be significantly more depressed, and with a greater tendency to somatise their emotional distress than those classified as low risk. High risk patients were also found to be less active in managing their pain condition, and to have a greater propensity to produce pessimistic and catastrophic thoughts about their pain symptoms. The association that emerged, between high PMQ scores and the presence of symptoms of depression, appears to be in line with the findings of Holmes et al. (2006) in their work assessing the long-term utility of the PMQ in 271 subjects. In this study the low risk patients had mean BDI scores that were significantly lower than those of the

Furthermore, based on the initial results, the PMQ has demonstrated adequate internal consistency and good reliability over time. This suggests that the items composing it measure a single construct, and that the tool provides a reliable estimate of the risk of medication misuse. In addition, completing the PMQ requires just over ten minutes of the

To summarise, the tool seems to possess a good predictive capacity in relation to the use that the patient will make of the drug, and his or her compliance with treatment. The total score on the questionnaire, and the stratification of risk based on the cut-offs suggested by the authors therefore appear to be reliable indicators that the clinician can use to plan regular treatment monitoring. The strong association between high PMQ scores and the presence of symptoms of depression, tendency to somatisation and catastrophization, suggest that pharmacological treatment with opioids needs to be combined with psychological treatment to reduce the affective and emotional distress and modify the

As for the Italian version DIRE, the preliminary results show that the total score for risk of drug misuse is a poor predictor with limited psychometric quality. The Risk category, which specifically assesses psychosocial aspects such as psychological adaptation, substance abuse, reliability in complying with previous treatments and perceived social support in life context, is an exception to this. The tool in fact has low internal consistency, which improves slightly when the Diagnosis factor is removed. This means that the items of which the tool is composed are very heterogeneous, and that the tool probably has a multifactorial structure. Our finding does not agree with the results reported by Belgrade et al. (2006) in the original validation study, in which the DIRE displayed a very high internal consistency. The total

patient's time, and this makes it easy to incorporate into clinical practice.

patient's dysfunctional convictions and behaviours in relation to use of the drug.

**2.5.6 Discussion** 

respectively.

after the start of the study.

high risk of misuse group.

The mean time required by the multidisciplinary team to complete the tool was 7'23" (SD=3.38; range: 1-16). The internal consistency of the Italian version of the tool was 0.48, which is very low; the item that contributed least to the internal consistency of the DIRE was Diagnosis (α if item deleted=0.51).

Fig. 5. Percentage of patients suitable or not suitable for treatment based on DIRE total Score.

As for the concurrent validity of the two tools, there were no significant correlations between the total scores of the PMQ and the DIRE. However, there was a moderate negative correlation (r=0.36; p< 0.05) between high total PMQ scores (high risk of opioid misuse) and low scores in the Risk category of the DIRE.

Both the PMQ and the DIRE proved to be more effective than the Medical risk prediction in estimating the risk of drug misuse: the subjective estimate of the physician based on his or her clinical experience does not in fact correlate with the aberrant drug behaviours displayed by the patient at 2 and 4 months.

In the urine toxicology screening, only one patient tested negative for the active principle at the two month follow-up, while all the patients were positive for the drug used at the four month follow-up. None of the patients tested positive for illegal substances.

In relation to aberrant drug behaviours, most of the subjects (71%) displayed no aberrant drug behaviour at the two month follow-up; there was a potential misuse indicator in 19%, and the remaining 10% displayed three or more. At the 4 month follow-up, 22% of the patients displayed three or more aberrant drug behaviours while no indicators of misuse were found in 56% of the subjects.

Regarding other factors that according to the literature might be predictive for improper use of opioids, none of the patients reported that they abused alcohol or narcotic substances at assessment; 4.9% reported a personal history of alcohol abuse and 5.4% stated that they had abused illegal substances in the past. 7.3% of the subjects had a family history of alcohol abuse and 2.4% had a family history of the use of narcotic substances. None of the patients reported that they had suffered sexual abuse in childhood or adolescence, 17.1% of the patients had a prior psychiatric diagnosis and 9.8% of the subjects were being treated by a psychiatrist at the time of the evaluation.

#### **2.5.6 Discussion**

446 Pain Management – Current Issues and Opinions

The mean time required by the multidisciplinary team to complete the tool was 7'23" (SD=3.38; range: 1-16). The internal consistency of the Italian version of the tool was 0.48, which is very low; the item that contributed least to the internal consistency of the DIRE was

Fig. 5. Percentage of patients suitable or not suitable for treatment based on DIRE total Score. As for the concurrent validity of the two tools, there were no significant correlations between the total scores of the PMQ and the DIRE. However, there was a moderate negative correlation (r=0.36; p< 0.05) between high total PMQ scores (high risk of opioid misuse) and

Both the PMQ and the DIRE proved to be more effective than the Medical risk prediction in estimating the risk of drug misuse: the subjective estimate of the physician based on his or her clinical experience does not in fact correlate with the aberrant drug behaviours

In the urine toxicology screening, only one patient tested negative for the active principle at the two month follow-up, while all the patients were positive for the drug used at the four

In relation to aberrant drug behaviours, most of the subjects (71%) displayed no aberrant drug behaviour at the two month follow-up; there was a potential misuse indicator in 19%, and the remaining 10% displayed three or more. At the 4 month follow-up, 22% of the patients displayed three or more aberrant drug behaviours while no indicators of misuse

Regarding other factors that according to the literature might be predictive for improper use of opioids, none of the patients reported that they abused alcohol or narcotic substances at assessment; 4.9% reported a personal history of alcohol abuse and 5.4% stated that they had abused illegal substances in the past. 7.3% of the subjects had a family history of alcohol abuse and 2.4% had a family history of the use of narcotic substances. None of the patients reported that they had suffered sexual abuse in childhood or adolescence, 17.1% of the patients had a prior psychiatric diagnosis and 9.8% of the subjects were being treated by a

month follow-up. None of the patients tested positive for illegal substances.

Diagnosis (α if item deleted=0.51).

low scores in the Risk category of the DIRE.

displayed by the patient at 2 and 4 months.

were found in 56% of the subjects.

psychiatrist at the time of the evaluation.

The main purpose of this study was to identify clinical procedures that allow to estimate the risk of opioid misuse in patients with chronic non-cancer pain treated as outpatients in a pain relief centre. With this aim, two tools were selected and adapted in Italian – the Pain Medication Questionnaire (PMQ) and the Diagnosis, Intractability, Risk and Efficacy Score (DIRE). These tools examine the perspectives of the patient and the multispecialist team, respectively.

The preliminary results reported above show that the PMQ has a good capacity to predict the risk of drug misuse by the patient. A strong correlation was found between high PMQ scores and the number of aberrant drug behaviours reported by the physician 4 months after the start of the study.

From the PMQ scores, 36% of the subjects were found to be at high risk of misuse, 20% at moderate risk, and the remaining 44% at low risk. High PMQ scores (high risk of misuse) were found to be associated with higher levels of anxiety, depression and persistent bodyrelated worries. Furthermore, those patients classified as high risk of misuse, based on the cut-offs suggested by Dowling et al. (2007), were found to be significantly more depressed, and with a greater tendency to somatise their emotional distress than those classified as low risk. High risk patients were also found to be less active in managing their pain condition, and to have a greater propensity to produce pessimistic and catastrophic thoughts about their pain symptoms. The association that emerged, between high PMQ scores and the presence of symptoms of depression, appears to be in line with the findings of Holmes et al. (2006) in their work assessing the long-term utility of the PMQ in 271 subjects. In this study the low risk patients had mean BDI scores that were significantly lower than those of the high risk of misuse group.

Furthermore, based on the initial results, the PMQ has demonstrated adequate internal consistency and good reliability over time. This suggests that the items composing it measure a single construct, and that the tool provides a reliable estimate of the risk of medication misuse. In addition, completing the PMQ requires just over ten minutes of the patient's time, and this makes it easy to incorporate into clinical practice.

To summarise, the tool seems to possess a good predictive capacity in relation to the use that the patient will make of the drug, and his or her compliance with treatment. The total score on the questionnaire, and the stratification of risk based on the cut-offs suggested by the authors therefore appear to be reliable indicators that the clinician can use to plan regular treatment monitoring. The strong association between high PMQ scores and the presence of symptoms of depression, tendency to somatisation and catastrophization, suggest that pharmacological treatment with opioids needs to be combined with psychological treatment to reduce the affective and emotional distress and modify the patient's dysfunctional convictions and behaviours in relation to use of the drug.

As for the Italian version DIRE, the preliminary results show that the total score for risk of drug misuse is a poor predictor with limited psychometric quality. The Risk category, which specifically assesses psychosocial aspects such as psychological adaptation, substance abuse, reliability in complying with previous treatments and perceived social support in life context, is an exception to this. The tool in fact has low internal consistency, which improves slightly when the Diagnosis factor is removed. This means that the items of which the tool is composed are very heterogeneous, and that the tool probably has a multifactorial structure. Our finding does not agree with the results reported by Belgrade et al. (2006) in the original validation study, in which the DIRE displayed a very high internal consistency. The total

Risk Factors in Opioid Treatment of Chronic Non-Cancer Pain: A Multidisciplinary Assessment 449

personality disorders is more frequent in these patients (Banta-Green et al., 2009a; Haller & Acosta; 2010), and therefore it is advisable to involve a psychotherapist or psychiatrist in the treatment process (Chou, 2009; Chou et al, 2009a; Chou et al, 2009b; Chou et al, 2009c;

The analyses carried out to date have shown that only one patient in twenty five did not test positive to the prescribed drug; and no patients tested positive for illegal substances in the urine toxicology screening. These data seem very different to those of other studies, which found the prevalence of abuse of illegal substances in patients being treated with opioid to be 16% (Machikanti et al., 2006), 20% (Heit & Gourlay, 2004) or 40.3% (Ives et al., 2006). The preliminary results seem to suggest that in our context the more frequent problem may be the underuse of opioid analgesics rather than their compulsive use and abuse: this interpretation is supported by the difficulty, frequently expressed by our patient, in accepting these drugs for fear of dependence, loss of mental lucidity or being socially stigmatised as drug addicted. A further important objective of the management of patients who are candidates for opioid treatment in a multidisciplinary setting is thus to assess their convictions about the use of these drugs and their expectations of treatment, so as to be able to modify any dysfunctional beliefs and unrealistic hopes for the outcome of treatment. The limitations of this study are primarily the small number of subjects examined and the differing distribution of men and women. In addition, the limited number of patients did not allow us to examine the effect of other variables that, based on the reference literature, can constitute risk factors for opioid addiction, such as a personal or family history of alcohol and/or substance abuse, or episodes of sexual abuse in childhood or adolescence. Despite these limits, the high degree of correlation between risk of misuse and the psychological aspects supports the view that an in-depth assessment of the affectiveemotional, cognitive and behavioural variables of the patient is crucial. So future research may be focused on understanding which psychological variables are most connected to the risk of opioid misuse (e.g. personality traits, anxiety, depression, etc.) so as to be able to develop tailored psychological interventions that maximise treatment efficacy, with positive

Overall the results that have emerged so far highlight the need for a multidisciplinary assessment of patients who are candidates for opioid treatment so as to improve compliance and treatment benefits. The use of tools specifically designed to determine the risk of inappropriate use of the drug has proved to be more efficacious that the opinion expressed by the clinician based on his or her experience. The strong association between psychosocial distress and high risk of opioid misuse also suggests that pharmacological treatment should be combined with psychological interventions that can reduce the anxiety-depression symptoms and correct any irrational ideas about the use of these drugs. Furthermore, systemic monitoring of treatment and regular urine drug screen can contribute to improve

Chronic non-cancer pain remains a condition that affects a large number of people throughout the world, and is associated with significantly compromised quality of life. Although many pharmacological and non-pharmacological treatments have been proposed to manage chronic pain, the results have proved disappointing for a significant proportion

Trescot et al., 2006; Trescot at al., 2008).

outcomes for quality of life and overall well-being, as well.

adherence to treatment.

**3. Conclusions** 

of patients.

score of the DIRE - Italian version - is not at present predictive of the number of aberrant drug behaviours detected by the physician at the follow-ups. This seems to be in line with the work of Moore et al. (2007), who found that the DIRE had low sensitivity (0.17) in predicting aberrant drug behaviours. The authors suggest that the DIRE is more than simply an addiction risk tool and some of its items may not to be appropriate to predict drug misuse. However, as mentioned above, the score of the Risk category was found to be predictive of the number of aberrant drug behaviours at 4- months follow-up. This result is coherent with the findings of many studies on opioid abuse risk factors, which found that the factors considered to be most predictive of opioid abuse are the presence of psychiatric disorders (Compton et al., 1998; Sullivan et al., 2006) and a personal and/or family history of substance abuse or drug abuse (Dunbar & Katz, 1996; Schieffer et al., 2005). Our data indicate that a low score (not suitable for opioid treatment) is associated with depressive symptoms, the presence of paranoid personality traits and family and work difficulties. Completing the DIRE requires a few minutes of the team's time, but this must be preceded by an in-depth psychological assessment of the patient to determine if psychiatric disorders and past abuse, or current alcohol or substance abuse, are present.

The two tools selected do not appear to be correlated; instead, it is clear that there is an association between high PMQ scores (high risk of misuse) and low scores in the DIRE Risk category.

The prediction made by the physician based on his or her clinical experience was not found to be valid in estimating the risk of opioid misuse. This result highlights the need to use tools specifically created to assess the risk of opioid addiction in the chronic pain patient; clinical experience can be used to understand and contextualize the results obtained from these scales, but seems to be insufficient on its own.

So far as the experience of pain and the indicators of psychophysical function are concerned, the use of opioid drugs proved efficacious in reducing the maximum and minimum intensity of the perceived pain 2 months after the start of the treatment. A parallel improvement in the quality of life of the patients was not recorded by the questionnaire used in this study. This result seems to be in line with the data in the literature: despite ongoing research and the growing use of opioids in clinical practice, the effect of this treatment on the quality of life of the patient remains a subject of debate (Dillie et al., 2008). The reduction in pain, unaccompanied by an improvement in physical function and quality of life, indicates that these patients need psychological support, to examine their life habits, coping strategies and any secondary gain that might interfere with recovery of a state of psychophysical well-being. Quality of life is in fact a wide ranging concept, influenced by perception of one's health in a biopsychosocial sense, level of independence, social relationships and interaction with one's own specific environmental context in a complex way (Apolone et al., 1997).

As for the psychological variables considered in the study, half of the men and 60% of the women reported clinically significant levels of depression; and almost 30% of the women displayed high levels of anxiety. These data are in line with the findings of many authors, that clinically significant levels of depression and anxiety are very frequent in patients with chronic pain (Banks & Kerns, 1996; Boersma & Linton, 2006; Dersh et al., 2006; Gatchel, 2005; Vlayen & Linton, 2000). In addition, there was a high incidence of alterations in patients' personality profiles: over half of the women and approximately one third of the men reported high scores in at least one of the clinical content scales of the MMPI-2. This result too seems coherent with the reports in the literature, that the presence of psychiatric and personality disorders is more frequent in these patients (Banta-Green et al., 2009a; Haller & Acosta; 2010), and therefore it is advisable to involve a psychotherapist or psychiatrist in the treatment process (Chou, 2009; Chou et al, 2009a; Chou et al, 2009b; Chou et al, 2009c; Trescot et al., 2006; Trescot at al., 2008).

The analyses carried out to date have shown that only one patient in twenty five did not test positive to the prescribed drug; and no patients tested positive for illegal substances in the urine toxicology screening. These data seem very different to those of other studies, which found the prevalence of abuse of illegal substances in patients being treated with opioid to be 16% (Machikanti et al., 2006), 20% (Heit & Gourlay, 2004) or 40.3% (Ives et al., 2006). The preliminary results seem to suggest that in our context the more frequent problem may be the underuse of opioid analgesics rather than their compulsive use and abuse: this interpretation is supported by the difficulty, frequently expressed by our patient, in accepting these drugs for fear of dependence, loss of mental lucidity or being socially stigmatised as drug addicted. A further important objective of the management of patients who are candidates for opioid treatment in a multidisciplinary setting is thus to assess their convictions about the use of these drugs and their expectations of treatment, so as to be able to modify any dysfunctional beliefs and unrealistic hopes for the outcome of treatment.

The limitations of this study are primarily the small number of subjects examined and the differing distribution of men and women. In addition, the limited number of patients did not allow us to examine the effect of other variables that, based on the reference literature, can constitute risk factors for opioid addiction, such as a personal or family history of alcohol and/or substance abuse, or episodes of sexual abuse in childhood or adolescence.

Despite these limits, the high degree of correlation between risk of misuse and the psychological aspects supports the view that an in-depth assessment of the affectiveemotional, cognitive and behavioural variables of the patient is crucial. So future research may be focused on understanding which psychological variables are most connected to the risk of opioid misuse (e.g. personality traits, anxiety, depression, etc.) so as to be able to develop tailored psychological interventions that maximise treatment efficacy, with positive outcomes for quality of life and overall well-being, as well.

Overall the results that have emerged so far highlight the need for a multidisciplinary assessment of patients who are candidates for opioid treatment so as to improve compliance and treatment benefits. The use of tools specifically designed to determine the risk of inappropriate use of the drug has proved to be more efficacious that the opinion expressed by the clinician based on his or her experience. The strong association between psychosocial distress and high risk of opioid misuse also suggests that pharmacological treatment should be combined with psychological interventions that can reduce the anxiety-depression symptoms and correct any irrational ideas about the use of these drugs. Furthermore, systemic monitoring of treatment and regular urine drug screen can contribute to improve adherence to treatment.

#### **3. Conclusions**

448 Pain Management – Current Issues and Opinions

score of the DIRE - Italian version - is not at present predictive of the number of aberrant drug behaviours detected by the physician at the follow-ups. This seems to be in line with the work of Moore et al. (2007), who found that the DIRE had low sensitivity (0.17) in predicting aberrant drug behaviours. The authors suggest that the DIRE is more than simply an addiction risk tool and some of its items may not to be appropriate to predict drug misuse. However, as mentioned above, the score of the Risk category was found to be predictive of the number of aberrant drug behaviours at 4- months follow-up. This result is coherent with the findings of many studies on opioid abuse risk factors, which found that the factors considered to be most predictive of opioid abuse are the presence of psychiatric disorders (Compton et al., 1998; Sullivan et al., 2006) and a personal and/or family history of substance abuse or drug abuse (Dunbar & Katz, 1996; Schieffer et al., 2005). Our data indicate that a low score (not suitable for opioid treatment) is associated with depressive symptoms, the presence of paranoid personality traits and family and work difficulties. Completing the DIRE requires a few minutes of the team's time, but this must be preceded by an in-depth psychological assessment of the patient to determine if psychiatric disorders

The two tools selected do not appear to be correlated; instead, it is clear that there is an association between high PMQ scores (high risk of misuse) and low scores in the DIRE Risk

The prediction made by the physician based on his or her clinical experience was not found to be valid in estimating the risk of opioid misuse. This result highlights the need to use tools specifically created to assess the risk of opioid addiction in the chronic pain patient; clinical experience can be used to understand and contextualize the results obtained from

So far as the experience of pain and the indicators of psychophysical function are concerned, the use of opioid drugs proved efficacious in reducing the maximum and minimum intensity of the perceived pain 2 months after the start of the treatment. A parallel improvement in the quality of life of the patients was not recorded by the questionnaire used in this study. This result seems to be in line with the data in the literature: despite ongoing research and the growing use of opioids in clinical practice, the effect of this treatment on the quality of life of the patient remains a subject of debate (Dillie et al., 2008). The reduction in pain, unaccompanied by an improvement in physical function and quality of life, indicates that these patients need psychological support, to examine their life habits, coping strategies and any secondary gain that might interfere with recovery of a state of psychophysical well-being. Quality of life is in fact a wide ranging concept, influenced by perception of one's health in a biopsychosocial sense, level of independence, social relationships and interaction with one's own specific environmental context in a complex

As for the psychological variables considered in the study, half of the men and 60% of the women reported clinically significant levels of depression; and almost 30% of the women displayed high levels of anxiety. These data are in line with the findings of many authors, that clinically significant levels of depression and anxiety are very frequent in patients with chronic pain (Banks & Kerns, 1996; Boersma & Linton, 2006; Dersh et al., 2006; Gatchel, 2005; Vlayen & Linton, 2000). In addition, there was a high incidence of alterations in patients' personality profiles: over half of the women and approximately one third of the men reported high scores in at least one of the clinical content scales of the MMPI-2. This result too seems coherent with the reports in the literature, that the presence of psychiatric and

and past abuse, or current alcohol or substance abuse, are present.

these scales, but seems to be insufficient on its own.

category.

way (Apolone et al., 1997).

Chronic non-cancer pain remains a condition that affects a large number of people throughout the world, and is associated with significantly compromised quality of life. Although many pharmacological and non-pharmacological treatments have been proposed to manage chronic pain, the results have proved disappointing for a significant proportion of patients.

Risk Factors in Opioid Treatment of Chronic Non-Cancer Pain: A Multidisciplinary Assessment 451

needs to be monitored not only in medical term, but also from a psychological perspective, to be able to make cognitive, emotional and behavioural changes that can enhance and

From our experience in the Italian context, the prevalence of addiction or misuse in patients with chronic pain in treatment with opioids appears to be low. The systematic assessment of risk using the tools created in recent years allows the clinician to overcome some biases, such as the overestimation of the risk of addiction, and hence avoid considering the entire

The treatment of pain is a public health problem that is of such critical importance as to constitute an international imperative, as well as a fundamental human right (Brennan et al., 2007); opioid drugs appear as a potential resource to manage chronic pain efficaciously. However, their targeted use must be preceded by a suitable assessment of the patient by a multidisciplinary team that clarifies not only the causes of the pain, but also any risk factors or dysfunctional psychological aspects related to use of the drug, so as to increase the

We would like to thank all the medical and nursing staff of the Pain and Palliative Care Unit

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**4. Acknowledgments** 

**5. References** 

population of chronic pain patients to be at risk of abuse.

Opioid drugs seem promising for the management of chronic pain of medium-severe intensity, but many uncertainties remain about the long-term use of these drugs and the risk of dependence and abuse. In this respect, many guidelines and protocols with recommendations have been developed in recent years precisely to allow safer and more targeted use of opioid drugs in chronic non-cancer pain syndromes; these recommendations highlight, primarily, the importance of carrying out stratification of risk in the patient who is a candidate for pharmacological treatment with opioids. A number of standardised tools have been developed with the aim of identifying and objectively measuring the risk of abuse, dependence and aberrant drug behaviours.

This chapter has presented the preliminary results of a study that aims to analyse the clinical utility of the Italian adaptation of two tools for stratification of the risk: a self-administered patient questionnaire, the Pain Medication Questionnaire, and a team assessment tool, the Diagnosis Intractability Risk and Efficacy Score.

These tools have been used as part of a multidisciplinary medical and psychological assessment and treatment protocol; the data in the literature, confirmed in our study, clearly indicates that there is a frequent association between high risk of opioid misuse and the presence of psychological distress (Banta-Green et al., 2009a; Haller & Acosta; 2010). This emphasizes the importance of a physical, psychological and social assessment before starting treatment with opioids. In this respect, based on literature data and the preliminary results of the study described, we believe that an effective psychological assessment must consist of an initial clinical interview, specific tools to assess the risk of drug misuse, and questionnaires that investigate the patient's subjective experience of pain, perceived quality of life and personality characteristics. The interview, which may be more or less structured, is essential to understand the individual's experience of pain and its interference in the patient's family, professional, social and emotional life; it also allows the clinician to investigate behaviour habits related to opioid misuse (e.g. prior abuse of alcohol or illegal substances) and the presence of traumatic experiences such as sexual abuse in childhood or adolescence. During the interview the clinician may also identify any fears and worries about taking these drugs, the patient's expectations of the treatment and their reliability in following the indications of the therapist. Further areas of investigation concern the strategies that the patient uses to deal with the pain, and the possible presence of secondary gain that could compromise the efficacy of the treatment. Our results show that the indications provided by the specifically designed tools are more reliable than the clinical experience of the specialist physician in estimated aberrant drug behaviours. Investigation of the emotional-affective state of the patient, and his or her personality characteristics, always an important aspect of the multidimensional assessment of chronic pain, appears indispensable when long-term opioid therapy is initiated, since the presence of depression, anxiety or personality disorders has been found to be correlated with a greater risk of addiction. Pain coping strategies and any tendency to "catastrophize" must also be investigated using suitable questionnaires. Based on our experience, patients at greater risk of opioid misuse in fact seem to display a passive attitude to the management of their pain condition, and to have exaggeratedly pessimistic expectations of the progress of their symptoms. Finally, it is important to systematically assess the quality of life of these patients, as effective pain relief should always be accompanied by functional improvements in their physical, psychological and social area. The preliminary results of our study show that reduction in pain intensity of pain due to opioids does not seem to be accompanied by an improvement in physical and psychological functionality. This indicates that the patient needs to be monitored not only in medical term, but also from a psychological perspective, to be able to make cognitive, emotional and behavioural changes that can enhance and consolidate the efficacy of the treatment.

From our experience in the Italian context, the prevalence of addiction or misuse in patients with chronic pain in treatment with opioids appears to be low. The systematic assessment of risk using the tools created in recent years allows the clinician to overcome some biases, such as the overestimation of the risk of addiction, and hence avoid considering the entire population of chronic pain patients to be at risk of abuse.

The treatment of pain is a public health problem that is of such critical importance as to constitute an international imperative, as well as a fundamental human right (Brennan et al., 2007); opioid drugs appear as a potential resource to manage chronic pain efficaciously. However, their targeted use must be preceded by a suitable assessment of the patient by a multidisciplinary team that clarifies not only the causes of the pain, but also any risk factors or dysfunctional psychological aspects related to use of the drug, so as to increase the benefits of treatment and reduce the costs.

#### **4. Acknowledgments**

We would like to thank all the medical and nursing staff of the Pain and Palliative Care Unit from Vicenza Hospital for the precious contribution to the realization of this study.

#### **5. References**

450 Pain Management – Current Issues and Opinions

Opioid drugs seem promising for the management of chronic pain of medium-severe intensity, but many uncertainties remain about the long-term use of these drugs and the risk of dependence and abuse. In this respect, many guidelines and protocols with recommendations have been developed in recent years precisely to allow safer and more targeted use of opioid drugs in chronic non-cancer pain syndromes; these recommendations highlight, primarily, the importance of carrying out stratification of risk in the patient who is a candidate for pharmacological treatment with opioids. A number of standardised tools have been developed with the aim of identifying and objectively measuring the risk of

This chapter has presented the preliminary results of a study that aims to analyse the clinical utility of the Italian adaptation of two tools for stratification of the risk: a self-administered patient questionnaire, the Pain Medication Questionnaire, and a team assessment tool, the

These tools have been used as part of a multidisciplinary medical and psychological assessment and treatment protocol; the data in the literature, confirmed in our study, clearly indicates that there is a frequent association between high risk of opioid misuse and the presence of psychological distress (Banta-Green et al., 2009a; Haller & Acosta; 2010). This emphasizes the importance of a physical, psychological and social assessment before starting treatment with opioids. In this respect, based on literature data and the preliminary results of the study described, we believe that an effective psychological assessment must consist of an initial clinical interview, specific tools to assess the risk of drug misuse, and questionnaires that investigate the patient's subjective experience of pain, perceived quality of life and personality characteristics. The interview, which may be more or less structured, is essential to understand the individual's experience of pain and its interference in the patient's family, professional, social and emotional life; it also allows the clinician to investigate behaviour habits related to opioid misuse (e.g. prior abuse of alcohol or illegal substances) and the presence of traumatic experiences such as sexual abuse in childhood or adolescence. During the interview the clinician may also identify any fears and worries about taking these drugs, the patient's expectations of the treatment and their reliability in following the indications of the therapist. Further areas of investigation concern the strategies that the patient uses to deal with the pain, and the possible presence of secondary gain that could compromise the efficacy of the treatment. Our results show that the indications provided by the specifically designed tools are more reliable than the clinical experience of the specialist physician in estimated aberrant drug behaviours. Investigation of the emotional-affective state of the patient, and his or her personality characteristics, always an important aspect of the multidimensional assessment of chronic pain, appears indispensable when long-term opioid therapy is initiated, since the presence of depression, anxiety or personality disorders has been found to be correlated with a greater risk of addiction. Pain coping strategies and any tendency to "catastrophize" must also be investigated using suitable questionnaires. Based on our experience, patients at greater risk of opioid misuse in fact seem to display a passive attitude to the management of their pain condition, and to have exaggeratedly pessimistic expectations of the progress of their symptoms. Finally, it is important to systematically assess the quality of life of these patients, as effective pain relief should always be accompanied by functional improvements in their physical, psychological and social area. The preliminary results of our study show that reduction in pain intensity of pain due to opioids does not seem to be accompanied by an improvement in physical and psychological functionality. This indicates that the patient

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**21** 

*China* 

FuZhou Wang

**Psychological Strategies in Pain Management:** 

Pain is the most awful sensory suffering that makes people exhausted. Although pain itself possesses protective role in keeping patients from further injury, it is still obliged to be treated for its negative effect on patients' physiological and psychological well-beings. Great progress has been made in our understanding of the therapeutic strategies with different agents and techniques on pain in the past decades, but the analgesic result is not as effective as we desired specifically when the acute process tends to be chronic (Li et al., 2011). As one of the important parts of somatosensory system, pain nets closely with spiritual and psychological feelings, which often results in analgesic failure when conventional pharmacological methods and means are used, and also raises questions on how to alleviate pain through psychotherapeutics (Manchikanti et al., 2011). Given the big difference in methods of psychological interventions and the association with the changing therapeutic context, the analgesic efficacy of psychosocial support fluctuates. Therefore, standardizing and optimizing the psychotherapeutic strategies in clinical practice would make it more effective in relieving pain. Here we review and prospect the psychological management of pain, and then give a

recommendation of the therapeutic flow of the standardized optimal procedures.

Two hundreds years ago, the word "placebo" was defined by Robert Hooper in his dictionary to a more modern medical meaning as "any medicine adapted more to please than benefit the patient" (Hooper, 1811). In fact, this is the original description of psychological intervention in the field of medicine of which the meaning is broadened further during the following years. However, placebo therapies were becoming popular until the past century. To date, placebo medicine generally means (i) containing pharmacologically inactive ingredients, and (ii) the contents have pharmacological activity. The effect of placebo is mainly dependent on the psychological state of patients, therapeutic context and physicians' console. In contrast to placebo, nocebo was adapted to describe the negative effect (i.e. unpleasant consequence) occurs in expectation of a harmful occurrence when an inert substance was used. In pain medicine, both placebo and nocebo are also two majorities that can be used in psychological intervention. Therefore, psychological placebo

**2. Origins of psychological analgesia** 

**1. Introduction** 

**Optimizing Procedures in Clinics** 

*Department of Anesthesiology and Critical Care Medicine,* 

*Nanjing Medical University, Nanjing,* 

*The Affiliated Nanjing Maternity and Child Health Care Hospital,* 


### **Psychological Strategies in Pain Management: Optimizing Procedures in Clinics**

#### FuZhou Wang

*Department of Anesthesiology and Critical Care Medicine, The Affiliated Nanjing Maternity and Child Health Care Hospital, Nanjing Medical University, Nanjing, China* 

#### **1. Introduction**

458 Pain Management – Current Issues and Opinions

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(2011). Impact of fibromyalgia severity on health economic costs: results from a European cross-sectional study. *Applied Health Economics and Health Policy*. Vol. 9, Pain is the most awful sensory suffering that makes people exhausted. Although pain itself possesses protective role in keeping patients from further injury, it is still obliged to be treated for its negative effect on patients' physiological and psychological well-beings. Great progress has been made in our understanding of the therapeutic strategies with different agents and techniques on pain in the past decades, but the analgesic result is not as effective as we desired specifically when the acute process tends to be chronic (Li et al., 2011). As one of the important parts of somatosensory system, pain nets closely with spiritual and psychological feelings, which often results in analgesic failure when conventional pharmacological methods and means are used, and also raises questions on how to alleviate pain through psychotherapeutics (Manchikanti et al., 2011). Given the big difference in methods of psychological interventions and the association with the changing therapeutic context, the analgesic efficacy of psychosocial support fluctuates. Therefore, standardizing and optimizing the psychotherapeutic strategies in clinical practice would make it more effective in relieving pain. Here we review and prospect the psychological management of pain, and then give a recommendation of the therapeutic flow of the standardized optimal procedures.

#### **2. Origins of psychological analgesia**

Two hundreds years ago, the word "placebo" was defined by Robert Hooper in his dictionary to a more modern medical meaning as "any medicine adapted more to please than benefit the patient" (Hooper, 1811). In fact, this is the original description of psychological intervention in the field of medicine of which the meaning is broadened further during the following years. However, placebo therapies were becoming popular until the past century. To date, placebo medicine generally means (i) containing pharmacologically inactive ingredients, and (ii) the contents have pharmacological activity. The effect of placebo is mainly dependent on the psychological state of patients, therapeutic context and physicians' console. In contrast to placebo, nocebo was adapted to describe the negative effect (i.e. unpleasant consequence) occurs in expectation of a harmful occurrence when an inert substance was used. In pain medicine, both placebo and nocebo are also two majorities that can be used in psychological intervention. Therefore, psychological placebo

Psychological Strategies in Pain Management: Optimizing Procedures in Clinics 461

different types of pain is also yet to be guaranteed. A body of literature has confirmed the role of emotions in pain perception and alleviation. Anxiety and stress are two main factors of emotion-associated psychological mediator. It is believed that anxiety is the cause of increased levels of pain, and reduction in anxiety produces analgesia (Luciano et al., 2011). Stress sometimes is related with increased levels of pain, but in some contexts, stress can produce analgesia (Donello et al., 2011; Wang et al., 2008). Therefore, the purpose of psychological suggestion in pain control is to alleviate patients' anxiety and stress, which in

As described in the general model of the placebo-associated psychological analgesia, three consecutive stages exist when psychological treatment was given: the induction, psychophysiological mediation, and actualization (Goffaux et al., 2010). In the induction stage, three aspects compose the major contents including the introduction or initiation (therapeutic message; method of administration; follow-up and booster sessions; assessment of side effects), idiosyncratic variables (beliefs and values; personal history; innate predisposition) and therapeutic context (treatment objectives; therapeutic alliance; sociocultural factors). In the second stage, psychophysiological mediation composes of psychological and biological mechanisms. Psychological mechanisms include abovementioned conditioning, expectancy, motivation, and emotion, and the biological mechanisms include neurochemical mediators (endorphins, dopamine, and other neurotransmitters/neuromodulators) and neurophysiology (activation of central modulatory mechanisms including descending inhibitory circuits). In the actualization stage, three main aspects exist including subjective experience (pain, emotions, quality of life, satisfaction, and related relief), behavioral markers (amount of analgesics consumed and overt pain behaviors), and physiological markers (physiological nociceptive activity, objective clinical indicators). As thus, when a psychological intervention is given, these three stages would be experienced. However, in consideration of the multiple phases of these stages, the actual effect of psychological analgesia may be variable in different

The analgesic effect of psychological approaches depends on types of pain, individual status, caregivers' attitude and contextual frame, which finally determines the efficacy of psychological analgesia. For postoperative pain, preoperative hypnosis could accelerate wound healing and alleviate pain intensity after mammoplasty (Ginandes et al., 2003), and reduce post-surgical pain and distress in patients undergone excisional breast biopsy (Schnur et al., 2008). However, in other surgical contexts, psychological interventions did not produce detectable difference compared with the control: relaxation training for spinal surgeries could not reduce postoperative pain (Gavin et al., 2006), and intraoperative music therapy also could not produce analgesia in Cesarean patients (Reza et al., 2007). Contrary to this, postoperative music can alleviate the pain and reduce the need for analgesics in patients who undergone Cesarean section (Ebneshahidi & Mohseni, 2008). Besides, in cardiac surgeries, music therapy produced effective role in alleviating anxiety and pain (Sendelbach et al., 2006). These different even controversial results raise questions on the real analgesia efficacy of psychological interventions. In fact, difference in interventional methods, types of surgeries, and professionals of investigators may all contribute to the changeable results of psychological analgesia. An attractive study performed to observe the

turn produces a feedback analgesia effect.

individuals under different circumstances.

**4. Efficacy of psychological analgesia** 

(positive) or psychological nocebo (negative) are derived from the traditional conceptions of placebo or nocebo. Although the key patterns of psychological therapy is on the basis of the linguistic console from physicians or investigators, psychological analgesia with series of strategies of psychology is the result of the above-mentioned placebo or nocebo.

#### **3. Mechanisms of psychological analgesia**

Psychological analgesia is a broad concept that includes all aspects referring to the psychological intervention. Hypnosis, music therapy, preoperative education, and linguistic suggestion all belong to psychological approaches in pain control (Hobson et al., 2006; Patterson et al., 2010; Sen et al., 2010; Wang et al., 2008). Whatever psychological methods used in analgesia, common neurophysiological mechanisms exist and different models explain its function.

Functional magnetic resonance imaging (fMRI) verified an increase in neural activity during placebo associated psychological stimulation that is related to two major pain modulation mechanisms (Craggs et al., 2008): i) affective regulation which includes activation of the rostral anterior cingulate cortex, bilateral amygdala, and medial prefrontal cortex; and ii) higher cognitive regulation during which the posterior cingulate, pre-cuneus, rostral anterior cingulate cortex, perihippocampal gyrus, and the temporal lobes are activated. As the "gate theory" described that afferent inhibition blocks ascending signals from the periphery, psychological stimuli at the early period produce analgesic effect through a selfreinforcing feedback mechanism (Vase et al., 2005).

Several models give an in-depth understanding of the psychological stimulation associated analgesia. Conditioning, expectancy, motivation, and emotion are four psychological mediators involving in the process of analgesia. Conditioning model says that the interventional effect presented when the individual without knowing the stimulation would be and this process would not produce cognition (Williams & Rhudy, 2007). In this model, the perception of pain after psychological treatment largely depends on the learning history of the individual which determines the response variability under different context. The psychological conditioning as well as the verbal suggestion can turn tactile stimuli into pain and low-intensity pain into high-intensity pain. For this, the direct evidence was the conditioned pain reduction could be absolutely removed when the psychological stimuli were explained (Montgomery & Kirsch, 1997). Originally, conditioning is the primary response to psychological analgesia. Following conditioning, expectancy of the psychological stimuli to produce an effective analgesia takes place. Once the patients expect to have an improvement in pain management, the effect of psychological analgesia would play its role. Due to anxiety and fear to pain, patients generally want to have rapid and effective methods that can relieve their pain (Cornally & McCarthy, 2011; den Hollander et al., 2010; Kennedy et al., 2011), which consequently leads to an expectancy of their pain therapies. Under this condition, physicians' attitude and enthusiasm takes an important part in whether or not the psychological analgesia comes into play (Weintraub, 2005). Give patients the hope to conquer pain accompanying with a warmth care, the expected effect of psychological analgesia would be maximized. After expectancy, motivation of analgesia is another aspect in determining the effect of psychological interventions. If the patient desires for a relief of pain, the real analgesic role of psychological stimuli would be magnitude (Radat & Koleck, 2011). The motivation itself whether or not could predict the psychological effect on one type of pain needs to be explored at length, and could it be effective for

(positive) or psychological nocebo (negative) are derived from the traditional conceptions of placebo or nocebo. Although the key patterns of psychological therapy is on the basis of the linguistic console from physicians or investigators, psychological analgesia with series of

Psychological analgesia is a broad concept that includes all aspects referring to the psychological intervention. Hypnosis, music therapy, preoperative education, and linguistic suggestion all belong to psychological approaches in pain control (Hobson et al., 2006; Patterson et al., 2010; Sen et al., 2010; Wang et al., 2008). Whatever psychological methods used in analgesia, common neurophysiological mechanisms exist and different models

Functional magnetic resonance imaging (fMRI) verified an increase in neural activity during placebo associated psychological stimulation that is related to two major pain modulation mechanisms (Craggs et al., 2008): i) affective regulation which includes activation of the rostral anterior cingulate cortex, bilateral amygdala, and medial prefrontal cortex; and ii) higher cognitive regulation during which the posterior cingulate, pre-cuneus, rostral anterior cingulate cortex, perihippocampal gyrus, and the temporal lobes are activated. As the "gate theory" described that afferent inhibition blocks ascending signals from the periphery, psychological stimuli at the early period produce analgesic effect through a self-

Several models give an in-depth understanding of the psychological stimulation associated analgesia. Conditioning, expectancy, motivation, and emotion are four psychological mediators involving in the process of analgesia. Conditioning model says that the interventional effect presented when the individual without knowing the stimulation would be and this process would not produce cognition (Williams & Rhudy, 2007). In this model, the perception of pain after psychological treatment largely depends on the learning history of the individual which determines the response variability under different context. The psychological conditioning as well as the verbal suggestion can turn tactile stimuli into pain and low-intensity pain into high-intensity pain. For this, the direct evidence was the conditioned pain reduction could be absolutely removed when the psychological stimuli were explained (Montgomery & Kirsch, 1997). Originally, conditioning is the primary response to psychological analgesia. Following conditioning, expectancy of the psychological stimuli to produce an effective analgesia takes place. Once the patients expect to have an improvement in pain management, the effect of psychological analgesia would play its role. Due to anxiety and fear to pain, patients generally want to have rapid and effective methods that can relieve their pain (Cornally & McCarthy, 2011; den Hollander et al., 2010; Kennedy et al., 2011), which consequently leads to an expectancy of their pain therapies. Under this condition, physicians' attitude and enthusiasm takes an important part in whether or not the psychological analgesia comes into play (Weintraub, 2005). Give patients the hope to conquer pain accompanying with a warmth care, the expected effect of psychological analgesia would be maximized. After expectancy, motivation of analgesia is another aspect in determining the effect of psychological interventions. If the patient desires for a relief of pain, the real analgesic role of psychological stimuli would be magnitude (Radat & Koleck, 2011). The motivation itself whether or not could predict the psychological effect on one type of pain needs to be explored at length, and could it be effective for

strategies of psychology is the result of the above-mentioned placebo or nocebo.

**3. Mechanisms of psychological analgesia** 

reinforcing feedback mechanism (Vase et al., 2005).

explain its function.

different types of pain is also yet to be guaranteed. A body of literature has confirmed the role of emotions in pain perception and alleviation. Anxiety and stress are two main factors of emotion-associated psychological mediator. It is believed that anxiety is the cause of increased levels of pain, and reduction in anxiety produces analgesia (Luciano et al., 2011). Stress sometimes is related with increased levels of pain, but in some contexts, stress can produce analgesia (Donello et al., 2011; Wang et al., 2008). Therefore, the purpose of psychological suggestion in pain control is to alleviate patients' anxiety and stress, which in turn produces a feedback analgesia effect.

As described in the general model of the placebo-associated psychological analgesia, three consecutive stages exist when psychological treatment was given: the induction, psychophysiological mediation, and actualization (Goffaux et al., 2010). In the induction stage, three aspects compose the major contents including the introduction or initiation (therapeutic message; method of administration; follow-up and booster sessions; assessment of side effects), idiosyncratic variables (beliefs and values; personal history; innate predisposition) and therapeutic context (treatment objectives; therapeutic alliance; sociocultural factors). In the second stage, psychophysiological mediation composes of psychological and biological mechanisms. Psychological mechanisms include abovementioned conditioning, expectancy, motivation, and emotion, and the biological mechanisms include neurochemical mediators (endorphins, dopamine, and other neurotransmitters/neuromodulators) and neurophysiology (activation of central modulatory mechanisms including descending inhibitory circuits). In the actualization stage, three main aspects exist including subjective experience (pain, emotions, quality of life, satisfaction, and related relief), behavioral markers (amount of analgesics consumed and overt pain behaviors), and physiological markers (physiological nociceptive activity, objective clinical indicators). As thus, when a psychological intervention is given, these three stages would be experienced. However, in consideration of the multiple phases of these stages, the actual effect of psychological analgesia may be variable in different individuals under different circumstances.

#### **4. Efficacy of psychological analgesia**

The analgesic effect of psychological approaches depends on types of pain, individual status, caregivers' attitude and contextual frame, which finally determines the efficacy of psychological analgesia. For postoperative pain, preoperative hypnosis could accelerate wound healing and alleviate pain intensity after mammoplasty (Ginandes et al., 2003), and reduce post-surgical pain and distress in patients undergone excisional breast biopsy (Schnur et al., 2008). However, in other surgical contexts, psychological interventions did not produce detectable difference compared with the control: relaxation training for spinal surgeries could not reduce postoperative pain (Gavin et al., 2006), and intraoperative music therapy also could not produce analgesia in Cesarean patients (Reza et al., 2007). Contrary to this, postoperative music can alleviate the pain and reduce the need for analgesics in patients who undergone Cesarean section (Ebneshahidi & Mohseni, 2008). Besides, in cardiac surgeries, music therapy produced effective role in alleviating anxiety and pain (Sendelbach et al., 2006). These different even controversial results raise questions on the real analgesia efficacy of psychological interventions. In fact, difference in interventional methods, types of surgeries, and professionals of investigators may all contribute to the changeable results of psychological analgesia. An attractive study performed to observe the

Psychological Strategies in Pain Management: Optimizing Procedures in Clinics 463

Individual expectancy status is the second factor that needs to be standardized. Every one expects to have an effective method that can conquer the pain because of the unpleasant experience. Once a patient has such a hope, the psychological analgesia would play its role. However the psychological complexity makes people doubt the real efficacy of the analgesia. Therefore, give a timely psychological intervention along with patients' expectancy is the best way for analgesia through matching their different time windows. Under this condition, careful assessment of patients' psychological status with proper means would give physicians more information on what, how and when a psychological stimulation could be employed. In fact, psychological intervention if given appropriately at this moment exactly fills patients' psychological gap. If want take effective steps to control the pain, time communication with patients is the guarantee. So, the following flow is recommended: talk to confirm the expectancy → predisposition for psychological

intervention → psychological preparation → increase confidence of conquering.

with psychological approaches.

psychological procedures even at different clinics.

performance.

Therapeutic context is the environment where the patients go and seek for pain management. Whether clinics could provide proper and humanistic care or not determines the final conclusion of psychological analgesia. Due to big difference in the contextual background, it is hard to standardize the consulting environment. Here just give a proposal that should at least be followed when administering psychological interventions for pain control: i) avoiding negative stimuli; ii) establishing a warm setting; iii) patient-centered communication; iv) one-stop services. A trusting relationship between medical environment and patients could pave the way to a successful analgesia

Professional level of physician is the "software" that needs to be updated step by step and improved gradually with practice. Of course, personal morality is another crucial part that can give patients the "be-taken-seriously" feeling. Further, if the physician trained in psychological treatment, such professional knowledge in psychology would make the psychological analgesia more effective, and would produce the best efficacy in alleviating pain. This section, in fact, is the easiest one that can be improved after training and practice. Following is the suggestion on how to get better results in psychological analgesia: i) take patients' claim into heart; ii) build friend relationship with patients; iii) serve with the best professional knowledge; iv) psycho-language communication; v) unchangeable attitude and

The changing window of man's mind is wide, and it is so easy to change when each abovementioned part cannot satisfy the expectancy. Besides, the prone-to-be-broken psychological state would be shattered by improper intervention. Therefore, patients with different types of pain have various expectancy of analgesia that needs to be treated with optimal

When performing psychological analgesia, following three-step procedure should be referred to. First step, induction: i) communicate without hint of psychological intervention; ii) confirm patient's psychological state; iii) predict patient's expectancy; iv) increase confidence that is bound to succeed. After this, the next step should be followed without interruption, i.e. performance: i) select a relatively quiet environment; ii) build a kind talking ambient; iii) give personalized linguistic intervention; iv) choose an interesting topic; v) talk without constraint; vi) observe psychological change during talking; vii) fine regulation in communication strategies. Following these procedures, the whole process of psychological intervention needs to be finalized, namely completion: i) conclude what have been talked; ii) thank patient's patience; iii) assess pain intensity with appropriate tools. Application of

influence of linguistic suggestion on postoperative pain management after abdominal surgeries, and found that negative words from nursing professionals results in therapeutic failure of patient-controlled analgesia, and suggested that a trusting psychological relationship between medical caregivers and patients should be established (Wang et al., 2008). Therefore, it is necessary to seek a standardized effective psychological method that can be employed at any time to alleviate pain and pain-associated psychological contributors.

Chronic pain, due to its multi-original property and hypo-responsiveness to traditional analgesics, is a complex pathological condition that needs to be cared with specific concentration. How to predict psychological problems in patients with chronic pain and then to take steps to overcome them plays pivotal role in alleviating this kind of pain. Modified Somatic Perception, Zung Questionnaires and Catastrophizing Scale are major means in predicting possible psychological factors in patients with chronic pain (Mannion et al., 1996; Meyer et al., 2008). These tools can help to identify psychological problems at early period that is crucial for understanding the development of acute pain into chronic and also possibly preventing its chronicity. Several studies considered psychological factors are contributors to patients' chronicity, but others did not find such a relationship (Roth et al., 2011a; Roth et al., 2011b; Roth et al., 2011c; Wallin et al., 2011; Xu et al., 2011). Various results in different studies questioned the real analgesic effect of psychological approaches in chronic pain management. Also, seek an optimized psychological procedure in chronic pain management is necessary for pain physicians.

#### **5. Optimizing psychological analgesic procedure**

Difference in methods of psychological interventions makes it difficult to reach a standardized uniform procedure that could be used for each individual at different pathological conditions. No matter what kind of methods employed, following four aspects are constant and also can be the interventional entry points: types of pain, individual expectancy status, therapeutic context, and professional level of physicians. Therefore, standardized psychological approach in analgesia should be based on these four factors. Besides, an optimized interventional flow of psychological analgesia from induction to performance to completion also will be standardized.

How to standardize the types of pain is so difficult because of its property of multiple originalities plus difference in its duration, intensity and responsiveness to pharmacological analgesics. To have a clear description and avoid an extra complexity of the standardization of the psychological procedure in the types of pain, here two major types of pain, acute and chronic, are discussed. First, acute pain is relatively easier to treat and generally resulted from traceable causes. So herein the acute pain is standardized on the basis of postoperative pain: surgical procedures → tissue injury → afferent fibers activation → dorsal root ganglion → spinal cord dorsal horn → ascending modulatory tracts → hypothalamus → cerebral cortex. However, chronic pain is refractory to pharmacological treatments and without assured causes. Here the standardization is based on chronic low back pain: regional chronic injury → persistent activation of peripheral fibers → spinal sensitization → reduction in pain threshold → activation of multiple brain regions. Although acute pain and chronic pain have different transduction pathways, they finally reach brain and then the perception is occur. This is the basis of the standardization when it is treated with psychological approaches.

influence of linguistic suggestion on postoperative pain management after abdominal surgeries, and found that negative words from nursing professionals results in therapeutic failure of patient-controlled analgesia, and suggested that a trusting psychological relationship between medical caregivers and patients should be established (Wang et al., 2008). Therefore, it is necessary to seek a standardized effective psychological method that can be employed at any time to alleviate pain and pain-associated psychological

Chronic pain, due to its multi-original property and hypo-responsiveness to traditional analgesics, is a complex pathological condition that needs to be cared with specific concentration. How to predict psychological problems in patients with chronic pain and then to take steps to overcome them plays pivotal role in alleviating this kind of pain. Modified Somatic Perception, Zung Questionnaires and Catastrophizing Scale are major means in predicting possible psychological factors in patients with chronic pain (Mannion et al., 1996; Meyer et al., 2008). These tools can help to identify psychological problems at early period that is crucial for understanding the development of acute pain into chronic and also possibly preventing its chronicity. Several studies considered psychological factors are contributors to patients' chronicity, but others did not find such a relationship (Roth et al., 2011a; Roth et al., 2011b; Roth et al., 2011c; Wallin et al., 2011; Xu et al., 2011). Various results in different studies questioned the real analgesic effect of psychological approaches in chronic pain management. Also, seek an optimized psychological procedure in chronic pain

Difference in methods of psychological interventions makes it difficult to reach a standardized uniform procedure that could be used for each individual at different pathological conditions. No matter what kind of methods employed, following four aspects are constant and also can be the interventional entry points: types of pain, individual expectancy status, therapeutic context, and professional level of physicians. Therefore, standardized psychological approach in analgesia should be based on these four factors. Besides, an optimized interventional flow of psychological analgesia from induction to

How to standardize the types of pain is so difficult because of its property of multiple originalities plus difference in its duration, intensity and responsiveness to pharmacological analgesics. To have a clear description and avoid an extra complexity of the standardization of the psychological procedure in the types of pain, here two major types of pain, acute and chronic, are discussed. First, acute pain is relatively easier to treat and generally resulted from traceable causes. So herein the acute pain is standardized on the basis of postoperative pain: surgical procedures → tissue injury → afferent fibers activation → dorsal root ganglion → spinal cord dorsal horn → ascending modulatory tracts → hypothalamus → cerebral cortex. However, chronic pain is refractory to pharmacological treatments and without assured causes. Here the standardization is based on chronic low back pain: regional chronic injury → persistent activation of peripheral fibers → spinal sensitization → reduction in pain threshold → activation of multiple brain regions. Although acute pain and chronic pain have different transduction pathways, they finally reach brain and then the perception is occur. This is the basis of the standardization when it is treated with psychological

contributors.

approaches.

management is necessary for pain physicians.

**5. Optimizing psychological analgesic procedure** 

performance to completion also will be standardized.

Individual expectancy status is the second factor that needs to be standardized. Every one expects to have an effective method that can conquer the pain because of the unpleasant experience. Once a patient has such a hope, the psychological analgesia would play its role. However the psychological complexity makes people doubt the real efficacy of the analgesia. Therefore, give a timely psychological intervention along with patients' expectancy is the best way for analgesia through matching their different time windows. Under this condition, careful assessment of patients' psychological status with proper means would give physicians more information on what, how and when a psychological stimulation could be employed. In fact, psychological intervention if given appropriately at this moment exactly fills patients' psychological gap. If want take effective steps to control the pain, time communication with patients is the guarantee. So, the following flow is recommended: talk to confirm the expectancy → predisposition for psychological intervention → psychological preparation → increase confidence of conquering.

Therapeutic context is the environment where the patients go and seek for pain management. Whether clinics could provide proper and humanistic care or not determines the final conclusion of psychological analgesia. Due to big difference in the contextual background, it is hard to standardize the consulting environment. Here just give a proposal that should at least be followed when administering psychological interventions for pain control: i) avoiding negative stimuli; ii) establishing a warm setting; iii) patient-centered communication; iv) one-stop services. A trusting relationship between medical environment and patients could pave the way to a successful analgesia with psychological approaches.

Professional level of physician is the "software" that needs to be updated step by step and improved gradually with practice. Of course, personal morality is another crucial part that can give patients the "be-taken-seriously" feeling. Further, if the physician trained in psychological treatment, such professional knowledge in psychology would make the psychological analgesia more effective, and would produce the best efficacy in alleviating pain. This section, in fact, is the easiest one that can be improved after training and practice. Following is the suggestion on how to get better results in psychological analgesia: i) take patients' claim into heart; ii) build friend relationship with patients; iii) serve with the best professional knowledge; iv) psycho-language communication; v) unchangeable attitude and performance.

The changing window of man's mind is wide, and it is so easy to change when each abovementioned part cannot satisfy the expectancy. Besides, the prone-to-be-broken psychological state would be shattered by improper intervention. Therefore, patients with different types of pain have various expectancy of analgesia that needs to be treated with optimal psychological procedures even at different clinics.

When performing psychological analgesia, following three-step procedure should be referred to. First step, induction: i) communicate without hint of psychological intervention; ii) confirm patient's psychological state; iii) predict patient's expectancy; iv) increase confidence that is bound to succeed. After this, the next step should be followed without interruption, i.e. performance: i) select a relatively quiet environment; ii) build a kind talking ambient; iii) give personalized linguistic intervention; iv) choose an interesting topic; v) talk without constraint; vi) observe psychological change during talking; vii) fine regulation in communication strategies. Following these procedures, the whole process of psychological intervention needs to be finalized, namely completion: i) conclude what have been talked; ii) thank patient's patience; iii) assess pain intensity with appropriate tools. Application of

Psychological Strategies in Pain Management: Optimizing Procedures in Clinics 465

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psychological linguistic suggestion should not be similar for one person at different visits, and the communicating environment should be changed time after time. The schematic flow of psychological intervention is presented in the Figure 1.

Fig. 1. Schematic flow of psychological analgesia.

#### **6. Concluding remarks**

Psychological activity is a complex emotional response that can be influenced by many factors. Psychological analgesia itself, however, is so complex that its efficacy is uncertain for different types of pain at different conditions. Therefore, how to select interventional methods and how to perform them for different patients with various psychological states is a thorny problem. Although here the optimized procedure of psychological analgesia is presented, it is necessary to be changed for different patients under different contextual conditions. Also this recommendation should favor the improvement of psychological intervention in pain management in future work.

#### **7. References**


psychological linguistic suggestion should not be similar for one person at different visits, and the communicating environment should be changed time after time. The schematic flow

Psychological activity is a complex emotional response that can be influenced by many factors. Psychological analgesia itself, however, is so complex that its efficacy is uncertain for different types of pain at different conditions. Therefore, how to select interventional methods and how to perform them for different patients with various psychological states is a thorny problem. Although here the optimized procedure of psychological analgesia is presented, it is necessary to be changed for different patients under different contextual conditions. Also this recommendation should favor the improvement of psychological

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Craggs, J.G.; Price, D.D.; Perlstein, W.M.; Verne, G.N. & Robinson, M.E. (2008) The dynamic

mechanisms of placebo induced analgesia: Evidence of sustained and transient

of psychological intervention is presented in the Figure 1.

Fig. 1. Schematic flow of psychological analgesia.

intervention in pain management in future work.

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regional involvement. *Pain* 139(3): 660-669.

**6. Concluding remarks** 

**7. References** 


**Part 5** 

**Cancer Pain** 


**Part 5** 

**Cancer Pain** 

466 Pain Management – Current Issues and Opinions

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excisional breast biopsy patients. *Anesth Analg* 106(2): 440-444.

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Negative words on surgical wards result in therapeutic failure of patient-controlled analgesia and further release of cortisol after abdominal surgeries. *Minerva* 

**22** 

 *India* 

**Radiation Mucositis** 

*Department of Oral Medicine and Radiology, Government Dental College, Trivandrum, Kerala* 

Mucosal injury remains an undesirable, painful, and expensive side effect of cytotoxic cancer therapy and is disheartening for patients and frustrating for caregivers.[1,2] Mucositis and associated outcomes in patients receiving radiotherapy (RT) for head and neck cancer shows that the mean incidence was 80%.[3] Rates of hospitalization due to mucositis are reported to be 16% overall and 32% for RT-AF (altered fraction radio therapy) patients.[3 Patients in the high risk of developing oral mucositis group fall into the head and neck

Oral mucositis is a distressing toxic effect of chemotherapy and radiotherapy. It can increase the need for total parenteral nutrition and opioids analgesics, prolong hospital stays, increase the risk of infection, and greatly affect the patient's quality of life [4]. All patients treated with high-dose chemotherapy requiring hematopoietic stem cell or bone marrow transplantation develop oral mucositis of varying severity. In addition, up to 80% of patients receiving radiotherapy for head or neck tumours and almost 90% of pediatric patients

Radiation induced mucositis is initiated by direct injury to basal epithelial cells and cells in the underlying tissue. DNA-strand breaks can result in cell death or injury. Non-DNA injury is initiated through a variety of mechanisms, some of which are mediated by the generation of reactive oxygen species. Radiation and chemotherapy are effective activators of several injury-producing pathways in endothelia, fibroblasts, and epithelia. In these cells, the activation of transcription factors such as nuclear factor-κB (NF-κB) and NRF-2 leads to the upregulation of genes that modulate the damage response. Immune cells (macrophages) produce pro-inflammatory cytokines, such as tumor-necrosis factor-α (TNF-α) and interleukin-6, which causes further tissue injury.[7] These signaling molecules also participate in a positive-feedback loop that amplifies the original effects of radiation and chemotherapy. For example, TNF-α activates NF-κB and sphingomyelinase activity in the mucosa, leading to more cell death. In addition, direct and indirect damages to epithelial stem cells result in a loss of renewal capacity. As a result, the epithelium begins to thin and

cancer population where the incidence of mucositis is high in this group.[3]

treated for cancer also develop oral mucositis[5,6]

patients start to experience the early symptoms of mucositis.[8]

**2. Mechanism of development** 

**1. Introduction** 

P. S. Satheesh Kumar

### **Radiation Mucositis**

#### P. S. Satheesh Kumar

*Department of Oral Medicine and Radiology, Government Dental College, Trivandrum, Kerala India* 

#### **1. Introduction**

Mucosal injury remains an undesirable, painful, and expensive side effect of cytotoxic cancer therapy and is disheartening for patients and frustrating for caregivers.[1,2] Mucositis and associated outcomes in patients receiving radiotherapy (RT) for head and neck cancer shows that the mean incidence was 80%.[3] Rates of hospitalization due to mucositis are reported to be 16% overall and 32% for RT-AF (altered fraction radio therapy) patients.[3 Patients in the high risk of developing oral mucositis group fall into the head and neck cancer population where the incidence of mucositis is high in this group.[3]

Oral mucositis is a distressing toxic effect of chemotherapy and radiotherapy. It can increase the need for total parenteral nutrition and opioids analgesics, prolong hospital stays, increase the risk of infection, and greatly affect the patient's quality of life [4]. All patients treated with high-dose chemotherapy requiring hematopoietic stem cell or bone marrow transplantation develop oral mucositis of varying severity. In addition, up to 80% of patients receiving radiotherapy for head or neck tumours and almost 90% of pediatric patients treated for cancer also develop oral mucositis[5,6]

#### **2. Mechanism of development**

Radiation induced mucositis is initiated by direct injury to basal epithelial cells and cells in the underlying tissue. DNA-strand breaks can result in cell death or injury. Non-DNA injury is initiated through a variety of mechanisms, some of which are mediated by the generation of reactive oxygen species. Radiation and chemotherapy are effective activators of several injury-producing pathways in endothelia, fibroblasts, and epithelia. In these cells, the activation of transcription factors such as nuclear factor-κB (NF-κB) and NRF-2 leads to the upregulation of genes that modulate the damage response. Immune cells (macrophages) produce pro-inflammatory cytokines, such as tumor-necrosis factor-α (TNF-α) and interleukin-6, which causes further tissue injury.[7] These signaling molecules also participate in a positive-feedback loop that amplifies the original effects of radiation and chemotherapy. For example, TNF-α activates NF-κB and sphingomyelinase activity in the mucosa, leading to more cell death. In addition, direct and indirect damages to epithelial stem cells result in a loss of renewal capacity. As a result, the epithelium begins to thin and patients start to experience the early symptoms of mucositis.[8]

Radiation Mucositis 471

Clinically, mucositis presents with multiple complex symptoms. It begins with a symptomatic redness and erythema and progresses through solitary white elevated desquamative patches that are slightly painful to contact pressure. Following this, large, painful contiguous pseudo membranous lesions develop with associated dysphagia and decreased oral intake. The nonkeratinized mucosa is the most affected one. The most common sites include the labial, buccal, and soft palate mucosa, as well as, the floor of the mouth and the ventral surface of the tongue. Oral lesions usually heal within two to three

**3. Clinical presentation**

Fig. 1. Oral mucositis in a patient.

weeks [Figure 1].

An oropharyngeal epithelial surface has a rapid rate of cell turnover and appears to be at high risk of injury from ionizing radiation. A healthy oral mucosa serves to clear microorganism and provides a chemical barrier that limits penetration of many compounds into the epithelium. A damaged mucosal surface increases the risk of a secondary infection. Acute mucositis results from the loss of squamous epithelial cells owing to the sterilization of mucosal stem cells and the inhibition of transit cell proliferation. This leads to a gradual linear decrease in epithelial cell numbers. Normally, cells of the mouth undergo rapid renewal over a 7–14 day cycle. Radiation therapy interferes with cellular mitosis and reduces the ability of the oral mucosa to regenerate. [9]

As radiation therapy continues, a steady state between mucosal cell death and regeneration may occur because of an increased cell production rate from the surviving cells. Usually, however, cell regeneration cannot keep up with cell death, and therefore, partial or complete denudation develops. This presents as patchy or confluent mucositis. As the mucositis becomes more severe, pseudomembranes and ulceration develops. Poor nutritional status further interferes with mucosal regeneration by decreasing cellular migration and renewal. The loss of the epithelial barrier enhances insults from physical, chemical, and microbial agents.

Stages of mode l[10] for the pathogenesis of mucositis are based on the evidence available to date:


A number of authors have reported that the oropharyngeal flora may contribute to radiation-induced mucositis. In health, the oral mucosa has a number of distinct habitats which are colonized by micro-organism that are able to establish a homeostatic community.[12] These homeostatic microbial communities are protective for the host by preventing or interfering with the colonization of exogenous pathogens; this potent defense mechanism is called "colonization resistance". When the oral tissues are irradiated, the colonization resistance is practically abolished. Irradiation mucositis is caused by a combination of alteration of the normal oral microflora with concomitant changes in the tissues. However, healing eventually occurs when cells regenerate from the surviving mucosal stem cells.

An oropharyngeal epithelial surface has a rapid rate of cell turnover and appears to be at high risk of injury from ionizing radiation. A healthy oral mucosa serves to clear microorganism and provides a chemical barrier that limits penetration of many compounds into the epithelium. A damaged mucosal surface increases the risk of a secondary infection. Acute mucositis results from the loss of squamous epithelial cells owing to the sterilization of mucosal stem cells and the inhibition of transit cell proliferation. This leads to a gradual linear decrease in epithelial cell numbers. Normally, cells of the mouth undergo rapid renewal over a 7–14 day cycle. Radiation therapy interferes with cellular mitosis and

As radiation therapy continues, a steady state between mucosal cell death and regeneration may occur because of an increased cell production rate from the surviving cells. Usually, however, cell regeneration cannot keep up with cell death, and therefore, partial or complete denudation develops. This presents as patchy or confluent mucositis. As the mucositis becomes more severe, pseudomembranes and ulceration develops. Poor nutritional status further interferes with mucosal regeneration by decreasing cellular migration and renewal. The loss of the epithelial barrier enhances insults from physical, chemical, and microbial

Stages of mode l[10] for the pathogenesis of mucositis are based on the evidence available to

1. **Initiation of tissue injury:** Radiation and/or chemotherapy induce cellular damage resulting in death of the basal epithelial cells. The generation of reactive oxygen species (free radicals) by radiation or chemotherapy is also believed to exert a role in the initiation of mucosal injury. These small highly reactive molecules are by-products of

2. **Up-regulation of inflammation via generation of messenger signals:** In addition to causing direct cell death, free radicals activate second messengers that transmit signals from receptors on the cellular surface to the inside of cell. This leads to up-regulation of

3. **Signaling and amplification:** Up-regulation of pro-inflammatory cytokines, such as TNF-a, produced mainly by macrophages, causes injury to mucosal cells, and also

4. **Ulceration and inflammation:** There is a significant inflammatory cell infiltrate associated with the mucosal ulcerations, based in part on metabolic by-products of the colonizing oral microflora. Production of pro-inflammatory cytokines is also further up-

5. **Healing:** This phase is characterized by epithelial proliferation, as well as, cellular and

A number of authors have reported that the oropharyngeal flora may contribute to radiation-induced mucositis. In health, the oral mucosa has a number of distinct habitats which are colonized by micro-organism that are able to establish a homeostatic community.[12] These homeostatic microbial communities are protective for the host by preventing or interfering with the colonization of exogenous pathogens; this potent defense mechanism is called "colonization resistance". When the oral tissues are irradiated, the colonization resistance is practically abolished. Irradiation mucositis is caused by a combination of alteration of the normal oral microflora with concomitant changes in the tissues. However, healing eventually occurs when cells regenerate from the surviving

oxygen metabolism and can cause significant cellular damage.

pro-inflammatory cytokines, tissue injury, and cell death.

activates molecular pathways that amplify mucosal injury.

tissue differentiation,[11] restoring the integrity of the epithelium.

regulated as a result of this secondary infection.[10]

reduces the ability of the oral mucosa to regenerate. [9]

agents.

date:

mucosal stem cells.

### **3. Clinical presentation**

Clinically, mucositis presents with multiple complex symptoms. It begins with a symptomatic redness and erythema and progresses through solitary white elevated desquamative patches that are slightly painful to contact pressure. Following this, large, painful contiguous pseudo membranous lesions develop with associated dysphagia and decreased oral intake. The nonkeratinized mucosa is the most affected one. The most common sites include the labial, buccal, and soft palate mucosa, as well as, the floor of the mouth and the ventral surface of the tongue. Oral lesions usually heal within two to three weeks [Figure 1].

Fig. 1. Oral mucositis in a patient.

Radiation Mucositis 473

stastitically significant differences in mucositis; however, the sucralfate group reported less oral pain, and other topical and systemic analgesics were started later in the course of radiation [20]. A prospective double-blind study compared the effectiveness of sucralfate suspension versus diphenhydramine syrup plus kaolin-pectin on radiotherapy-induced mucositis. Data were collected daily, including perceived pain, helpfulness of mouth rinses, weekly mucositis grade, weight change, and interruption of therapy. Analysis of the two groups revealed no statistically significant differences between the two groups. In a retrospective review, 15 patients who had not used daily oral rinses were compared with the two groups, and the results suggested that the use of a daily oral rinse with a mouth-coating agent may result in less pain, reduce weight loss, and help prevent interruption of radiation

because of severe mucositis[21].

Fig. 2. Oral mucositis in a patient.

Mucositis is an inevitable side effect of radiation. Its severity is dependent on the type of ionizing radiation, the volume of irradiated tissue, the dose per day, and cumulative dose. It has been noted in a considerable number of clinical trials that the severity of acute normal tissue responses, particularly oral mucositis, is significantly increased when the overall treatment time is shortened.[12,13] The clinical course of oral mucositis may sometimes be complicated by local infection, particularly in immunosuppressed patients. Viral infections such as herpes simplex virus (HSV), and fungal infections such as candidiasis can sometimes be superimposed on oral mucositis. Although HSV infections do not cause oral mucositis, they can complicate its diagnosis and management.

Histopathologically, edema of the retepegs is noted, along with vascular changes that demonstrate a thickening of the tunica intima with concomitant reduction in the lumen size and destruction of the elastic and muscle fibers of the vessel walls. The loss of the epithelial cells to the basement membrane exposes the underlying connective tissue stroma with its associated innervations, which, as the mucosal lesions enlarge, contributes to increasing pain. If the patient develops both severe mucositis and thrombocytopenia, oral bleeding may occur, which is very difficult to treat.

#### **4. Clinical management of oral mucositis**

Management of oral mucositis can be divided into the following sections: pain control, nutritional support, oral decontamination, palliation of dry mouth, management of oral bleeding, and therapeutic interventions for oral mucositis.

#### **4.1 Pain control**

The most common symptom of oral mucositis is pain. Pain significantly affects the nutritional intake, the mouth care, and the quality of life. Thus, management of mucositis pain is a primary component of any mucositis management strategy. Many centers use saline mouth rinses, ice chips, and topical mouth rinses containing an anesthetic, such as 2% viscous lidocaine, which may be mixed with equal volumes of diphenhydramine and a soothing covering agent in equal volumes. Such topical anesthetic agents may provide short-term relief. Sucralfate is the most commonly used and widely studied, even though there is no significant decrease in the pain control.[14,15] In addition to the use of topical agents, most patients with severe mucositis require systemic analgesics, often including opioids, for satisfactory pain relief. Though, the so called '*magic mouthwash*' (lidocaine, diphenhydramine, magnesium aluminum hydroxide) has been observed to be beneficial, morphine mouth washes are preferable.[16,17] It was significantly better at reducing intensity and duration of pain and functional impairment, with fewer adverse effects.

#### **4.1.1 Sucralfate**

Sucralfate also has been tested in patients receiving radiation therapy. One study compared 21 patients who received standard oral care to the head and neck with 24 patients who received sucralfate suspension four times daily. Results revealed a significant difference in mucosal edema, pain, dysphagia, and weight loss in patients receiving sucralfate [18]. In a pilot study done by Pfeiffer et al. [19], sequential patients who received radiation therapy to the head and neck received sucralfate at the onset of mucositis. Most patients had a decrease in pain following the use of sucralfate. A double-blind, placebo-controlled study with sucralfate in 33 patients who received. irradiation to the head and neck reported no

Mucositis is an inevitable side effect of radiation. Its severity is dependent on the type of ionizing radiation, the volume of irradiated tissue, the dose per day, and cumulative dose. It has been noted in a considerable number of clinical trials that the severity of acute normal tissue responses, particularly oral mucositis, is significantly increased when the overall treatment time is shortened.[12,13] The clinical course of oral mucositis may sometimes be complicated by local infection, particularly in immunosuppressed patients. Viral infections such as herpes simplex virus (HSV), and fungal infections such as candidiasis can sometimes be superimposed on oral mucositis. Although HSV infections do not cause oral

Histopathologically, edema of the retepegs is noted, along with vascular changes that demonstrate a thickening of the tunica intima with concomitant reduction in the lumen size and destruction of the elastic and muscle fibers of the vessel walls. The loss of the epithelial cells to the basement membrane exposes the underlying connective tissue stroma with its associated innervations, which, as the mucosal lesions enlarge, contributes to increasing pain. If the patient develops both severe mucositis and thrombocytopenia, oral bleeding

Management of oral mucositis can be divided into the following sections: pain control, nutritional support, oral decontamination, palliation of dry mouth, management of oral

The most common symptom of oral mucositis is pain. Pain significantly affects the nutritional intake, the mouth care, and the quality of life. Thus, management of mucositis pain is a primary component of any mucositis management strategy. Many centers use saline mouth rinses, ice chips, and topical mouth rinses containing an anesthetic, such as 2% viscous lidocaine, which may be mixed with equal volumes of diphenhydramine and a soothing covering agent in equal volumes. Such topical anesthetic agents may provide short-term relief. Sucralfate is the most commonly used and widely studied, even though there is no significant decrease in the pain control.[14,15] In addition to the use of topical agents, most patients with severe mucositis require systemic analgesics, often including opioids, for satisfactory pain relief. Though, the so called '*magic mouthwash*' (lidocaine, diphenhydramine, magnesium aluminum hydroxide) has been observed to be beneficial, morphine mouth washes are preferable.[16,17] It was significantly better at reducing intensity

Sucralfate also has been tested in patients receiving radiation therapy. One study compared 21 patients who received standard oral care to the head and neck with 24 patients who received sucralfate suspension four times daily. Results revealed a significant difference in mucosal edema, pain, dysphagia, and weight loss in patients receiving sucralfate [18]. In a pilot study done by Pfeiffer et al. [19], sequential patients who received radiation therapy to the head and neck received sucralfate at the onset of mucositis. Most patients had a decrease in pain following the use of sucralfate. A double-blind, placebo-controlled study with sucralfate in 33 patients who received. irradiation to the head and neck reported no

and duration of pain and functional impairment, with fewer adverse effects.

mucositis, they can complicate its diagnosis and management.

may occur, which is very difficult to treat.

**4.1 Pain control** 

**4.1.1 Sucralfate** 

**4. Clinical management of oral mucositis** 

bleeding, and therapeutic interventions for oral mucositis.

stastitically significant differences in mucositis; however, the sucralfate group reported less oral pain, and other topical and systemic analgesics were started later in the course of radiation [20]. A prospective double-blind study compared the effectiveness of sucralfate suspension versus diphenhydramine syrup plus kaolin-pectin on radiotherapy-induced mucositis. Data were collected daily, including perceived pain, helpfulness of mouth rinses, weekly mucositis grade, weight change, and interruption of therapy. Analysis of the two groups revealed no statistically significant differences between the two groups. In a retrospective review, 15 patients who had not used daily oral rinses were compared with the two groups, and the results suggested that the use of a daily oral rinse with a mouth-coating agent may result in less pain, reduce weight loss, and help prevent interruption of radiation because of severe mucositis[21].

Fig. 2. Oral mucositis in a patient.

Radiation Mucositis 475

The RTOG and MASCC/ISOO (Mucositis study group of the multinational association for supportive care in cancer and the International society of oral oncology) guidelines recommend use of a standardized oral care protocol, including brushing with a soft toothbrush, flossing, and the use of nonmedicated rinses (for example, saline or sodium bicarbonate rinses). Patients and caregivers should be educated regarding the importance of

In cancer therapy, patients often develop transient or permanent xerostomia and hyposalivation. Hyposalivation can further aggravate inflamed tissues, increase risk for local infection, and make mastication difficult. Many patients also complain of a thickening of salivary secretions, because of a decrease in the serous component of saliva. The

Sip water as needed to alleviate mouth dryness; several supportive products including

 Rinse with a solution of half a teaspoon of baking soda half in one cup warm water several times a day to clean and lubricate the oral tissues and to buffer the oral

Kaolin pectin, combined with diphenhydramine, which is a H1-histamine antagonist and local anesthetic, was found to reduce oral pain without reducing the degree of mucositis in a

One of the problem faced by the therapy is the loss of proliferation of the oral epithelial cells, it has seen that various growth factors that can increase epithelial cell proliferation have been studied for the management of oral mucositis. Recent evidence shows that intravenous recombinant human keratinocyte growth factor-1, Palifermin, significantly reduced incidence of WHO grades 3 and 4 oral mucositis in patients with hematologic malignancies (for example, lymphoma and multiple myeloma) receiving high-dose chemotherapy and total body

Human keratinocyte growth factor-2, Repifermin, was found to be ineffective in reducing the percentage of subjects who experienced severe mucositis.[29] Intravenous human fibroblast growth factor-20, Velafermin, is currently in clinical development for reduction of mucositis secondary to high-dose chemotherapy in autologous hematopoietic cell transplant patients.[30] The safety of this class of growth factors has not been established in patients with nonhematologic malignancies. There is a theoretical concern that these growth factors may promote growth of tumor cells, which may have receptors for the respective growth factor. However, one recent study found no significant difference in survival between subjects with colorectal cancer receiving Palifermin or placebo at a median follow-up duration of 14.5 months.[31] Further studies are ongoing to confirm the safety of epithelial growth factors in the solid tumor setting, including patients receiving radiation therapy for

following measures can be taken for palliation of a dry mouth:

Chew sugarless gum to stimulate salivary flow.

double blind randomized and controlled study.[27]

irradiation before autologous hematopoietic cell transplantation.[28]

effective oral hygiene [26, 52, 53].

**4.5 Palliation of dry mouth** 

environment.

**4.6 Kaolin pectin** 

**5. Growth factors** 

head and neck cancer.

artificial saliva are available.

Use cholinergic agents as necessary.

#### **4.1.2 Morphine in pain control**

In a study to compare the effect of locally applied morphine mouthwash(MO) with Magic mouth wash (MG) on mucositis-related oral pain and on the maintenance of oral intake in patients with tumors of the head and neck area treated with a chemoradiotherapy regimen51. Additional objectives were to evaluate the safety of MO by determining the frequency of treatment-emergent drug-related adverse events (local and systemic) or hematologic and biochemical abnormalities, the intensity of chemoradiotherapy administered, tumor response, weight loss, need of a nasogastric tube, and mucositis-related hospitalizations. The duration of severe pain was 3.5 days less in the Morphine group compared with the Magic mouth wash group (*P* \_ 0.032). The intensity of oral pain was also significantly lower in the MO group compared with the MG group .More patients in the MG group needed supplementary (oral or parenteral) analgesia compared with the MO group (*P* \_ 0.019). Nevertheless, the time elapsed before the first supplemental analgesic and the total amount of analgesics taken was similar for both groups. Of 12 patients in the MG group, 3 (25%) and none in the MO group required third-step opiates for alleviation of mouth pain. However, the differences in the maximum WHO step needed for control of pain were not statistically significant. There was a significant difference in duration of severe functional impairment. Nevertheless, the body weight change was similar for both groups. There were no significant differences in documented or highly suspected infections, change in performance status, tumor response rate, and intensity of the chemoradiotherapy delivered between the two treatment groups. No patients required hospitalization due to mucositis during the study. Patients in the MG group reported more local side effects [51].

#### **4.2 Nutritional support**

A soft diet or liquid diet was more easily tolerated than a normal diet, when oral mucositis is present; gastrostomy tube is more beneficial, when there is severe mucositis.

#### **4.3 Selective oral decontamination**

It has been hypothesized that microbial colonization of oral mucositis lesions exacerbates the severity of oral mucositis and, therefore, decontamination may help to reduce mucositis. Due to the fact that the oral cavity contains a high amount of Gram-negative bacilli and considering its etiological role in mucositis, the concept of 'Selective Decontamination' has been developed. In this regard, lozenges composed of polymyxin E, tobramycin, and amphotericin B have been studied in patients receiving radiation for cancers of head and neck in a randomized trial that compared lozenges with placebo or chlorhexidine rinses, the antimicrobial lozenges provided more effective mucositis prevention in patients receiving head and neck irradiation. Addition of ciprofloxacin or ampicillin with clotrimazole to Sucralfate has shown reduction in mucositis.[22]

#### **4.4 Oral hygiene**

Significant reduction in oral mucositis can be attained by proper oral hygiene measures.[23] It was noted that proper oral care also reduced oral toxicity of radiation therapy. Indeed, multiple studies have demonstrated that maintenance of good oral hygiene can reduce the severity of oral mucositis. Furthermore, oral decontamination can reduce infection of the oral cavity by opportunistic pathogens.[24] Therefore, a second function of oral decontamination can be to reduce the risk of systemic sepsis from resident oral and/or opportunistic pathogens. Intensive oral care protocol decreased risk of oral mucositis, but not the percentage of patients with a documented septicemia.[25]

In a study to compare the effect of locally applied morphine mouthwash(MO) with Magic mouth wash (MG) on mucositis-related oral pain and on the maintenance of oral intake in patients with tumors of the head and neck area treated with a chemoradiotherapy regimen51. Additional objectives were to evaluate the safety of MO by determining the frequency of treatment-emergent drug-related adverse events (local and systemic) or hematologic and biochemical abnormalities, the intensity of chemoradiotherapy administered, tumor response, weight loss, need of a nasogastric tube, and mucositis-related hospitalizations. The duration of severe pain was 3.5 days less in the Morphine group compared with the Magic mouth wash group (*P* \_ 0.032). The intensity of oral pain was also significantly lower in the MO group compared with the MG group .More patients in the MG group needed supplementary (oral or parenteral) analgesia compared with the MO group (*P* \_ 0.019). Nevertheless, the time elapsed before the first supplemental analgesic and the total amount of analgesics taken was similar for both groups. Of 12 patients in the MG group, 3 (25%) and none in the MO group required third-step opiates for alleviation of mouth pain. However, the differences in the maximum WHO step needed for control of pain were not statistically significant. There was a significant difference in duration of severe functional impairment. Nevertheless, the body weight change was similar for both groups. There were no significant differences in documented or highly suspected infections, change in performance status, tumor response rate, and intensity of the chemoradiotherapy delivered between the two treatment groups. No patients required hospitalization due to mucositis during the study. Patients in the MG group reported more local side effects [51].

A soft diet or liquid diet was more easily tolerated than a normal diet, when oral mucositis

It has been hypothesized that microbial colonization of oral mucositis lesions exacerbates the severity of oral mucositis and, therefore, decontamination may help to reduce mucositis. Due to the fact that the oral cavity contains a high amount of Gram-negative bacilli and considering its etiological role in mucositis, the concept of 'Selective Decontamination' has been developed. In this regard, lozenges composed of polymyxin E, tobramycin, and amphotericin B have been studied in patients receiving radiation for cancers of head and neck in a randomized trial that compared lozenges with placebo or chlorhexidine rinses, the antimicrobial lozenges provided more effective mucositis prevention in patients receiving head and neck irradiation. Addition of ciprofloxacin or ampicillin with clotrimazole to

Significant reduction in oral mucositis can be attained by proper oral hygiene measures.[23] It was noted that proper oral care also reduced oral toxicity of radiation therapy. Indeed, multiple studies have demonstrated that maintenance of good oral hygiene can reduce the severity of oral mucositis. Furthermore, oral decontamination can reduce infection of the oral cavity by opportunistic pathogens.[24] Therefore, a second function of oral decontamination can be to reduce the risk of systemic sepsis from resident oral and/or opportunistic pathogens. Intensive oral care protocol decreased risk of oral mucositis, but

is present; gastrostomy tube is more beneficial, when there is severe mucositis.

**4.1.2 Morphine in pain control** 

**4.2 Nutritional support** 

**4.4 Oral hygiene** 

**4.3 Selective oral decontamination** 

Sucralfate has shown reduction in mucositis.[22]

not the percentage of patients with a documented septicemia.[25]

The RTOG and MASCC/ISOO (Mucositis study group of the multinational association for supportive care in cancer and the International society of oral oncology) guidelines recommend use of a standardized oral care protocol, including brushing with a soft toothbrush, flossing, and the use of nonmedicated rinses (for example, saline or sodium bicarbonate rinses). Patients and caregivers should be educated regarding the importance of effective oral hygiene [26, 52, 53].

#### **4.5 Palliation of dry mouth**

In cancer therapy, patients often develop transient or permanent xerostomia and hyposalivation. Hyposalivation can further aggravate inflamed tissues, increase risk for local infection, and make mastication difficult. Many patients also complain of a thickening of salivary secretions, because of a decrease in the serous component of saliva. The following measures can be taken for palliation of a dry mouth:


#### **4.6 Kaolin pectin**

Kaolin pectin, combined with diphenhydramine, which is a H1-histamine antagonist and local anesthetic, was found to reduce oral pain without reducing the degree of mucositis in a double blind randomized and controlled study.[27]

#### **5. Growth factors**

One of the problem faced by the therapy is the loss of proliferation of the oral epithelial cells, it has seen that various growth factors that can increase epithelial cell proliferation have been studied for the management of oral mucositis. Recent evidence shows that intravenous recombinant human keratinocyte growth factor-1, Palifermin, significantly reduced incidence of WHO grades 3 and 4 oral mucositis in patients with hematologic malignancies (for example, lymphoma and multiple myeloma) receiving high-dose chemotherapy and total body irradiation before autologous hematopoietic cell transplantation.[28]

Human keratinocyte growth factor-2, Repifermin, was found to be ineffective in reducing the percentage of subjects who experienced severe mucositis.[29] Intravenous human fibroblast growth factor-20, Velafermin, is currently in clinical development for reduction of mucositis secondary to high-dose chemotherapy in autologous hematopoietic cell transplant patients.[30] The safety of this class of growth factors has not been established in patients with nonhematologic malignancies. There is a theoretical concern that these growth factors may promote growth of tumor cells, which may have receptors for the respective growth factor. However, one recent study found no significant difference in survival between subjects with colorectal cancer receiving Palifermin or placebo at a median follow-up duration of 14.5 months.[31] Further studies are ongoing to confirm the safety of epithelial growth factors in the solid tumor setting, including patients receiving radiation therapy for head and neck cancer.

Radiation Mucositis 477

increasing fibroblast and collagen synthesis.[36] In a Phase III study, this topical agent reduced the incidence of clinically significant chemotherapy-induced oral mucositis compared to placebo.[37] By comparison, the MASCC/ISOO guidelines recommend that systemically administered

It (phosphothiorate, radiation protection agent) is thought to act as a scavenger for harmful reactive oxygen species that are known to potentiate mucositis.[39] However, because of insufficient evidence of benefit, various guidelines could not be established regarding the use of this agent in oral mucositis in chemotherapy or radiation therapy patients. The use of amifostine has been recommended for the prevention of esophagitis in patients receiving

It consists of the antioxidant, *N-acetylcysteine*, in a proprietary matrix for topical application in the oral cavity. In a placebo-controlled phase II trial in patients with head and neck cancer, this agent significantly reduced the incidence of severe oral mucositis up to doses of

Beta carotene, a vitamin A derivative, is a scavenger of singlet oxygen. Based on the findings of different randomized controlled study, it is of the view that supplemental dietary betacarotene lead to a mild decrease in the severity of chemotherapy and radiotherapy-induced

Oral pentoxiphylline reduced the frequency and severity of all major complications after BMT, including reduction of oral mucositis.[43] Contradictory to this, other workers reported a significant aggravation of symptoms when they studied the effect of IV Pentoxiphylline in 92 patients.[44] However, no difference in symptoms was noted in patients who undergone

Indomethacin, a nonsteroidal antiinflammatory drug inhibiting prostaglandin synthesis is

Treatment with low-dose intra muscular immunoglobulin is said to decrease the severity and duration of radio therapy-induced oral mucositis. Immunoglobulin has also been tried as a therapeutic agent in radiation-induced mucositis in various clinical trials and the

Preclinical models have been used to demonstrate that the cytokines interleukin-1, interleukin-2, epidermal growth factor, interleukin-11, and transforming growth factor*-*beta

glutamine not be used for the prevention of GI mucositis because of lack of efficacy.[38]

**6.3 Amifostine** 

**6.4 RK- 0202 (RxKinetix)** 

50-Gy radiation therapy.[41]

**7. Immunomodulatory drugs** 

noted to delay the onset of mucositis.

observations were promising.[45]

**6.5 Beta carotene** 

oral mucositis.[42]

**7.1 Pentoxifylline** 

chemo radio therapy.

**7.3 Immunoglobulin** 

**7.4 Cytokines** 

**7.2 Indomethacin** 

chemoradiation for nonsmall-cell lung cancer.[40]


Table 1. Comparison of commonly used mucositis scoring system

#### **6. Anti-inflammatory agents**

#### **6.1 Benzydamine hydrochloride**

It is a nonsteroidal antiinflammatory drug that inhibits proinflammatory cytokines including TNF-a. In a Phase III trial, Benzydamine hydrochloride mouthrinse reduced the severity of mucositis in patients with head and neck cancer undergoing radiation therapy of cumulative doses up to 50-Gy radiation therapy.[32] Based on this and previous studies, the MASCC/ISOO guidelines recommends use of this agent in patients receiving moderatedose radiation therapy.[33]

#### **6.2 Saforis**

It is a proprietary oral suspension of L-glutamine that enhances the uptake of this amino acid into epithelial cells. Glutamine may reduce mucosal injury by reducing the production of proinflammatory cytokines and cytokine-related apoptosis;[34,35] and may promote healing by

Patchy mucositis may have a serosanguinous discharge. May experience pain requiring analgesics. < 1.5 cm, noncontiguous

erythema,oedema or ulcers, but can eat.

Significant dysphasia, semi soft foods only, focal mucosal vesicles or denuded patches.

Generalized erythema without pain or localized erythema or ulcers with mild pain.

without ulcerations

erythema,oedema,or ulcers, but can eat

Moderate erythema and ulcerations or white patches.pain, but can eat, drink and swallow.

It is a nonsteroidal antiinflammatory drug that inhibits proinflammatory cytokines including TNF-a. In a Phase III trial, Benzydamine hydrochloride mouthrinse reduced the severity of mucositis in patients with head and neck cancer undergoing radiation therapy of cumulative doses up to 50-Gy radiation therapy.[32] Based on this and previous studies, the MASCC/ISOO guidelines recommends use of this agent in patients receiving moderate-

It is a proprietary oral suspension of L-glutamine that enhances the uptake of this amino acid into epithelial cells. Glutamine may reduce mucosal injury by reducing the production of proinflammatory cytokines and cytokine-related apoptosis;[34,35] and may promote healing by

Painful

**Spijkervet** *et al*None White discoloration Erythema Pseudomembrane ulceration

50%

Type : severe erythematous area: 25-

**schueren** *et al*None Slight erythema Pronounced erythema Spotted mucositis Confluent mucositis

Ulcers; requires liquid

Confluent fibrinous mucositis/may include severe pain requiring narcotics, > 1.5 cm, contiguous

painful erythema, edema or ulcers can not

Fluids only tolerated, obviously large confluent patches of mucosal denudation

Multiple ulcers or generalized erythema with moderate pain

Ulceration with or

erythema,oedema,or ulcers, but can not eat

Type: spotted mucositis

severe erythema and ulcerations or white patches. Severe Pain and can not eat, drink or swallow.

Painful

area >50%

without bleeding -------

eat.

Alimentation not possible

Requires Parenteral or enteral support

Parenteral fluids only, severe confluent mucosal denudation with bleeding.

Generalized erythema or ulcers with moderate to severe pain.

Mucosal necrosis and/or requires Parenteral or

support,dehydration.

Type:confluent mucosistis

enteral


patches >0.5cm.

Necrosis or deep ulceration, ± bleeding .

diet only

**Source Grade 0 Grade 1 Grade 2 Grade 3 Grade 4** 

can eat solids

Painful

**WHO** No change Soreness/erythema Erythema,ulcers,

May experience mild pain not requiring analgesic

Painless ulcers, erythema or mild soreness

Minimal dysphasia, thinning but no overt break in mucosal integrity.

with no pain

**Eilers** *et al*----- Pink and moist Reddened or white film

Painless ulcers,erythema,or mild soreness.

Type: mild erythematous area:

Whitish gingival or slight burning sensation or discomfort.

Table 1. Comparison of commonly used mucositis scoring system

<25%

**RTOG** No change

**NCI CTC** None

**Byfield** *et al*---

**NCIC** None

**Maceijewski** None

**Hickey** *et al* No stomatitis

**6. Anti-inflammatory agents 6.1 Benzydamine hydrochloride** 

dose radiation therapy.[33]

**6.2 Saforis** 

**Van der** 

over baseline

**Seto** *et al*----- Localized erythema

increasing fibroblast and collagen synthesis.[36] In a Phase III study, this topical agent reduced the incidence of clinically significant chemotherapy-induced oral mucositis compared to placebo.[37] By comparison, the MASCC/ISOO guidelines recommend that systemically administered glutamine not be used for the prevention of GI mucositis because of lack of efficacy.[38]

#### **6.3 Amifostine**

It (phosphothiorate, radiation protection agent) is thought to act as a scavenger for harmful reactive oxygen species that are known to potentiate mucositis.[39] However, because of insufficient evidence of benefit, various guidelines could not be established regarding the use of this agent in oral mucositis in chemotherapy or radiation therapy patients. The use of amifostine has been recommended for the prevention of esophagitis in patients receiving chemoradiation for nonsmall-cell lung cancer.[40]

#### **6.4 RK- 0202 (RxKinetix)**

It consists of the antioxidant, *N-acetylcysteine*, in a proprietary matrix for topical application in the oral cavity. In a placebo-controlled phase II trial in patients with head and neck cancer, this agent significantly reduced the incidence of severe oral mucositis up to doses of 50-Gy radiation therapy.[41]

#### **6.5 Beta carotene**

Beta carotene, a vitamin A derivative, is a scavenger of singlet oxygen. Based on the findings of different randomized controlled study, it is of the view that supplemental dietary betacarotene lead to a mild decrease in the severity of chemotherapy and radiotherapy-induced oral mucositis.[42]

#### **7. Immunomodulatory drugs**

#### **7.1 Pentoxifylline**

Oral pentoxiphylline reduced the frequency and severity of all major complications after BMT, including reduction of oral mucositis.[43] Contradictory to this, other workers reported a significant aggravation of symptoms when they studied the effect of IV Pentoxiphylline in 92 patients.[44] However, no difference in symptoms was noted in patients who undergone chemo radio therapy.

#### **7.2 Indomethacin**

Indomethacin, a nonsteroidal antiinflammatory drug inhibiting prostaglandin synthesis is noted to delay the onset of mucositis.

#### **7.3 Immunoglobulin**

Treatment with low-dose intra muscular immunoglobulin is said to decrease the severity and duration of radio therapy-induced oral mucositis. Immunoglobulin has also been tried as a therapeutic agent in radiation-induced mucositis in various clinical trials and the observations were promising.[45]

#### **7.4 Cytokines**

Preclinical models have been used to demonstrate that the cytokines interleukin-1, interleukin-2, epidermal growth factor, interleukin-11, and transforming growth factor*-*beta

Radiation Mucositis 479

The mechanism of low-level laser therapy is not understood, but many studies have proved the efficacy of the same in reducing the symptoms related to oral mucositis. Low-level laser therapy may reduce levels of reactive oxygen species and/or proinflammatory cytokines that contribute to the pathogenesis of mucositis.[49] The various guidelines suggest the use of low-level laser therapy for reducing the severity of chemotherapy and radiotherapy-

A study on AMP18 (AMP-18 is a protein constitutively expressed in epithelial cells of the gastric antrum that is cell protective, mitogenic and motogenic in cell culture and in vivo) shows, AMP peptide, by activating CCKBR (cholecystokinin-B/gastrin receptor), targets TJs(Tight Junctions) to maintain mucosal integrity, and sets in motion protective and cell regenerative mechanisms for the prevention and treatment of OM. Treatment with AMP peptide protected the surface epithelium of the mouse oral mucosa. AMP-18 peptide

Mucositis is an inevitable side effect of radiation. The severity of the mucositis depends on the type of ionizing radiation, the volume of irradiated tissue, the daily dose, and the cumulative dose. As the mucositis becomes more severe, pseudomembranes and ulcerations develop. Poor nutritional status further interferes with mucosal regeneration by decreasing cellular migration and renewal. Radiation-induced oral mucositis affects the quality of life of the patients and the family concerned. The present day management of oral mucositis is mostly palliative and or supportive care. Management includes good oral hygiene, avoiding irritating or abrasive substances, use of bland rinses, topical anesthetic agents, and systemic analgesics. Though, the newer guidelines are suggesting Palifermin, which is the first active mucositis drug as well as Amifostine, for radiation protection and cryotherapy for symptoms related to high-dose melphalan; the role of safe radiotherapy remains the ultimate goal in reducing the symptoms of radiation-induced oral mucositis. Future research for the newer drugs in the field of radiation-induced oral mucositis is a must, and the current management should focus more on palliative measures, such as pain

[1] Sonis ST. Is mucositis an inevitable consequence of intensive therapy for hematologic

[2] Keefe DM. Mucositis guidelines: What have they achieved, and where to from here?

[3] Trotti A, Bellm LA, Epstein JB, Frame D, Fuchs HJ, Gwede CK, *et al*. Mucositis incidence,

[4] Satheesh Kumar PS, Balan A, Sankar A, Bose T. Radiation induced oral mucositis. Indian

severity and associated outcomes in patients with head and neck cancer receiving radiotherapy with or without chemotherapy: A systematic literature review.

stimulates growth of diverse types of epithelial cells including HaCaT cells [54].

management, nutritional support, and maintenance, of good oral hygiene.

cancers? Nat Clin Pract Oncol 2005;2:134-5.

Support Care Cancer 2006;14:489-91.

Cancer 2008;113:2704-13.

J Palliat Care 2009;15:95-102

**9.2 Low-level laser therapy** 

induced oral mucositis.[50]

**10. Summary** 

**11. References** 

**9.3 AMP-18 (Antral mucosal protein) 18** 

have direct effect on intestinal or oral mucosa. Interleukin-1 increases thymidine labeling, and protects oral and intestinal mucosa, when given to mice before radiation. Interleukin-11 can decrease mucositis, when given to hamster models.

#### **7.5 G-CSF, GM-CSF**

The mucosal protection effects of granulocyte colony stimulating factor G-CSF were observed in patients treated with various chemotherapy regimens by many authors.[46] But controversies to this exist in other clinical trials. In a recent preliminary report of a pilot study found significant reduction in oral mucositis.[47] The study was to evaluate the effect of GM-CSF in reduction of radiotherapy induced oral mucositis. At about second week of radiotherapy, when oral pain was experienced 400 g of GM-CSF was administered locally once a day, until completion of radiotherapy. The patients were evaluated weekly for mucosal reaction and functional impairment. The result of the study was prompting with reduction and almost healing of oral mucositis in 14 out of 17 patients with completion of radiotherapy within the preplanned schedule. Moreover patients did not show a significant weight loss or functional impairment.

#### **8. Anti-viral drugs**

#### **8.1 Acyclovir**

Although acyclovir prophylaxis is effective in preventing oropharyngeal shedding of the virus in herpes simplex virus seropositive patients receiving intensive chemotherapy or BMT, it did not influence chemotherapy, radiotherapy and BMT-related oral toxicity.

#### **9. Role of safe radiotherapy**

Normal tissue reactions can be reduced in a substantial number of patients with head and neck cancer by the use of computed tomography (CT)-based target delineation, Intensity-Modulated Radiation Therapy (IMRT), and simple, custom-made, intraoral devices that are designed to exclude uninvolved tissues from the treatment portals or to provide shielding of tissues within the treatment area.[43] Stents can be useful in excluding the palate mucosa during treatment of the tongue or floor of the mouth. These shielding stents can decrease the amount of radiation that is delivered to the contra-lateral mucosa. More frequent use of electron-beam and/or sophisticated three-dimensional conformal, multibeam, wedged-pair, or oblique treatment plans will also help to exclude or minimize the radiation dose to uninvolved mucosa. Packing gauze between metallic dental restorations and mucosa of the lateral tongue and buccal area appears to be very beneficial in minimizing the dose from scattered radiation.

#### **9.1 Antifungal therapy**

The mucosa of patients undergoing radiation therapy to the oral cavity should be examined at least once a week, and antibiotic or antifungal medications should be prescribed when infections are documented. Clotrimazole troches, dissolved in the mouth five times a day for 14 days, generally works well for oral candidiasis. However, if significant mucositis, altered taste, or xerostomia has developed, the troches might not be tolerated. In this situation, nystatin oral suspension or Fluconazole in tablet or liquid form is often effective. Fluconazole is more effective than nystatin and might need to be given at a higher dose and/or for an extended period of time in patients who are receiving combined chemotherapy and radiation therapy due to infections with resistant species.[48]

have direct effect on intestinal or oral mucosa. Interleukin-1 increases thymidine labeling, and protects oral and intestinal mucosa, when given to mice before radiation. Interleukin-11

The mucosal protection effects of granulocyte colony stimulating factor G-CSF were observed in patients treated with various chemotherapy regimens by many authors.[46] But controversies to this exist in other clinical trials. In a recent preliminary report of a pilot study found significant reduction in oral mucositis.[47] The study was to evaluate the effect of GM-CSF in reduction of radiotherapy induced oral mucositis. At about second week of radiotherapy, when oral pain was experienced 400 g of GM-CSF was administered locally once a day, until completion of radiotherapy. The patients were evaluated weekly for mucosal reaction and functional impairment. The result of the study was prompting with reduction and almost healing of oral mucositis in 14 out of 17 patients with completion of radiotherapy within the preplanned schedule. Moreover patients did not show a significant

Although acyclovir prophylaxis is effective in preventing oropharyngeal shedding of the virus in herpes simplex virus seropositive patients receiving intensive chemotherapy or BMT, it did not influence chemotherapy, radiotherapy and BMT-related oral toxicity.

Normal tissue reactions can be reduced in a substantial number of patients with head and neck cancer by the use of computed tomography (CT)-based target delineation, Intensity-Modulated Radiation Therapy (IMRT), and simple, custom-made, intraoral devices that are designed to exclude uninvolved tissues from the treatment portals or to provide shielding of tissues within the treatment area.[43] Stents can be useful in excluding the palate mucosa during treatment of the tongue or floor of the mouth. These shielding stents can decrease the amount of radiation that is delivered to the contra-lateral mucosa. More frequent use of electron-beam and/or sophisticated three-dimensional conformal, multibeam, wedged-pair, or oblique treatment plans will also help to exclude or minimize the radiation dose to uninvolved mucosa. Packing gauze between metallic dental restorations and mucosa of the lateral tongue and buccal area appears to be very beneficial in minimizing the dose from scattered radiation.

The mucosa of patients undergoing radiation therapy to the oral cavity should be examined at least once a week, and antibiotic or antifungal medications should be prescribed when infections are documented. Clotrimazole troches, dissolved in the mouth five times a day for 14 days, generally works well for oral candidiasis. However, if significant mucositis, altered taste, or xerostomia has developed, the troches might not be tolerated. In this situation, nystatin oral suspension or Fluconazole in tablet or liquid form is often effective. Fluconazole is more effective than nystatin and might need to be given at a higher dose and/or for an extended period of time in patients who are receiving combined

chemotherapy and radiation therapy due to infections with resistant species.[48]

can decrease mucositis, when given to hamster models.

**7.5 G-CSF, GM-CSF** 

**8. Anti-viral drugs** 

**9.1 Antifungal therapy**

**8.1 Acyclovir** 

weight loss or functional impairment.

**9. Role of safe radiotherapy** 

#### **9.2 Low-level laser therapy**

The mechanism of low-level laser therapy is not understood, but many studies have proved the efficacy of the same in reducing the symptoms related to oral mucositis. Low-level laser therapy may reduce levels of reactive oxygen species and/or proinflammatory cytokines that contribute to the pathogenesis of mucositis.[49] The various guidelines suggest the use of low-level laser therapy for reducing the severity of chemotherapy and radiotherapyinduced oral mucositis.[50]

#### **9.3 AMP-18 (Antral mucosal protein) 18**

A study on AMP18 (AMP-18 is a protein constitutively expressed in epithelial cells of the gastric antrum that is cell protective, mitogenic and motogenic in cell culture and in vivo) shows, AMP peptide, by activating CCKBR (cholecystokinin-B/gastrin receptor), targets TJs(Tight Junctions) to maintain mucosal integrity, and sets in motion protective and cell regenerative mechanisms for the prevention and treatment of OM. Treatment with AMP peptide protected the surface epithelium of the mouse oral mucosa. AMP-18 peptide stimulates growth of diverse types of epithelial cells including HaCaT cells [54].

#### **10. Summary**

Mucositis is an inevitable side effect of radiation. The severity of the mucositis depends on the type of ionizing radiation, the volume of irradiated tissue, the daily dose, and the cumulative dose. As the mucositis becomes more severe, pseudomembranes and ulcerations develop. Poor nutritional status further interferes with mucosal regeneration by decreasing cellular migration and renewal. Radiation-induced oral mucositis affects the quality of life of the patients and the family concerned. The present day management of oral mucositis is mostly palliative and or supportive care. Management includes good oral hygiene, avoiding irritating or abrasive substances, use of bland rinses, topical anesthetic agents, and systemic analgesics. Though, the newer guidelines are suggesting Palifermin, which is the first active mucositis drug as well as Amifostine, for radiation protection and cryotherapy for symptoms related to high-dose melphalan; the role of safe radiotherapy remains the ultimate goal in reducing the symptoms of radiation-induced oral mucositis. Future research for the newer drugs in the field of radiation-induced oral mucositis is a must, and the current management should focus more on palliative measures, such as pain management, nutritional support, and maintenance, of good oral hygiene.

#### **11. References**


Radiation Mucositis 481

[22] Barker G, Loffus L, Cuddy P, Barker B. The effects of of sucralfate suspension and

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[24] von Bultzingslowen I, Brennan MT, Spijkervet FK, Logan R, Stringer A, Raber-

oral and gastrointestinal mucositis. Support Care Cancer 2006;14:519-27. [25] Scherlacher A, Beaufort-Spontin E. Radiotherapy of head-neck neo-plasms:prevention of inflammation of the mucosa by sucralafate treatment. HNO 1990;38:24-28. [26] Pfeiffer P, Hansen O, Madsen el, et al. A prospective pilot study on the effect of

[27] Epstein jb, Wong FLW The efficacy of sucralafate suspension in the prevention of oral mucositis due to radiation therapy. Int J Radiat Oncol Biol Phys 1994;28:693-698. [28] Barker G, Loftus L, Cuddy P, et al. The effects of sucralafate suspension and

[30] Rosen LS, Abdi E, Davis ID, Gutheil J, Schnell FM, Zalcberg J, *et al*. Palifermin reduces

[32] Lalla RV, Schubert MM, Bensadoun RJ, Keefe D. Anti-inflammatory agents in the management of alimentary mucositis. Support Care Cancer 2006;14:558-65. [33] Coeffier M, Marion R, Leplingard A, Lerebours E, Ducrotté P, Déchelotte P. Glutamine

[34] Evans ME, Jones DP, Ziegler TR. Glutamine prevents cytokine-induced apoptosis in

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Benzydamine HCl for prophylaxis of radiation-induced oral mucositis: Results from a multicenter, randomized, double-blind, placebo-controlled clinical trial.

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for prevention and treatment of oral mucositis in breast cancer patients receiving

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[5] Satheeshkumar PS, Chamba MS, Balan A, Sreelatha KT, Bhatathiri VN, Bose T.

[6] P.S Satheeshkumar, A. Balan.Subjective response of pain on patients treated with

[7] Logan RM, Gibson RJ, Sonis ST, Keefe DM. Nuclear factor-κappaB (NF-kappaB) and

[8] Gibson RJ, Bowen JM, Cummins AG, Logan R, Healey T, Keefe DM. Ultrastructural

[9] Sonis ST, Elting LS, Keefe D, Peterson DE, Schubert M, Hauer-Jensen M, *et al*. Perspectives

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[12] Dorr W, Emmendorfer H, Haide E. Proliferation equivalent of 'accelerated repopulation' in mouse oral mucosa. Int J Radiat Biol 1994;66:157-67. [13] Epstein JB, Gorsky M, Guglietta A, Le N, Sonis ST. The correlation between epidermal

[14] Dodd MJ, Miaskowski C, Greenspan D, MacPhail L, Shih AS, Shiba G, *et al*. Radiation-

[15] Nottage M, McLachlan SA, Brittain MA, Oza A, Hedley D, Feld R, *et al*. Sucralfate

[18] Matthews RH, Ercal N. Prevention of mucositis in irradiated head and neck cancer

[19] Borowski B, Benhamou E, Pico JL, Laplanche A, Margainaud JP, Hayat M. Prevention

[20] Yoneda S, Imai S, Hanada N, Yamazaki T, Senpuku H, Ota Y, *et al*. Effects of oral care

[21] McGuire DB, Correa ME, Johnson J, Wienandts P. The role of basic oral care and good

randomized, placebo-controlled trial. Support Care Cancer 2003;11:41-7. [16] Barclay L. Morphine mouthwash relieves pain of oral mucositis. Cancer 2002;95:2230-6. [17] Spijkevet FK, van saene JJ, Panders AK, Vermy A, Mehta DM, Filder V. Effect of

randomized clinical trial. J Can Res Ther 2010;6:466-72.

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[abstract A-373]. Support Care Cancer 2004;12:389.

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and soda mouthwashes. Cancer Invest 2003;21:21-33.

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aqueous base Hexidine and weekly dentist assisted oral hygiene maintenance for radiation induced oral mucositis- An interventional study." Oral Oncology,

cyclooxygenase-2 (COX-2) expression in the oral mucosa following cancer

changes occur early within the oral mucosa following cancer chemotherapy

on cancer therapy-induced mucosal injury: Pathogenesis, measurement,

Perspectives on cancer therapy-induced mucosal injury: Pathogenesis, measurement,

mechanisms of action of interleukin-11 on the progression of radiation-induced

growth factor levels in saliva and the severity of oral mucositis during

induced mucositis: A randomized clinical trial of micronized sucralfate versus salt

mouthwash for prevention and treatment of 5-fluorouracil-induced mucositis: A

selective elimination of the oral flora on mucositis in irradiated head and neck

of oral mucositis in patients treated with high-dose chemotherapy and bone marrow transplantation: A randomized controlled trial comparing two protocols of

on development of oral mucositis and microorganisms in patients with esophageal

clinical practice principles in the management of oral mucositis. Support Care


**Part 6** 

**Non Pharmacological Treatments** 


**Part 6** 

**Non Pharmacological Treatments** 

482 Pain Management – Current Issues and Opinions

[39] Bensadoun RJ, Schubert MM, Lalla RV, Keefe D. Amifostine in the management of radiation induced and chemo-induced mucositis. Support Care Cancer 2006;14:566-72. [40] Barasch A, Peterson DE, Tanzer JM, D'Ambrosio JA, Nuki K, Schubert MM, *et al*.

[41] Mills EE. The modifying effect of beta-carotene on radiation and radiotherapy and

[42] Bianco JA, Appelbaum FR, Nemunaitis J, Almgren J, Andrews F, Kettner P, *et al*. Phase

[43] Clift RA, Bianco JA, Appelbaum FR, Buckner CD, Singer JW, Bakke L, *et al*. A

[44] Mose S, Adametz IA, Saran F, Thilmann C, Hayd R, Knecht R, *et al*. Can Prophylactic

[45] Hermann F, Schuiz G, Weser M, Kolbe K, Nicolay U, Noack M, *et al*. Effect of

morbidity induced by myelotoxic chemotherapy. Am J Med 1990;88:619-24. [46] Gluckman E, Lotsberg J, Devergie A, Zhao XM, Melo R, Gomez-Morales M, *et al*. Oral

[47] Kaanders JH, Fleming TJ, Ang KK, Maor MH, Peters LJ. Devices valuable in head and

[48] Dahiya MC, Redding SW, Dahiya RS, Eng TY, Kirkpatrick WR, Coco BJ, *et* 

[49] Bensadoun RJ, Franquin JC, Ciais G, Darcourt V, Schubert MM, Viot M, *et al*. Low-

[50] Migliorati CA, Oberle-Edwards L, Schubert M. The role of alternative and natural

[51] Cerchietti LC, Navigante AH, Bonomi MR, Zaderajko MA, Menéndez PR, Pogany CE,

[52] S.K. Poolakkad Sankaran, A. Balan. Neighbourhood Dental Clinic programme (NDCP)

[53] S.K. Poolakkad Sankaran, A. Balan. The degree of discomfort due to mucositis is

[54] Chen P, Lingen M, Sonis ST, Walsh-Reitz MM, Toback FG. Role of AMP-18 in oral

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Cancer (2011) 19 (Suppl 2):S67–S370.

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neck radiotherapy. Int J Radiat Oncol Biol Phys 1992;23:639-45.

Helium-neon laser effects on conditioning induced oral mucositis in bone marrow

I-II trial of pentoxifyline for the prevention of transplant-related toxicities following

randomized controlled trial of pentoxifylline for the prevention of regimen-related toxicities in patients undergoing allogeneic marrow transplantation. Blood

application of immunoglobulin decrease radiotherapy-induced oral mucositis. Am

granulocyte-macrophage colony stimulating factor on neutropenia and related

acyclovir prophylactic treatment of herpes simplex infection after bone marrow

*al*. Oropharyngeal candidiasis caused by non-albicans yeast in patients receiving external beam radiotherapy for head-and-neck cancer. Int J Radiat Oncol Biol

energy He/Ne laser in the prevention of radiation-induced mucositis: A multicenter phase III randomized study in patient's with head and neck cancer.

agents, cryotherapy, and/or laser for management of alimentary mucositis.

Roth BM. Effect of topical morphine for mucositis-associated pain following concomitant chemoradiotherapy for head and neck carcinoma. Cancer. 2002 Nov

for oral care in patients undergoing head and neck cancer therapy. Support Care

related to the prior patient awareness? Support Care Cancer (2011) 19 (Suppl

**23** 

*Turkey* 

Yurdanur Demir

**Non-Pharmacological** 

**Therapies in Pain Management** 

*Abant İzzet Baysal University, Bolu Health Sciences High School,* 

Pain is an unpleasant feeling and emotional experience that is related to real or potential tissue damage or a damage that is defined similarly. Pain is mostly subjective (Merskey, Bogduk 1986). From many points of view, the pain is a common symptom intended for seeking aid (Dickens et al. 2002). International Association for the Study of Pain (IASP) defines the pain as "an unpleasant emotional situation which is originating from a certain area, which is dependant or non-dependant on tissue damage and which is related to the

Although there is an increase of knowledge and developments in technological resources regarding the pain, many patients still experience pain (Nash et al. 1999). This situation causes for reduction in living quality and functional situation of the patients, increase in the fatigue levels (Kim et al. 2004) and impairments in daily life activities in working capacity and social interactions (McMillan et al., 2000; Allard et al., 2001). Also this situation will cause loss of workforce and will affect not only the patients but also his/her family members in economical terms thus causing undesired problems in psychological and social well being status (Uçan and Ovayolu 2007). All of these elements have directed both the patients and caregivers to seek for different searches in pain management (Evans and Rosner, 2005). For this reason in addition to the pharmacological treatment options for pain management, today, non-pharmacological treatment options and complementary medical attempts have started to be used (Kwekkeboom et al., 2003; Menefee and Monti, 2005). It is stated that such kind of therapies can be useful in pain management (Uçan and Ovayolu 2007). In a study conducted with the participation of 31.044 adults in United States, Barnes et al. (2004) determined that the usage rate of the complementary methods for the last year has been 36% and back pain and lumbago come first with 16.8% and neck pain comes third with 6.6% in terms of usage reasons of the complementary methods . Sherman et al. (2004)

have stated that 24% of the patients with chronic lumbago used massage therapy.

It is considered that these therapies help the standard pharmacological treatment in pain management. While medical drugs are being used for treating the somatic (physiological and emotional) dimension of the pain non-pharmacological therapies aim to treat the affective, cognitive, behavioral and socio-cultural dimensions of the pain (Yavuz 2006).

**2. Non-pharmacological therapies in pain management** 

past experience of the person in question" (Merskey, IASP 1986).

**1. Introduction** 

### **Non-Pharmacological Therapies in Pain Management**

Yurdanur Demir

*Abant İzzet Baysal University, Bolu Health Sciences High School, Turkey* 

#### **1. Introduction**

Pain is an unpleasant feeling and emotional experience that is related to real or potential tissue damage or a damage that is defined similarly. Pain is mostly subjective (Merskey, Bogduk 1986). From many points of view, the pain is a common symptom intended for seeking aid (Dickens et al. 2002). International Association for the Study of Pain (IASP) defines the pain as "an unpleasant emotional situation which is originating from a certain area, which is dependant or non-dependant on tissue damage and which is related to the past experience of the person in question" (Merskey, IASP 1986).

Although there is an increase of knowledge and developments in technological resources regarding the pain, many patients still experience pain (Nash et al. 1999). This situation causes for reduction in living quality and functional situation of the patients, increase in the fatigue levels (Kim et al. 2004) and impairments in daily life activities in working capacity and social interactions (McMillan et al., 2000; Allard et al., 2001). Also this situation will cause loss of workforce and will affect not only the patients but also his/her family members in economical terms thus causing undesired problems in psychological and social well being status (Uçan and Ovayolu 2007). All of these elements have directed both the patients and caregivers to seek for different searches in pain management (Evans and Rosner, 2005). For this reason in addition to the pharmacological treatment options for pain management, today, non-pharmacological treatment options and complementary medical attempts have started to be used (Kwekkeboom et al., 2003; Menefee and Monti, 2005). It is stated that such kind of therapies can be useful in pain management (Uçan and Ovayolu 2007). In a study conducted with the participation of 31.044 adults in United States, Barnes et al. (2004) determined that the usage rate of the complementary methods for the last year has been 36% and back pain and lumbago come first with 16.8% and neck pain comes third with 6.6% in terms of usage reasons of the complementary methods . Sherman et al. (2004) have stated that 24% of the patients with chronic lumbago used massage therapy.

#### **2. Non-pharmacological therapies in pain management**

It is considered that these therapies help the standard pharmacological treatment in pain management. While medical drugs are being used for treating the somatic (physiological and emotional) dimension of the pain non-pharmacological therapies aim to treat the affective, cognitive, behavioral and socio-cultural dimensions of the pain (Yavuz 2006).

Non-Pharmacological Therapies in Pain Management 487

Fig. 1. a) *http://www.ib3health.com/products/TensandEMS/Literature/ApplicationChart.shtml*

Fig. 1. b) *http://www.ib3health.com/products/TensandEMS/Literature/ApplicationChart.shtml*

June/2011

June/2011

These therapies can treat the pain as adjuvant or complementary at middle level and severe pain experiences as an adjuvant or complementary treatment. (Delaune & Ladner 2002). *Non-pharmacological methods,* 


Non-pharmacological methods used in pain management can be classified in different ways. In general; they are stated as physical, cognitive, behavioral and other complementary methods or as invasive or -non-invasive methods. Meditation, progressive relaxation, dreaming, rhythmic respiration, biofeedback, therapeutic touching, transcutaneous electrical nerve stimulation (TENS), hypnosis, musical therapy, acupressure and cold-hot treatments are non-invasive methods (Black & Matassarin Jacobs, 1997). The most famous and common method among the invasive methods is acupuncture (Menifee and Monti, 2005). It is considered that these methods control the gates that are vehicles for pain to be transmitted to the brain and affect pain transmission or the release of natural opioids of the body such as endorphin (Black & Matassarin Jacobs, 1997; Menefee & Monti, 2005; Uçan & Ovayolu 2007).

Non-pharmacological methods used in pain management have been examined below in three groups such as peripheral therapies (physical agents/skin stimulation methods), cognitive-behavioral therapies and other therapies. Some of these methods require special training (Turan et al. 2010).

#### **2.1 Peripheral therapies (physical agents/skin stimulation)**

Skin stimulation that provides analgesia is defined as stimulating the patient's skin in a harmless manner to treat the pain (Yldrm 2006). Skin stimulation attempts (physical therapies) can be classified as hot-cold treatments, exercise, positioning, movement restriction-resting, acupuncture, hydrotherapy, TENS, massage and therapeutic touch. If used in an appropriate manner these methods are effective on secondary pathologies such as inflammation, edema, progressive tissue damage, muscle spasm and function loss which takes part in acute pain. (Yldrm 2006).

#### **2.1.1 TENS (Transcutaneous Electrical Nerve Stimulation)**

TENS has been defined by the American Physical Therapy Association as applying electrical stimulation to the skin to manage the pain (Sluka & Walsh 2003). Usually, it may be used in addition or instead of pharmacological agents to manage acute, chronic and post-operative pain. It is an electro-analgesia method (Mucuk and Başer, 2009). That is to say, thick and rapid transmitting nerve fibers are stimulated artificially with TENS and the pain transmission is tried to be stopped or reduced. TENS, which functions in that way, has an effect to reduce the narcotic drugs usage and pain level (Arslan & Çelebioğlu; Chen et al. 1998). TENS has various mechanisms of action regarding pain. Gate Control Theory is a theory used to define how TENS affects the pain perception which also has a part in improving TENS. Gate control theory regarding pain management is very commonly used by TENS in defining the process to

These therapies can treat the pain as adjuvant or complementary at middle level and severe pain experiences as an adjuvant or complementary treatment. (Delaune & Ladner 2002).

Reduces the needed dosage of analgesic drugs thus decreasing the side effects of the

Non-pharmacological methods used in pain management can be classified in different ways. In general; they are stated as physical, cognitive, behavioral and other complementary methods or as invasive or -non-invasive methods. Meditation, progressive relaxation, dreaming, rhythmic respiration, biofeedback, therapeutic touching, transcutaneous electrical nerve stimulation (TENS), hypnosis, musical therapy, acupressure and cold-hot treatments are non-invasive methods (Black & Matassarin Jacobs, 1997). The most famous and common method among the invasive methods is acupuncture (Menifee and Monti, 2005). It is considered that these methods control the gates that are vehicles for pain to be transmitted to the brain and affect pain transmission or the release of natural opioids of the body such as endorphin (Black & Matassarin Jacobs, 1997; Menefee & Monti, 2005;

Non-pharmacological methods used in pain management have been examined below in three groups such as peripheral therapies (physical agents/skin stimulation methods), cognitive-behavioral therapies and other therapies. Some of these methods require special

Skin stimulation that provides analgesia is defined as stimulating the patient's skin in a harmless manner to treat the pain (Yldrm 2006). Skin stimulation attempts (physical therapies) can be classified as hot-cold treatments, exercise, positioning, movement restriction-resting, acupuncture, hydrotherapy, TENS, massage and therapeutic touch. If used in an appropriate manner these methods are effective on secondary pathologies such as inflammation, edema, progressive tissue damage, muscle spasm and function loss which

TENS has been defined by the American Physical Therapy Association as applying electrical stimulation to the skin to manage the pain (Sluka & Walsh 2003). Usually, it may be used in addition or instead of pharmacological agents to manage acute, chronic and post-operative pain. It is an electro-analgesia method (Mucuk and Başer, 2009). That is to say, thick and rapid transmitting nerve fibers are stimulated artificially with TENS and the pain transmission is tried to be stopped or reduced. TENS, which functions in that way, has an effect to reduce the narcotic drugs usage and pain level (Arslan & Çelebioğlu; Chen et al. 1998). TENS has various mechanisms of action regarding pain. Gate Control Theory is a theory used to define how TENS affects the pain perception which also has a part in improving TENS. Gate control theory regarding pain management is very commonly used by TENS in defining the process to

*Non-pharmacological methods,* 

Reduces stress and anxiety.

treatment (Yldrm 2006).

Uçan & Ovayolu 2007).

training (Turan et al. 2010).

takes part in acute pain. (Yldrm 2006).

 Increase the individual control feeling. Decrease the feeling of weakness.

Improves the activity level and functional capacity.

Reduces the pain behavior and focused pain level.

**2.1 Peripheral therapies (physical agents/skin stimulation)** 

**2.1.1 TENS (Transcutaneous Electrical Nerve Stimulation)** 

Fig. 1. a) *http://www.ib3health.com/products/TensandEMS/Literature/ApplicationChart.shtml* June/2011

Fig. 1. b) *http://www.ib3health.com/products/TensandEMS/Literature/ApplicationChart.shtml* June/2011

Non-Pharmacological Therapies in Pain Management 489

Hot treatment moves the reflex arcs that inhibit the pain by means of heat receptors and reduces pain by vasodilatation effect. It is cheap and easy to use and it has a minimum amount of side effects when used regularly. It can be applied deeply or on surfaces. Application to the surface includes hot compresses, warm baths and paraphine usage. Deep applications such as ultrasound may increase the temperature of the tissues which are three

On the other hand, cold treatment consists of applying a cooling material or device on any part of the body. Cold treatment which is a simple and cheap treatment method has an important place in non-drug therapies for pain management(Yavuz, 2006). Cold gel packages and ice packages commonly used in the application should be used by placing a tin towel/gauze between the skin and the package for being able to withstand extreme cold feeling during the first contact of the package, for having a homogenous cooling and providing hygiene. Cold treatment may be done for 15-30 minutes averagely until the anesthesia is felt on the area of application. The cold ice packs should be applied for at least 20 minutes. As a matter of fact, the affect of cold treatment on the human skin reveals itself in 4 stages. The patient will feel the cold within 1 to 3 minutes after the application, then feel a burning and pain sensation within 2 to 7 minutes and the pain and lethargy will decrease within 5 to 12 minutes, a breaking occurs for the pain-spasm vicious-circle and transmission of the nerve fibers in the area will decrease. An increase will occur for the metabolism within 12 to 15 minutes after cold treatment and a reflex vasodilatation occurs on the deep tissue. Thus, the edema and the pain will reduce and the tissue will be nourished with vasodilatation that will develop 15 minutes later (Karagözlüoğlu, 2001). Results of the studies made in the area have shown that the cold treatment has increased the pain threshold (Koç et al. 2006; Raynor et al. 2005; Sarifakioğlu & Sarifakioğlu 2004). So, the cold treatments that are applied locally are used to reduce the edema and treat the pain by taking the inflammation process under control (Saeki 2002; Sarifakioğlu & Sarifakioğlu 2004; Van

It has been stated that cold treatment over the area where surgical sutures are found after lumbar disc surgery reduces both the pain during first 24 hours and the need for morphine (Brandner et al. 1996). Also, it has been shown that fluoromethane spray applications are a cheap method that are rapidly effective in managing the injection pain due to vaccination (Mawhorter et al. 2004) and cold package and ice applications have reduced the pain due to heparin injections (Kuzu ve Uçar 2001; Ross and Soltes 1995). In the study that they conducted, Demir and Khorshid (2010) have stated that cold treatment that is applied to the skin around the chest tube reduced the severity of the pain that is felt due to exclusion of chest tube and it has extended the time between exclusion of chest tube and taking an analgesic. It is stated that cold treatment is contraindicated for the situations such as urticaria/hypersensitivity, hypertension, Reynaud's phenomenon and sickle cell anemia

Acupuncture which is one of the important components of traditional Chinese medicine has become a largely complementary in the West together with the conventional medicine. Acupuncture is accepted as a scientific treatment method that provides the body to restore its balance by means of stimulating some special points on the body with needles (Taşç & Sevil 2007). Mechanism of action for the acupuncture could not be completely understood

**2.1.2 Hot-cold treatment** 

der Westhuijzen et al. 2005).

which are related to cold (Mucuk & Başer, 2009).

**2.1.3 Acupuncture and acupressure** 

to five centimeter deep (Arslan & Çelebioğlu, 2004).

prevent the pain (Sluka & Walsh 2003; Johnson 2002). In a study that has been conducted, it has been determined that the placebo group experienced 2-4 times less pain when TENS is used with pharmacological methods in post-operative pain management (Rakel & Frantz 2003), and in another study it has been determined that TENS usage in post-operative pain management has helped reducing the pain level and dosage of using analgesics (Bjordal et al. 2003). In addition to that, in some other studies it has been determined that first phase of labor in TENS group has been shorter and TENS treatment has been effective in relieving the pain (Kaplan et al. 1998; Simkin and Bolding 2004).

*Points to Take into Consideration While Using Tens:* 


Dewit, S.C., (2009), *Fundamental concepts and skills for nursing,* 3rd Edition, W.B. Saunders Comp. Philadelphia, p.603-614.

Fig. 2. TENS Usage

#### **2.1.2 Hot-cold treatment**

488 Pain Management – Current Issues and Opinions

prevent the pain (Sluka & Walsh 2003; Johnson 2002). In a study that has been conducted, it has been determined that the placebo group experienced 2-4 times less pain when TENS is used with pharmacological methods in post-operative pain management (Rakel & Frantz 2003), and in another study it has been determined that TENS usage in post-operative pain management has helped reducing the pain level and dosage of using analgesics (Bjordal et al. 2003). In addition to that, in some other studies it has been determined that first phase of labor in TENS group has been shorter and TENS treatment has been effective in relieving the pain

TENS devices should be used with caution in the areas where the pain could not be

You should use the device after controlling machine or motor vehicle producing TENS.

People who are using cardiac pacemaker should consult to their doctors about whether

Electronic materials such as ECG monitors and ECG alarms may not work in full

It can cause damages on skin. That can be prevented by changing the type of gel and

There are not reliable study results describing TENS usage during pregnancy (Yavuz

Dewit, S.C., (2009), *Fundamental concepts and skills for nursing,* 3rd Edition, W.B. Saunders Comp.

TENS device should be used under the control of a health personnel.

Electrical stimulation should not be used in front parts of the neck.

 This device should not be used on metal prostheses or monitors. TENS should be kept at places where the children cannot reach.

Device should be turned off while placing the materials.

TENS usage will be harmful for them or not.

capacity while using TENS.

electrodes that are used.

2006).

Philadelphia, p.603-614. Fig. 2. TENS Usage

(Kaplan et al. 1998; Simkin and Bolding 2004). *Points to Take into Consideration While Using Tens:* 

defined exactly.

Hot treatment moves the reflex arcs that inhibit the pain by means of heat receptors and reduces pain by vasodilatation effect. It is cheap and easy to use and it has a minimum amount of side effects when used regularly. It can be applied deeply or on surfaces. Application to the surface includes hot compresses, warm baths and paraphine usage. Deep applications such as ultrasound may increase the temperature of the tissues which are three to five centimeter deep (Arslan & Çelebioğlu, 2004).

On the other hand, cold treatment consists of applying a cooling material or device on any part of the body. Cold treatment which is a simple and cheap treatment method has an important place in non-drug therapies for pain management(Yavuz, 2006). Cold gel packages and ice packages commonly used in the application should be used by placing a tin towel/gauze between the skin and the package for being able to withstand extreme cold feeling during the first contact of the package, for having a homogenous cooling and providing hygiene. Cold treatment may be done for 15-30 minutes averagely until the anesthesia is felt on the area of application. The cold ice packs should be applied for at least 20 minutes. As a matter of fact, the affect of cold treatment on the human skin reveals itself in 4 stages. The patient will feel the cold within 1 to 3 minutes after the application, then feel a burning and pain sensation within 2 to 7 minutes and the pain and lethargy will decrease within 5 to 12 minutes, a breaking occurs for the pain-spasm vicious-circle and transmission of the nerve fibers in the area will decrease. An increase will occur for the metabolism within 12 to 15 minutes after cold treatment and a reflex vasodilatation occurs on the deep tissue. Thus, the edema and the pain will reduce and the tissue will be nourished with vasodilatation that will develop 15 minutes later (Karagözlüoğlu, 2001). Results of the studies made in the area have shown that the cold treatment has increased the pain threshold (Koç et al. 2006; Raynor et al. 2005; Sarifakioğlu & Sarifakioğlu 2004). So, the cold treatments that are applied locally are used to reduce the edema and treat the pain by taking the inflammation process under control (Saeki 2002; Sarifakioğlu & Sarifakioğlu 2004; Van der Westhuijzen et al. 2005).

It has been stated that cold treatment over the area where surgical sutures are found after lumbar disc surgery reduces both the pain during first 24 hours and the need for morphine (Brandner et al. 1996). Also, it has been shown that fluoromethane spray applications are a cheap method that are rapidly effective in managing the injection pain due to vaccination (Mawhorter et al. 2004) and cold package and ice applications have reduced the pain due to heparin injections (Kuzu ve Uçar 2001; Ross and Soltes 1995). In the study that they conducted, Demir and Khorshid (2010) have stated that cold treatment that is applied to the skin around the chest tube reduced the severity of the pain that is felt due to exclusion of chest tube and it has extended the time between exclusion of chest tube and taking an analgesic. It is stated that cold treatment is contraindicated for the situations such as urticaria/hypersensitivity, hypertension, Reynaud's phenomenon and sickle cell anemia which are related to cold (Mucuk & Başer, 2009).

#### **2.1.3 Acupuncture and acupressure**

Acupuncture which is one of the important components of traditional Chinese medicine has become a largely complementary in the West together with the conventional medicine. Acupuncture is accepted as a scientific treatment method that provides the body to restore its balance by means of stimulating some special points on the body with needles (Taşç & Sevil 2007). Mechanism of action for the acupuncture could not be completely understood

Non-Pharmacological Therapies in Pain Management 491

Acupressure is one of the traditional Chinese medicine approaches used for pain relief, diseases and injuries. Acupressure is a therapy that is conducted by applying physical pressure on various points on body surface by means of energy circulation and balance in cases of pain symptoms. This therapy is similar to the acupuncture and it is conducted by applying pressure on selected points of the body by fingers, hands, palms, wrists and knees in order to provide internal flow of energy. Acupressure technique is a noninvasive, safe and effective application (Hakverdioğlu, & Türk, 2006). It is suggested that acupressure reduces back, head, osteoarthritis, musculoskeletal and neck pains, pre-operative and postoperative pains, nausea-vomiting and sleeping problems (Tsay, Rong and Lin 2003; Tsay &

Exercise includes active-passive movements, bed movements and ambulation. Exercise increases the movement and provides continuity thus increasing the blood flow, preventing

It is applied to help or support the patient. This application can be supported by pillows, special beds and weight lifting. Position changes, which prevent the subsequent development of pain and reducing the acute pain, also increase the blood flow and prevent muscle contraction and spasms (Akdağ & Ovayolu, 2008). Positioning has been determined

These are applied for the patients who need certain bed rest and which are in traction. However, it should not be used alone for pain management. It can be used for fractures and back surgeries. Restriction of movement can also decrease edema development (Arslan &

Massage is a manipulation applied on the soft tissue with various techniques (such as friction, percussion, vibration and tapotement) for recovery and supporting health. It is thought that the massage relieve the mind and muscles and increase the pain threshold (Karagöz 2006). Peripheral receptors on the body are stimulated with massage and stimulants reach the brain by means of spinal cord. In addition to pleasant feeling, a general relief is provided here (Turan et al. 2010). It is underlined that especially therapeutic massage is effective on chronic lumbago and that effect is stated to be a short term effect (Hsieh et al. 2004). Melancon and Miller (2005) draw attention to the fact that pain management in patient groups with lumbago that are treated with massage and pharmacological therapies are similar and they recommend the sue of massage as an alternative treatment option for the patients with lumbago within the framework of a integrated care. Nixon et al (1997) has stated that massage played a role in reducing the pain. In addition to that it is determined in some randomized controlled studies that massage made during labor decreases pain and anxiety; it also improves the general well being and progression of birth process and less reaction is given to the pain (Caton et.al

spasm and contractures of the muscles and relieving the pain (Musclow et al., 2002).

as the most common post-operative non-pharmacological method (Carroll 1999).

Chen 2003; Hakverdioğlu, & Türk 2006).

**2.1.6 Restriction of movement /resting** 

**2.1.4 Exercise** 

**2.1.5 Positioning** 

Çelebioğlu, 2004).

**2.1.7 Massage** 

2002; Simkin & O'Hora 2002).

until now. Effect of the acupunctures is tried to be explained by Gate Control Theory. According to this theory, effect of a sensory stimulant (for example lumbago) can be suppressed with another stimulant (picking a needle) within a neural system. Another theory that explains the effect of acupuncture is Raising Pain Threshold Theory. That is a theory in which inhibitor effect of acupuncture is defined. In this theory, it is predicted to stimulate the analgesia mechanisms of the body by causing various pains on the area where an individual is feeling the pain to be treated. In addition to these, it has also been evidence that the acupuncture stimulates the production of endorphin, serotonin and acetyl choline within the central nerve system (Van Tulder et al. 2005). It has been shown in the studies that have been conducted that the acupuncture had positive effects on post-traumatic somatic pain, patella-femoral pain, rheumatoid arthritis and idiopathic head pain. (Snyder & Wieland 2003). It is sated in the literature that the acupuncture is especially useful in treating the lumbago but it is underlined that the patients should be informed in terms of increasing or carrying on the activities (Öztekin, 2005). Although there are some strong evidences showing the benefit of acupuncture in acute pain, the evidence regarding the cancer pain is limited (Black & Matassarin Jacobs, 1997; Filshie & Thompson 2004; Menefee & Monti, 2005). In spite of that, Alimi et al. (2003) stated that the acupuncture applied to cancer patient has decreased the pain level.

Fig. 3. http://suphecimelek.wordpress.com/2010/10/31/akupunktur June/2011

Acupressure is one of the traditional Chinese medicine approaches used for pain relief, diseases and injuries. Acupressure is a therapy that is conducted by applying physical pressure on various points on body surface by means of energy circulation and balance in cases of pain symptoms. This therapy is similar to the acupuncture and it is conducted by applying pressure on selected points of the body by fingers, hands, palms, wrists and knees in order to provide internal flow of energy. Acupressure technique is a noninvasive, safe and effective application (Hakverdioğlu, & Türk, 2006). It is suggested that acupressure reduces back, head, osteoarthritis, musculoskeletal and neck pains, pre-operative and postoperative pains, nausea-vomiting and sleeping problems (Tsay, Rong and Lin 2003; Tsay & Chen 2003; Hakverdioğlu, & Türk 2006).

#### **2.1.4 Exercise**

490 Pain Management – Current Issues and Opinions

until now. Effect of the acupunctures is tried to be explained by Gate Control Theory. According to this theory, effect of a sensory stimulant (for example lumbago) can be suppressed with another stimulant (picking a needle) within a neural system. Another theory that explains the effect of acupuncture is Raising Pain Threshold Theory. That is a theory in which inhibitor effect of acupuncture is defined. In this theory, it is predicted to stimulate the analgesia mechanisms of the body by causing various pains on the area where an individual is feeling the pain to be treated. In addition to these, it has also been evidence that the acupuncture stimulates the production of endorphin, serotonin and acetyl choline within the central nerve system (Van Tulder et al. 2005). It has been shown in the studies that have been conducted that the acupuncture had positive effects on post-traumatic somatic pain, patella-femoral pain, rheumatoid arthritis and idiopathic head pain. (Snyder & Wieland 2003). It is sated in the literature that the acupuncture is especially useful in treating the lumbago but it is underlined that the patients should be informed in terms of increasing or carrying on the activities (Öztekin, 2005). Although there are some strong evidences showing the benefit of acupuncture in acute pain, the evidence regarding the cancer pain is limited (Black & Matassarin Jacobs, 1997; Filshie & Thompson 2004; Menefee & Monti, 2005). In spite of that, Alimi et al. (2003) stated that the acupuncture applied to

Fig. 3. http://suphecimelek.wordpress.com/2010/10/31/akupunktur June/2011

cancer patient has decreased the pain level.

Exercise includes active-passive movements, bed movements and ambulation. Exercise increases the movement and provides continuity thus increasing the blood flow, preventing spasm and contractures of the muscles and relieving the pain (Musclow et al., 2002).

#### **2.1.5 Positioning**

It is applied to help or support the patient. This application can be supported by pillows, special beds and weight lifting. Position changes, which prevent the subsequent development of pain and reducing the acute pain, also increase the blood flow and prevent muscle contraction and spasms (Akdağ & Ovayolu, 2008). Positioning has been determined as the most common post-operative non-pharmacological method (Carroll 1999).

#### **2.1.6 Restriction of movement /resting**

These are applied for the patients who need certain bed rest and which are in traction. However, it should not be used alone for pain management. It can be used for fractures and back surgeries. Restriction of movement can also decrease edema development (Arslan & Çelebioğlu, 2004).

#### **2.1.7 Massage**

Massage is a manipulation applied on the soft tissue with various techniques (such as friction, percussion, vibration and tapotement) for recovery and supporting health. It is thought that the massage relieve the mind and muscles and increase the pain threshold (Karagöz 2006). Peripheral receptors on the body are stimulated with massage and stimulants reach the brain by means of spinal cord. In addition to pleasant feeling, a general relief is provided here (Turan et al. 2010). It is underlined that especially therapeutic massage is effective on chronic lumbago and that effect is stated to be a short term effect (Hsieh et al. 2004). Melancon and Miller (2005) draw attention to the fact that pain management in patient groups with lumbago that are treated with massage and pharmacological therapies are similar and they recommend the sue of massage as an alternative treatment option for the patients with lumbago within the framework of a integrated care. Nixon et al (1997) has stated that massage played a role in reducing the pain. In addition to that it is determined in some randomized controlled studies that massage made during labor decreases pain and anxiety; it also improves the general well being and progression of birth process and less reaction is given to the pain (Caton et.al 2002; Simkin & O'Hora 2002).

Non-Pharmacological Therapies in Pain Management 493

Most of the individuals with chronic pains use the praying method. It is indicated that praying has positive results for decreasing the body pain in old people and relieving their physical functional disorders and it is suggested to use the praying method in order to reduce the depression and anxiety that is caused by chronic pain (Meisenhelder & Chandler,

In the traditional meaning, meditation is generally focusing on the moment. Meditation; can also be defined as focusing on the present. This act is realized with an individual focusing on his own respiration, a word or picture. Duration of the meditation can last from a few minutes to 30 minutes or take more (Snyder & Wieland, 2003; Gray, 2004). Considering the fact that meditation helps relaxation, it is thought to be effective in relieving the pain (Gray, 2004). Carson et al (2005) have stated that an 8-week meditation is useful for relieving the

Yoga is providing relaxation by using respiration exercises and meditation with slow movements. It is considered that it can be useful against musculoskeletal pain in terms of using physical stretching moves and increasing strength (Dillard & Knapp, 2005). Individuals that use yoga have stated that they believe in the benefit of this method and it is a cost-effective method. It is stated in a study that applying yoga for 16 weeks has cured the chronic lumbago (Williams et al. 2005). Also, in a study conducted by Williams et al (2005) it has been stated that functional insufficiency experienced with chronic lumbago and use of

Hypnosis; it is the state of conscious change similar to sleep. Hypnosis requires the body to relax and the patient to focus on an object, a stimulant or memory. Hypnosis is *"the deep physical relaxation state during which subconscious can be reached and important abilities are suspended".* In this state, ability of people to be dominated increases (Taşç & Sevil, 2007). Besides mechanism of action of hypnosis over the pain is not known exactly and it is mentioned that the pain is reduced with some physiological changes that occur as a result of hypnosis. Hypnosis has been used in a positive manner in terms of cancer pain, pains in headneck region and phantom pain which is the sensations felt by amputees (Black & Matassarin Jacobs, 1997). Jensens and Patterson (2006) has stated that hypnotherapy/hypnosis is used for analgesia in various types of chronic pains and it has been stated that hypnosis has been effective for neck pain. Also Liossi et al (2006) has made a study with pediatric cancer patients in which it has been determined that hypnosis application has decreased pain and anxiety

Biological feedback is based informing the patient in order to help relaxation or control a physiological function. For example, in cases of tension type headache, it is provided for the electrical activity received by means of head muscles and facial muscles to be perceived as colors or sounds by the patient. Thus, observing the color changes or decreases in the sound,

**2.2.3 Praying** 

2000; Karagöz, 2006).

pain for patients with chronic lumbago.

pain killers have been reduced by means of yoga.

**2.2.4 Meditation** 

**2.2.5 Yoga** 

**2.2.6 Hypnosis** 

level in patients (Liossi et al. 2006).

**2.2.7 Bio-feedback** 

#### **2.1.8 Hydrotherapy (Balneotherapy)**

Using water for treatment by means of thermal springs, potable water resources and other methods is defined as "hydrotherapy" while using the water for therapy by means of temperature effect is defined as "hydrothermal treatment". Effect of hydrotherapy is related to its mechanical or thermal effect. Hot application stimulates the immune system, provides hormones that are suppressing the stress to be released, stimulates the circulation and digestion systems, increases the blood flow and provides muscle relaxation thus reducing the sensitivity developed against the pain (Karagöz, 2006). It is stated in the literature that hydrotherapy is effective while treating back and chronic lumbago (Balogh et al. 2005; Hartel & Volger 2004).

#### **2.2 Cognitive-behavioral therapies**

Cognitive-behavioral therapies are a part of multimodal approach in pain management. These attempts affect not only the pain level but also helps the patients to establish a management feeling of theirselves while dealing with pain and develop management behaviors and improved self-esteem. Cognitive-behavioral therapies can generally be applied by all members of the pain team. Most of the special techniques can be learned and applied by doctors, nurses, social service specialists and psychologists (Yldrm 2006). These therapies should be thought and applied as early as possible before the patient experiences pain (Delaune & Ladner 2002).

#### **2.2.1 Relaxation - respiration techniques and dreaming**

Relaxation techniques cause an increase in slow brain waves in EEG by decreasing oxygen consumption, blood pressure, respiration amount and the number of pulse. Therefore, it is stated that the sensitivity developed against the pain should be prevented by means of these techniques (Karagöz, 2006).

Techniques used in providing the spiritual and physical relaxation are summarized below:


#### **2.2.2 Distraction**

Getting the attention away from the pain reduces its severity. The aim in using that technique is to increases the tolerance for pain and decrease the sensitivity for pain. This method includes listening to music, watching television, reading books and dreaming (Arslan & Çelebioğlu, 2004). There are some sources which supports that distraction is a method used in decreasing the pain (Seers & Carroll 1998; Petry 2002).

#### **2.2.3 Praying**

492 Pain Management – Current Issues and Opinions

Using water for treatment by means of thermal springs, potable water resources and other methods is defined as "hydrotherapy" while using the water for therapy by means of temperature effect is defined as "hydrothermal treatment". Effect of hydrotherapy is related to its mechanical or thermal effect. Hot application stimulates the immune system, provides hormones that are suppressing the stress to be released, stimulates the circulation and digestion systems, increases the blood flow and provides muscle relaxation thus reducing the sensitivity developed against the pain (Karagöz, 2006). It is stated in the literature that hydrotherapy is effective while treating back and chronic lumbago (Balogh et al. 2005;

Cognitive-behavioral therapies are a part of multimodal approach in pain management. These attempts affect not only the pain level but also helps the patients to establish a management feeling of theirselves while dealing with pain and develop management behaviors and improved self-esteem. Cognitive-behavioral therapies can generally be applied by all members of the pain team. Most of the special techniques can be learned and applied by doctors, nurses, social service specialists and psychologists (Yldrm 2006). These therapies should be thought and applied as early as possible before the patient experiences

Relaxation techniques cause an increase in slow brain waves in EEG by decreasing oxygen consumption, blood pressure, respiration amount and the number of pulse. Therefore, it is stated that the sensitivity developed against the pain should be prevented by means of these

Techniques used in providing the spiritual and physical relaxation are summarized below: - *Respiration providing the relaxation:* It is provided to focus on the respiration and avoid disturbing thoughts by taking a deep breath slowly through the nose and giving it back in a long time through the mouth. These techniques can be applied for 5-10 minutes per



Getting the attention away from the pain reduces its severity. The aim in using that technique is to increases the tolerance for pain and decrease the sensitivity for pain. This method includes listening to music, watching television, reading books and dreaming (Arslan & Çelebioğlu, 2004). There are some sources which supports that distraction is a

obtained by directing the patients to dreaming for more than 4 days.

method used in decreasing the pain (Seers & Carroll 1998; Petry 2002).

**2.1.8 Hydrotherapy (Balneotherapy)** 

**2.2 Cognitive-behavioral therapies** 

pain (Delaune & Ladner 2002).

techniques (Karagöz, 2006).

day (Nordin 2002).

**2.2.2 Distraction** 

on his body (Nordin 2002).

**2.2.1 Relaxation - respiration techniques and dreaming** 

Hartel & Volger 2004).

Most of the individuals with chronic pains use the praying method. It is indicated that praying has positive results for decreasing the body pain in old people and relieving their physical functional disorders and it is suggested to use the praying method in order to reduce the depression and anxiety that is caused by chronic pain (Meisenhelder & Chandler, 2000; Karagöz, 2006).

#### **2.2.4 Meditation**

In the traditional meaning, meditation is generally focusing on the moment. Meditation; can also be defined as focusing on the present. This act is realized with an individual focusing on his own respiration, a word or picture. Duration of the meditation can last from a few minutes to 30 minutes or take more (Snyder & Wieland, 2003; Gray, 2004). Considering the fact that meditation helps relaxation, it is thought to be effective in relieving the pain (Gray, 2004). Carson et al (2005) have stated that an 8-week meditation is useful for relieving the pain for patients with chronic lumbago.

#### **2.2.5 Yoga**

Yoga is providing relaxation by using respiration exercises and meditation with slow movements. It is considered that it can be useful against musculoskeletal pain in terms of using physical stretching moves and increasing strength (Dillard & Knapp, 2005). Individuals that use yoga have stated that they believe in the benefit of this method and it is a cost-effective method. It is stated in a study that applying yoga for 16 weeks has cured the chronic lumbago (Williams et al. 2005). Also, in a study conducted by Williams et al (2005) it has been stated that functional insufficiency experienced with chronic lumbago and use of pain killers have been reduced by means of yoga.

#### **2.2.6 Hypnosis**

Hypnosis; it is the state of conscious change similar to sleep. Hypnosis requires the body to relax and the patient to focus on an object, a stimulant or memory. Hypnosis is *"the deep physical relaxation state during which subconscious can be reached and important abilities are suspended".* In this state, ability of people to be dominated increases (Taşç & Sevil, 2007). Besides mechanism of action of hypnosis over the pain is not known exactly and it is mentioned that the pain is reduced with some physiological changes that occur as a result of hypnosis. Hypnosis has been used in a positive manner in terms of cancer pain, pains in headneck region and phantom pain which is the sensations felt by amputees (Black & Matassarin Jacobs, 1997). Jensens and Patterson (2006) has stated that hypnotherapy/hypnosis is used for analgesia in various types of chronic pains and it has been stated that hypnosis has been effective for neck pain. Also Liossi et al (2006) has made a study with pediatric cancer patients in which it has been determined that hypnosis application has decreased pain and anxiety level in patients (Liossi et al. 2006).

#### **2.2.7 Bio-feedback**

Biological feedback is based informing the patient in order to help relaxation or control a physiological function. For example, in cases of tension type headache, it is provided for the electrical activity received by means of head muscles and facial muscles to be perceived as colors or sounds by the patient. Thus, observing the color changes or decreases in the sound,

Non-Pharmacological Therapies in Pain Management 495

products in addition to their medical treatments with drugs without consulting to any professional (Turan et al. 2010 ; Deng et al. 2005). It is stated in the literature that herbal medicine has been commonly used to treat lumbago and back pains (Gray, 2004; Gagnier et

Aromatherapy is using the essential oils that are obtained from flowers, herbs and trees to improve health and well being. These oils are applied by being respired through oily gauze that is placed under the nostrils of the patient or as massage oils being applied on skin. It has been evidenced that the aroma oils reached the lymph system by means of blood circulation and provided recovery by means of intercellular fluids (Turan et al. 2010). It is thought that aromatherapy may be able to help reducing stress, treating cold, sniffles, skin and menstruation problems and relieving pain (Karagöz, 2006; Jennings, 2004; Yldrm et al. 2006; Deng et al. 2005). It is known that lavender oil is used in treating migraine pain, osteoarthritis, rheumatoid arthritis and lumbago. It is also known that eucalyptus, black pepper, ginger, daisy, licorice, rosemary and myrrh oils are used in relieving pain. But it is stated that lavender oil can cause hypersomnia and using licorice for long time can cause hypertension (Delaune & Ladner 2002). Although the usage of aromatherapy within health system increases day by day it is seen that the researches in this meaning is quite insufficient. Data regarding the efficiency of essential oils depend only on individual experiences. For this reason, it is necessary to conduct studies with large samples and high level of evidence to determine the efficiency of essential oils in pain management (Snyder &

Chiropractics is the neck-pulling movement used in treatment of the disorders in connective tissues and musculoskeletal system which consists of muscles, joints, bones, tendon, cartilage and ligaments. The main principle of this approach is the fact that to relieve the pain and to improve health with the applications made on spine and joints which have had a positive effect on neural system and natural defense mechanisms (Gray, 2004). Chiropractics have focused on the connection between body structure and the functions of the neural system and manipulation of bones and joints to regain the health. It is known that the application that is taken, decreases the amount of burden on the neck and relives the pain. However, the individuals who have serious disorders such as severe cervical disc hernia, complaints due to rheumatoid arthritis , tumors and infection have to avoid from

Many studies that have been conducted have sown that the music had positive effects on pain and anxiety and increased the living quality of the patient or healthy individuals. Music reduces heart rate, blood pressure, body temperature and respiration rate and it distraction the attention of the patient to another point thus reducing the pain perception and reducing especially the nausea due to chemotherapy so that increasing living quality of patients in terminal period of cancer (Chase, 2003; Hilliard, 2003; Deng et al. 2005; Stefano et al. 2004, Uçan & Ovayolu 2007). In a study that states listening to music stimulates the alpha waves of brain which have been determined as a stimulator for the release of endorphin and

these applications (Turan et al. 2010; Karagöz 2006; Deng et al. 2005).

al. 2006; Hartel & Volger 2004).

**2.3.3 Aromatherapy** 

Wieland 2003; Tseng 2005)

**2.3.4 Chiropractics** 

**2.3.5 Musical therapy** 

the patient understands whether the relaxation occurred or not (Uçan & Ovayolu 2007). Biofeedback is used for treatment in the cases of pain, migraine pain, spinal cord injuries and movement disorders. It is aimed to control of physiological reactions such as muscle tension, body temperature, heart rate, brain wave activity and other vital parameters. Efficiency of the treatment depends on the desire that a patient shows for learning of how controlling of these functions and participation of patient in the process. Biofeedback appliers train the patient in terms of mental and physical exercises, visualization and deep breaths ( Eidelson, 2005). In many types of chronic pain the bio-feedback has been shown to be effective (Moseikin 2003; Teyhen et al. 2005).

#### **2.2.8 Behavioral therapy**

Aim of this therapy is to increase the functional level of the patient decrease the maladaptive behaviors and firstly reduce and then completely stop painkiller usage. The family is trained by the treatment team; description of pain (grimacing, moaning, and remaining motionless) is avoided and well-adaptive behaviors such as physical activities are reinforced (Brietbart et al. 2004).

#### **2.3 Other non-pharmacological therapies**

#### **2.3.1 Reflexology**

Reflexology is a technique that is based on the principle that suggests there are reflex points on our feet corresponding to all parts of our bodies , all organs and systems and these points are the mirrors of the body anatomy. Pressure applied to these reflex points by special hand and finger techniques provides the stress to be relieved and cause physiological changes and a reduction in pain perception (Yldrm, Fadloğlu and Uyar, 2006). There are totally five pressurizing techniques to make massage on reflex areas: Thumb move, finger move, rubbing move, patting move and compressing move. These moves are applied to ears, hands and feet similarly. The important thing here is to know how this technique will be applied to whom. Physical structure of an individual, age and current health status are taken into consideration. Treatment consists of applying pressure with the side of a thumb or other fingers and turning it clockwise. This pressure is generally deep but it does not have to be painful. A good reflexologist prefers repetition of short and painless seances to a single but painful seances for the whole disease. Intensity of the pressure can be low at the beginning and increased as the treatment progresses. Each seance takes from 10 minutes to 30 minutes and it is decided according to the situation of the person how many seance will be necessary (Stephenson et al. 2000; Bolsoy 2008).

It is stated in the literature that reflexology is used especially for reducing migraine pain, back pain, muscle pain, end stage cancer pain and side effects of chemotherapy and to increase living quality (Long et al. 2001; McNeill et al. 2006; Mollart 2003; Quattrin et al.2006; Wringht et al.2002) In spite of that, it is stated that it is unfavorable to use reflexology in acute infections and fever situation, deep venous thrombosis, surgical situations and in cases of open scars, malign melanoma and during first trimester of the pregnancy or with the patients that has miscarriage or premature birth risks (Long et al. 2001; Lett 2002).

#### **2.3.2 Herbal treatments**

Herbal medicine is using the chemical materials obtained from inside, root, leave, seed and flower parts of the herbs for treatment (Karagöz 2006). Today, most individuals use herbal products in addition to their medical treatments with drugs without consulting to any professional (Turan et al. 2010 ; Deng et al. 2005). It is stated in the literature that herbal medicine has been commonly used to treat lumbago and back pains (Gray, 2004; Gagnier et al. 2006; Hartel & Volger 2004).

#### **2.3.3 Aromatherapy**

494 Pain Management – Current Issues and Opinions

the patient understands whether the relaxation occurred or not (Uçan & Ovayolu 2007). Biofeedback is used for treatment in the cases of pain, migraine pain, spinal cord injuries and movement disorders. It is aimed to control of physiological reactions such as muscle tension, body temperature, heart rate, brain wave activity and other vital parameters. Efficiency of the treatment depends on the desire that a patient shows for learning of how controlling of these functions and participation of patient in the process. Biofeedback appliers train the patient in terms of mental and physical exercises, visualization and deep breaths ( Eidelson, 2005). In many types of chronic pain the bio-feedback has been shown to be effective

Aim of this therapy is to increase the functional level of the patient decrease the maladaptive behaviors and firstly reduce and then completely stop painkiller usage. The family is trained by the treatment team; description of pain (grimacing, moaning, and remaining motionless) is avoided and well-adaptive behaviors such as physical activities are reinforced (Brietbart

Reflexology is a technique that is based on the principle that suggests there are reflex points on our feet corresponding to all parts of our bodies , all organs and systems and these points are the mirrors of the body anatomy. Pressure applied to these reflex points by special hand and finger techniques provides the stress to be relieved and cause physiological changes and a reduction in pain perception (Yldrm, Fadloğlu and Uyar, 2006). There are totally five pressurizing techniques to make massage on reflex areas: Thumb move, finger move, rubbing move, patting move and compressing move. These moves are applied to ears, hands and feet similarly. The important thing here is to know how this technique will be applied to whom. Physical structure of an individual, age and current health status are taken into consideration. Treatment consists of applying pressure with the side of a thumb or other fingers and turning it clockwise. This pressure is generally deep but it does not have to be painful. A good reflexologist prefers repetition of short and painless seances to a single but painful seances for the whole disease. Intensity of the pressure can be low at the beginning and increased as the treatment progresses. Each seance takes from 10 minutes to 30 minutes and it is decided according to the situation of the person how many seance will

It is stated in the literature that reflexology is used especially for reducing migraine pain, back pain, muscle pain, end stage cancer pain and side effects of chemotherapy and to increase living quality (Long et al. 2001; McNeill et al. 2006; Mollart 2003; Quattrin et al.2006; Wringht et al.2002) In spite of that, it is stated that it is unfavorable to use reflexology in acute infections and fever situation, deep venous thrombosis, surgical situations and in cases of open scars, malign melanoma and during first trimester of the pregnancy or with the patients that has miscarriage or premature birth risks (Long et al. 2001; Lett 2002).

Herbal medicine is using the chemical materials obtained from inside, root, leave, seed and flower parts of the herbs for treatment (Karagöz 2006). Today, most individuals use herbal

(Moseikin 2003; Teyhen et al. 2005).

**2.3 Other non-pharmacological therapies** 

be necessary (Stephenson et al. 2000; Bolsoy 2008).

**2.2.8 Behavioral therapy** 

et al. 2004).

**2.3.1 Reflexology** 

**2.3.2 Herbal treatments** 

Aromatherapy is using the essential oils that are obtained from flowers, herbs and trees to improve health and well being. These oils are applied by being respired through oily gauze that is placed under the nostrils of the patient or as massage oils being applied on skin. It has been evidenced that the aroma oils reached the lymph system by means of blood circulation and provided recovery by means of intercellular fluids (Turan et al. 2010). It is thought that aromatherapy may be able to help reducing stress, treating cold, sniffles, skin and menstruation problems and relieving pain (Karagöz, 2006; Jennings, 2004; Yldrm et al. 2006; Deng et al. 2005). It is known that lavender oil is used in treating migraine pain, osteoarthritis, rheumatoid arthritis and lumbago. It is also known that eucalyptus, black pepper, ginger, daisy, licorice, rosemary and myrrh oils are used in relieving pain. But it is stated that lavender oil can cause hypersomnia and using licorice for long time can cause hypertension (Delaune & Ladner 2002). Although the usage of aromatherapy within health system increases day by day it is seen that the researches in this meaning is quite insufficient. Data regarding the efficiency of essential oils depend only on individual experiences. For this reason, it is necessary to conduct studies with large samples and high level of evidence to determine the efficiency of essential oils in pain management (Snyder & Wieland 2003; Tseng 2005)

#### **2.3.4 Chiropractics**

Chiropractics is the neck-pulling movement used in treatment of the disorders in connective tissues and musculoskeletal system which consists of muscles, joints, bones, tendon, cartilage and ligaments. The main principle of this approach is the fact that to relieve the pain and to improve health with the applications made on spine and joints which have had a positive effect on neural system and natural defense mechanisms (Gray, 2004). Chiropractics have focused on the connection between body structure and the functions of the neural system and manipulation of bones and joints to regain the health. It is known that the application that is taken, decreases the amount of burden on the neck and relives the pain. However, the individuals who have serious disorders such as severe cervical disc hernia, complaints due to rheumatoid arthritis , tumors and infection have to avoid from these applications (Turan et al. 2010; Karagöz 2006; Deng et al. 2005).

#### **2.3.5 Musical therapy**

Many studies that have been conducted have sown that the music had positive effects on pain and anxiety and increased the living quality of the patient or healthy individuals. Music reduces heart rate, blood pressure, body temperature and respiration rate and it distraction the attention of the patient to another point thus reducing the pain perception and reducing especially the nausea due to chemotherapy so that increasing living quality of patients in terminal period of cancer (Chase, 2003; Hilliard, 2003; Deng et al. 2005; Stefano et al. 2004, Uçan & Ovayolu 2007). In a study that states listening to music stimulates the alpha waves of brain which have been determined as a stimulator for the release of endorphin and

Non-Pharmacological Therapies in Pain Management 497

In a study they conducted, Nilsson et al (2003) have stated that listening to music for one hour in earl post-operative period may reduce post-operative pain and morphine consumption of the patients. In a study conducted by Sahler and Hunter (2003) with the patients who had bone marrow transplantation, the patients were made to listen music which has a relaxing effect, at least twice a week for 45 minutes and it has been determined that the group which was not included to music therapy has a higher pain score when compared to the one that has received musical therapy. It has been stated that the musical also has positive effects during labor period. In a study that is conducted by Browning (2000) related to the mother's pain and anxiety levels to evaluate the effect of musical therapy applied to primipar mothers before delivery, the mothers have stated that the musical therapy relives their pain and it made them

Advantages and disadvantages of some non-pharmacological methods used in pain

As a result, the pain can be managed in a more effective manner with the combination of pharmacological and non-pharmacological therapies. Developments in pain management may provide different opportunities to the patients and their families thus providing the patients to carry on a more comfortable and productive life. Both health personnel and caregivers need to have important responsibilities while following these developments. For an effective care to be provided to patients, developments regarding pain management and updated pharmacological and non-pharmacological approaches regarding pain management and pain should be followed. Also these techniques may help reducing pain and it must be encouraged as a part of the comprehensive pain management efforts. For this reason, abilities and preferences of the patient regarding the use of non-pharmacological methods should be taken into consideration; it should be underlined for the patients that these are used together with medical and pharmacological treatments and the use of nonpharmacological methods should be included to the care plan when patient is appropriate and willing. From this point of view, it is recommended to use various non-pharmacological methods for pain management but we need more study results that support the efficiency of these methods. For this reason, it will provide the evidence-based results to be put forward if randomized controlled experimental studies, which examine the efficiency of these

Akdağ, R. G. & Ovayolu, N. (2008). Hemşirelerin Ağr Yönetimi ile İlgili Bilgi, Tutum ve

Alimi, D.; Rubino, C.; Pichard-Leandri, E.; Fernand, B.S.; Dubreuil-Lemaire, M.L. & et al.

Allard, P.; Maunsell, E.; Labbe, J. & Dorval, M. (2001). Educational interventions to improve

Klinik Karar Verme Durumlarnn Değerlendirilmesi. *Gaziantep Üniversitesi Sağlk* 

(2003). Analgesic effect of auricular acupuncture for cancer pain: randomized, blinded, controlled trial. *Journal of Clinical Oncology*, 15;21(22): 4120-4126; Nov 2003.

cancer pain control: a systematic review . *Journal of Palliative Medicine*, Vol.4 , No:2 ,

feel themselves more comfortable and calm.

**3. Conclusion** 

**4. References** 

pp.191-203.

management have been specified below (Table 1).

methods in taking the pain under control, are conducted.

*Bilimleri Enstitüsü,* Master's Thesis.

creates a relaxation state and therefore music has played a role not only in relieving the pain but also decreasing blood pressure, heartbeat rate and other physiological responses (Henry, 1995). A point to be taken into consideration here is to let the music type to be prefered by the patient (Delaune & Ladner, 2002). New studies show that slow music creates a relaxing effect. According to the literature musical therapy should not be used continuously to be an effective method. Applying musical therapy form 25 to 90 minutes per day will provide sufficient treatment period.


Table 1. Advantages and Disadvantages of Some Non-pharmacological Methods

In a study they conducted, Nilsson et al (2003) have stated that listening to music for one hour in earl post-operative period may reduce post-operative pain and morphine consumption of the patients. In a study conducted by Sahler and Hunter (2003) with the patients who had bone marrow transplantation, the patients were made to listen music which has a relaxing effect, at least twice a week for 45 minutes and it has been determined that the group which was not included to music therapy has a higher pain score when compared to the one that has received musical therapy. It has been stated that the musical also has positive effects during labor period. In a study that is conducted by Browning (2000) related to the mother's pain and anxiety levels to evaluate the effect of musical therapy applied to primipar mothers before delivery, the mothers have stated that the musical therapy relives their pain and it made them feel themselves more comfortable and calm.

Advantages and disadvantages of some non-pharmacological methods used in pain management have been specified below (Table 1).

#### **3. Conclusion**

496 Pain Management – Current Issues and Opinions

creates a relaxation state and therefore music has played a role not only in relieving the pain but also decreasing blood pressure, heartbeat rate and other physiological responses (Henry, 1995). A point to be taken into consideration here is to let the music type to be prefered by the patient (Delaune & Ladner, 2002). New studies show that slow music creates a relaxing effect. According to the literature musical therapy should not be used continuously to be an effective method. Applying musical therapy form 25 to 90 minutes per day will provide

**Attempt Advantage Disadvantage** 

 The patients should be aware of using the management strategies by

 An appropriate time zone is needed to teach the

It requires an experienced

increase the bleeding or edema after acute injuries.

It requires an experienced

 There is a risk for bleeding and infection. There are no reliable

> results for use in cases of pregnant women.

 It may cause hypersomnia. Some herbs should not be used with other antidepressants and alcohol.

It requires an experienced

therapist.

therapist.

theirselves.

attempts.

therapist.

Hot application can

 Cold application is contraindicate for the situations such as uritcaria/hypersensitivity, hypertension, Reynaud's phenomenon and sickle cell anemia which are related to cold.

without having drug-related side effects. It can be used more likely as an adjuvant therapy together with other methods. It may increase the management feeling of

 Most of them are not expensive, they do not require special equipment and they are

 It may reduce the pain and anxiety of the patients who have pains that are relatively

 It may increase the number of methods that the patient uses to manage.

 It can be used more likely as an adjuvant therapy together with other methods. It may increase the controlling ability of pain feeling of the patient.

It may be applied by the patients or

It reduces the pain without having any

 It can be used more likely as an adjuvant therapy together with other methods. It gives the feeling of pain management to

It has a sedative and relaxing effect.

It may provide pain reduction without any

 It can be used more likely as an adjuvant therapy together with other methods.

Table 1. Advantages and Disadvantages of Some Non-pharmacological Methods

drug-related side effects.

It may reduce the pain and anxiety

the patient.

easily applicable.

difficult to manage.

It is so easy to use.

families. It is a cheap method.

the patient.

side effects.

Aromatherapy It has an analgesic effect.

 It may reduce muscle spasms, inflammation and pain.

sufficient treatment period.

Relaxation Bio-feedback Distraction

Psychotherapy, Hypnosis

Stimulation/Cutane ous Stimulation (superficial hot-cold application and massage)

Transcutaneous Electrical Nerve Stimulation (TENS)

Acupuncture

Skin

As a result, the pain can be managed in a more effective manner with the combination of pharmacological and non-pharmacological therapies. Developments in pain management may provide different opportunities to the patients and their families thus providing the patients to carry on a more comfortable and productive life. Both health personnel and caregivers need to have important responsibilities while following these developments. For an effective care to be provided to patients, developments regarding pain management and updated pharmacological and non-pharmacological approaches regarding pain management and pain should be followed. Also these techniques may help reducing pain and it must be encouraged as a part of the comprehensive pain management efforts. For this reason, abilities and preferences of the patient regarding the use of non-pharmacological methods should be taken into consideration; it should be underlined for the patients that these are used together with medical and pharmacological treatments and the use of nonpharmacological methods should be included to the care plan when patient is appropriate and willing. From this point of view, it is recommended to use various non-pharmacological methods for pain management but we need more study results that support the efficiency of these methods. For this reason, it will provide the evidence-based results to be put forward if randomized controlled experimental studies, which examine the efficiency of these methods in taking the pain under control, are conducted.

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**24** 

*1,2Taiwan 3Japan* 

**Overview of Collateral** 

*3Painless Hospital, Ginza, Tokyo,* 

**Meridian Therapy in Pain Management:** 

Chih-Shung Wong1, Chun-Chang Yeh2 and Shan-Chi Ko3 *1Department of Anaesthesiology, Cathay General Hospital, Taipei, 2Department of Anaesthesiology, Tri-Service General Hospital, Taipei,* 

**A Modified Formulated Chinese Acupuncture** 

The Western approach to pain management is focused on the use of pharmacotherapy, physical therapy, nerve blocks, nerve ablations, implantable devices. Even though increasing of understanding of the mechanisms of pain for the treatments; some pains remain intractable (Hariharan et al, 2007; Wagner et al, 2007; Laxmaiah et al, 2009). In contrast, traditional Chinese medicine (TCM) centres primarily on the energy relationship among the environment and the body and organs, without a clear understanding of pathophysiology or the mechanisms of diseases and its effects are varied and inconsistent. The collateral meridian therapy (CMT), offers an alternative treatment for different types of pain by taking a systematic approach to a variant of traditional Chinese acupuncture (TCA). Here, we highlight the recent development of CMT by describing the main theory, discussing the differences between CMT and TCA, defining abbreviations associated with CMT, explaining acupoint localization principles, and providing clinical reports for

To achieve an understanding of CMT, it is necessary to revisit the modality on which it is based. In TCA, it is believed that the manipulation of certain points on the skin can affect the movement of energy, or "Qi", throughout the body. It is assumed that "Qi" flows in channels, or meridians, along the body, and that good health is maintained through balancing the circulation of Qi along these channels. In TCA, there are 12 established meridians. On these 12 meridians, a total 361 acupoints are located through which the flow of Qi can be manipulated. The selection of points for treatment, following the "one-needle effect", where therapeutic effect is obtained from manipulation of one strong acupoint, is based on the nature of the disease treated as defined by the five-element theory of TCM, and by a number of personal factors. As a result, the treatment for disease is changed on a case-by-case basis. There has no

standard method; the effectiveness of TCA varies from patient to patient.

**1. Introduction** 

application in pain management.

**2. The theory behind CMT** 


## **Overview of Collateral Meridian Therapy in Pain Management: A Modified Formulated Chinese Acupuncture**

Chih-Shung Wong1, Chun-Chang Yeh2 and Shan-Chi Ko3 *1Department of Anaesthesiology, Cathay General Hospital, Taipei, 2Department of Anaesthesiology, Tri-Service General Hospital, Taipei, 3Painless Hospital, Ginza, Tokyo, 1,2Taiwan 3Japan* 

#### **1. Introduction**

502 Pain Management – Current Issues and Opinions

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The Western approach to pain management is focused on the use of pharmacotherapy, physical therapy, nerve blocks, nerve ablations, implantable devices. Even though increasing of understanding of the mechanisms of pain for the treatments; some pains remain intractable (Hariharan et al, 2007; Wagner et al, 2007; Laxmaiah et al, 2009). In contrast, traditional Chinese medicine (TCM) centres primarily on the energy relationship among the environment and the body and organs, without a clear understanding of pathophysiology or the mechanisms of diseases and its effects are varied and inconsistent. The collateral meridian therapy (CMT), offers an alternative treatment for different types of pain by taking a systematic approach to a variant of traditional Chinese acupuncture (TCA). Here, we highlight the recent development of CMT by describing the main theory, discussing the differences between CMT and TCA, defining abbreviations associated with CMT, explaining acupoint localization principles, and providing clinical reports for application in pain management.

#### **2. The theory behind CMT**

To achieve an understanding of CMT, it is necessary to revisit the modality on which it is based. In TCA, it is believed that the manipulation of certain points on the skin can affect the movement of energy, or "Qi", throughout the body. It is assumed that "Qi" flows in channels, or meridians, along the body, and that good health is maintained through balancing the circulation of Qi along these channels. In TCA, there are 12 established meridians. On these 12 meridians, a total 361 acupoints are located through which the flow of Qi can be manipulated. The selection of points for treatment, following the "one-needle effect", where therapeutic effect is obtained from manipulation of one strong acupoint, is based on the nature of the disease treated as defined by the five-element theory of TCM, and by a number of personal factors. As a result, the treatment for disease is changed on a case-by-case basis. There has no standard method; the effectiveness of TCA varies from patient to patient.

Overview of Collateral Meridian Therapy in Pain

both TyI, TyII, TyIII and AyI, AyII, AyIII).

**2.2 Abbreviations in CMT** 

extremity (T) (see Fig. 8a).

Management: A Modified Formulated Chinese Acupuncture 505

Fig. 2. The numbers 6, 5, 4, 3, 2, 1 and letters a, b, c are the treatment function points of six yin meridians. The blue points indicated control-point of each yang meridian (3, 2, and 3 for

The abbreviations used in CMT are defined as follows: "T" represents the upper extremity (Te is the pronunciation of "arm" in Japanese); "A" represents the lower extremity (Ashi is the pronunciation of "leg" in Japanese); the roman numerals, I, II and III represent the meridians on the radial, median and unlar side of the upper extremities, and the meridians on the anterior, medial (or lateral), and posterior aspect on the lower extremities, respectively. The use of "x" symbolizes the yin aspect, and use of "y" denotes the yang aspect of the extremities. Each extremity had nine acupoints in which point a, b and c are located on the hand or foot, and point 1 to 6 are located on the arm or leg (Figs. 1 and 2). The letters "r" and "l" represent the right and left side of the limb, respectively. For example, "lTyI" describes a meridian on the dorsal aspect (y) of the radial side (I) of the left (l) upper

**2.3 How CMT identifies the diseased meridian and formulates a treatment protocol**  For the purpose of simplicity, the symbols "/", "()" and "." are used to describe diseased or treatment meridians. For example, if the diseased region is over the right wrist (corresponding to "a", Fir. 3) of the TyI meridian, it is represented by rTyI/a. If the treatment meridian selected is lTxI/1:a, then constant pressure is applied on the C-point "1' of the lTxI meridian (Fig. 1), while a "remove" manoeuvre at the corresponding "a" point is simultaneously performed on the lTxI meridian. The letter "1" before ":" signifies the Cpoint of the lTxI meridian, while the letter "a" after ":" expresses the F-point "a". T denote a supplement or enhancement manoeuvre, place "()" around "a" to make the treatment

In CMT, however, two acuponts are manipulated, instead of one. The meridian lines are the same as in TCA, but each meridian has only nice standard acuponits (a total of 108). Two acupoints are used for redirection the flow of Qi from one meridian to another. As such, in CMT, the points selected for treatment are commonly on non-diseased meridians. CMT also follows the use of a standardized set of protocol for treatment, instead of the individual varied treatments given in TCA. The two points manipulated are known as control C-point and functional F-point. These points are specific to each meridian and allow the flow of Qi to be linked from the diseased meridian to a healthy one.

#### **2.1 Two-point theory: C-point and F-point**

The C-point is used to connect the diseased meridian and the healthy meridian. In treatment, practitioners manipulate the healthy meridian to relieve the pain or symptoms. Obstructed energy Qi is allowed to flow from the lesion site to the unobstructed healthy meridian, through which the disease will be discharged. Each meridian has its own C-point. For the location of C-points, please see figures 1 and 2. For the abbreviations and anatomical definition of C-points, please see table 1. The C-point is for linking the diseased meridian to the treatment meridian, and the F-point is for the treatment of the disease symptom or painful location. The F-points in the different regions of the body are shown in figure 3. Each region of pain or disease in the body is represented by its own F-point. For instance, if the patient had pain in the neck of shoulder, the practitioner should select "a" as an F-point for treatment (Fig. 3). If a patient has an acute lumbar strain, the F-point over the lumbar L4-5 region would be "4"; the F-point over the lumbar L3-4 region would be "5" (Fig. 3).

Fig. 1. The numbers 6, 5, 4, 3, 2, 1 and letters a, b, c are the treatment function points of six yin meridians. The blue points indicated control-point of each yin meridian (1, 2, and 1 for TxI, TxII, TxIII; b, 2 and a for AxI, AxII, AxIII).

In CMT, however, two acuponts are manipulated, instead of one. The meridian lines are the same as in TCA, but each meridian has only nice standard acuponits (a total of 108). Two acupoints are used for redirection the flow of Qi from one meridian to another. As such, in CMT, the points selected for treatment are commonly on non-diseased meridians. CMT also follows the use of a standardized set of protocol for treatment, instead of the individual varied treatments given in TCA. The two points manipulated are known as control C-point and functional F-point. These points are specific to each meridian and allow the flow of Qi

The C-point is used to connect the diseased meridian and the healthy meridian. In treatment, practitioners manipulate the healthy meridian to relieve the pain or symptoms. Obstructed energy Qi is allowed to flow from the lesion site to the unobstructed healthy meridian, through which the disease will be discharged. Each meridian has its own C-point. For the location of C-points, please see figures 1 and 2. For the abbreviations and anatomical definition of C-points, please see table 1. The C-point is for linking the diseased meridian to the treatment meridian, and the F-point is for the treatment of the disease symptom or painful location. The F-points in the different regions of the body are shown in figure 3. Each region of pain or disease in the body is represented by its own F-point. For instance, if the patient had pain in the neck of shoulder, the practitioner should select "a" as an F-point for treatment (Fig. 3). If a patient has an acute lumbar strain, the F-point over the lumbar L4-5 region would be "4"; the F-point over the lumbar L3-4 region would be "5" (Fig. 3).

Fig. 1. The numbers 6, 5, 4, 3, 2, 1 and letters a, b, c are the treatment function points of six yin meridians. The blue points indicated control-point of each yin meridian (1, 2, and 1 for

to be linked from the diseased meridian to a healthy one.

**2.1 Two-point theory: C-point and F-point** 

TxI, TxII, TxIII; b, 2 and a for AxI, AxII, AxIII).

Fig. 2. The numbers 6, 5, 4, 3, 2, 1 and letters a, b, c are the treatment function points of six yin meridians. The blue points indicated control-point of each yang meridian (3, 2, and 3 for both TyI, TyII, TyIII and AyI, AyII, AyIII).

#### **2.2 Abbreviations in CMT**

The abbreviations used in CMT are defined as follows: "T" represents the upper extremity (Te is the pronunciation of "arm" in Japanese); "A" represents the lower extremity (Ashi is the pronunciation of "leg" in Japanese); the roman numerals, I, II and III represent the meridians on the radial, median and unlar side of the upper extremities, and the meridians on the anterior, medial (or lateral), and posterior aspect on the lower extremities, respectively. The use of "x" symbolizes the yin aspect, and use of "y" denotes the yang aspect of the extremities. Each extremity had nine acupoints in which point a, b and c are located on the hand or foot, and point 1 to 6 are located on the arm or leg (Figs. 1 and 2). The letters "r" and "l" represent the right and left side of the limb, respectively. For example, "lTyI" describes a meridian on the dorsal aspect (y) of the radial side (I) of the left (l) upper extremity (T) (see Fig. 8a).

#### **2.3 How CMT identifies the diseased meridian and formulates a treatment protocol**

For the purpose of simplicity, the symbols "/", "()" and "." are used to describe diseased or treatment meridians. For example, if the diseased region is over the right wrist (corresponding to "a", Fir. 3) of the TyI meridian, it is represented by rTyI/a. If the treatment meridian selected is lTxI/1:a, then constant pressure is applied on the C-point "1' of the lTxI meridian (Fig. 1), while a "remove" manoeuvre at the corresponding "a" point is simultaneously performed on the lTxI meridian. The letter "1" before ":" signifies the Cpoint of the lTxI meridian, while the letter "a" after ":" expresses the F-point "a". T denote a supplement or enhancement manoeuvre, place "()" around "a" to make the treatment

Overview of Collateral Meridian Therapy in Pain

Management: A Modified Formulated Chinese Acupuncture 507

The C-point ensures the link to channel Qi from the diseased meridian to the healthy one. Four different types of links are available to channel Qi: 1) Zang-Fu (TA-xy). 2) Exterior-Interior (x-y), 3) Namesake (T-A), and 4) Original meridian links (Fig. 4). The selection of treatment from the diseased meridian is shown in Figure 4. Zang-Fu (TA-xy) is the most common link for treatment. For example, if the diseased meridian is AxI, the treatment meridian is TyIII (TA-xy link) and vice versa. The determination of the treatment meridian, whether ipsilateral or contralateral, is based on the location of the lesion, as shown in Figure 5. For example, if the diseased meridian is rAyI, the treatment meridian is TxII (according to the TA-xy link in Fig. 4). Figure 5 shows that the treatment side for the TxII meridian is contralateral side to the diseased meridian; thus the left side is selected as the treatment side. Figure 6 illustrates the usage of the C-point to link the diseased meridian (rAyI) to the lTxII meridian by the TA-xy link (visceral Znag-Fu link) for treatment, acting as an area of energy discharge. By simultaneously manipulating the C-point and the F-point that corresponds to the painful site, the pain in rAyI will flow to lTxII, and the pain will be removed or reduced by manipulating the functional F-point pressed against the body flow direction (yin meridian). Similarly for the lAyIII or rAyIII problem in post-regional anesthesia/analgesia backache, the treatment meridian will be chosen as rTxI or lTxI (Yeh et al, 2009). Most acupoints are located along the edge of the bony shaft or on the tendinomuscular grooves. The accurate localization of the acupoint can be achieved through patient reports of soreness or painful sensation when the area is pressed deeply. For detailed anatomical localization of acupoints, please refer to 10b, and book by Ko and Chao (2007).

**2.4 How CMT links to channel Qi and diverts the body flow in the meridians** 

Fig. 4. The four types of links used to choose the treatment meridian.

formula lTxI/1:a); otherwise, "a" without "()" represents a removal manoeuvre on point "a". When there is no need to use the C-point, the symbol "0" is used for the treatment meridian. Examples of cases where no C-point is used included yin to yin or yang to yang meridians for namesake (T-A) links, or for the original meridian manipulation. Therefore, the colon symbol ":" is used to differentiate the diseased from the treatment meridian because only the presence of an F-point on the diseased meridian is necessary.

Fig. 3. This figure indicates specific body regions corresponding to F-points. The unique "d" system, different form the ordinary 9-point (6, 5, 4, 3, 2, 1, a, b, c) system on the treatment meridians, corresponds to intracranial, perineum and digits. al: the most painful point between point-a and point-1 on the treatment meridian, ac: the most painful point between point-c and point-b on the treatment meridian.

formula lTxI/1:a); otherwise, "a" without "()" represents a removal manoeuvre on point "a". When there is no need to use the C-point, the symbol "0" is used for the treatment meridian. Examples of cases where no C-point is used included yin to yin or yang to yang meridians for namesake (T-A) links, or for the original meridian manipulation. Therefore, the colon symbol ":" is used to differentiate the diseased from the treatment meridian

Fig. 3. This figure indicates specific body regions corresponding to F-points. The unique "d" system, different form the ordinary 9-point (6, 5, 4, 3, 2, 1, a, b, c) system on the treatment meridians, corresponds to intracranial, perineum and digits. al: the most painful point between point-a and point-1 on the treatment meridian, ac: the most painful point between

point-c and point-b on the treatment meridian.

because only the presence of an F-point on the diseased meridian is necessary.

#### **2.4 How CMT links to channel Qi and diverts the body flow in the meridians**

The C-point ensures the link to channel Qi from the diseased meridian to the healthy one. Four different types of links are available to channel Qi: 1) Zang-Fu (TA-xy). 2) Exterior-Interior (x-y), 3) Namesake (T-A), and 4) Original meridian links (Fig. 4). The selection of treatment from the diseased meridian is shown in Figure 4. Zang-Fu (TA-xy) is the most common link for treatment. For example, if the diseased meridian is AxI, the treatment meridian is TyIII (TA-xy link) and vice versa. The determination of the treatment meridian, whether ipsilateral or contralateral, is based on the location of the lesion, as shown in Figure 5. For example, if the diseased meridian is rAyI, the treatment meridian is TxII (according to the TA-xy link in Fig. 4). Figure 5 shows that the treatment side for the TxII meridian is contralateral side to the diseased meridian; thus the left side is selected as the treatment side. Figure 6 illustrates the usage of the C-point to link the diseased meridian (rAyI) to the lTxII meridian by the TA-xy link (visceral Znag-Fu link) for treatment, acting as an area of energy discharge. By simultaneously manipulating the C-point and the F-point that corresponds to the painful site, the pain in rAyI will flow to lTxII, and the pain will be removed or reduced by manipulating the functional F-point pressed against the body flow direction (yin meridian). Similarly for the lAyIII or rAyIII problem in post-regional anesthesia/analgesia backache, the treatment meridian will be chosen as rTxI or lTxI (Yeh et al, 2009). Most acupoints are located along the edge of the bony shaft or on the tendinomuscular grooves. The accurate localization of the acupoint can be achieved through patient reports of soreness or painful sensation when the area is pressed deeply. For detailed anatomical localization of acupoints, please refer to 10b, and book by Ko and Chao (2007).

Fig. 4. The four types of links used to choose the treatment meridian.

Overview of Collateral Meridian Therapy in Pain

Meridian in

TxI Lung 1

TxIII Heart 1

AxI Spleen b

Energizer <sup>2</sup>

Intestine <sup>3</sup>

AyI Stomach 3

AyII Gall Bladder 2

AyIII Bladder 3

Table 1. Anatomical location of C-points.

TyI Large

TyII Triple

TyIII Small

Meridian in CMT

Management: A Modified Formulated Chinese Acupuncture 509

TxII Pericardia 2 Approximately three finger breadths proximal to

AxII Liver 2 Approximately 1 cm posterior to the AxI/2 at the

AxIII Kidney a On the tangent line to the posterior border of the

(Fig. 8a).

(Fig. 10a).

10a, b).

CMT: Collateral Meridian Therapy; TCA: Traditional Chinese Acupuncture

the TxI/a (Fig. 7b).

On the junction of the metaphysis and diaphysis over the distal radius. The pressure should be applied on the radial side of the flexor carbi radialis directly on the bone; pressure to the radial artery should be avoided (Fig. 7a).

On the radial depression of the flexor carbi ulnaris at the junction of the metaphysis and diaphysis over the distal ulna (Fig. 7a).

On the tangent line to the plantar-medial

diaphysis over the proximal end of first

same horizontal level as AxI/2 (Fig. 9a).

at the musculotendinous junction (Fig. 8a).

Between the distal ulna and radius about onesixth of the distance above TyII/a toward the olecranon (approximately three finger breadths

On the tangent line to the radial border of the dorsal ulna at the musculotendinous junction

On the tangent line to the anterior border of the fibula at the same horizontal level as AyIII/3

First identify the Chinese traditional acupoint BL57 (Chengshan), which is in the depression below the belly of the gastrocnemius when the leg is stretched or the heel is lifted. After pressing BL57, find two lines running from it lateroinferiorly and medioinferiorly; AyIII/3 point is at the lateroinferior end on the tangent line to the posterior surface of the fibula (Fig.

At the same horizontal level as AyIII/3, approximately one finger breadth posterior to the anterior crest of the tibia (Fig. 10a).

metatarsal bone (Fig. 9a, b).

medial malleolus (Fig. 9a).

proximal to TyII/a) (Fig. 8b).

Intestine 3 On the tangent line to the ulnar side of the radius

depression at the junction of the metaphysis and

TCA C-Point Actual anatomical location


Fig. 5. Determination to choose contralateral or ipsilateral side or ipsilateral side of treatment meridian. For yin meridians used as the treatment ones to divert the obstructed flow, all of them must choose the opposite side to the diseased meridian, except for TxIII. On the other hand, for yang meridians used, all must choose the same side as the diseased meridian, except for TyI.

Fig. 6. Illustratin of the proposed mechanism of pain reduction.

#### **2.5 Clinical reports for application in pain management**

Case studies have shown the effectiveness of CMT on the treatment of intractable pain (Wong et al, 2006). Patients suffering from intricate chronic pain, such as post-herpetic neuralgia and complex regional pain syndrome, are responded dramatically to the CMT treatment (Wong et al, 2007). Moreover, CMT is also observed effectively on local musculoskeletal pain that resulted from such injuries as sprains or strains and demonstrated positive effect on shoulder pain relief after laparcoscopic surgery (Yeh et al, 2008). CMT is also an effect technique to reduce painful dysmenorrhea (Lin et al, 2010). Moreover, CMT is also highly effective in the treatment of post-neuraxial block backache in patients who were failed to treated by the conventional treatment (Yeh et al, 2009). Over the post few years, Dr. Ko and his team have repeatedly demonstrated positive results of this therapy through workshops, courses and pain clinics throughout Japan., Taiwan, Singapore and the United States (Hoka et al, 2008). A mini-symposium on CMT was also offered in the 13th World Society of Pain Clinicians Congress for the World Institute of Pain Meeting in 2008.

(x) (y)

Fig. 5. Determination to choose contralateral or ipsilateral side or ipsilateral side of treatment meridian. For yin meridians used as the treatment ones to divert the obstructed flow, all of them must choose the opposite side to the diseased meridian, except for TxIII. On the other hand, for yang meridians used, all must choose the same side as the diseased

Fig. 6. Illustratin of the proposed mechanism of pain reduction.

Case studies have shown the effectiveness of CMT on the treatment of intractable pain (Wong et al, 2006). Patients suffering from intricate chronic pain, such as post-herpetic neuralgia and complex regional pain syndrome, are responded dramatically to the CMT treatment (Wong et al, 2007). Moreover, CMT is also observed effectively on local musculoskeletal pain that resulted from such injuries as sprains or strains and demonstrated positive effect on shoulder pain relief after laparcoscopic surgery (Yeh et al, 2008). CMT is also an effect technique to reduce painful dysmenorrhea (Lin et al, 2010). Moreover, CMT is also highly effective in the treatment of post-neuraxial block backache in patients who were failed to treated by the conventional treatment (Yeh et al, 2009). Over the post few years, Dr. Ko and his team have repeatedly demonstrated positive results of this therapy through workshops, courses and pain clinics throughout Japan., Taiwan, Singapore and the United States (Hoka et al, 2008). A mini-symposium on CMT was also offered in the 13th World

Society of Pain Clinicians Congress for the World Institute of Pain Meeting in 2008.

**2.5 Clinical reports for application in pain management** 

meridian, except for TyI.


CMT: Collateral Meridian Therapy; TCA: Traditional Chinese Acupuncture

Table 1. Anatomical location of C-points.

Overview of Collateral Meridian Therapy in Pain

Management: A Modified Formulated Chinese Acupuncture 511

Fig. 8. (a) Dorsal view of upper extremity for localization of acupoints on TyI and TyIII.

(b) Dorsal view of upper extremity for localization of acupoints on TyII.

Fig. 7. (a) Volar view of upper extremity for localization of acupoints on TxI and TxIII. (b) Volar view of upper extremity for localization of acupoints on TxII.

Fig. 7. (a) Volar view of upper extremity for localization of acupoints on TxI and TxIII.

(b) Volar view of upper extremity for localization of acupoints on TxII.

Fig. 8. (a) Dorsal view of upper extremity for localization of acupoints on TyI and TyIII. (b) Dorsal view of upper extremity for localization of acupoints on TyII.

Overview of Collateral Meridian Therapy in Pain

Management: A Modified Formulated Chinese Acupuncture 513

Fig. 10. (a) Lateral view of lower extremity for localization of acupoints on AyI, AyII and AyIII. (b) Posterior view of lower extremity for localization of acupoints on AyII and AyIII.

Fig. 9. (a) Medial view of lower extremity for localization of acupoints on AxI and most of AxII and AxIII (except for AxII/b AxII/c and AxIII/c). (b) Anterior view of lower extremity for localization of on AxI and AxII. The dotted line is extended along the curve of the lower border of the medial gastrocnemius belly.

Fig. 9. (a) Medial view of lower extremity for localization of acupoints on AxI and most of AxII and AxIII (except for AxII/b AxII/c and AxIII/c). (b) Anterior view of lower extremity for localization of on AxI and AxII. The dotted line is extended along the curve of the lower

border of the medial gastrocnemius belly.

Fig. 10. (a) Lateral view of lower extremity for localization of acupoints on AyI, AyII and AyIII. (b) Posterior view of lower extremity for localization of acupoints on AyII and AyIII.

Overview of Collateral Meridian Therapy in Pain

(year) [Ref] Condition treated

CMT, collateral meridian therapy. +, Yes; –, Not observed Table 3. Clinical reports of CMT for pain management

understanding of this technique and theory.

First author

**3. Conclusion** 

**4. Acknowledgment** 

2007, 22: 485-490.

this chapter.

**5. References** 

Management: A Modified Formulated Chinese Acupuncture 515

Wong et al (2006) Acute and chronic intractable pain + + Lin et al (2010) Primary dysmenorrhea + – Wong et al (2007) Complex regional pain syndrome + + Hoka et al (2008) Complex regional pain syndrome + + Yeh et al (2008) Shoulder-tip pain + + Yeh et al (2009) Post-regional anesthesia/analgesia backache + +

CMT provides a different approach for managing intractable pain and various illnesses. It may play a role in the field of complementary and alternative medicine. The role of CMT in pain management looks promising for both acute and chronic pain, even including intractable pains, even though published randomized controlled trials are so far lacking. It is our hope that future research can focus on methodologically strong randomized controlled trials to validate the efficacy of CMT with high evidence level. The purpose of this article is to introduce the theory of CMT to interest physicians to achieve a greater awareness and

The authors thank the Ko Medical System Inc. for providing the illustrations and figures for

Carlsson C, Sjolund B. Acupuncture for chronic low back pain: a randomized placebocontrolled study with long-term follow-up. *Clin J Pain* 2001, 17:296-305. Ezzo J, Hadhazy V, Birch S, Lao L, Kaplan G, Hochberg M, Berman B. Acupuncture for osteoarthritis of the knee: a systematic review. *Arthr Rheum* 2001, 44:819-25. Hariharan J, Lamb GC, Neuner JM. Long-Term Opioid Contract Use for Chronic Pain

Hoka S, Kanai A, Ko SC, Suzuki A. Collateral Meridian Therapy Alleviates Intractable Pain

Ko SC, Chao HR. Atlas of Ko medicine pressure points. (ISBN:978-986-83890-0-7, 2007) Laxmaiah M, Mark VB, Vijay S, Ramsin M. B, Bert F, Salahadin A, Ricardo M B, Ann C,

and Disablity in CRPS Patients. *ASA meeting* 2008: A904 .

spinal pain. *Pain Physician* 2009; 12: 699-802.

Management in Primary Care Practice. A Five Year Experience. J of Gen Intern Med

Sukdeb D, Richard D, Frank JE F, Stephanie E, Sudhir D, Salim M. H, Standiford H, Allan T. P, David M S, Howard S S, Lee R W, Joshua A H. Interventional techniques: evidence-based practice guidelines in the management of chronic

Post intervention

Physical function recovery

Pain reduction

The National Institute of Health consensus, published in 1998, states that acupuncture shows effectiveness in the treatment of postoperative and chemotherapy induced nausea and vomiting and postoperative dental pain. The statement concludes that acupuncture may be useful in other conditions, including myofascial pain, osteoarthritis, low back pain, menstrual cramps and so on. In addition, we conducted a MEDLINE search and found that acupuncture therapy is also effective for low back pain (LBP) and myofascial pain. From prospective randomized controlled trials published in the peer-reviewed medical literature after 1998, we summarize the acupoints/meridians use for TCA and CMT in the management of LBP in table 2. According to the rules that we have introduced in this article, we can choose the corresponding healthy meridian and formats a set of acupoints for the treatment of LBP, whereas in TCA, one usually uses the diseased meridian, with different acupoints chosen in different reports (Ezzo et al, 2001; Leibing et al, 2002; Meng et al, 2004; Trinh et al, 2007; Wang et al, 2008; Yeh et al; 2009). Based on our literature review, patients with LBP received at lease short-term pain relief after TCA treatment; the CMT also provides significant pain relief via different approach with a standardized formulated protocol. Table 3 shows as summary of published CMT clinical reports for different types of pain (Wong et al, 2006; 2007; Hoka, 2008; Yeh et al, 2008; 2009, Lin et al, 2010). Furthermore to date, no clinical reports described the use of TCA to treat complex regional pain syndrome which patients may not tolerate the direct stimulation/acupuncture to the painful area. In contrast, CMT provides a promising technique for treating complex regional pain syndrome that can be used without touching the painful sites (Wong et al, 2007; Hoka, 2008).


TCM: traditional Chinese medicine; CMT: collateral meridian therapy. (+): treatment meridian. Number: reference number.

Table 2. Acupunture points/meridians used for TCM and CMT in the management of low back pain and lumbar myofascial pain syndrome


CMT, collateral meridian therapy. +, Yes; –, Not observed

Table 3. Clinical reports of CMT for pain management

#### **3. Conclusion**

514 Pain Management – Current Issues and Opinions

The National Institute of Health consensus, published in 1998, states that acupuncture shows effectiveness in the treatment of postoperative and chemotherapy induced nausea and vomiting and postoperative dental pain. The statement concludes that acupuncture may be useful in other conditions, including myofascial pain, osteoarthritis, low back pain, menstrual cramps and so on. In addition, we conducted a MEDLINE search and found that acupuncture therapy is also effective for low back pain (LBP) and myofascial pain. From prospective randomized controlled trials published in the peer-reviewed medical literature after 1998, we summarize the acupoints/meridians use for TCA and CMT in the management of LBP in table 2. According to the rules that we have introduced in this article, we can choose the corresponding healthy meridian and formats a set of acupoints for the treatment of LBP, whereas in TCA, one usually uses the diseased meridian, with different acupoints chosen in different reports (Ezzo et al, 2001; Leibing et al, 2002; Meng et al, 2004; Trinh et al, 2007; Wang et al, 2008; Yeh et al; 2009). Based on our literature review, patients with LBP received at lease short-term pain relief after TCA treatment; the CMT also provides significant pain relief via different approach with a standardized formulated protocol. Table 3 shows as summary of published CMT clinical reports for different types of pain (Wong et al, 2006; 2007; Hoka, 2008; Yeh et al, 2008; 2009, Lin et al, 2010). Furthermore to date, no clinical reports described the use of TCA to treat complex regional pain syndrome which patients may not tolerate the direct stimulation/acupuncture to the painful area. In contrast, CMT provides a promising technique for treating complex regional pain syndrome that can be used without touching the painful

Meridian TCM [ref] CMT [ref]

Leibing et al (2002)

Lung meridian (TxI) (+) Yeh et al (2008) Heart meridian (TxIII) (+) Yeh et al (2008)

TCM: traditional Chinese medicine; CMT: collateral meridian therapy. (+): treatment meridian.

Table 2. Acupunture points/meridians used for TCM and CMT in the management of low

(+) Wang et al (2008) Leibing et al (2002) Meng et al (2004) Ezzo et al (2001) Trinh et al (2007)

Carlsson & Sjolund (2001)

sites (Wong et al, 2007; Hoka, 2008).

Urinary bladder meridian (AyIII)

Number: reference number.

Governing vessel meridian (+) Wang et al (2008)

Spleen meridian (AxI) (+) Wang et al (2008)

Large intestine meridian (TyI) (+) Wang et al (2008)

back pain and lumbar myofascial pain syndrome

CMT provides a different approach for managing intractable pain and various illnesses. It may play a role in the field of complementary and alternative medicine. The role of CMT in pain management looks promising for both acute and chronic pain, even including intractable pains, even though published randomized controlled trials are so far lacking. It is our hope that future research can focus on methodologically strong randomized controlled trials to validate the efficacy of CMT with high evidence level. The purpose of this article is to introduce the theory of CMT to interest physicians to achieve a greater awareness and understanding of this technique and theory.

#### **4. Acknowledgment**

The authors thank the Ko Medical System Inc. for providing the illustrations and figures for this chapter.

#### **5. References**


**Part 7** 

**Nursing and Pain** 


## **Part 7**

**Nursing and Pain** 

516 Pain Management – Current Issues and Opinions

Leibing E, Leonhardt U, Koster G, Goerlitz A, Rosenfeldt J, Hilgers R, Ramadori G.

Lin JA, Wong CS, Lee MS, Ko SC, Chan SM, Chen JJY, Chen TL. Successful treatment of

Meng C, Wang D, Ngeow J, Lao L, Peterson M, Paget S. Acupuncture for chronic low back

Trinh K, Graham N, Gross A, Goldsmith C, Wang E, Careron I, Kay T. Acupuncture for neck

Wagner E, Ehrenhofer B, Lackerbauer E, Pawelak U, Siegmeth W. Rehabilitation of non-

Wang SM, Kain ZN, White PF. Acupuncture Analgesia: II. Clinical Considerations. *Anesth* 

Wong CS, Kuo CP, Ko SC. Can we do better, in addition to the pharmacological treatment, on pain: collateral meridian therapy. *Acta Anaesthesiol Taiwanica* 2006, 44:59-60. Wong CS, Kuo CP, Fan YM, Ko SC. Collateral meridian therapy dramatically attenuates

Yeh CC, Ko SC, Huh BK, Kuo CP, Wu CT, Cherng CH, Wong CS. Shoulder-tip pain

controlled trial with 9-month follow up. *Pain* 2002, 96:189-196.

case report. *J Manipulative Physiol Ther* 2010, 33:70-5.

*Analg* 2004, 98:1359-64.

*Analg* 2008, 106:611-21.

2007, 21: 228-33.

pain disorder. *Spine* 2007, 32:236-43.

syndrome. *Anesth Analg* 2007, 104:452.

Five Cases. *South Med J* 2009, 102:1179-1182.

Acupuncture treatment of chronic low-back pain- a randomized, blinded, placebo-

primary dysmenorrhea by collateral meridian acupressure therapy – a time series

pain through adjuvant electrical versus manual auricular acupuncture. *Anesth* 

specific low back pain. Results of a multidisciplinary in-patient program. Schmerz

pain and improves functional activity of a patient with complex regional pain

following laparoscopic surgery analgesia by collateral meridian acupressure (shiatsu) therapy—report of two cases. *J Manipul Physiol Therap* 2008, 31:484-8. Yeh CC, Wu CT, Huh BK, Lee SM, Wong CS. Collateral Meridian Acupressure Therapy

Effectively Relieves Post-Regional Anesthesia/Analgesia Backache –The Report of

**25** 

*Iceland* 

**When Theoretical Knowledge Is Not Enough:** 

Relieving the suffering of patients is a paramount responsibility for all health professionals. The fact that hospitalised patients still suffer from pain despite increasing technology and a wealth of research during recent decades, calls for an audit and new approaches in pain management. Nurses are professionally responsible for pain assessment and the administration of analgesia and are often considered the key persons in the management of pain. However, for many reasons nurses are unable to achieve the desired results of pain relief. Our study on nurses' experiences of caring for patients in pain indicates that previous studies in this field have often been limited to isolated aspects of pain management (Blondal & Halldorsdottir, 2009). Furthermore, they have been rather negative towards nurses. Our position is that many researchers have not appreciated the complexity of the nurse's multifaceted assignment of caring for patients in pain. We suggest that knowledge, in this respect, may often have been too narrowly defined. We challenge statements that propose that nurses do not believe that pain relief is a priority for nurses (Brockopp et al., 1998) or their responsibility (Twycross, 2002). Successful pain relief may provide satisfaction for the nurses involved (Blondal & Halldorsdottir, 2009), which is a rarely identified outcome by means of professional achievements. Various research results indicate that nurses' knowledge is less than adequate (Howell et al., 2000; Kuuppelomäki; 2002a; Van Niekerk & Martin, 2002). Therefore, the main methods that have previously been employed in order to improve nurses' performance and to achieve better pain control are formal education about pain assessment and the use of pain medication. Interestingly, programmes that aim at increasing this knowledge, however, often fail to help in diminishing patients' pain. Some programmes may demonstrate changes in practice (e.g. Carr, 2002) where other findings are contradictory regarding their effectiveness, indicating that the effect of nurses' re-education is not maintained over time (Howell et al., 2000) and that more theoretical knowledge does not necessarily correlate with patients reporting less pain (Watt-Watson et al.*,* 2001). Furthermore, Wilson's (2007) survey on nurses' knowledge of pain also indicates that nurses may be incapable of managing pain, despite their knowledge of the existence of the patients' pain. It is, therefore, important to search for other explanations for inadequate pain management of

**1. Introduction** 

**Introduction of an Explanatory Model** 

*1Landspitali -National University Hospital of Iceland, University of Iceland,* 

**on Nurse's Pain Management** 

Katrin Blondal1 and Sigridur Halldorsdottir2

*School of Health Sciences, Faculty of Nursing, Reykjavik, 2School of Health Sciences, University of Akureyri, Akureyri,* 

### **When Theoretical Knowledge Is Not Enough: Introduction of an Explanatory Model on Nurse's Pain Management**

Katrin Blondal1 and Sigridur Halldorsdottir2

*1Landspitali -National University Hospital of Iceland, University of Iceland, School of Health Sciences, Faculty of Nursing, Reykjavik, 2School of Health Sciences, University of Akureyri, Akureyri, Iceland* 

#### **1. Introduction**

Relieving the suffering of patients is a paramount responsibility for all health professionals. The fact that hospitalised patients still suffer from pain despite increasing technology and a wealth of research during recent decades, calls for an audit and new approaches in pain management. Nurses are professionally responsible for pain assessment and the administration of analgesia and are often considered the key persons in the management of pain. However, for many reasons nurses are unable to achieve the desired results of pain relief. Our study on nurses' experiences of caring for patients in pain indicates that previous studies in this field have often been limited to isolated aspects of pain management (Blondal & Halldorsdottir, 2009). Furthermore, they have been rather negative towards nurses. Our position is that many researchers have not appreciated the complexity of the nurse's multifaceted assignment of caring for patients in pain. We suggest that knowledge, in this respect, may often have been too narrowly defined. We challenge statements that propose that nurses do not believe that pain relief is a priority for nurses (Brockopp et al., 1998) or their responsibility (Twycross, 2002). Successful pain relief may provide satisfaction for the nurses involved (Blondal & Halldorsdottir, 2009), which is a rarely identified outcome by means of professional achievements. Various research results indicate that nurses' knowledge is less than adequate (Howell et al., 2000; Kuuppelomäki; 2002a; Van Niekerk & Martin, 2002). Therefore, the main methods that have previously been employed in order to improve nurses' performance and to achieve better pain control are formal education about pain assessment and the use of pain medication. Interestingly, programmes that aim at increasing this knowledge, however, often fail to help in diminishing patients' pain. Some programmes may demonstrate changes in practice (e.g. Carr, 2002) where other findings are contradictory regarding their effectiveness, indicating that the effect of nurses' re-education is not maintained over time (Howell et al., 2000) and that more theoretical knowledge does not necessarily correlate with patients reporting less pain (Watt-Watson et al.*,* 2001). Furthermore, Wilson's (2007) survey on nurses' knowledge of pain also indicates that nurses may be incapable of managing pain, despite their knowledge of the existence of the patients' pain. It is, therefore, important to search for other explanations for inadequate pain management of

When Theoretical Knowledge Is Not Enough:

The challenge of caring for patients in pain: from the nurse's perspective

Feelings of powerlessness in relation to pain: ascribed causes and reported strategies

Pain management problems in patients' terminal phase as assessed by nurses in Finland

The pattern of personal knowing in nurse clinical

Advocacy in nursing – perceptions of practising

Culture and organizational climate: nurses' insights into their relationship with

Strategies used by burns nurses to cope with the infliction of pain on patients

analgesia: what nurses say

Bridging the gap: a study of general nurses' perceptions of patient advocacy in Ireland

The impact of the nursephysician professional relationship on nurses'

experience of ethical dilemmas in effective pain management

Doctors' and nurses' perceptions of ethical problems in end-of-life

nurses

physicians

Nash et al., 1999 Pain and the administration of

decisions

Table 1. Key research used to develop the theory

decision making

**Authors,** 

Blondal & Halldorsdottir,

De Schepper et.

2009

al, 1997

Jenks, 1993

2002

2009

Kuuppelomäki,

Mallik, 1997

Malloy et al,

Nagy, 1999

Oberle & Hughes, 2001

O'Connor & Kelly, 2005

Van Niekerk & Martin, 2002

Introduction of an Explanatory Model on Nurse's Pain Management 521

**published Research Participants, N Data collection** 

Nurses caring for patients with pain in hospital wards, N= 10

Community nurses caring for cancer patients with pain,

Nurses working in various hospital

Nurses on inpatient wards of 32 municipal

Experienced nurses from various settings,

Nurses from various settings in 4 countries,

Registered nurses and BSc nursing students in acute and community

7 doctors and 14 nurses working in acute care adult medical-surgical

health centres, N= 328

N= 24

settings, N= 23

N= 104

N= 42

Nurses within paediatric and adult

burn units, N= 32

settings, N= 19

areas, N= 21

hospitals, N= 20

N= 1,015

Practicing nurses in

Nurses within public and private settings,

20 in-depth interviews

13 individual and 3 group interviews

Four focus groups/ participant observation

Questionnaire and an open end

question

Focus group interviews

Focus groups

84 unstructured interviews

Three focus group interviews

Unstructured interviews

3 focus group interviews

Questionnaire

nurses. Therefore, perhaps other patterns of knowledge are needed in addition to the often traditional emphasis on formal education about pain assessment and analgesics.

#### **1.1 Aim of the theory**

Theory is the acknowledged foundation to practise methodology, professional identity and the growth of formalized knowledge. Practice must not only be evidence based but also theory based. Hence, pain management must be theory based because theories serve as a broad framework for practice and may also articulate the goals of a profession and its core values. Our aim was to develop a theory, an explanatory model, which can explain nurses' complex task of pain management.

#### **2. Methodology**

In our evaluation of the various methods for this theory development we found *theory synthesis* as described by Walker and Avant (2004) a good method for constructing our explanatory model. They posit that more theory synthesis is needed to advance practice disciplines so we found a perfect fit. In the theory synthesis the theorists combine isolated pieces of information that may even be theoretically unconnected. Theory synthesis entails constructing a theory from study findings and scholarly writings, which may be numerous. It enables the theorist to organise and integrate a large number of findings into a single theory which can be presented as a model. The theory put forth in this chapter is based on 11 study findings, e.g. on our own phenomenological study on nurses' experience of taking care of patients in pain and ten other research findings from various researchers about: nursing advocacy; moral obligation; organisational barriers; patient based hindrances; and the nurse-doctor relationship (see Table 1). All these different studies helped us to clarify the manifold task of a nurse's pain management. This method can be compared with painting a picture where in step one the picture is drawn and step two (the literature in this case) is used to compare the "picture" drawn with other similar "pictures" for confirmation and clarification. In step three the picture is presented (Figure 1).

#### **3. Findings**

The theory provides a holistic view of the complicated task of relieving pain. The main tenets of this theory are: *the role of the nurses as the patient's advocates*, *multiple patterns of knowledge* and *the doctor-nurse relationship*. The theory is introduced in the form of an exploratory model which illustrates the main tenets, how they interact and how other aspects simultaneously mould nurses' actions and reactions while taking care of patients in pain (Figure 1).

#### **3.1 The explanatory model**

To understand and explain the nurses' central role of caring for patients in pain and their potential for providing adequate pain management, their position may be portrayed as that of *patients' advocates* (Mallik, 1997) within a goal-directed mission aimed at patients' pain relief. In figure 1, this journey is presented in an explanatory model where its main tenets have been arranged into a figure with a definite beginning and an end from top to bottom. As may be seen from the four central tenets of the model, acting as *patient's advocate*, *moral obligation*, *formal and tacit knowledge*, *knowing persons* and *the system,* initially dominate, followed by the concepts of *internal and external hindrances,* as well as *potential outcomes.*

nurses. Therefore, perhaps other patterns of knowledge are needed in addition to the often

Theory is the acknowledged foundation to practise methodology, professional identity and the growth of formalized knowledge. Practice must not only be evidence based but also theory based. Hence, pain management must be theory based because theories serve as a broad framework for practice and may also articulate the goals of a profession and its core values. Our aim was to develop a theory, an explanatory model, which can explain nurses'

In our evaluation of the various methods for this theory development we found *theory synthesis* as described by Walker and Avant (2004) a good method for constructing our explanatory model. They posit that more theory synthesis is needed to advance practice disciplines so we found a perfect fit. In the theory synthesis the theorists combine isolated pieces of information that may even be theoretically unconnected. Theory synthesis entails constructing a theory from study findings and scholarly writings, which may be numerous. It enables the theorist to organise and integrate a large number of findings into a single theory which can be presented as a model. The theory put forth in this chapter is based on 11 study findings, e.g. on our own phenomenological study on nurses' experience of taking care of patients in pain and ten other research findings from various researchers about: nursing advocacy; moral obligation; organisational barriers; patient based hindrances; and the nurse-doctor relationship (see Table 1). All these different studies helped us to clarify the manifold task of a nurse's pain management. This method can be compared with painting a picture where in step one the picture is drawn and step two (the literature in this case) is used to compare the "picture" drawn with other similar "pictures" for confirmation and

The theory provides a holistic view of the complicated task of relieving pain. The main tenets of this theory are: *the role of the nurses as the patient's advocates*, *multiple patterns of knowledge* and *the doctor-nurse relationship*. The theory is introduced in the form of an exploratory model which illustrates the main tenets, how they interact and how other aspects simultaneously

To understand and explain the nurses' central role of caring for patients in pain and their potential for providing adequate pain management, their position may be portrayed as that of *patients' advocates* (Mallik, 1997) within a goal-directed mission aimed at patients' pain relief. In figure 1, this journey is presented in an explanatory model where its main tenets have been arranged into a figure with a definite beginning and an end from top to bottom. As may be seen from the four central tenets of the model, acting as *patient's advocate*, *moral obligation*, *formal and tacit knowledge*, *knowing persons* and *the system,* initially dominate, followed by the concepts of *internal and external hindrances,* as well as *potential outcomes.*

mould nurses' actions and reactions while taking care of patients in pain (Figure 1).

traditional emphasis on formal education about pain assessment and analgesics.

**1.1 Aim of the theory** 

**2. Methodology** 

**3. Findings** 

**3.1 The explanatory model** 

complex task of pain management.

clarification. In step three the picture is presented (Figure 1).


Table 1. Key research used to develop the theory

When Theoretical Knowledge Is Not Enough:

Fig. 2. Nurses' moral obligation and formal and tacit knowledge

relating with patients and doctors (Blondal & Halldorsdottir, 2009).

**3.3 The nurse as the patient's advocate** 

*Voice* 

referred to physicians (Blondal & Halldorsdottir, 2009).

Fig. 3. Central position of the nurse as the patient's advocate

Introduction of an Explanatory Model on Nurse's Pain Management 523

Moral obligation

**Main drives**

Formal and tacit knowledge

**THE NURSE AS THE PATIENT´S ADVOCATE**

The nurses' moral orientation is displayed in accounts like this one: *"*If the patients report pain, then they're in pain … and of course you must do something about it" (Blondal & Halldorsdottir, 2009, p. 4). Possessing *formal or theoretical knowledge* about pain assessment, pain management and medication is of importance but *tacit knowledge* is no less important, as experience and learning from other colleagues creates a sense of self confidence and increased empowerment in following their convictions to be the *patient's advocate* (Blondal & Halldorsdottir, 2009; Mallik, 1997; Nash et al., 1999). "I suppose I believe advocacy is utilizing our own clinical knowledge as well as our own knowledge of the patient and putting the two of them together and then doing what you feel is best for the patient." (O'Connor & Kelly, 2005, p. 460). This approach assists nurses to keep on advocating and

As may be seen from our model, its central tenet portrays the position of the nurse as the *patient´s advocate* (Figure 3). Here, the mission's journey begins with the nurse's assessment of the patient's pain, which leads to further decisions and reactions and where the nurse will direct his or her responses; what she or he can solve alone and what problems must be

> **THE GATE**  Communicating with doctors/mutual decision-making

**THE NURSE AS THE PATIENT´S ADVOCATE**  *Silenced voice* 

Fig. 1. An explanatory model of nurses´ pain management

#### **3.2 Nurses' two main drives: Moral obligation and formal and tacit knowledge**

The first two concepts we introduce in our explanatory model are *moral obligation* (Mallik, 1997; Oberle and Hughes, 2001) and *formal and tacit knowledge* (Blondal & Halldorsdottir, 2009; Mallik, 1997; Nash et al., 1999). We propose that on the nurses' journey to fulfil their mission of relieving patients' pain these two important drives prevail, as illustrated in figure 2 in the shadowed boxes.

Formal and tacit External obstacles

**Facilitating factors Main drives Hindrances**

Moral obligation

Fig. 1. An explanatory model of nurses´ pain management

decision making Successful

2 in the shadowed boxes.

outcome **Pain relief**  Nurse´s satisfaction and empowerment

*Voice* 

Knowing persons; the patient, the doctor and your oneself Having self-confidence and conviction

Knowing the system

Access to specialists

**3.2 Nurses' two main drives: Moral obligation and formal and tacit knowledge** 

Sidestepping the gate

**-OR-**

**THE GATE**  Communicating with doctors/mutual

**THE NURSE AS THE PATIENT´S ADVOCATE** 

knowledge

Distress Coping mechanisms

Unsuccessful outcome **No pain relief**  Nurse´s dissatisfaction and disempowerment

*Silenced voice* 

Internal obstacles Moral dilemmas and doubts

 **T i m e** 

The first two concepts we introduce in our explanatory model are *moral obligation* (Mallik, 1997; Oberle and Hughes, 2001) and *formal and tacit knowledge* (Blondal & Halldorsdottir, 2009; Mallik, 1997; Nash et al., 1999). We propose that on the nurses' journey to fulfil their mission of relieving patients' pain these two important drives prevail, as illustrated in figure

Fig. 2. Nurses' moral obligation and formal and tacit knowledge

The nurses' moral orientation is displayed in accounts like this one: *"*If the patients report pain, then they're in pain … and of course you must do something about it" (Blondal & Halldorsdottir, 2009, p. 4). Possessing *formal or theoretical knowledge* about pain assessment, pain management and medication is of importance but *tacit knowledge* is no less important, as experience and learning from other colleagues creates a sense of self confidence and increased empowerment in following their convictions to be the *patient's advocate* (Blondal & Halldorsdottir, 2009; Mallik, 1997; Nash et al., 1999). "I suppose I believe advocacy is utilizing our own clinical knowledge as well as our own knowledge of the patient and putting the two of them together and then doing what you feel is best for the patient." (O'Connor & Kelly, 2005, p. 460). This approach assists nurses to keep on advocating and relating with patients and doctors (Blondal & Halldorsdottir, 2009).

#### **3.3 The nurse as the patient's advocate**

As may be seen from our model, its central tenet portrays the position of the nurse as the *patient´s advocate* (Figure 3). Here, the mission's journey begins with the nurse's assessment of the patient's pain, which leads to further decisions and reactions and where the nurse will direct his or her responses; what she or he can solve alone and what problems must be referred to physicians (Blondal & Halldorsdottir, 2009).

Fig. 3. Central position of the nurse as the patient's advocate

When Theoretical Knowledge Is Not Enough:

**Facilitating factors Main drives** 

Knowing the patient, the doctor and your oneself

Having self-confidence and conviction

Knowing the system

Access to specialists

*Voice* 

Introduction of an Explanatory Model on Nurse's Pain Management 525

Moral obligation

Formal and tacit knowledge

Fig. 4. Facilitating factors; Knowing persons and knowing the system

the best for the patient." (Nash et al., 1999, p. 185)

Halldorsdottir, 2009).

**3.4.4 Knowing the system and access to specialists** 

**3.4.3 Knowing your own self, having self-confidence and conviction** 

It is no less important for nurses to know their own potential and believe in themselves, since experience creates a *sense of self-confidence* and increased empowerment in following their own *convictions*. Therefore, individual factors influence nurses' decisions on pain management; "I'm quite happy to make those decisions, because I'm happy to be answerable for them…so I do things that I am comfortable with and I feel that I am doing

**THE GATE**  Communicating with doctors /mutual decisionmaking

**THE NURSE AS THE PATIENT´S ADVOCATE**  *Silenced voice* 

Organizational knowledge, to *know how the system works*, together with knowledge of the wishes of patients, allows nurses to advocate in an effective way; therefore "[A]n advocate to me would be somebody who uses whatever knowledge they have in a situation to do the best for the patient." (O'Connor & Kelly, 2005, p. 460). Then *having access to a specialist in pain management* and pain teams within the organisation is of utmost importance as they serve as nurses' guides and help to turn distress into satisfaction (Blondal &

#### **3.3.1 Communicating with doctors at the gate/mutual decision-making**

Since medication is often the major pain treatment, and physicians are required to be responsible for all drug prescriptions, a crucial element in this process is the nurses' contribution to mutual *decision-making with the doctor*, where nurses assume the responsibility of advocates (Blondal & Halldorsdottir, 2009). At this point, which may be referred to as "*the gate*", *having a voice* is pivotal for nurses (Blondal & Halldorsdottir, 2009; Van Niekerk and Martin, 2002) because they represent the patient, and by using their influence they try to fulfil their mission (Blondal & Halldorsdottir, 2009; Jenks, 1993; O'Connor & Kelly, 2005). As two different nurses put it: "Well, unfortunately the decisionmaking is not ours. We are restricted to what's ordered… I mean, if the doctor's ordered it, you can't very well make a decision" (Nash et al., 1999, p. 186), and further: "I don't stand by and watch the patients and do nothing if I think they are wild with pain, I keep on pushing until something is done." (Blondal & Halldorsdottir, 2009, pp. 5-6). If the nurse and the doctor do not reach reciprocal decision or agreement the nurses may have to keep on insisting or else give up -- feeling *silenced* (Malloy, 2009; Blondal & Halldorsdottir, 2009*)*. "We don't have any nal authority – perhaps that's what's most difficult…and we have to put up with that, naturally, but it's very important, of course, that we feel we are listened to, that our voice is heard." (Blondal & Halldorsdottir, 2009, p. 2901). Furthermore, to maintain trust between all involved, the nurses sometimes take on the role of a mediator or intermediary (Blondal & Halldorsdottir, 2009; O'Connor & Kelly, 2005), but the importance of co-operation and holding a mutual vision crystallises in this description: "I just think it´s lot of give and take between doctors and nursing staff and patients; you´ve got to work together to actively relieve pain." (Nash et al., 1999, p. 185).

#### **3.4 Facilitating factors for a successful outcome**

The main drives, moral obligation and formal and tacit knowledge may not be enough for successful pain management. There are several facilitating factors which are necessary to make use of, together with the main drives, in order to achieve a positive outcome of pain management (See Figure 4).

#### **3.4.1 Knowing the patient**

One of the *facilitating factors* that are important motivating factors for advocacy (Mallik, 1997), requires that the nurse *knows the patient as a person,* that is, as an individual, which allows the nurse to interpret information and select individualised interventions (Jenks, 1993). "I think, knowing the patient's background and seeing more than just, say, a medical condition or a surgical wound, that makes you more able to advocate." (O'Connor & Kelly, 2005, p. 459).

#### **3.4.2 Knowing the doctor**

In the explanatory model we propose that *to know the gatekeeper,* i.e. the doctor, greatly influences the nurse's success (Jenks, 1993). "Sometimes I think the nurses are underheard if you go and you're telling the doctor, this patient is in pain. This patient is in pain, ah yeah, we'll change this. The patient is still in pain. Sometimes they don't actually listen to what you're saying. It depends on how you say it, or who you're actually saying it to." (Malloy et al., 2009, p. 726). Then on the other hand, "It's a good feeling when you know that someone respects your opinion and respects your assessment of the patient also." (Jenks, 1993, p. 403).

Since medication is often the major pain treatment, and physicians are required to be responsible for all drug prescriptions, a crucial element in this process is the nurses' contribution to mutual *decision-making with the doctor*, where nurses assume the responsibility of advocates (Blondal & Halldorsdottir, 2009). At this point, which may be referred to as "*the gate*", *having a voice* is pivotal for nurses (Blondal & Halldorsdottir, 2009; Van Niekerk and Martin, 2002) because they represent the patient, and by using their influence they try to fulfil their mission (Blondal & Halldorsdottir, 2009; Jenks, 1993; O'Connor & Kelly, 2005). As two different nurses put it: "Well, unfortunately the decisionmaking is not ours. We are restricted to what's ordered… I mean, if the doctor's ordered it, you can't very well make a decision" (Nash et al., 1999, p. 186), and further: "I don't stand by and watch the patients and do nothing if I think they are wild with pain, I keep on pushing until something is done." (Blondal & Halldorsdottir, 2009, pp. 5-6). If the nurse and the doctor do not reach reciprocal decision or agreement the nurses may have to keep on insisting or else give up -- feeling *silenced* (Malloy, 2009; Blondal & Halldorsdottir, 2009*)*. "We don't have any nal authority – perhaps that's what's most difficult…and we have to put up with that, naturally, but it's very important, of course, that we feel we are listened to, that our voice is heard." (Blondal & Halldorsdottir, 2009, p. 2901). Furthermore, to maintain trust between all involved, the nurses sometimes take on the role of a mediator or intermediary (Blondal & Halldorsdottir, 2009; O'Connor & Kelly, 2005), but the importance of co-operation and holding a mutual vision crystallises in this description: "I just think it´s lot of give and take between doctors and nursing staff and patients; you´ve got to work

The main drives, moral obligation and formal and tacit knowledge may not be enough for successful pain management. There are several facilitating factors which are necessary to make use of, together with the main drives, in order to achieve a positive outcome of pain

One of the *facilitating factors* that are important motivating factors for advocacy (Mallik, 1997), requires that the nurse *knows the patient as a person,* that is, as an individual, which allows the nurse to interpret information and select individualised interventions (Jenks, 1993). "I think, knowing the patient's background and seeing more than just, say, a medical condition or a surgical wound, that makes you more able to advocate." (O'Connor & Kelly,

In the explanatory model we propose that *to know the gatekeeper,* i.e. the doctor, greatly influences the nurse's success (Jenks, 1993). "Sometimes I think the nurses are underheard if you go and you're telling the doctor, this patient is in pain. This patient is in pain, ah yeah, we'll change this. The patient is still in pain. Sometimes they don't actually listen to what you're saying. It depends on how you say it, or who you're actually saying it to." (Malloy et al., 2009, p. 726). Then on the other hand, "It's a good feeling when you know that someone respects your opinion and respects your assessment of the patient also." (Jenks, 1993, p. 403).

**3.3.1 Communicating with doctors at the gate/mutual decision-making** 

together to actively relieve pain." (Nash et al., 1999, p. 185).

**3.4 Facilitating factors for a successful outcome** 

management (See Figure 4).

**3.4.1 Knowing the patient** 

**3.4.2 Knowing the doctor** 

2005, p. 459).

Fig. 4. Facilitating factors; Knowing persons and knowing the system

#### **3.4.3 Knowing your own self, having self-confidence and conviction**

It is no less important for nurses to know their own potential and believe in themselves, since experience creates a *sense of self-confidence* and increased empowerment in following their own *convictions*. Therefore, individual factors influence nurses' decisions on pain management; "I'm quite happy to make those decisions, because I'm happy to be answerable for them…so I do things that I am comfortable with and I feel that I am doing the best for the patient." (Nash et al., 1999, p. 185)

#### **3.4.4 Knowing the system and access to specialists**

Organizational knowledge, to *know how the system works*, together with knowledge of the wishes of patients, allows nurses to advocate in an effective way; therefore "[A]n advocate to me would be somebody who uses whatever knowledge they have in a situation to do the best for the patient." (O'Connor & Kelly, 2005, p. 460). Then *having access to a specialist in pain management* and pain teams within the organisation is of utmost importance as they serve as nurses' guides and help to turn distress into satisfaction (Blondal & Halldorsdottir, 2009).

When Theoretical Knowledge Is Not Enough:

Fig. 6. Coping mechanisms

Coping mechanisms

Successful outcome

**Pain relief**  Nurse's satisfaction and empowerment

**3.7 Potential outcomes** 

Introduction of an Explanatory Model on Nurse's Pain Management 527

**THE NURSE AS PATIENT´S ADVOCATE** 

> **THE GATE**  Communicating with doctors / mutual decision making

*Silenced voice* 

Unsuccessful outcome

Distress

**No pain relief**  Nurse's dissatisfaction and disempowerment

The most important factor is support provided by colleagues (De Schepper et al., 1997; Nagy, 1999) and specialists in pain management that serve as their guides (Blondal & Halldorsdottir, 2009). "The people that we work with. You can go up and say 'So-and-so, I can't cope with this any longer! Can you either give me a hand or do it for me?' And people where we are working at the moment will do that. So if we're getting too fed up someone else will either help you out or do it for you so you can go and have a rest. They understand what it's like!" (Nagy, 1999, p. 1433). Furthermore, "I get a lot of support from the team here. They give me [the] feedback I need and I can have a good moan." *(*De Schepper et al., 1997, p. 426). Assistance can, therefore, like other coping strategies, transform *distress* into *satisfaction* (Blondal & Halldorsdottir, 2009) which may keep them satisfied despite unfavourable outcomes. Some nurses do *sidestep the gate* by using independent nursing interventions, take control and thread the risky road of bypassing the gate by altering the medication on their own initiative or bend existing rules and directions (Blondal &

Sidestepping the gate

**-OR-** 

Halldorsdottir, 2009). But this also may be the result of the distress mentioned above.

degree to which nurses are able to fulfil their commitments (see figure 7).

action (Blondal & Halldorsdottir, 2009; Mallik, 1997).

As suggested by this model, the nurse's journey has two potential outcomes, based on the

Successful pain relief leads to nurses' *satisfaction* and *empowerment* and *patients' satisfaction*  and possibly mutual trust (Blondal & Halldorsdottir, 2009). Conversely, pain management is burdensome when the patients' sufferings are not relieved (Nagy, 1999) or the nurses are *silenced*, with consequent *dissatisfaction and distress* (De Schepper et al., 1997; Oberle and Hughes, 2001), *disempowerment* and possibly mutual distrust. "I think, really, it's one of the more difficult things one experiences… I was so upset inside… so angry inside, not being able to help and not really knowing where to turn, because the doctors said just that [dose of medication], and it didn't work at all, so I was somehow defenceless about what to do." (Blondal & Halldorsdottir, 2009, p. 6). However, importantly, we want to point out that perceived discomfort or *dissatisfaction* with the outcome can serve as a drive for further

#### **3.5 Hindrances to successful pain management**

This journey is complicated, however, by several obstacles that emerge either as *internal* or *external obstacles* (see figure 5).

Fig. 5. Internal and external obstacles

#### **3.5.1 Internal obstacles**

Internal obstacles that can complicate this process are the nurses' inner struggle of *moral dilemma and doubt,* of doing right and trusting one's own judgement, that appear to be the result of tension between doubt and duty. Here a prevailing feature includes the fear of giving too much medication and caring for addicts (Blondal & Halldorsdottir, 2009; Nash et al., 1999). "I felt it [to give pain medication to an addict] was a strain, really, on human nature – are you doing something wrong? Or are you doing right? Or are you just cruel to refuse to give it to him? – really, what should you do?"(Blondal & Halldorsdottir, 2009, p. 5).

#### **3.5.2 External obstacles**

*External obstacles* are connected to organisational structures (Kuuppelomäki, 2002a) such as absence of or an inadequate prescription, lack of access to accountable physicians, and the lack of directions and clear rules. Moreover, decisions regarding palliative care are imperative for successful pain relief (Blondal & Halldorsdottir, 2009; Kuuppelomäki, 2002a); "Accepting death and the transition from acute care to terminal care are a problem." (Kuuppelomäki, 2002a, p. 706). External hindrances may also be patient related, such as their unwillingness to report pain and to accept analgesics (Blondal & Halldorsdottir, 2009; Kuuppelomäki, 2002a), which further complicates the assessment of pain and pain relief. "He was a difficult man and so withdrawn. You just couldn't get through [to] him and you don't know why not. Cases like that make me feel so uncertain, I start to doubt myself." (De Schepper et al., 1997, p. 424).

#### **3.6 Coping mechanisms**

Further action can involve the use of various *coping mechanisms* in order to share the burden, seek better solutions for the patient and/or control their feelings (Blondal & Halldorsdottir, 2009; Nagy, 1999). (See figure 6.)

Fig. 6. Coping mechanisms

This journey is complicated, however, by several obstacles that emerge either as *internal* or

Moral obligation

**Main drives** 

Internal obstacles Moral dilemmas and doubts

**Hindrances**

External obstacles

*Silenced voice* 

Internal obstacles that can complicate this process are the nurses' inner struggle of *moral dilemma and doubt,* of doing right and trusting one's own judgement, that appear to be the result of tension between doubt and duty. Here a prevailing feature includes the fear of giving too much medication and caring for addicts (Blondal & Halldorsdottir, 2009; Nash et al., 1999). "I felt it [to give pain medication to an addict] was a strain, really, on human nature – are you doing something wrong? Or are you doing right? Or are you just cruel to refuse to give it to him? – really, what should you do?"(Blondal & Halldorsdottir, 2009, p. 5).

**THE NURSE AS THE PATIENT´S ADVOCATE**

Formal and tacit knowledge

*External obstacles* are connected to organisational structures (Kuuppelomäki, 2002a) such as absence of or an inadequate prescription, lack of access to accountable physicians, and the lack of directions and clear rules. Moreover, decisions regarding palliative care are imperative for successful pain relief (Blondal & Halldorsdottir, 2009; Kuuppelomäki, 2002a); "Accepting death and the transition from acute care to terminal care are a problem." (Kuuppelomäki, 2002a, p. 706). External hindrances may also be patient related, such as their unwillingness to report pain and to accept analgesics (Blondal & Halldorsdottir, 2009; Kuuppelomäki, 2002a), which further complicates the assessment of pain and pain relief. "He was a difficult man and so withdrawn. You just couldn't get through [to] him and you don't know why not. Cases like that make me feel so uncertain, I start to doubt myself." (De Schepper et al., 1997, p. 424).

Further action can involve the use of various *coping mechanisms* in order to share the burden, seek better solutions for the patient and/or control their feelings (Blondal & Halldorsdottir,

**3.5 Hindrances to successful pain management** 

*external obstacles* (see figure 5).

Fig. 5. Internal and external obstacles

**3.5.1 Internal obstacles** 

*Voice* 

**3.5.2 External obstacles** 

**3.6 Coping mechanisms** 

2009; Nagy, 1999). (See figure 6.)

The most important factor is support provided by colleagues (De Schepper et al., 1997; Nagy, 1999) and specialists in pain management that serve as their guides (Blondal & Halldorsdottir, 2009). "The people that we work with. You can go up and say 'So-and-so, I can't cope with this any longer! Can you either give me a hand or do it for me?' And people where we are working at the moment will do that. So if we're getting too fed up someone else will either help you out or do it for you so you can go and have a rest. They understand what it's like!" (Nagy, 1999, p. 1433). Furthermore, "I get a lot of support from the team here. They give me [the] feedback I need and I can have a good moan." *(*De Schepper et al., 1997, p. 426). Assistance can, therefore, like other coping strategies, transform *distress* into *satisfaction* (Blondal & Halldorsdottir, 2009) which may keep them satisfied despite unfavourable outcomes. Some nurses do *sidestep the gate* by using independent nursing interventions, take control and thread the risky road of bypassing the gate by altering the medication on their own initiative or bend existing rules and directions (Blondal & Halldorsdottir, 2009). But this also may be the result of the distress mentioned above.

#### **3.7 Potential outcomes**

As suggested by this model, the nurse's journey has two potential outcomes, based on the degree to which nurses are able to fulfil their commitments (see figure 7).

Successful pain relief leads to nurses' *satisfaction* and *empowerment* and *patients' satisfaction*  and possibly mutual trust (Blondal & Halldorsdottir, 2009). Conversely, pain management is burdensome when the patients' sufferings are not relieved (Nagy, 1999) or the nurses are *silenced*, with consequent *dissatisfaction and distress* (De Schepper et al., 1997; Oberle and Hughes, 2001), *disempowerment* and possibly mutual distrust. "I think, really, it's one of the more difficult things one experiences… I was so upset inside… so angry inside, not being able to help and not really knowing where to turn, because the doctors said just that [dose of medication], and it didn't work at all, so I was somehow defenceless about what to do." (Blondal & Halldorsdottir, 2009, p. 6). However, importantly, we want to point out that perceived discomfort or *dissatisfaction* with the outcome can serve as a drive for further action (Blondal & Halldorsdottir, 2009; Mallik, 1997).

When Theoretical Knowledge Is Not Enough:

without the requisite motivation.

**4.1.2 Formal and tacit knowledge** 

assess the patient's pain.

nursing education as well as organisational statements.

**4.2 The nurse as patient's advocate in pain management** 

2002a; Taylor et al., 1993; Van Niekerk and Martin, 2002).

Introduction of an Explanatory Model on Nurse's Pain Management 529

and to initiate the process of pain management. Our notion of nurses' obligation to relieve pain is supported by several studies (Oberle and Hughes, 2001; O'Connor & Kelly, 2005; Rejeh et al., 2009*)*. However, it may have been underestimated up till now because even if nurses possess the relevant theoretical knowledge, they may not necessarily make use of it

We want to emphasize that non-professional and professional *moral values* that motivate and direct individuals' choices can be inculcated through education or socialisation (Omery, 1989), and nurses recognise that a sense of responsibility in pain management needs to be learned (Rejeh et al., 2009). Taylor et al. (1993) also conclude that nurses' education about pain management must include professional ethical obligations and the suitability of their professional values. Importantly, moral values may also be generated by an organisation's philosophy statement or policy (Omery, 1989) and moral values should, therefore, be part of

In accordance with our propositions, professional responsibility and moral obligation are considered key initiates for advocacy. Twycross (2002) posits that in order to advocate, a theoretical knowledge base is needed. Vaartio et al. (2006) and O'Connor & Kelly (2005) add to this by stating that theoretical as well as practical knowledge of pain management is a necessary antecedent of advocacy. Where sound empirical knowledge about pain assessment and various methods for management of pain are vital, it must be kept in mind that nurses learn no less through experience, where they learn to utilise their own potential and personal knowledge through their own practice and role modelling. This drive for taking action by using theoretical or formal knowledge along with experience and selfconfidence is congruent with Mallik's (1997) statement that 'intervening conditions' facilitate advocacy. These factors have also been found important for nurses' decisionmaking (Nash et al., 1999). Where knowledge of theoretical origins may be the type of knowledge that is most easily recognised and is emphasised during formal education at school and in continuous education, we stress that the role of tacit knowledge gained through experience and role modelling has more rarely been pointed out, perhaps because it is rather of personal and aesthetic origins. Importantly, as we see it, this knowledge supplements formal knowledge, for instance in the early stages of the process where nurses

Patients in pain have been recognised as a vulnerable group of patients that are in need of nurses to advocate on their behalf (Ware et al., 2011), and nurses see it as their role to safeguard their interests (Blondal & Halldorsdottir, 2009; Ware et al., 2011). As portrayed in our explanatory model nurses assume a central role in assessing and managing patients' pain. However, since doctors are responsible for prescribing analgesia, nurses' concerns about pain relief are often affected by their relationship with the doctors (Kuuppelomäki,

On the nurses' journey *the gate*, where they enter these relations with *the gatekeeper*—the doctor, is an important turning point (Blondal & Halldorsdottir, 2009). Having a *voice* at the

**4.2.1 Communicating with doctors at "***the gate***" and mutual decision-making** 

Fig. 7. Potential outcomes

From this overview we conclude that theoretical knowledge is only one aspect of nurses' pain management. They require knowledge from various other sources, ethical, personal, and aesthetic, as well as many skills, e.g. communication and negotiation skills, in order to fulfil their obligations and role. In our view, lack of recognition of these other kinds of knowledge may stem from the fact that many studies focus only on isolated aspects of pain management. All too commonly the studies provide only a somewhat fragmented analysis of isolated factors of pain management. In contrast, the explanatory model presented here provides a more holistic view of the nurses' complex situation when caring for patients in pain and may reveal that neglecting these other facets may have contributed to the permanent inadequacy in pain management of patients that is so widely described.

### **4. Discussion**

This explanatory model clarifies how nurses require various coexisting patterns of knowledge, within a favourable organisational environment, to be able to perform in accord with their role as key persons in pain management and how their performance may predict a positive or negative outcome for the patient and the nurse. This model further explains the relationships of nurses with patients and physicians where nurses seek to act as patients' advocates and how having a voice is pivotal for nurses. Furthermore, we depict how internal and external barriers can hinder the performance of nurses and how an unsuccessful outcome that evokes profound distress may concurrently stimulate further actions and turn a negative outcome into a more favourable one. This explanatory model of a nurse's journey therefore denotes nurses' encounters with, and reactions to, the multiple demanding assignments they continually meet on their mission towards pain relief.

#### **4.1 Nurses´ two main drives: Moral obligation and formal and tacit knowledge 4.1.1 Knowledge of ethical origins**

According to our explanatory model *the role of ethical knowledge in pain management must be highlighted*, as it may be the fundamental component needed for nurses to act as advocates and to initiate the process of pain management. Our notion of nurses' obligation to relieve pain is supported by several studies (Oberle and Hughes, 2001; O'Connor & Kelly, 2005; Rejeh et al., 2009*)*. However, it may have been underestimated up till now because even if nurses possess the relevant theoretical knowledge, they may not necessarily make use of it without the requisite motivation.

We want to emphasize that non-professional and professional *moral values* that motivate and direct individuals' choices can be inculcated through education or socialisation (Omery, 1989), and nurses recognise that a sense of responsibility in pain management needs to be learned (Rejeh et al., 2009). Taylor et al. (1993) also conclude that nurses' education about pain management must include professional ethical obligations and the suitability of their professional values. Importantly, moral values may also be generated by an organisation's philosophy statement or policy (Omery, 1989) and moral values should, therefore, be part of nursing education as well as organisational statements.

#### **4.1.2 Formal and tacit knowledge**

528 Pain Management – Current Issues and Opinions

**THE NURSE AS THE PATIENT´S ADVOCATE** 

From this overview we conclude that theoretical knowledge is only one aspect of nurses' pain management. They require knowledge from various other sources, ethical, personal, and aesthetic, as well as many skills, e.g. communication and negotiation skills, in order to fulfil their obligations and role. In our view, lack of recognition of these other kinds of knowledge may stem from the fact that many studies focus only on isolated aspects of pain management. All too commonly the studies provide only a somewhat fragmented analysis of isolated factors of pain management. In contrast, the explanatory model presented here provides a more holistic view of the nurses' complex situation when caring for patients in pain and may reveal that neglecting these other facets may have contributed to the permanent inadequacy in pain management of patients that is so

Unsuccessful outcome **No pain relief**  Nurse's dissatisfaction and disempowerment

Distress

*Silenced voice* 

This explanatory model clarifies how nurses require various coexisting patterns of knowledge, within a favourable organisational environment, to be able to perform in accord with their role as key persons in pain management and how their performance may predict a positive or negative outcome for the patient and the nurse. This model further explains the relationships of nurses with patients and physicians where nurses seek to act as patients' advocates and how having a voice is pivotal for nurses. Furthermore, we depict how internal and external barriers can hinder the performance of nurses and how an unsuccessful outcome that evokes profound distress may concurrently stimulate further actions and turn a negative outcome into a more favourable one. This explanatory model of a nurse's journey therefore denotes nurses' encounters with, and reactions to, the multiple

demanding assignments they continually meet on their mission towards pain relief.

**4.1 Nurses´ two main drives: Moral obligation and formal and tacit knowledge** 

According to our explanatory model *the role of ethical knowledge in pain management must be highlighted*, as it may be the fundamental component needed for nurses to act as advocates

Fig. 7. Potential outcomes

Coping mechanisms

*Voice* 

Successful outcome **Pain relief**  Nurse's satisfaction and empowerment

widely described.

**4. Discussion** 

**4.1.1 Knowledge of ethical origins** 

In accordance with our propositions, professional responsibility and moral obligation are considered key initiates for advocacy. Twycross (2002) posits that in order to advocate, a theoretical knowledge base is needed. Vaartio et al. (2006) and O'Connor & Kelly (2005) add to this by stating that theoretical as well as practical knowledge of pain management is a necessary antecedent of advocacy. Where sound empirical knowledge about pain assessment and various methods for management of pain are vital, it must be kept in mind that nurses learn no less through experience, where they learn to utilise their own potential and personal knowledge through their own practice and role modelling. This drive for taking action by using theoretical or formal knowledge along with experience and selfconfidence is congruent with Mallik's (1997) statement that 'intervening conditions' facilitate advocacy. These factors have also been found important for nurses' decisionmaking (Nash et al., 1999). Where knowledge of theoretical origins may be the type of knowledge that is most easily recognised and is emphasised during formal education at school and in continuous education, we stress that the role of tacit knowledge gained through experience and role modelling has more rarely been pointed out, perhaps because it is rather of personal and aesthetic origins. Importantly, as we see it, this knowledge supplements formal knowledge, for instance in the early stages of the process where nurses assess the patient's pain.

#### **4.2 The nurse as patient's advocate in pain management**

Patients in pain have been recognised as a vulnerable group of patients that are in need of nurses to advocate on their behalf (Ware et al., 2011), and nurses see it as their role to safeguard their interests (Blondal & Halldorsdottir, 2009; Ware et al., 2011). As portrayed in our explanatory model nurses assume a central role in assessing and managing patients' pain. However, since doctors are responsible for prescribing analgesia, nurses' concerns about pain relief are often affected by their relationship with the doctors (Kuuppelomäki, 2002a; Taylor et al., 1993; Van Niekerk and Martin, 2002).

#### **4.2.1 Communicating with doctors at "***the gate***" and mutual decision-making**

On the nurses' journey *the gate*, where they enter these relations with *the gatekeeper*—the doctor, is an important turning point (Blondal & Halldorsdottir, 2009). Having a *voice* at the

When Theoretical Knowledge Is Not Enough:

**4.3.1 Knowing the patient** 

Introduction of an Explanatory Model on Nurse's Pain Management 531

this could also apply to other pain management decisions and call for more discussions

As represented in our explanatory model, facilitating factors for successful advocacy and a favourable outcome require knowing persons and the system. Jenks' (1993) exploration of nurses' clinical decision-making, proposing that clinical decisions depend on the quality and dynamics of nurses' interpersonal relationships is in harmony with our interpretation of the process from pain assessment to reaction. However, we also want to add the dimension of knowing your own self and the organisation that also are essential facilitating factors. These important features that enhance nurses' possibilities for using their knowledge and moral motivation are opposed to the factors that hinder them in making use of their potential, and

As repeatedly has been pointed out, insufficient pain assessment by nurses interferes with successful pain relief (Carr, 2002). According to McCaffery (Pasero et al., 1999, as cited in McCaffery, 1968) "[P]ain is whatever the experiencing person says it is, existing whenever he says it does" (p. 17). However, because individuals express pain very differently, this definition creates some problems for nurses. For instance, although the risk of addiction is minor (McCaffery et al*.,* 1990), caring for a patient who is, or is suspected of being, an abuser can be very stressful (Blondal & Halldorsdottir, 2009; Nash et al*.*, 1999). Moreover, McCaffery and Ferrell (1997) assert that nurses must appreciate that "the only scientific tool for measuring pain intensity is the patient's report using a pain rating scale" (p. 183). These scales may, however, be difficult to use with patients that are disoriented (Coker et al., 2010) or unconscious (Kuuppelomäki, 2002a) and many nurses are hesitant to use them (Schafheutle et al., 2001). Then many elderly patients suffer in silence with their pain and discomforts and do not seek help and more effort is required if those with pain are to be identified, supported and cared for as Gudmannsdottir & Halldorsdottir (2009) suggest. Whereas the use of various pain scales for pain assessment build on theoretical knowledge, conversely, *knowing the patient* as a person can greatly assist nurses to assess the patient's pain (Blondal and Halldorsdottir, 2009); this approach is more related to personal and aesthetic knowledge. Knowing the patient as a person strongly facilitates the assessment of patients' needs and clinical decision-making (Liaschenko, 1997), and allows nurses to interpret information and select individualised interventions (Takman and Severinsson, 1999). Furthermore, the nurse-patient relationship is a motivating factor for advocacy (Mallik, 1997; O'Connor & Kelly, 2005) and analysing the patient and the situation is a fundamental element of advocacy (Vaartio et al., 2008). Therefore, we suggest that more emphasis is given to this special aspect of pain management. Still, yet another pattern of knowledge may also be needed here; *unknowing the patient.* When nurses admit to themselves that they do not know the patient and his or her point of view, it allows them to hold their former biases and prejudices in abeyance (Munhall, 1993). We suggest that assuming this type of knowledge is of utmost importance as it may prevent nurses from making assumptions about patients´ pain intensity that is based on diagnosis and course of treatment (Clabo, 2008; Manias, 2003; Schafheutle et al., 2001) that is associated with underestimation of pain (Sjöström et al., 2000), and a barrier to effective pain relief (Schafheutle et al., 2001). Adopting this stance of unknowing could also avoid the

about the ethical aspects of pain management across professions.

may, to some degree, be used to overcome their negative effects.

**4.3 Facilitating factors for a successful outcome** 

gate is pivotal, because there the nurses represent the patient, and by using their influence try to fulfil their mission. Subsequently, the doctor decides what medication the patient can or cannot receive; i.e. whether the nurses pass through the gate (Blondal & Halldorsdottir, 2009). Within the *gate* the nurses can also assume the role of 'conciliator' or 'intermediary'. Nurses' accounts of their advocating position have, therefore, also been described as 'bridging the gap' between the patients and the medical profession. This involves the translation of information between patients and doctors and in both directions (O'Connor & Kelly, 2005). As we envision it, yet another aspect of personal knowledge is revealed here where, inevitably, nurses must communicate with doctors to achieve the best outcome for patients.

Many nurses do not find it difficult to communicate with doctors or to confront them and are ready to push boundaries to acquire what the patient needs (Blondal & Halldorsdottir, 2009; Vaartio et al., 2008; Ware et al., 2011). For others, communicational problems are a matter of fact and they feel uncomfortable about trespassing on the doctors´ domain (De Schepper et al. 1997; Willson, 2000). Nurses in cancer-related home care, for instance, complain about physicians' lack of knowledge and collaboration, and problems with contacting them (Ferrell et al., 1993). Nurses then also describe physicians' fear of overmedicating patients with dementia or delirium in medical wards (Coker et al., 2010). Communicational problems cause feelings of powerlessness and distress (Blondal & Halldorsdottir, 2009; Malloy et al., 2009) and ethical dilemmas and they are sometimes punished for their advocating activities (Clabo, 2008; Mallik, 1997; Malloy et al., 2009). Mallik (1997) maintains that to achieve their goals, advocates often play the doctor-nurse game of recommending actions without appearing to do so (Stein et al*.*, 1990) or assume the attitude of a 'stubborn rebel' with an over-determined and even hostile behaviour (Stein et al., 1990). In our study, however, the nurses emphasise assertiveness, rather than pushiness, for success (Blondal & Halldorsdottir, 2009). When nurses are straightforward in their requests, this could be explained by their perceptions of being respected and *having a voice*, and therefore in keeping with Van Niekerk and Martin (2002) that nurses who feel adequately consulted by physicians are more likely to initiate the consultation process. The use of assertiveness further matches the argument of Keenan et al. (1998) that conveying ideas in a forceful and confrontational manner increases the likelihood for successful collaboration. We claim that when nurses choose to bypass the *gate* by bending rules (Blondal & Halldorsdottir, 2009; Ware et al., 2011) despite the risk of jeopardising their career, this might indicate a lack of self-confidence, negotiating competence or communicational competence skills. For nurses, ethical problems may often be related to their hierarchical position, where their voices are not heard or they are being silenced in spite of their professional knowledge (Blondal & Halldorsdottir, 2009; Malloy et al., 2009; Oberle and Hughes, 2001). From this, it might be understood that the views of nurses and doctors are incompatible, for instance because of the different orientation of *care* versus *cure*  (Malloy et al., 2009). However, doctors can also experience an inability to exercise moral agency and experience powerlessness, because of hierarchical structures, and they are faced with the same kinds of ethical dilemmas as nurses. Furthermore, the obligation to respond is the same for all and this difference could rather be explained by different roles and responsibilities and unawareness of each others' responses (Oberle and Hughes, 2001). This also may reflect the reality that nurses and doctors act independently, without mutually agreed principles or practices rather than as a team in managing pain (Kuuppelomäki, 2002a). Although this statement is made in regard to end-of-life situations, we conclude that this could also apply to other pain management decisions and call for more discussions about the ethical aspects of pain management across professions.

#### **4.3 Facilitating factors for a successful outcome**

As represented in our explanatory model, facilitating factors for successful advocacy and a favourable outcome require knowing persons and the system. Jenks' (1993) exploration of nurses' clinical decision-making, proposing that clinical decisions depend on the quality and dynamics of nurses' interpersonal relationships is in harmony with our interpretation of the process from pain assessment to reaction. However, we also want to add the dimension of knowing your own self and the organisation that also are essential facilitating factors. These important features that enhance nurses' possibilities for using their knowledge and moral motivation are opposed to the factors that hinder them in making use of their potential, and may, to some degree, be used to overcome their negative effects.

#### **4.3.1 Knowing the patient**

530 Pain Management – Current Issues and Opinions

gate is pivotal, because there the nurses represent the patient, and by using their influence try to fulfil their mission. Subsequently, the doctor decides what medication the patient can or cannot receive; i.e. whether the nurses pass through the gate (Blondal & Halldorsdottir, 2009). Within the *gate* the nurses can also assume the role of 'conciliator' or 'intermediary'. Nurses' accounts of their advocating position have, therefore, also been described as 'bridging the gap' between the patients and the medical profession. This involves the translation of information between patients and doctors and in both directions (O'Connor & Kelly, 2005). As we envision it, yet another aspect of personal knowledge is revealed here where, inevitably, nurses must communicate with doctors to achieve the best outcome for

Many nurses do not find it difficult to communicate with doctors or to confront them and are ready to push boundaries to acquire what the patient needs (Blondal & Halldorsdottir, 2009; Vaartio et al., 2008; Ware et al., 2011). For others, communicational problems are a matter of fact and they feel uncomfortable about trespassing on the doctors´ domain (De Schepper et al. 1997; Willson, 2000). Nurses in cancer-related home care, for instance, complain about physicians' lack of knowledge and collaboration, and problems with contacting them (Ferrell et al., 1993). Nurses then also describe physicians' fear of overmedicating patients with dementia or delirium in medical wards (Coker et al., 2010). Communicational problems cause feelings of powerlessness and distress (Blondal & Halldorsdottir, 2009; Malloy et al., 2009) and ethical dilemmas and they are sometimes punished for their advocating activities (Clabo, 2008; Mallik, 1997; Malloy et al., 2009). Mallik (1997) maintains that to achieve their goals, advocates often play the doctor-nurse game of recommending actions without appearing to do so (Stein et al*.*, 1990) or assume the attitude of a 'stubborn rebel' with an over-determined and even hostile behaviour (Stein et al., 1990). In our study, however, the nurses emphasise assertiveness, rather than pushiness, for success (Blondal & Halldorsdottir, 2009). When nurses are straightforward in their requests, this could be explained by their perceptions of being respected and *having a voice*, and therefore in keeping with Van Niekerk and Martin (2002) that nurses who feel adequately consulted by physicians are more likely to initiate the consultation process. The use of assertiveness further matches the argument of Keenan et al. (1998) that conveying ideas in a forceful and confrontational manner increases the likelihood for successful collaboration. We claim that when nurses choose to bypass the *gate* by bending rules (Blondal & Halldorsdottir, 2009; Ware et al., 2011) despite the risk of jeopardising their career, this might indicate a lack of self-confidence, negotiating competence or communicational competence skills. For nurses, ethical problems may often be related to their hierarchical position, where their voices are not heard or they are being silenced in spite of their professional knowledge (Blondal & Halldorsdottir, 2009; Malloy et al., 2009; Oberle and Hughes, 2001). From this, it might be understood that the views of nurses and doctors are incompatible, for instance because of the different orientation of *care* versus *cure*  (Malloy et al., 2009). However, doctors can also experience an inability to exercise moral agency and experience powerlessness, because of hierarchical structures, and they are faced with the same kinds of ethical dilemmas as nurses. Furthermore, the obligation to respond is the same for all and this difference could rather be explained by different roles and responsibilities and unawareness of each others' responses (Oberle and Hughes, 2001). This also may reflect the reality that nurses and doctors act independently, without mutually agreed principles or practices rather than as a team in managing pain (Kuuppelomäki, 2002a). Although this statement is made in regard to end-of-life situations, we conclude that

patients.

As repeatedly has been pointed out, insufficient pain assessment by nurses interferes with successful pain relief (Carr, 2002). According to McCaffery (Pasero et al., 1999, as cited in McCaffery, 1968) "[P]ain is whatever the experiencing person says it is, existing whenever he says it does" (p. 17). However, because individuals express pain very differently, this definition creates some problems for nurses. For instance, although the risk of addiction is minor (McCaffery et al*.,* 1990), caring for a patient who is, or is suspected of being, an abuser can be very stressful (Blondal & Halldorsdottir, 2009; Nash et al*.*, 1999). Moreover, McCaffery and Ferrell (1997) assert that nurses must appreciate that "the only scientific tool for measuring pain intensity is the patient's report using a pain rating scale" (p. 183). These scales may, however, be difficult to use with patients that are disoriented (Coker et al., 2010) or unconscious (Kuuppelomäki, 2002a) and many nurses are hesitant to use them (Schafheutle et al., 2001). Then many elderly patients suffer in silence with their pain and discomforts and do not seek help and more effort is required if those with pain are to be identified, supported and cared for as Gudmannsdottir & Halldorsdottir (2009) suggest. Whereas the use of various pain scales for pain assessment build on theoretical knowledge, conversely, *knowing the patient* as a person can greatly assist nurses to assess the patient's pain (Blondal and Halldorsdottir, 2009); this approach is more related to personal and aesthetic knowledge. Knowing the patient as a person strongly facilitates the assessment of patients' needs and clinical decision-making (Liaschenko, 1997), and allows nurses to interpret information and select individualised interventions (Takman and Severinsson, 1999). Furthermore, the nurse-patient relationship is a motivating factor for advocacy (Mallik, 1997; O'Connor & Kelly, 2005) and analysing the patient and the situation is a fundamental element of advocacy (Vaartio et al., 2008). Therefore, we suggest that more emphasis is given to this special aspect of pain management. Still, yet another pattern of knowledge may also be needed here; *unknowing the patient.* When nurses admit to themselves that they do not know the patient and his or her point of view, it allows them to hold their former biases and prejudices in abeyance (Munhall, 1993). We suggest that assuming this type of knowledge is of utmost importance as it may prevent nurses from making assumptions about patients´ pain intensity that is based on diagnosis and course of treatment (Clabo, 2008; Manias, 2003; Schafheutle et al., 2001) that is associated with underestimation of pain (Sjöström et al., 2000), and a barrier to effective pain relief (Schafheutle et al., 2001). Adopting this stance of unknowing could also avoid the

When Theoretical Knowledge Is Not Enough:

**4.3.4 Knowing the system** 

**4.4.1 Internal hindrances** 

positive outcome both for the patients and themselves.

**4.4 Hindrances for successful pain management** 

Introduction of an Explanatory Model on Nurse's Pain Management 533

themselves are more capable of entering into and coping positively with difficult relations with others —patients, families and doctors, and are more likely to gain what is needed for a

Yet another facet that is worth more consideration is nurses´ knowledge of the organisation. Knowing the system and the environment is part of nurses' advocacy, for instance when nurses must mediate between the patient and the system through interpretation of medical terminology or advocating for a group of patients (O´Connor et al., 2005). It also seems necessary to recognise what options or resources are available within the organisation, for instance whom to turn to for assistance. Here, the support of professionals — specialists in pain management within organisations, must be present at all times to assist them in dealing with difficult cases (Blondal and Halldorsdottir, 2009; Nash et al., 1999). Moreover, nurses must recognise the availability of specialists and when they should be contacted and involved.

As the model portrays, some inhibiting factors hinder nurses´ potentials for taking action and therefore interfere with their drives, moral obligation, and formal and tacit knowledge. It may also be seen that these factors are somewhat in opposition to the facilitating factors. The main obstacles are grouped as external — originating in the nurses´ environment, or internal — concerned with inner doubts or dilemmas. This gives an example of how these model elements are interconnected and should not be taken out of the immediate context.

As previously mentioned, nurses´ moral motivation is complicated by some dilemmas as the nurses encounter variable decisional and ethical conflicts (Taylor et al. 1993) that directly affect the pain management process and its outcome. The dilemma of inflicting pain to serve other goals of treatment (De Schepper, 1997; Willson, 2000), fear of giving too much pain medication because of respiratory depression (Ferrell et al., 1991; Howell et al., 2000; Wilson, 2007), sedation (Howell et al., 2000), fear of the addictive properties of narcotics (Brockopp et al., 1998), and doubt whether the pain is real (Nash, 1999; Rejeh et al., 2009) has repeatedly been described. So are the difficulties of distinguishing between physical pain and psychological distress (Kuuppellomäki, 2002a), patients' non-compliance in accepting analgesia (Kuuppellomäki, 2002a), patients' reticence (De Schepper et al 1997; Rejeh et al., 2009) and nurses' concerns about giving a dying person the last dose (Brockopp et al., 1998), as for some, hastening death through pain relief is morally unacceptable (O'Rourke, 1992). Ethical problems may also arise from a lack of permission to be honest with patients (Rejeh et al., 2009) or because of the attitudes of family members towards pain medication (Kuuppelomäki, 2002a). Nurses also frequently describe how difficult it is for them to care for patients that are known abusers or suspected of being addicts, and believing their words (Blondal & Halldorsdottir, 2009; Nash et al., 1999; Rejeh et al., 2009*)*. Dilemmas may also be caused by preconceived notions about certain groups of patients that negatively interfere with nurses' decision-making (Brockopp et al., 2003). Interestingly, Van Niekerk and Martin (2002) point out that nurses with greater knowledge of pain assessment are less likely to experience ethical conflicts regarding overmedication, addiction or doubt about the existence of pain. Hence, more knowledge could prevent such ethical conflicts. Accounts

stereotyping of patients, such as those who may be addicts, homeless or prisoners (Rejeh et al., 2009) or with a lifestyle that may affect nurses' pain management behaviours (Wilson, 2007). Therefore, we advise that strategies nurses use to connect to patients which may be based on personal knowledge (Carper, 1978) and unknowing (Munhall, 1993) are highlighted along with the current emphasis on using pain rating scales (e.g. Paice and Cohen, 1997).

According to our model, competent communication with patients may be a powerful way to overcome internal hindrances in addition to theoretical knowledge about pain assessment, addiction, respiratory depression and other possible side effects of pain medication that also may stem from the ethical orientation of preventing harm to the patients. When nurses' emphasise individualised pain management, knowing the patient as a person, recognising his/her special needs and responding to these needs on the basis of envisioned results, portrays the importance of aesthetic knowledge and comprehension of the particularity of the situation (Carper, 1978). Empathy is also an important component mode of the aesthetic pattern in nursing (Carper, 1978), and apparent in nurses' accounts of pain management (Blondal & Halldorsdottir, 2009; Rejeh et al., 2009) and should be not only acknowledged but utilised more often.

#### **4.3.2 Knowing the doctor**

Since nurses call for equality, mutual decision-making and respect for their judgement (Blondal & Halldorsdottir, 2009), knowing the doctor is a factor worth further exploration. In accordance with our explanatory model Jenks (1993) maintains that *knowing the doctor* creates mutual trust in each others' perceptions. Therefore, a good nurse-physician relationship, in accordance with our metaphor of nurses passing through the *gate*, knowing *the gatekeeper* may add to optimal pain relief and consequently affects nurses' and patients' wellbeing. It is, therefore, imperative that both doctors and nurses be aware of the need for good rapport and be knowledgeable about good communication techniques and that both groups of professionals make every effort to encourage collaboration and to find ways to get to know each other as persons. Again, we propose that personal knowledge and communicational skills that nurses must use in relations with patients and doctors is vital because, as before, possessing theoretical knowledge and the motivation to use it (moral orientation) may become of little use if not employed because of lack of communication or negotiating abilities or lack of self-confidence or if nurses cannot react because their voice is silenced. Therefore, nurses must be taught to act as the patients' advocates, represent themselves and act like the patients' representative.

#### **4.3.3 Knowing oneself, having self-confidence and conviction**

We further want to draw attention to how nurses' awareness of their feelings such as distress and empathy, recognition of their own capabilities, self-confidence and persistence may be important facilitating factors. As mentioned before, motivational factors such as experience and self-confidence are congruent with Mallik's (1997) 'intervening conditions' that facilitate advocacy and are important for nurses' decision-making (Nash et al., 1999). As further discussed later, emotional responses such as anger and frustration are also potent motivators for advocacy (Mallik, 1997). Such knowledge is of both personal and aesthetical origins and nurses must learn to identify and accept such feelings and be empowered to use them to be capable of following their convictions, both for their own sakes and for the good of the patient. According to our model, nurses that hold such knowledge and believe in themselves are more capable of entering into and coping positively with difficult relations with others —patients, families and doctors, and are more likely to gain what is needed for a positive outcome both for the patients and themselves.

#### **4.3.4 Knowing the system**

532 Pain Management – Current Issues and Opinions

stereotyping of patients, such as those who may be addicts, homeless or prisoners (Rejeh et al., 2009) or with a lifestyle that may affect nurses' pain management behaviours (Wilson, 2007). Therefore, we advise that strategies nurses use to connect to patients which may be based on personal knowledge (Carper, 1978) and unknowing (Munhall, 1993) are highlighted along with the current emphasis on using pain rating scales (e.g. Paice and

According to our model, competent communication with patients may be a powerful way to overcome internal hindrances in addition to theoretical knowledge about pain assessment, addiction, respiratory depression and other possible side effects of pain medication that also may stem from the ethical orientation of preventing harm to the patients. When nurses' emphasise individualised pain management, knowing the patient as a person, recognising his/her special needs and responding to these needs on the basis of envisioned results, portrays the importance of aesthetic knowledge and comprehension of the particularity of the situation (Carper, 1978). Empathy is also an important component mode of the aesthetic pattern in nursing (Carper, 1978), and apparent in nurses' accounts of pain management (Blondal & Halldorsdottir, 2009; Rejeh et al., 2009) and should be not only acknowledged

Since nurses call for equality, mutual decision-making and respect for their judgement (Blondal & Halldorsdottir, 2009), knowing the doctor is a factor worth further exploration. In accordance with our explanatory model Jenks (1993) maintains that *knowing the doctor* creates mutual trust in each others' perceptions. Therefore, a good nurse-physician relationship, in accordance with our metaphor of nurses passing through the *gate*, knowing *the gatekeeper* may add to optimal pain relief and consequently affects nurses' and patients' wellbeing. It is, therefore, imperative that both doctors and nurses be aware of the need for good rapport and be knowledgeable about good communication techniques and that both groups of professionals make every effort to encourage collaboration and to find ways to get to know each other as persons. Again, we propose that personal knowledge and communicational skills that nurses must use in relations with patients and doctors is vital because, as before, possessing theoretical knowledge and the motivation to use it (moral orientation) may become of little use if not employed because of lack of communication or negotiating abilities or lack of self-confidence or if nurses cannot react because their voice is silenced. Therefore, nurses must be taught to act as the patients' advocates, represent

We further want to draw attention to how nurses' awareness of their feelings such as distress and empathy, recognition of their own capabilities, self-confidence and persistence may be important facilitating factors. As mentioned before, motivational factors such as experience and self-confidence are congruent with Mallik's (1997) 'intervening conditions' that facilitate advocacy and are important for nurses' decision-making (Nash et al., 1999). As further discussed later, emotional responses such as anger and frustration are also potent motivators for advocacy (Mallik, 1997). Such knowledge is of both personal and aesthetical origins and nurses must learn to identify and accept such feelings and be empowered to use them to be capable of following their convictions, both for their own sakes and for the good of the patient. According to our model, nurses that hold such knowledge and believe in

Cohen, 1997).

but utilised more often.

**4.3.2 Knowing the doctor** 

themselves and act like the patients' representative.

**4.3.3 Knowing oneself, having self-confidence and conviction** 

Yet another facet that is worth more consideration is nurses´ knowledge of the organisation. Knowing the system and the environment is part of nurses' advocacy, for instance when nurses must mediate between the patient and the system through interpretation of medical terminology or advocating for a group of patients (O´Connor et al., 2005). It also seems necessary to recognise what options or resources are available within the organisation, for instance whom to turn to for assistance. Here, the support of professionals — specialists in pain management within organisations, must be present at all times to assist them in dealing with difficult cases (Blondal and Halldorsdottir, 2009; Nash et al., 1999). Moreover, nurses must recognise the availability of specialists and when they should be contacted and involved.

#### **4.4 Hindrances for successful pain management**

As the model portrays, some inhibiting factors hinder nurses´ potentials for taking action and therefore interfere with their drives, moral obligation, and formal and tacit knowledge. It may also be seen that these factors are somewhat in opposition to the facilitating factors. The main obstacles are grouped as external — originating in the nurses´ environment, or internal — concerned with inner doubts or dilemmas. This gives an example of how these model elements are interconnected and should not be taken out of the immediate context.

#### **4.4.1 Internal hindrances**

As previously mentioned, nurses´ moral motivation is complicated by some dilemmas as the nurses encounter variable decisional and ethical conflicts (Taylor et al. 1993) that directly affect the pain management process and its outcome. The dilemma of inflicting pain to serve other goals of treatment (De Schepper, 1997; Willson, 2000), fear of giving too much pain medication because of respiratory depression (Ferrell et al., 1991; Howell et al., 2000; Wilson, 2007), sedation (Howell et al., 2000), fear of the addictive properties of narcotics (Brockopp et al., 1998), and doubt whether the pain is real (Nash, 1999; Rejeh et al., 2009) has repeatedly been described. So are the difficulties of distinguishing between physical pain and psychological distress (Kuuppellomäki, 2002a), patients' non-compliance in accepting analgesia (Kuuppellomäki, 2002a), patients' reticence (De Schepper et al 1997; Rejeh et al., 2009) and nurses' concerns about giving a dying person the last dose (Brockopp et al., 1998), as for some, hastening death through pain relief is morally unacceptable (O'Rourke, 1992). Ethical problems may also arise from a lack of permission to be honest with patients (Rejeh et al., 2009) or because of the attitudes of family members towards pain medication (Kuuppelomäki, 2002a). Nurses also frequently describe how difficult it is for them to care for patients that are known abusers or suspected of being addicts, and believing their words (Blondal & Halldorsdottir, 2009; Nash et al., 1999; Rejeh et al., 2009*)*. Dilemmas may also be caused by preconceived notions about certain groups of patients that negatively interfere with nurses' decision-making (Brockopp et al., 2003). Interestingly, Van Niekerk and Martin (2002) point out that nurses with greater knowledge of pain assessment are less likely to experience ethical conflicts regarding overmedication, addiction or doubt about the existence of pain. Hence, more knowledge could prevent such ethical conflicts. Accounts

When Theoretical Knowledge Is Not Enough:

Introduction of an Explanatory Model on Nurse's Pain Management 535

willing or able to attend to patients' suffering. Such strategies should, therefore, be detected,

Effective pain relief may provide *satisfaction*, both by means of professional achievements and benefits for the patient and the nurse (Blondal & Halldorsdottir, 2009; De Schepper et al. 1997; Vaartio et al., 2008). However, such positive outcomes are seldom mentioned. We believe that this aspect should receive more attention and nurses should be enabled to reap satisfaction from overcoming challenges and learning from them. As successful pain relief may enhance autonomy and a sense of *empowerment*, this is relevant to both quality of pain management and job satisfaction. Conversely, much more attention is given to the negative aspects: dissatisfaction, distress and frustration (e.g. Nagy, 1998; Söderhamn and Idvall, 2003) following insufficient or unsuccessful pain management that leads in turn to nurses' suffering and *disempowerment* (Blondal & Halldorsdottir, 2009; Oberle and Hughes, 2001).

Since *dissatisfaction* and nurses´ *distress* may be the inevitable results of nurses' inability to ease the patients' pain, for instance because of silencing or lack of resources, it is important to note that nurses' distress can impel further actions. This is in agreement with Mallik's (1997) argument that emotional responses of anger and frustration can be potent motivators for advocacy. It, therefore, seems important that nurses accept and recognise such feelings, not least because those who acknowledge and try to deal with feelings of powerlessness are more capable of coping (De Schepper et al., 1997). All these responses require, once again, both personal and aesthetic knowledge where nurses as individuals must learn to know themselves and their reactions and be able to develop and maintain a view of what they want to achieve with their actions. Here we come back to earlier discussion about nurses'

Theory provides a more complete picture of practice than factual knowledge alone, and theories formulate, identify, and articulate the science and practice of every discipline (Butcher, 2006). Nursing scholars need to identify and articulate the processes and components of the art and science of pain management. This theory is an attempt to do so in an endeavour to continue the discipline's development by assisting in the understanding and practice of creating further theoretical discourse, processes and products for pain management, similar to what Kagan (2006) has described. All theories are reconstructed in the light of new data. The theory presented here is, therefore, seen as always being in the process of emerging, as is our world view. According to Walker and Avant (2004), the next steps in the phases of our theory development are: theory testing involving concept revision, statement revision, and theory revision, followed by further theory testing. We encourage our colleagues to critique the theory and use it to generate research questions and take part

From our explanatory model many suggestions can be made about how to contribute to

and those nurses helped to adopt more constructive coping strategies.

**4.6.1 Dissatisfaction and distress as motivators for a successful outcome** 

requirements of knowing their own "selves", their own feelings and capabilities.

in testing the theory as well as in concept, statement and theory revision.

changes in the education of nurses, their work environment and future research.

**6. Implications for practice and future research** 

**5. Further development of this theory** 

**4.6 Potential outcomes of pain management and advocacy** 

like this further sustain our claims about how the separate parts introduced in our model are interconnected and cannot be separated from the complete picture.

#### **4.4.2 External obstacles**

Organisational barriers have formerly been extensively described, where lack of time, workload (Ware et al., 2011; Rejeh et al., 2009) financial restraints and staffing cutbacks (Oberle and Hughes, 2001; Rejeh et al., 2009), restraints of routine (Willson, 2000), insufficient prescribing of analgesics (Schafheutle et al., 2001; Kuuppelomäki, 2002a) based on habits instead of individualised needs (Boer et al, 1997), and unavailability of physicians (Kuuppelomäki, 2002a; Rejeh et al., 2009) interfere with pain relief. Other related hindrances that are part of the system have also been identified such as unavailable non-pharmacological pain relief measures and disorganised systems of care (Coker et al., 2010). Rejeh et al. (2009) also point out that defective equipment and interruptions can lead to ethical problems in pain management. The importance of a decision on palliative care for good pain relief is endorsed by Kuuppelomäki (2002b) who reports physicians' hesitancy about starting terminal care, and delayed decisions of using a strong analgesia (Kuuppelomäki, 2002a). The organisation must, therefore, provide an *optimal organisational environment* since organisational barriers such as unclear rules, lack of prescriptions or time and resources such as specialised pain services, may hinder nurses from acting according to their best knowledge, potential and goals. The presence of prescriptions, rules and directives are important to be able to give the patient what she or he needs. Inflexible protocols and strict policies or routines, on the other hand, impede good pain management (Rajeh et al., 2009; Willson, 2000) resulting in the nurses giving up and leaving them feeling silenced and disempowered (Blondal & Halldorsdottir, 2009; Malloy et al., 2009). Alternatively, nurses may feel compelled to choose to bypass the *gate*, by bending rules (Blondal & Halldorsdottir, 2009; Ware et al., 2011), to obtain favourable results for the patient, as is portrayed in our model. Our emphasis on organisational structures is supported by the results of Willson's (2000) participant observation study on factors affecting analgesia administration; Willson suggests that because of the interplay between multiple organisational and interpersonal features, more education of the nurses will not necessarily improve the administration of analgesics.

#### **4.5 Coping mechanisms**

How nurses *cope* with their challenges predicts to some extent how they perceive the outcome of pain relief and they seem to use various methods to cope and protect themselves. Applying methods such as concentrating on patients' positive attributes is a component of strategies that prevent burnout (Simoni and Paterson, 1997), and sharing feelings with colleagues (De Schepper et al., 1997; Nagy, 1999) and having the opportunity to stand back from situations (De Schepper et al., 1997; Rejeh et al., 2009) are consistent with strategies that reduce powerlessness (De Schepper et al., 1997). Seeking and receiving support from pain teams and specialists in pain management is vital, and such assistance can transform distress into satisfaction. Ironically, those who accept the responsibility as seeing to pain relief run the risk of experiencing ethical problems which may lead to a sense of loss of control and subsequently burnout, resulting in decreased quality of care (Schmitz et al., 2000). If nurses give up their advocating efforts and instead assume *coping methods* such as avoidance, which indicates unsuccessful coping (Simoni and Paterson, 1997), it may desensitise them to patients' needs (Nagy's, 1999), which means in turn that they may not be

like this further sustain our claims about how the separate parts introduced in our model are

Organisational barriers have formerly been extensively described, where lack of time, workload (Ware et al., 2011; Rejeh et al., 2009) financial restraints and staffing cutbacks (Oberle and Hughes, 2001; Rejeh et al., 2009), restraints of routine (Willson, 2000), insufficient prescribing of analgesics (Schafheutle et al., 2001; Kuuppelomäki, 2002a) based on habits instead of individualised needs (Boer et al, 1997), and unavailability of physicians (Kuuppelomäki, 2002a; Rejeh et al., 2009) interfere with pain relief. Other related hindrances that are part of the system have also been identified such as unavailable non-pharmacological pain relief measures and disorganised systems of care (Coker et al., 2010). Rejeh et al. (2009) also point out that defective equipment and interruptions can lead to ethical problems in pain management. The importance of a decision on palliative care for good pain relief is endorsed by Kuuppelomäki (2002b) who reports physicians' hesitancy about starting terminal care, and delayed decisions of using a strong analgesia (Kuuppelomäki, 2002a). The organisation must, therefore, provide an *optimal organisational environment* since organisational barriers such as unclear rules, lack of prescriptions or time and resources such as specialised pain services, may hinder nurses from acting according to their best knowledge, potential and goals. The presence of prescriptions, rules and directives are important to be able to give the patient what she or he needs. Inflexible protocols and strict policies or routines, on the other hand, impede good pain management (Rajeh et al., 2009; Willson, 2000) resulting in the nurses giving up and leaving them feeling silenced and disempowered (Blondal & Halldorsdottir, 2009; Malloy et al., 2009). Alternatively, nurses may feel compelled to choose to bypass the *gate*, by bending rules (Blondal & Halldorsdottir, 2009; Ware et al., 2011), to obtain favourable results for the patient, as is portrayed in our model. Our emphasis on organisational structures is supported by the results of Willson's (2000) participant observation study on factors affecting analgesia administration; Willson suggests that because of the interplay between multiple organisational and interpersonal features, more education of the nurses

How nurses *cope* with their challenges predicts to some extent how they perceive the outcome of pain relief and they seem to use various methods to cope and protect themselves. Applying methods such as concentrating on patients' positive attributes is a component of strategies that prevent burnout (Simoni and Paterson, 1997), and sharing feelings with colleagues (De Schepper et al., 1997; Nagy, 1999) and having the opportunity to stand back from situations (De Schepper et al., 1997; Rejeh et al., 2009) are consistent with strategies that reduce powerlessness (De Schepper et al., 1997). Seeking and receiving support from pain teams and specialists in pain management is vital, and such assistance can transform distress into satisfaction. Ironically, those who accept the responsibility as seeing to pain relief run the risk of experiencing ethical problems which may lead to a sense of loss of control and subsequently burnout, resulting in decreased quality of care (Schmitz et al., 2000). If nurses give up their advocating efforts and instead assume *coping methods* such as avoidance, which indicates unsuccessful coping (Simoni and Paterson, 1997), it may desensitise them to patients' needs (Nagy's, 1999), which means in turn that they may not be

interconnected and cannot be separated from the complete picture.

will not necessarily improve the administration of analgesics.

**4.4.2 External obstacles** 

**4.5 Coping mechanisms** 

willing or able to attend to patients' suffering. Such strategies should, therefore, be detected, and those nurses helped to adopt more constructive coping strategies.

#### **4.6 Potential outcomes of pain management and advocacy**

Effective pain relief may provide *satisfaction*, both by means of professional achievements and benefits for the patient and the nurse (Blondal & Halldorsdottir, 2009; De Schepper et al. 1997; Vaartio et al., 2008). However, such positive outcomes are seldom mentioned. We believe that this aspect should receive more attention and nurses should be enabled to reap satisfaction from overcoming challenges and learning from them. As successful pain relief may enhance autonomy and a sense of *empowerment*, this is relevant to both quality of pain management and job satisfaction. Conversely, much more attention is given to the negative aspects: dissatisfaction, distress and frustration (e.g. Nagy, 1998; Söderhamn and Idvall, 2003) following insufficient or unsuccessful pain management that leads in turn to nurses' suffering and *disempowerment* (Blondal & Halldorsdottir, 2009; Oberle and Hughes, 2001).

#### **4.6.1 Dissatisfaction and distress as motivators for a successful outcome**

Since *dissatisfaction* and nurses´ *distress* may be the inevitable results of nurses' inability to ease the patients' pain, for instance because of silencing or lack of resources, it is important to note that nurses' distress can impel further actions. This is in agreement with Mallik's (1997) argument that emotional responses of anger and frustration can be potent motivators for advocacy. It, therefore, seems important that nurses accept and recognise such feelings, not least because those who acknowledge and try to deal with feelings of powerlessness are more capable of coping (De Schepper et al., 1997). All these responses require, once again, both personal and aesthetic knowledge where nurses as individuals must learn to know themselves and their reactions and be able to develop and maintain a view of what they want to achieve with their actions. Here we come back to earlier discussion about nurses' requirements of knowing their own "selves", their own feelings and capabilities.

#### **5. Further development of this theory**

Theory provides a more complete picture of practice than factual knowledge alone, and theories formulate, identify, and articulate the science and practice of every discipline (Butcher, 2006). Nursing scholars need to identify and articulate the processes and components of the art and science of pain management. This theory is an attempt to do so in an endeavour to continue the discipline's development by assisting in the understanding and practice of creating further theoretical discourse, processes and products for pain management, similar to what Kagan (2006) has described. All theories are reconstructed in the light of new data. The theory presented here is, therefore, seen as always being in the process of emerging, as is our world view. According to Walker and Avant (2004), the next steps in the phases of our theory development are: theory testing involving concept revision, statement revision, and theory revision, followed by further theory testing. We encourage our colleagues to critique the theory and use it to generate research questions and take part in testing the theory as well as in concept, statement and theory revision.

#### **6. Implications for practice and future research**

From our explanatory model many suggestions can be made about how to contribute to changes in the education of nurses, their work environment and future research.

When Theoretical Knowledge Is Not Enough:

**6.3 Future research** 

optimal pain relief.

**7. Conclusion** 

Introduction of an Explanatory Model on Nurse's Pain Management 537

pain management and psychological support at all times are also fundamental. Moreover, the opportunity to discuss difficult cases with philosophers or leaders from different faiths and denominations should be provided in every health care setting. Subsequently, conversations about nurses' ethical responsibilities and dilemmas should be offered and should be open for both nurses and doctors. As pain assessment is partly dependent on positive nurse-patient relationships and knowing the patient as a person, nursing models and interventions that encourage such relations should be introduced and supported. Another aspect of organisational culture that may enhance successful pain management is good collaboration and maintenance of trust between nurses and in the nurse-physician relationships. All efforts that strengthen dialogue and a culture that enables nurses to seek support and advice from colleagues and encourages open discussions about feelings and coping may therefore have positive outcomes in this respect. Lastly, an atmosphere of

The explanatory model can be a great source of ideas for future research. Firstly, a quantitative study could be conducted, to assess nurses' level of empirical, aesthetic and ethical knowledge along with personal knowledge regarding pain relief; including communication, collaboration and coping. Secondly, it would be interesting to explore the ethical component of the nursing and medical curricula and further to investigate to what extent nurses and doctors are guided by moral values in their pain relief at work. Thirdly, studies on how nurses' moral orientation is balanced with the effectiveness of the pain relief they provide could also be conducted. Fourthly, it seems necessary to conduct more studies where the communication of nurses and doctors connected with pain management is explored, for instance by using an ethnographic approach. Fifthly, it seems important to run more field studies within each organization to identify the main obstructions for effective pain management. It seems vital to begin with identifying what hindrances are most prominent before embarking on a campaign for better pain management within organisations. A part of these studies could be to inspect the effects of workload, lack of time and constraining directives on nurses' potentials for providing

Our explanatory model is at odds with statements proposing that pain relief is not the nurses' priority (Brockopp et al., 1998) or their responsibility (Twycross, 2002). We assert, however, that various reasons inhibit the nurses' potential for taking action. We conclude that nurses are the patients´ advocates in pain management and successful pain management is rewarded with a sense of satisfaction, empowerment and fulfilment of their duty. They are in a key position to assess and manage pain and their mediatory position within the hospital is unique. It is vital that nurses are adequately prepared for their role educationally by possessing multidimensional knowledge about pain management. We assert that good theoretical knowledge may be inadequate if the nurse does not have the right motivation, i.e. the *moral inclination* to use it in practice. Furthermore, *personal knowledge* that nurses must use in relations with patients and doctors is also necessary because theoretical knowledge alone may be of little use if it cannot be employed because of lack of communication or negotiation competence or

persistence and seeking the best available solution should be supported.

#### **6.1 Nurses' knowledge and formal education**

Firstly, we propose that alterations should be made within nurses' basic education at school and continuous education at the institutional level. Nurses' formal education at school must include extensive knowledge about pain assessment and pain management and it is also necessary that courses are offered regularly within all health care settings on pain assessment, analgesia, adverse reactions, and respiratory depression. However, in addition to the traditional emphasis on the use of pain scales for the assessment of patients' pain, it is also important to emphasise *personal and aesthetic knowledge* that contains strategies that contribute to knowing and involving the patient, and nurses' availability. Then education about the pain management of dying patients, addiction and prejudices must also be increased, both at schools and within organisations. The *ethical aspects of pain management* should be included in all courses along with empirical knowledge and should contain discussions about moral responsibility, bioethical principles, nurses' professional code of conduct and the Patients' Rights Act together with religious discussions about pain management. Furthermore, despite differences in educational programmes and the cultures of nurses and doctors, these professions must reach a mutual understanding to achieve suitable and consistent care for their patients (Malloy et al., 2009). One method to bring together their views could, therefore, be to organise courses that these professionals attend together. That said, as nurses' socialisation occurs to a great extent during their nursing education (Stein et al., 1990), nursing students should be taught to make claims for mutual decision-making, to recognise their own potential, and be *empowered* to make claims for resources and improvements. As many nurses may lack the vocabulary for ethical decision-making, thus contributing to the silenced voices of nurses (Malloy et al., 2009), *advocating competence*  should be taught at school. Moreover, they should be prepared for the need for *negotiation*, assertiveness, and effective *communication*. It is necessary that nurses are encouraged to reflect on their experience both as nurse students and as practicing nurses and also to establish positive working relationship with doctors. Moreover, since nurses seem to learn strategies such as self-confidence through role modelling we emphasize that during their nursing education and as novice nurses they should have access to role models for guidance that relate to their use of personal and aesthetic knowledge. During courses about pain management nurses' coping methods should be addressed, and they should be taught to recognise destructive methods and adopt more constructive ones. The method of *structured reflection* (Johns, 1995), for instance, could be used to assist nurses in learning about their own abilities and responses. However, not only should negative aspects of their practice or difficult cases be inspected, but also the positive ones.

#### **6.2 Organisational environment**

Firstly, it is imperative that pain relief is highlighted within all health care settings and organisational nursing policies or visions for nursing, which must reflect this important aspect of care. It should be stressed that pain management is a priority and recognised that time and adequate resources are important aspects of pain management. Protocols that exemplify the responsibility of each member of the health care team should exist, but all rules that are created should also be flexible; for instance nurses must be enabled to choose an analgesic from a range of individualised prescriptions. It also seems vital that clear directives exist for the pain relief of addicts and access to support from specialists in the management of this group of patients available at all times. Support from specialists in pain management and psychological support at all times are also fundamental. Moreover, the opportunity to discuss difficult cases with philosophers or leaders from different faiths and denominations should be provided in every health care setting. Subsequently, conversations about nurses' ethical responsibilities and dilemmas should be offered and should be open for both nurses and doctors. As pain assessment is partly dependent on positive nurse-patient relationships and knowing the patient as a person, nursing models and interventions that encourage such relations should be introduced and supported. Another aspect of organisational culture that may enhance successful pain management is good collaboration and maintenance of trust between nurses and in the nurse-physician relationships. All efforts that strengthen dialogue and a culture that enables nurses to seek support and advice from colleagues and encourages open discussions about feelings and coping may therefore have positive outcomes in this respect. Lastly, an atmosphere of persistence and seeking the best available solution should be supported.

#### **6.3 Future research**

536 Pain Management – Current Issues and Opinions

Firstly, we propose that alterations should be made within nurses' basic education at school and continuous education at the institutional level. Nurses' formal education at school must include extensive knowledge about pain assessment and pain management and it is also necessary that courses are offered regularly within all health care settings on pain assessment, analgesia, adverse reactions, and respiratory depression. However, in addition to the traditional emphasis on the use of pain scales for the assessment of patients' pain, it is also important to emphasise *personal and aesthetic knowledge* that contains strategies that contribute to knowing and involving the patient, and nurses' availability. Then education about the pain management of dying patients, addiction and prejudices must also be increased, both at schools and within organisations. The *ethical aspects of pain management* should be included in all courses along with empirical knowledge and should contain discussions about moral responsibility, bioethical principles, nurses' professional code of conduct and the Patients' Rights Act together with religious discussions about pain management. Furthermore, despite differences in educational programmes and the cultures of nurses and doctors, these professions must reach a mutual understanding to achieve suitable and consistent care for their patients (Malloy et al., 2009). One method to bring together their views could, therefore, be to organise courses that these professionals attend together. That said, as nurses' socialisation occurs to a great extent during their nursing education (Stein et al., 1990), nursing students should be taught to make claims for mutual decision-making, to recognise their own potential, and be *empowered* to make claims for resources and improvements. As many nurses may lack the vocabulary for ethical decision-making, thus contributing to the silenced voices of nurses (Malloy et al., 2009), *advocating competence*  should be taught at school. Moreover, they should be prepared for the need for *negotiation*, assertiveness, and effective *communication*. It is necessary that nurses are encouraged to reflect on their experience both as nurse students and as practicing nurses and also to establish positive working relationship with doctors. Moreover, since nurses seem to learn strategies such as self-confidence through role modelling we emphasize that during their nursing education and as novice nurses they should have access to role models for guidance that relate to their use of personal and aesthetic knowledge. During courses about pain management nurses' coping methods should be addressed, and they should be taught to recognise destructive methods and adopt more constructive ones. The method of *structured reflection* (Johns, 1995), for instance, could be used to assist nurses in learning about their own abilities and responses. However, not only should negative

aspects of their practice or difficult cases be inspected, but also the positive ones.

Firstly, it is imperative that pain relief is highlighted within all health care settings and organisational nursing policies or visions for nursing, which must reflect this important aspect of care. It should be stressed that pain management is a priority and recognised that time and adequate resources are important aspects of pain management. Protocols that exemplify the responsibility of each member of the health care team should exist, but all rules that are created should also be flexible; for instance nurses must be enabled to choose an analgesic from a range of individualised prescriptions. It also seems vital that clear directives exist for the pain relief of addicts and access to support from specialists in the management of this group of patients available at all times. Support from specialists in

**6.2 Organisational environment** 

**6.1 Nurses' knowledge and formal education** 

The explanatory model can be a great source of ideas for future research. Firstly, a quantitative study could be conducted, to assess nurses' level of empirical, aesthetic and ethical knowledge along with personal knowledge regarding pain relief; including communication, collaboration and coping. Secondly, it would be interesting to explore the ethical component of the nursing and medical curricula and further to investigate to what extent nurses and doctors are guided by moral values in their pain relief at work. Thirdly, studies on how nurses' moral orientation is balanced with the effectiveness of the pain relief they provide could also be conducted. Fourthly, it seems necessary to conduct more studies where the communication of nurses and doctors connected with pain management is explored, for instance by using an ethnographic approach. Fifthly, it seems important to run more field studies within each organization to identify the main obstructions for effective pain management. It seems vital to begin with identifying what hindrances are most prominent before embarking on a campaign for better pain management within organisations. A part of these studies could be to inspect the effects of workload, lack of time and constraining directives on nurses' potentials for providing optimal pain relief.

#### **7. Conclusion**

Our explanatory model is at odds with statements proposing that pain relief is not the nurses' priority (Brockopp et al., 1998) or their responsibility (Twycross, 2002). We assert, however, that various reasons inhibit the nurses' potential for taking action. We conclude that nurses are the patients´ advocates in pain management and successful pain management is rewarded with a sense of satisfaction, empowerment and fulfilment of their duty. They are in a key position to assess and manage pain and their mediatory position within the hospital is unique. It is vital that nurses are adequately prepared for their role educationally by possessing multidimensional knowledge about pain management. We assert that good theoretical knowledge may be inadequate if the nurse does not have the right motivation, i.e. the *moral inclination* to use it in practice. Furthermore, *personal knowledge* that nurses must use in relations with patients and doctors is also necessary because theoretical knowledge alone may be of little use if it cannot be employed because of lack of communication or negotiation competence or

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All the factors previously mentioned coexist and are interdependent and cannot be taken out of the immediate context, as may be seen from our model. Therefore, developments in pain management that focus only on one aspect of pain management may be ineffective, as many factors affect this process. We, therefore, propose that knowledge in this respect has often been too narrowly defined and we call for a more holistic approach in pain management by nurses and other health care personnel where multiple types of knowledge and skills as well as the organisational context are included and taken into consideration during educational efforts and reform of pain management within organisations.

#### **8. References**


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patient advocacy by pain management nurses: Results of the American society for pain management nursing survey. *Pain Management Nurs*ing, (Epub 2010 Jul 24),

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Rejeh, N., Ahmadi, F., Mohamadi, E., Anoosheh, M. & Kazemnejad, A. (2009). Ethical

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**Part 8** 

**Complex Regional Pain** 

**Syndrome and Reflex Sympathetic Dystrophy** 


## **Part 8**

**Complex Regional Pain Syndrome and Reflex Sympathetic Dystrophy** 

542 Pain Management – Current Issues and Opinions

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**26** 

*USA* 

**Complex** 

**Regional Pain Syndrome** 

*2Department of Anesthesiology and Pain Management, Eugene McDermott Center for Pain Mangement, Univerisity of Texas Southwestern Medical Center,* 

Complex regional pain syndromes (CRPS) are pain syndromes characterized by pain out of proportion to an inciting injury, swelling, discoloration, stiffness, hyperhidrosis (sudomotor), temperature (vasomotor) and trophic changes. Also commonly seen are fine tremor and less often spasms involving upper and lower extremities. Dr. Silas Wier Mitchell described CRPS II, or causalgia, during the American Civil War. CRPS I was described about the end of the 19th century by Sudek (Sudek's atrophy). Evans described reflex sympathetic dystrophy (RSD). Numerous other terms used to describe similar syndromes include algodystrophy and shoulder- hand syndrome. Bonica described 3 stages of RSD.

Specific inclusion criteria are needed for research studies but from a clinical perspective, many patients seem to have a constellation of signs and symptoms of CRPS without meeting strict criteria. The diagnosis is made by the process of exclusion. While avoiding over

The prognosis for CRPS is highly variable and to a large extent is influenced by the treatment. Functional restoration and involving the patient in ongoing range of motion and resistive exercises is helpful. Timely pain relief and interventional pain procedures, as well as psychological support, are important. Patients need to be followed closely and treatments adjusted accordingly. Timely and appropriate referral to experienced pain physicians that are able to offer multimodal therapies may prevent costly delays and

**1. Introduction** 

**2. Diagnostic criteria** 

**3. Prognosis** 

complications.

Roberts described sympathetically maintained pain.

diagnosing and over treatment, the patients need to be treated.

Gabor B. Racz1 and Carl E. Noe2 *1Department of Anesthesiology, Pain Center, Texas Tech University Health Sciences Center,* 

## **Complex Regional Pain Syndrome**

Gabor B. Racz1 and Carl E. Noe2

*1Department of Anesthesiology, Pain Center, Texas Tech University Health Sciences Center, 2Department of Anesthesiology and Pain Management, Eugene McDermott Center for Pain Mangement, Univerisity of Texas Southwestern Medical Center, USA* 

#### **1. Introduction**

Complex regional pain syndromes (CRPS) are pain syndromes characterized by pain out of proportion to an inciting injury, swelling, discoloration, stiffness, hyperhidrosis (sudomotor), temperature (vasomotor) and trophic changes. Also commonly seen are fine tremor and less often spasms involving upper and lower extremities. Dr. Silas Wier Mitchell described CRPS II, or causalgia, during the American Civil War. CRPS I was described about the end of the 19th century by Sudek (Sudek's atrophy). Evans described reflex sympathetic dystrophy (RSD). Numerous other terms used to describe similar syndromes include algodystrophy and shoulder- hand syndrome. Bonica described 3 stages of RSD. Roberts described sympathetically maintained pain.

#### **2. Diagnostic criteria**

Specific inclusion criteria are needed for research studies but from a clinical perspective, many patients seem to have a constellation of signs and symptoms of CRPS without meeting strict criteria. The diagnosis is made by the process of exclusion. While avoiding over diagnosing and over treatment, the patients need to be treated.

#### **3. Prognosis**

The prognosis for CRPS is highly variable and to a large extent is influenced by the treatment. Functional restoration and involving the patient in ongoing range of motion and resistive exercises is helpful. Timely pain relief and interventional pain procedures, as well as psychological support, are important. Patients need to be followed closely and treatments adjusted accordingly. Timely and appropriate referral to experienced pain physicians that are able to offer multimodal therapies may prevent costly delays and complications.

Complex Regional Pain Syndrome 547

discoloration after injuries and will improve within a month with usual therapeutic

Infection is always a concern after surgery or other penetrating trauma. Other causes of acute inflammation, swelling and discoloration need to be considered such as malignancy, deep venous thrombosis as well as peripheral nerve entrapment, peripheral neuropathy and

3 stages of RSD have been described however it is unclear that staging has much value

Much has been made about early sympathetic blocks and failure to diagnose early. There is no data to support "emergent" sympathetic blocks and some patients have a favorable

Pain from CRPS can spread, in rare instances, proximally and contra- laterally. (Shah, Racz)

Osteopenia and fractures can occur in severe cases and aquatic therapy is useful to

The natural history of CRPS 1 is variable but in an interesting report, approximately 25% of patients that had Colles' fractures developed signs of CRPS. (Atkins) Approximately 40% of these patients improved in 6 months. This suggests that mild cases may not require extensive treatment. Not treating the patients early can be problematic if the condition worsens. Appropriate examination and follow up is important where the disease can take a benign course. Patients obtain information on the Internet that is usually about catastrophic cases that needs to be dealt with by educating patients in an appropriate and caring manner where therapy is timely yet one can avoid catastrophizing based on inaccurate information.

Much of "standard care" is not evidence based, but good outcome based. Additionally, it is based on physician experience and the outcome is superior in the hands of better-trained physicians. As new information becomes available, dogma can be weeded out and treatments based on randomized controlled trails can be incorporated into treatment

Lower extremity pain can spread to upper extremities and vice versa.

interventions.

**9. Stages** 

**10. Timing** 

natural history.

**11. Spreading** 

**12. Bone loss** 

**14. Dogma** 

guidelines.

rehabilitate these patients.

**13. Natural history** 

other neuropathic pains.

regarding decision making.

### **4. Theories of mechanisms**

Multiple possible mechanisms exist for CRPS including psychological, inflammatory, vascular, neurogenic and combinations of several mechanisms. Debate regarding definitions of neuropathic pain has led to the notion that CRPS may not be neuropathic pain. Psychogenic pain could be construed as being "pain arising as a direct consequence of a lesion or disease affecting the somatosensory system" but few would think of it as neuropathic pain which should be treated with anticonvulsants.

CRPS II is generally agreed to be caused by an injury to a peripheral nerve. CRPS 1 is caused by a lesion in or injury to a small nerve or multiple small nerves. It is difficult to accept that it is not neuropathic pain since it resembles CRPS II so closely. Denial of care based on psychological explanations is neither reasonable nor justifiable yet in rare instances pain can be of psychological origin. Commonly the onset of CRPS is 1- 3 months after the injury.

#### **5. History**

The diagnosis is made by process of exclusion following history of pain that is out of proportion to an injury or period of immobilization. Swelling, temperature asymmetry, stiffness, atrophy, hair, skin nail, bone changes. Tremor or spasms and asymmetry in sweat function are all potential signs. It is important to remember that many injuries are associated with pain, discoloration and swelling without being CRPS. Infection and other causes of inflammation are sometimes mistakenly thought to be CRPS. A number of patients have CRPS symptoms following stroke and classifying this as central pain or CRPS is problematic.

#### **6. Physical exam**

Observation of upper extremity guarding or antalgic gait for lower extremity is important. Range of motion of affected joints is particularly important as many patients develop permanent stiffness without analgesia for specific range of motion therapy. Discoloration or asymmetrical coloration, swelling, atrophy and allodynia are other physical findings. The allodynia may be tactile or cold induced.

### **7. Diagnostic tests**

Bone scans, sweat tests and sympathetic blocks have been used but the diagnosis is a clinical one and can be made without confirmatory tests. Thermography has been used, but more commonly, the documentation of temperature differences is adequate. Early on in the evolution of the condition there may increased temperature and later reduction with the increased sympathetic activity. Three phase bone scan often show corresponding changes. Comparing contra lateral x-ray images can show osteopenia in the involved area. EMG usually does not change from the CRPS but may show nerve injury.

#### **8. Differential diagnosis**

While it important to be vigilant in diagnosing CRPS, as is important to avoid misdiagnosis and over- diagnosis. Many patients have "pain out of proportion", swelling and discoloration after injuries and will improve within a month with usual therapeutic interventions.

Infection is always a concern after surgery or other penetrating trauma. Other causes of acute inflammation, swelling and discoloration need to be considered such as malignancy, deep venous thrombosis as well as peripheral nerve entrapment, peripheral neuropathy and other neuropathic pains.

#### **9. Stages**

546 Pain Management – Current Issues and Opinions

Multiple possible mechanisms exist for CRPS including psychological, inflammatory, vascular, neurogenic and combinations of several mechanisms. Debate regarding definitions of neuropathic pain has led to the notion that CRPS may not be neuropathic pain. Psychogenic pain could be construed as being "pain arising as a direct consequence of a lesion or disease affecting the somatosensory system" but few would think of it as

CRPS II is generally agreed to be caused by an injury to a peripheral nerve. CRPS 1 is caused by a lesion in or injury to a small nerve or multiple small nerves. It is difficult to accept that it is not neuropathic pain since it resembles CRPS II so closely. Denial of care based on psychological explanations is neither reasonable nor justifiable yet in rare instances pain can be of psychological origin. Commonly the onset of CRPS is 1- 3 months after the injury.

The diagnosis is made by process of exclusion following history of pain that is out of proportion to an injury or period of immobilization. Swelling, temperature asymmetry, stiffness, atrophy, hair, skin nail, bone changes. Tremor or spasms and asymmetry in sweat function are all potential signs. It is important to remember that many injuries are associated with pain, discoloration and swelling without being CRPS. Infection and other causes of inflammation are sometimes mistakenly thought to be CRPS. A number of patients have CRPS

Observation of upper extremity guarding or antalgic gait for lower extremity is important. Range of motion of affected joints is particularly important as many patients develop permanent stiffness without analgesia for specific range of motion therapy. Discoloration or asymmetrical coloration, swelling, atrophy and allodynia are other physical findings. The

Bone scans, sweat tests and sympathetic blocks have been used but the diagnosis is a clinical one and can be made without confirmatory tests. Thermography has been used, but more commonly, the documentation of temperature differences is adequate. Early on in the evolution of the condition there may increased temperature and later reduction with the increased sympathetic activity. Three phase bone scan often show corresponding changes. Comparing contra lateral x-ray images can show osteopenia in the involved area. EMG

While it important to be vigilant in diagnosing CRPS, as is important to avoid misdiagnosis and over- diagnosis. Many patients have "pain out of proportion", swelling and

usually does not change from the CRPS but may show nerve injury.

symptoms following stroke and classifying this as central pain or CRPS is problematic.

neuropathic pain which should be treated with anticonvulsants.

**4. Theories of mechanisms** 

**5. History** 

**6. Physical exam** 

**7. Diagnostic tests** 

**8. Differential diagnosis** 

allodynia may be tactile or cold induced.

3 stages of RSD have been described however it is unclear that staging has much value regarding decision making.

#### **10. Timing**

Much has been made about early sympathetic blocks and failure to diagnose early. There is no data to support "emergent" sympathetic blocks and some patients have a favorable natural history.

#### **11. Spreading**

Pain from CRPS can spread, in rare instances, proximally and contra- laterally. (Shah, Racz) Lower extremity pain can spread to upper extremities and vice versa.

### **12. Bone loss**

Osteopenia and fractures can occur in severe cases and aquatic therapy is useful to rehabilitate these patients.

#### **13. Natural history**

The natural history of CRPS 1 is variable but in an interesting report, approximately 25% of patients that had Colles' fractures developed signs of CRPS. (Atkins) Approximately 40% of these patients improved in 6 months. This suggests that mild cases may not require extensive treatment. Not treating the patients early can be problematic if the condition worsens. Appropriate examination and follow up is important where the disease can take a benign course. Patients obtain information on the Internet that is usually about catastrophic cases that needs to be dealt with by educating patients in an appropriate and caring manner where therapy is timely yet one can avoid catastrophizing based on inaccurate information.

#### **14. Dogma**

Much of "standard care" is not evidence based, but good outcome based. Additionally, it is based on physician experience and the outcome is superior in the hands of better-trained physicians. As new information becomes available, dogma can be weeded out and treatments based on randomized controlled trails can be incorporated into treatment guidelines.

Complex Regional Pain Syndrome 549

may be less likely to accept dose reductions. Patients who are working or similarly productive and are without signs of poor coping and physical disability may need to continue taking the effective dosages. On the other hand, patients, who have been on stable

Washington State has new guidelines limiting the dose of opioid to 120 mg/day of morphine equivalents. Patients, who require doses above this level, are guided to seek a pain management consultation. The purpose and intervention of a medical pain management consultation is unclear. The practitioner doing the evaluation needs to have additional training and qualification as well as be informed and knowledgeable in treatment

JCAHO, Press Gainey and other organizations have changed the environment with respect to patient rights regarding pain. In the past, if a patient wasn't happy with their opioid dose, their recourse was limited. Now, patient satisfaction is used as a factor to determine healthcare provider's compensation. The implication is that patients can pressure providers

Regulators have become more active due to the increased rate of diversion and its consequences. However, the accidental overdose rate increase is even more concerning. Most drugs have dose limits. For example, antibiotics and drugs for hypertension are increased to upper limits but there are limits. Perhaps it is time to limit doses of opioids regardless of pain severity for patients with non palliative care pain syndromes and find

Other drugs classes that are problematic include benzodiazepines, muscle relaxers, sleeping pills and even anticonvulsants and antidepressants. Benzodiazepines are not prominent in the pain literature as analgesics. Baclofen and tizanidine are probably the first line muscle relaxers of choice. Hypnotic drugs are used too often for chronic sleep disturbances without sleep hygiene treatment or other medications which are better for long term use. Anticonvulsant use for chronic pain has exploded as opioids have. Antidepressants, even

The costs of these drugs are significant and usually of incremental benefit. Most patients with chronic pain go without an interdisciplinary evaluation and many who receive an evaluation do not complete treatment with cognitive behavioral therapy, education and conditioning physical therapy. Treatment goals are frequently not established and some patients just go through the motions and are considered as a treatment failure. There is very little evidence for the multidisciplinary and physical therapy based treatments specifically

The cognitive effects and psychological effects of chronic opioid treatment are not well

Patients who are on doses above 50 mg/ day of morphine equivalents need to have access to interdisciplinary pain and addictionology evaluations and treatment if needed. Treatment goals should include dose reduction to below 200mg/day of morphine equivalents for those

Testosterone levels in males are known to decrease with chronic opioid administration. It is proposed that patients with chronic pain have a short term trial of low dose opioid to access functional improvement before a treatment plan is finalized. Blinding patients to their drug and dose may be very helpful but has its critics on ethical and regulatory

to prescribe more opioid, which is dangerous for patients and providers.

those not associated with analgesia, are prescribed for pain.

for CRPS. Reimbursement has suffered for these kinds of therapies.

doses for a long time may need age related dose reductions.

options in addition to opioid management.

another way to treat the patient.

known.

grounds.

### **15. Cases**

One lady had not worn high-heeled shoes for a long time and then wore a pair for several hours at an event. She developed classic signs and symptoms of RSD. She experienced profound analgesia with sympathetic blockade and the condition resolved completely.

Another case was a woman who had a paper cut on her distal index finger on the job. She had classic signs and symptoms of CRPS, which resolved with a series of blocks. Both of these cases were challenged by insurance companies since the inciting injury was so minor but both patients were legitimate. The point is that physicians caring for these patients must be willing to serve as advocates for the patient even in an environment of cost containment. We have to be mindful of our "report cards" but not at the expense of a patient's outcome.

#### **16. Overmedication pain syndrome (OPS)**

Approximately 20 years ago, a movement began to improve the quality of pain care for cancer patients worldwide. The WHO analgesic ladder was promoted for cancer pain and then it was applied for other types of pain. Many patients are now taking large doses of opioid for chronic pain.

Overmedication pain syndrome is characterized by a chronic treatment program consisting of high doses of multiple analgesic medications without associated functional productivity and psychological coping ability.

Opioids are the most important class of drugs in pain management; however, it is clear that they are two edged swords and overmedication with opioids and other drugs classes have become a problem. Abuse may not be the largest problem. Lack of efficacy, unintended overdose, diversion, development of drug dependence, habituation and resistance to recovery and other unintended consequences may be more common.

Opioid induced hyperalgesia is a real clinical phenomenon and may be a subtle barrier to analgesia in many patients. Pain that is only incrementally responsive to opioid is also common.

Pseudo-addiction is defined in behavioral terms which are similar to addiction but related to pain and not addiction. The problem is that there are not good means to differentiate behaviors between the setting of pain and the setting of addiction.

Some have reported a lack of data to support doses of opioid over 200 mg/day of morphine equivalents. Also, there are no long term randomized controlled trials of opioid versus placebo. Additionally, fracture rates have been reported to be increased in patients on doses above 100 mg/day. (Sullivan) Overdose rates have been reported to increase above 50 mg/day. (Dunn) Drug interactions with other medications, reported and unreported to the treating physician, have been causes of fatalities.

Urine drug testing, opioid contracts and extensive documentation guidelines fail to help answer the clinical question: is the dose just too high?

Patients who are taking opioids chronically should be considered for an evaluation for a lack of meaningful efficacy, fall and fracture risk and overdose risk. An interdisciplinary evaluation may be a way to accomplish these objectives. Patients who are clearly doing well

One lady had not worn high-heeled shoes for a long time and then wore a pair for several hours at an event. She developed classic signs and symptoms of RSD. She experienced profound analgesia with sympathetic blockade and the condition resolved

Another case was a woman who had a paper cut on her distal index finger on the job. She had classic signs and symptoms of CRPS, which resolved with a series of blocks. Both of these cases were challenged by insurance companies since the inciting injury was so minor but both patients were legitimate. The point is that physicians caring for these patients must be willing to serve as advocates for the patient even in an environment of cost containment. We have to be mindful of our "report cards" but not at the expense of a

Approximately 20 years ago, a movement began to improve the quality of pain care for cancer patients worldwide. The WHO analgesic ladder was promoted for cancer pain and then it was applied for other types of pain. Many patients are now taking large doses of

Overmedication pain syndrome is characterized by a chronic treatment program consisting of high doses of multiple analgesic medications without associated functional productivity

Opioids are the most important class of drugs in pain management; however, it is clear that they are two edged swords and overmedication with opioids and other drugs classes have become a problem. Abuse may not be the largest problem. Lack of efficacy, unintended overdose, diversion, development of drug dependence, habituation and resistance to

Opioid induced hyperalgesia is a real clinical phenomenon and may be a subtle barrier to analgesia in many patients. Pain that is only incrementally responsive to opioid is also

Pseudo-addiction is defined in behavioral terms which are similar to addiction but related to pain and not addiction. The problem is that there are not good means to differentiate

Some have reported a lack of data to support doses of opioid over 200 mg/day of morphine equivalents. Also, there are no long term randomized controlled trials of opioid versus placebo. Additionally, fracture rates have been reported to be increased in patients on doses above 100 mg/day. (Sullivan) Overdose rates have been reported to increase above 50 mg/day. (Dunn) Drug interactions with other medications, reported and unreported to the

Urine drug testing, opioid contracts and extensive documentation guidelines fail to help

Patients who are taking opioids chronically should be considered for an evaluation for a lack of meaningful efficacy, fall and fracture risk and overdose risk. An interdisciplinary evaluation may be a way to accomplish these objectives. Patients who are clearly doing well

recovery and other unintended consequences may be more common.

behaviors between the setting of pain and the setting of addiction.

treating physician, have been causes of fatalities.

answer the clinical question: is the dose just too high?

**15. Cases** 

completely.

patient's outcome.

opioid for chronic pain.

common.

and psychological coping ability.

**16. Overmedication pain syndrome (OPS)** 

may be less likely to accept dose reductions. Patients who are working or similarly productive and are without signs of poor coping and physical disability may need to continue taking the effective dosages. On the other hand, patients, who have been on stable doses for a long time may need age related dose reductions.

Washington State has new guidelines limiting the dose of opioid to 120 mg/day of morphine equivalents. Patients, who require doses above this level, are guided to seek a pain management consultation. The purpose and intervention of a medical pain management consultation is unclear. The practitioner doing the evaluation needs to have additional training and qualification as well as be informed and knowledgeable in treatment options in addition to opioid management.

JCAHO, Press Gainey and other organizations have changed the environment with respect to patient rights regarding pain. In the past, if a patient wasn't happy with their opioid dose, their recourse was limited. Now, patient satisfaction is used as a factor to determine healthcare provider's compensation. The implication is that patients can pressure providers to prescribe more opioid, which is dangerous for patients and providers.

Regulators have become more active due to the increased rate of diversion and its consequences. However, the accidental overdose rate increase is even more concerning.

Most drugs have dose limits. For example, antibiotics and drugs for hypertension are increased to upper limits but there are limits. Perhaps it is time to limit doses of opioids regardless of pain severity for patients with non palliative care pain syndromes and find another way to treat the patient.

Other drugs classes that are problematic include benzodiazepines, muscle relaxers, sleeping pills and even anticonvulsants and antidepressants. Benzodiazepines are not prominent in the pain literature as analgesics. Baclofen and tizanidine are probably the first line muscle relaxers of choice. Hypnotic drugs are used too often for chronic sleep disturbances without sleep hygiene treatment or other medications which are better for long term use. Anticonvulsant use for chronic pain has exploded as opioids have. Antidepressants, even those not associated with analgesia, are prescribed for pain.

The costs of these drugs are significant and usually of incremental benefit. Most patients with chronic pain go without an interdisciplinary evaluation and many who receive an evaluation do not complete treatment with cognitive behavioral therapy, education and conditioning physical therapy. Treatment goals are frequently not established and some patients just go through the motions and are considered as a treatment failure. There is very little evidence for the multidisciplinary and physical therapy based treatments specifically for CRPS. Reimbursement has suffered for these kinds of therapies.

The cognitive effects and psychological effects of chronic opioid treatment are not well known.

Testosterone levels in males are known to decrease with chronic opioid administration.

It is proposed that patients with chronic pain have a short term trial of low dose opioid to access functional improvement before a treatment plan is finalized. Blinding patients to their drug and dose may be very helpful but has its critics on ethical and regulatory grounds.

Patients who are on doses above 50 mg/ day of morphine equivalents need to have access to interdisciplinary pain and addictionology evaluations and treatment if needed. Treatment goals should include dose reduction to below 200mg/day of morphine equivalents for those

Complex Regional Pain Syndrome 551

2. Interdisciplinary care is not isolated from medical pain management. Analgesic treatments are necessary to provide pain relief and allow functional restoration. 3. The course of an individual patient is highly variable and adjustments to the treatment

5. Numerous randomized controlled trials have been performed since our initial analgesic

6. However if there is treatment failure and functional restoration failure the patient needs to be referred to centers or individuals with recognized experience to be specialists in

Sympathetic blocks have been recommended early on in the management of the disorder but little data exists to support this practice. Only recently has any data from a randomized controlled trial been published to demonstrate efficacy of sympathetic blockade. (Meier) Spinal cord stimulation has been shown to produce significant analgesia even after 5 years of treatment. (Klemer) Cortical stimulation has been shown to have some benefit. (Velasco) Deep brain stimulation has been shown to be ineffective. Vitamin C has been studied by multiple investigators for the prevention of CRPS and has some effect. (Besse) Intravenous magnesium has been reported to be effective in an initial study. (Collins) Clodronate has been shown to be partially effective. (Varenna) Mirror therapy has been reported to have benefit in stroke patients with CRPS. (Cacchio) Multicenter comparison of spinal cord stimualtion and peripheral nerve stimulation showed that PNS is more effective than SCS

Intravenous regional anesthesia with the addtion of vasodilators such as phentolamine, reserpine and bretylium allow manipulation of hands without post procedure edema and speed up functional restoration without the pain associated with physical therapy.

An evidenced based review endorses bisphosphonates (alendronate, pamidronate, clodronate), corticosteroid, gabapentin, physiotherapy and psychotherapy/relaxation techniques as treatments. (Baron) Additionally intrathecal baclofen for associated dystonia and spinal cord stimulation for refractory caes are recommended. Topical DMSO and sympathetic blocks are not strongly recommended. Intravenous regional blocks with

Amputation is less common nowadays because it was rarely effective and usually resulted

IV regional with guanethidine has been shown to be ineffective in several studies as sole

High dose opioid should be avoided if possible due to possible opioid induced

plan should be made in a highly flexible manner.

the field.

(Heavner, Calvillo, Racz)

**19. Treatments to avoid** 

**20. Proposed treatment** 

agent.

**Step 1.**

Education

4. Limiting opioid doses to below 200mg/day morphine equivalents

but the best outcome was where both modalities were utilized. ( Calvillo)

guanethidine are not recommended as specific treatment (Van Eijs)

in a phantom pain plus different pain of greater severity

Deep brain stimulation has been shown to be ineffective.

hyperalgesia, addiction, diversion risk and over-dosage.

Screening for substance abuse, affective disorders and disability

ladder was proposed and these findings are incorporated.

taking more than that. Intermediate term treatment goals for patients taking less than 200 mg/day should strive for less than 100 mg/day and patients taking less than 100 mg/day, 50 mg/day.

There is no data to support this approach but there was no data 20 years ago to support using the WHO analgesic ladder for headaches, fibromyalgia, back pain or any other condition. Data for limited doses of opioid for arthritis and neuropathic pain exists and prescribing for opioid responsive pain should not be overly scrutinized by regulators. Never the less, diversion, addiction, opioid induced hyperalgesia and other adverse events associated with opioids need to be avoided more effectively before the first prescription is written.

Many patients in drug treatment programs were initially treated with opioid for perfectly legitimate pain. The patient and the doctor may not be the biggest problems. The biggest problem may be the drug and the dosage.

### **17. Treatment guideline history**

In 1994, the International Association for the Study of Pain (IASP) revised the terminology from RSD and causalgia to CRPS type I and II. 15 years ago we proposed an analgesic ladder for CRPS /RSD which included 3 steps. (Racz) Since then, well-respected groups have advanced other guidelines. (Van Eijs) (Stanton-Hicks)

Our initial proposal was:


At that time, little data existed to guide treatment and the initial analgesic ladder was based on opinion. Since that time, additional data has been produced leading to modifications to the analgesic ladder. This is categorically not intended to estabish a standard of care since data to do such is inadequate. Rather, our intention is to share our beliefs in hopes of helping patients with this disorder.

#### **18. New principles and information**

Our current analgesic ladder promotes several concepts:

1. Interdisciplinary pain treatment is recommended rather than multidisciplinary care which tends to be fragmented. Interdisciplinary treatment specifically provides coordinated medical care, education, cognitive behavioral therapy for pain, physical therapy and outcome documentation by the interdisciplinary team. Patients who receive care at different clinics for each component of care by a group of providers who do not meet on a weekly basis nor document comprehensive outcomes are not receiving interdisciplinary pain management.

taking more than that. Intermediate term treatment goals for patients taking less than 200 mg/day should strive for less than 100 mg/day and patients taking less than

There is no data to support this approach but there was no data 20 years ago to support using the WHO analgesic ladder for headaches, fibromyalgia, back pain or any other condition. Data for limited doses of opioid for arthritis and neuropathic pain exists and prescribing for opioid responsive pain should not be overly scrutinized by regulators. Never the less, diversion, addiction, opioid induced hyperalgesia and other adverse events associated with opioids need to be avoided more effectively before the first prescription is

Many patients in drug treatment programs were initially treated with opioid for perfectly legitimate pain. The patient and the doctor may not be the biggest problems. The biggest

In 1994, the International Association for the Study of Pain (IASP) revised the terminology from RSD and causalgia to CRPS type I and II. 15 years ago we proposed an analgesic ladder for CRPS /RSD which included 3 steps. (Racz) Since then, well-respected groups

**Step 1.** TENS, opioids, topicals, Tricyclic antidepressants, supportive psychotherapy,

**Step 2.** Regional or sympathetic block, evaluation and treatment of the emotional

At that time, little data existed to guide treatment and the initial analgesic ladder was based on opinion. Since that time, additional data has been produced leading to modifications to the analgesic ladder. This is categorically not intended to estabish a standard of care since data to do such is inadequate. Rather, our intention is to share our beliefs in hopes of

1. Interdisciplinary pain treatment is recommended rather than multidisciplinary care which tends to be fragmented. Interdisciplinary treatment specifically provides coordinated medical care, education, cognitive behavioral therapy for pain, physical therapy and outcome documentation by the interdisciplinary team. Patients who receive care at different clinics for each component of care by a group of providers who do not meet on a weekly basis nor document comprehensive outcomes are not receiving

baclofen, clonidine, corticosteroid, NSAID, mexiletine, other drug trials **Step 3.** Sympathectomy/sympatholysis, peripheral nerve decompression, lysis, continuous

vocational rehabilitation, patient education, physical therapy and occupational

component of pain, IV regional block, peripheral block-infusion, carbamazepine,

local anesthetic infusion epidural and or regional for five to seven days, Spinal Cord Stimulation (SCS), Peripheral Nerve Stimulation (PNS), intrathecal/epidural

100 mg/day, 50 mg/day.

problem may be the drug and the dosage.

have advanced other guidelines. (Van Eijs) (Stanton-Hicks)

**17. Treatment guideline history** 

Our initial proposal was:

therapy

analgesia.

helping patients with this disorder.

**18. New principles and information** 

interdisciplinary pain management.

Our current analgesic ladder promotes several concepts:

written.


Sympathetic blocks have been recommended early on in the management of the disorder but little data exists to support this practice. Only recently has any data from a randomized controlled trial been published to demonstrate efficacy of sympathetic blockade. (Meier)

Spinal cord stimulation has been shown to produce significant analgesia even after 5 years of treatment. (Klemer) Cortical stimulation has been shown to have some benefit. (Velasco)

Deep brain stimulation has been shown to be ineffective. Vitamin C has been studied by multiple investigators for the prevention of CRPS and has some effect. (Besse) Intravenous magnesium has been reported to be effective in an initial study. (Collins) Clodronate has been shown to be partially effective. (Varenna) Mirror therapy has been reported to have benefit in stroke patients with CRPS. (Cacchio) Multicenter comparison of spinal cord stimualtion and peripheral nerve stimulation showed that PNS is more effective than SCS but the best outcome was where both modalities were utilized. ( Calvillo)

Intravenous regional anesthesia with the addtion of vasodilators such as phentolamine, reserpine and bretylium allow manipulation of hands without post procedure edema and speed up functional restoration without the pain associated with physical therapy. (Heavner, Calvillo, Racz)

An evidenced based review endorses bisphosphonates (alendronate, pamidronate, clodronate), corticosteroid, gabapentin, physiotherapy and psychotherapy/relaxation techniques as treatments. (Baron) Additionally intrathecal baclofen for associated dystonia and spinal cord stimulation for refractory caes are recommended. Topical DMSO and sympathetic blocks are not strongly recommended. Intravenous regional blocks with guanethidine are not recommended as specific treatment (Van Eijs)

#### **19. Treatments to avoid**

Amputation is less common nowadays because it was rarely effective and usually resulted in a phantom pain plus different pain of greater severity

IV regional with guanethidine has been shown to be ineffective in several studies as sole agent.

Deep brain stimulation has been shown to be ineffective.

High dose opioid should be avoided if possible due to possible opioid induced hyperalgesia, addiction, diversion risk and over-dosage.

#### **20. Proposed treatment**

**Step 1.** Screening for substance abuse, affective disorders and disability Education

Complex Regional Pain Syndrome 553

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Besse, J., Gadeyene, S., Galand-Desme, S., et.al: Effect of vitamin C on prevention of complex

Cacchio, A., De Blasis, E., De Blasis, V., at.al.:Mirror Therapy in Complex Regional Pain

Calvillo O, Racz GBN, Diede J, Smith K: Neuroaugmentation in the treatment of complex

Collins, S., Zuurmond, W.W.A., de Lange, J.J., et.al.: Intravenous Magnesium for Complex

Dunn KM, Saunders KW, Rutter CM, et al.: Opioid prescriptions for chronic pain and overdose: a cohort study. Annals of Internal Medicine 2010; 152:85-92 Heavner JE, Calvillo O, Racz GB: Thermal grill illusion and complex regional pain

Klemer M.A., de Vet, H.C., Barendse, G.A.M., et.al.: Effect of spinal cord stimulation

Meier, P.M., Zurakowski, D., Berde, C. B., Sethna, M.B.: Lumbar sympathetic blockade in

Racz, Gabor B., Heavner, James E., Noe, Carl E.: Definitions, classification and Taxonomy:

Shah RV, Racz GB. Recurrence and spread of complex regional pain syndrome due to

Stanton-Hicks, M., Baron, R., Boas, R., et.al: Complex regional pain syndromes: guidelines

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**23. References** 

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Physical therapy Occupational therapy Vocational rehabilitation Topical lidocaine for allodynia Tricyclic antidepressants Gabapentin Tramadol Opioid doses limited to less than 200mg morphine equivalents per day and below 50mg/day if possible Corticosteroid **Step 2.** Interdisciplinary pain evaluation including psychological testing (MMPI-RF) and treatment (cognitive behavioral therapy, group psycho educational therapy and psychotropic medication management, addictionology, physical and occupational therapy, in a coordinated goal directed, outcome documenting rehabilitation program) Sympathetic block IV Regional block Peripheral block Other drug trials **Step 3.** Spinal cord stimulation Sympathectomy/sympatholysis Peripheral nerve stimulation Peripheral nerve decompression/lysis Intrathecal/epidural analgesia

#### **21. Interdisciplinary care**

Interdisciplinary pain management is a term that is poorly understood. It is best reserved to describe a team of healthcare professionals led by a physician and including a psychologist and physical therapist at a minimum. A care team of multiple physicians from different specialties is not an interdisciplinary team for pain management nor is a psychologically based treatment program in isolation from medical pain management. Cognitive behavioral therapy, education and functional rehabilitation must be provided in an interdisciplinary pain care model in addition to medical pain management therapies. Case management, psychiatry, outcome database management, nursing, vocational rehabilitation, occupational therapy, medical direction and program direction and administrative support are key disciplines to include in a mature pain program. Nutrition, chaplaincy and other medical specialties are needed for tertiary programs.

#### **22. Conclusion**

Complex regional pain syndrome is a challenging pain problem that frequently requires a comprehensive interdisciplinary assessment and treatment plan. Until a mechanism is discovered and a specific treatment for the syndrome is developed, an interdisciplinary approach, including pharmacologic and interventional pain management in a step wise fashion, will likely remain as the best route to follow.

#### **23. References**

552 Pain Management – Current Issues and Opinions

Opioid doses limited to less than 200mg morphine equivalents per day and below

Interdisciplinary pain evaluation including psychological testing (MMPI-RF) and treatment (cognitive behavioral therapy, group psycho educational therapy and psychotropic medication management, addictionology, physical and occupational therapy, in a

Interdisciplinary pain management is a term that is poorly understood. It is best reserved to describe a team of healthcare professionals led by a physician and including a psychologist and physical therapist at a minimum. A care team of multiple physicians from different specialties is not an interdisciplinary team for pain management nor is a psychologically based treatment program in isolation from medical pain management. Cognitive behavioral therapy, education and functional rehabilitation must be provided in an interdisciplinary pain care model in addition to medical pain management therapies. Case management, psychiatry, outcome database management, nursing, vocational rehabilitation, occupational therapy, medical direction and program direction and administrative support are key disciplines to include in a mature pain program. Nutrition, chaplaincy and other medical

Complex regional pain syndrome is a challenging pain problem that frequently requires a comprehensive interdisciplinary assessment and treatment plan. Until a mechanism is discovered and a specific treatment for the syndrome is developed, an interdisciplinary approach, including pharmacologic and interventional pain management in a step wise

coordinated goal directed, outcome documenting rehabilitation program)

Physical therapy Occupational therapy Vocational rehabilitation Topical lidocaine for allodynia Tricyclic antidepressants

Gabapentin Tramadol

**Step 2.**

**Step 3.**

50mg/day if possible Corticosteroid

Sympathetic block IV Regional block Peripheral block Other drug trials

Spinal cord stimulation

Sympathectomy/sympatholysis Peripheral nerve stimulation

Intrathecal/epidural analgesia

**21. Interdisciplinary care** 

**22. Conclusion** 

Peripheral nerve decompression/lysis

specialties are needed for tertiary programs.

fashion, will likely remain as the best route to follow.


Varenna, M., Zucchi, F., Ghiringhelli, D., et.al.: Intravenous clodronate in the treatment

Velasco, F., Carrillo-Ruiz, J.D., Castro, G., et.al.: Motor cortex stimulation applied to patients

with complex regional pain syndrome. Pain 147:91-98, 2009.

2000

of reflex symathetic dystrophy syndrome. Journal of Rheumatology 27:1477-83,

### *Edited by Gabor B. Racz and Carl E. Noe*

Pain Management - Current Issues and Opinions is written by international experts who cover a number of topics about current pain management problems, and gives the reader a glimpse into the future of pain treatment. Several chapters report original research, while others summarize clinical information with specific treatment options. The international mix of authors reflects the "casting of a broad net" to recruit authors on the cutting edge of their area of interest. Pain Management - Current Issues and Opinions is a must read for the up-to-date pain clinician.

Pain Management - Current Issues and Opinions

Pain Management

Current Issues and Opinions

*Edited by Gabor B. Racz and Carl E. Noe*

Photo by DimaSobko / iStock