**4. Potential for prevention**

All surgeries carry the risk of CPSP but not all surgeries are medically necessary to be done. Clinicians are looking to moderate the risks of CPSP by identifying patients who are at a high risk prior to the surgical procedure. The identification of high-risk patients can be used to a closer monitoring of these patients and to initiate timely interventions to prevent chronic pain. Assessment tools can be used before surgery to identify the risk probability of developing CPSP by including some predictors such as age, sex, pre-operative pain, type of surgery, incision size, and level of anxiety, among others [77]. Several modalities and interventions have been investigated in the context of prevention of CPSP. Each of these modalities will be discussed in the following parts of this chapter.

#### **4.1. Pre-emptive and preventive analgesia**

Pre-emptive analgesia is delivered prior to skin incision. It is initiated before the surgical procedure in order to reduce peripheral and central pain pathways sensitization.

## *4.1.1. Gabapentin*

Gabapentin has a well-established role in the treatment of several neuropathic pain conditions. It is also known to possess anti-nociceptive effects. Such effects result partially from its high affinity for the α 2 d subunit on pre-synaptic voltage-gated calcium channels, which are often upregulated following nerve injury. This leads to the inhibition of calcium influx and to the release of excitatory neurotransmitters, which produce central sensitization and the sensation of pain [78]. The use of gabapentin in CPSP has been extensively studied. The recent evidence indicated that perioperative gabapentin was effective in preventing CPSP. One recent meta-analysis supported the view that the perioperative administration of gabapentin was effective in reducing the incidence of CPSP [79]. Clarke et al. concluded that out of eight studies, four found that the perioperative administration of gabapentin decreased the incidence of chronic pain more than 2 months after surgery. Six out of the eight studies measured pain 6 months after surgery, and the pooled results demonstrated a moderate to large reduction in the development of CPSP (pooled odds ratio (OR) 0.52; 95% confidence interval (CI), 0.27–0.98; P 0.04) [79]. Two other studies, which investigated the effect of administering 1200 mg of gabapentin before surgery with placebo, reported a reduction in the incidence and severity of CPSP 6 months post -surgery [80, 81]. On the other hand, a systematic review done by Chaparro et al. [82] indicated that the effect of gabapentin was equivalent to placebo in preventing CPSP. Variations were observed in these studies in both the doses of gabapentin which were used (ranged from 300 to 1200 mg per day) and the duration of use (1 h before surgery to 10 days post surgery) [82]. Other variables, which could account for the conflicting evidence for the effectiveness of gabapentin, include diverse surgical procedures and small sample size.

#### *4.1.2. Pregabalin*

the risk of persistent pain. Significant differences were seen between open and laparoscopic procedures with a higher incidence of CPSP after open surgeries [71–73]. These findings were observed in different types of surgeries (hernia repair, cholecystectomy and hysterectomy) [71–73]. Less tissue handling and less intervention result in a lower incidence of chronic pain development. Wallace et al. [74] reported that the incidence of CPSP varied from 53% for mastectomy with reconstruction by implant, to 31% for mastectomy only, to 22% for breast reduction. Also, nerve protection during cutting and tissue handling in the operation site or in the neighbourhood during the perioperative period may decrease the incidence of CPSP. This is explained by the fact that nerve injury produces acute and lasting changes not only in the damaged nerves but also in the adjacent intact nerves [75]. Such effects would activate the pain pathways in the CNS, and motor and sympathetic systems [75]. The experience of the surgical team and the centre where the intervention took place have an impact on both morbidity and mortality [76]. CPSP was observed more commonly in surgical units with a lower number of

All surgeries carry the risk of CPSP but not all surgeries are medically necessary to be done. Clinicians are looking to moderate the risks of CPSP by identifying patients who are at a high risk prior to the surgical procedure. The identification of high-risk patients can be used to a closer monitoring of these patients and to initiate timely interventions to prevent chronic pain. Assessment tools can be used before surgery to identify the risk probability of developing CPSP by including some predictors such as age, sex, pre-operative pain, type of surgery, incision size, and level of anxiety, among others [77]. Several modalities and interventions have been investigated in the context of prevention of CPSP. Each of these modalities will be

Pre-emptive analgesia is delivered prior to skin incision. It is initiated before the surgical

Gabapentin has a well-established role in the treatment of several neuropathic pain conditions. It is also known to possess anti-nociceptive effects. Such effects result partially from its high affinity for the α 2 d subunit on pre-synaptic voltage-gated calcium channels, which are often upregulated following nerve injury. This leads to the inhibition of calcium influx and to the release of excitatory neurotransmitters, which produce central sensitization and the sensation of pain [78]. The use of gabapentin in CPSP has been extensively studied. The recent evidence indicated that perioperative gabapentin was effective in preventing CPSP. One recent meta-analysis supported the view that the perioperative administration of gabapentin was effective in reducing the incidence of CPSP [79]. Clarke et al. concluded that out of

procedure in order to reduce peripheral and central pain pathways sensitization.

cases and limited experience [76].

42 Pain Management in Special Circumstances

**4. Potential for prevention**

discussed in the following parts of this chapter.

**4.1. Pre-emptive and preventive analgesia**

*4.1.1. Gabapentin*

Pregabalin is a structural analogue of c-aminobutyric acid. It binds to the α 2 δ subunit of the voltage-gated calcium channel which subsequently lead to a decrease in the release of neurotransmitters such as glutamate, norepinephrine and substance P, thereby targeting the putative role of these transmitters in central sensitization in a similar way to gabapentin [83]. Chaparro et al. [82] conducted a systematic review in which five pregabalin trials with longterm pain outcomes were included. Two different dosing regimens were used in these clinical trials, either 150 mg 2 h prior to the induction of anaesthesia and 75 mg twice daily for two post-operative days or a 300-mg single dose pre-operatively followed by a 14-day twice-a-day (BID =50–150 mg). The heterogeneity (I2 of 28.5%) of dosing regimens was problematic with respect to comparing long-term outcomes. Two studies demonstrated a significant benefit of pregabalin as compared to placebo [84, 85]. While the pain outcomes differed at 3 months follow-up, an overall significant effect of pregabalin was reported [82]. Moreover, two additional studies showed a significant reduction in the incidence of CPSP 6 months following both total knee arthroplasty and off-pump coronary artery bypass surgery [84–86]. Therefore, despite the heterogeneity between studies, the available literature favours the perioperative use of pregabalin to prevent CPSP; however, the use of a high dose of pregabalin (300 mg) has been associated with serious adverse effects such as visual disturbances, sedation and confusion during the first day after surgery [85, 87, 88]. These adverse effects settled with continued use, but led to an overall recommendation of using lower doses of pregabalin, with the aim of reducing side effects and hence allowing the successful introduction of physiotherapy and intensive rehabilitation during the immediate post-operative period [85, 87, 88].

#### *4.1.3. Selective norepinephrine and serotonin re-uptake inhibitors (SNRIs)*

Venlafaxine hydrochloride is a selective norepinephrine and serotonin re-uptake inhibitor which is widely used as an antidepressant medication. It has a good safety profile as it does not bind to cholinergic, histamine or alpha 1-adrenergic receptors . The efficacy of Venlafaxine, which was administered perioperatively in patients with acute and chronic postmastectomy pain, has been investigated. The study concluded that venlafaxine significantly reduced the incidence of CPSP at 6 months . Duloxetine is another SNRI medication which has been effectively used in chronic neuropathic pain in patients with diabetic peripheral neuropathy and fibromyalgia [89–93]. However, its role in the prevention of CPSP has not been studied. The current evidence regarding the use of SNRIs in the prevention of CPSP is insufficient, and further studies are still needed.

*4.2.3. Intravenous lidocaine*

*4.2.4. Ketamine*

of ketamine to prevent CPSP.

months post-operatively [114].

*4.2.5. Intrathecal administration of morphine*

prevent CPSP after specific surgical procedures.

Lidocaine is a local anaesthetic which possesses analgesic, anti-hyperalgesic and anti-inflammatory properties. It is usually given intravenously, and it is used as part of a multimodal analgesic regimen. Five studies found significant effects on the incidence of CPSP following the administration of perioperative intravenous lidocaine infusion in several types of surgeries (breast surgery, robot-assisted thyroidectomy and nephrectomy) at 6 months post surgery [106–110]. In conclusion, the available literature supports the use of intravenous lidocaine to

Is Chronic Post-Surgical Pain Preventable? http://dx.doi.org/10.5772/intechopen.79500 45

Ketamine is a non-competitive NMDA receptor antagonist. The NMDA receptor plays a critical role in both the induction and maintenance of central sensitization and pathological pain. Ketamine is thought to reduce pain and analgesia consumption by preventing NMDAmediated sensitization of the dorsal horn neurons in the spinal cord [111]. Generally, the available evidence supports the perioperative use of ketamine to prevent CPSP. The effects of ketamine on CPSP were investigated in 14 clinical trials, out of which, 12 trials were of good quality to be included in a systematic review [82]. In most of these trials, pre-incisional loading doses of ketamine, which ranged from 0.15 to 1 mg kg−1, plus an intraoperative infusion was administered. While ketamine was not better than placebo for the reduction of CPSP at 3 months after surgery, a subgroup analysis of trials which only included patients who received ketamine for longer than 24 h demonstrated ketamine's superiority over placebo. A more definitive result was found for ketamine at 6 months following surgery, with an overall significant decrease in the incidence of CPSP. Interestingly, at 6 months following surgery, studies in which patients had received ketamine for less than 24 h demonstrated a reduction in the incidence of CPSP compared to studies in which ketamine was given for more than 24 h. The two clinical trials which were excluded from the systematic review reported no significant differences between ketamine and placebo [81, 112]. The reason for their exclusion was due to lack of reporting of the outcomes of interest. While the use of ketamine to reduce CPSP is empirically promising, the results still remain controversial due to the wide variability in clinical settings, ketamine dose and duration, and reported outcomes. In addition, some of the positive results were obtained using clinical anaesthesia regimens which are not accepted as standard treatments [112, 113]. Overall, the available literature supports the perioperative use

Moriyama et al. [114] studied the effect of intrathecal administration of 0.1 mg morphine in women undergoing caesarean section during surgery. No respiratory depression was reported. The study concluded that although no effect on acute pain was observed, intrathecal administration of morphine significantly decreased chronic pain after surgery by 50% at 3

#### **4.2. Perioperative prevention**

#### *4.2.1. Surgical technique*

Since nerve damage is considered as one of the major causes of chronic postsurgical pain, minimising nerve injury during any surgery is crucial. Nerve damage can be prevented or minimised by adopting several surgical techniques such as laparoscopic surgery, precise dissection during open surgery, the use of a lightweight mesh for inguinal hernia repair and the use of an intracostal suturing technique. Studies showed that laparoscopic herniorrhaphy and minimally invasive thoracoscopic techniques might decrease the risk of nerve damage and pain when compared with open surgery [94–96]. In addition, the avoidance of nerve damage by making more precise dissection during open surgery or by using the intracostal suturing technique to avoid direct nerve compression was also suggested to reduce the occurrence of CPSP [13, 97]. The use of a lightweight mesh in inguinal hernia repair was intended to produce less inflammatory response which would result in a reduction in the risk of CPSP [98, 99].

#### *4.2.2. Regional anaesthesia*

Regional anaesthesia is defined as the use of local anaesthetics to block the conduction of impulses along nerves and to minimise the transmission of signals to or within the spinal cord. Possibly, they prevent central sensitisation by preventing the nociceptive inputs into the dorsal horn [10]. Examples of regional anaesthesia are spinal and epidural techniques which act on the nerve roots. A recent Cochrane review concluded that epidural analgesia and paravertebral blocks were effective in reducing the risk of CPSP at 6 months after thoracotomy and breast cancer surgery, respectively [100], whereas a study by Capdevila et al. [101] did not show any benefit for epidural analgesia in reducing CPSP intensity after open nephrectomy. Spinal anaesthesia has also been shown to be beneficial compared to general anaesthesia in reducing the risk of chronic pain after caesarean section [102]. When comparing the route of regional anaesthesia, similar outcomes for paravertebral block (PVB) and thoracic epidural analgesia (TEA) were achieved [103]. In addition, a comparison between either of these techniques and opioids alone favoured RA [104]. Evidence was in favour for PVB for breast surgery and TEA for lung surgery [105]. The findings of these studies cannot be generalised to other surgical procedures due to small sample size and the experience of the centre where the procedure was conducted. In addition, the studies were heterogeneous in terms of agents used and routes of delivery. Currently, the available evidence suggests that regional anaesthetics as a class are equivocal to placebo for CPSP.

#### *4.2.3. Intravenous lidocaine*

pain, has been investigated. The study concluded that venlafaxine significantly reduced the incidence of CPSP at 6 months . Duloxetine is another SNRI medication which has been effectively used in chronic neuropathic pain in patients with diabetic peripheral neuropathy and fibromyalgia [89–93]. However, its role in the prevention of CPSP has not been studied. The current evidence regarding the use of SNRIs in the prevention of CPSP is insufficient, and

Since nerve damage is considered as one of the major causes of chronic postsurgical pain, minimising nerve injury during any surgery is crucial. Nerve damage can be prevented or minimised by adopting several surgical techniques such as laparoscopic surgery, precise dissection during open surgery, the use of a lightweight mesh for inguinal hernia repair and the use of an intracostal suturing technique. Studies showed that laparoscopic herniorrhaphy and minimally invasive thoracoscopic techniques might decrease the risk of nerve damage and pain when compared with open surgery [94–96]. In addition, the avoidance of nerve damage by making more precise dissection during open surgery or by using the intracostal suturing technique to avoid direct nerve compression was also suggested to reduce the occurrence of CPSP [13, 97]. The use of a lightweight mesh in inguinal hernia repair was intended to produce less inflammatory response which would result in a reduction in the risk of CPSP [98, 99].

Regional anaesthesia is defined as the use of local anaesthetics to block the conduction of impulses along nerves and to minimise the transmission of signals to or within the spinal cord. Possibly, they prevent central sensitisation by preventing the nociceptive inputs into the dorsal horn [10]. Examples of regional anaesthesia are spinal and epidural techniques which act on the nerve roots. A recent Cochrane review concluded that epidural analgesia and paravertebral blocks were effective in reducing the risk of CPSP at 6 months after thoracotomy and breast cancer surgery, respectively [100], whereas a study by Capdevila et al. [101] did not show any benefit for epidural analgesia in reducing CPSP intensity after open nephrectomy. Spinal anaesthesia has also been shown to be beneficial compared to general anaesthesia in reducing the risk of chronic pain after caesarean section [102]. When comparing the route of regional anaesthesia, similar outcomes for paravertebral block (PVB) and thoracic epidural analgesia (TEA) were achieved [103]. In addition, a comparison between either of these techniques and opioids alone favoured RA [104]. Evidence was in favour for PVB for breast surgery and TEA for lung surgery [105]. The findings of these studies cannot be generalised to other surgical procedures due to small sample size and the experience of the centre where the procedure was conducted. In addition, the studies were heterogeneous in terms of agents used and routes of delivery. Currently, the available evidence suggests that

regional anaesthetics as a class are equivocal to placebo for CPSP.

further studies are still needed.

44 Pain Management in Special Circumstances

**4.2. Perioperative prevention**

*4.2.1. Surgical technique*

*4.2.2. Regional anaesthesia*

Lidocaine is a local anaesthetic which possesses analgesic, anti-hyperalgesic and anti-inflammatory properties. It is usually given intravenously, and it is used as part of a multimodal analgesic regimen. Five studies found significant effects on the incidence of CPSP following the administration of perioperative intravenous lidocaine infusion in several types of surgeries (breast surgery, robot-assisted thyroidectomy and nephrectomy) at 6 months post surgery [106–110]. In conclusion, the available literature supports the use of intravenous lidocaine to prevent CPSP after specific surgical procedures.

#### *4.2.4. Ketamine*

Ketamine is a non-competitive NMDA receptor antagonist. The NMDA receptor plays a critical role in both the induction and maintenance of central sensitization and pathological pain. Ketamine is thought to reduce pain and analgesia consumption by preventing NMDAmediated sensitization of the dorsal horn neurons in the spinal cord [111]. Generally, the available evidence supports the perioperative use of ketamine to prevent CPSP. The effects of ketamine on CPSP were investigated in 14 clinical trials, out of which, 12 trials were of good quality to be included in a systematic review [82]. In most of these trials, pre-incisional loading doses of ketamine, which ranged from 0.15 to 1 mg kg−1, plus an intraoperative infusion was administered. While ketamine was not better than placebo for the reduction of CPSP at 3 months after surgery, a subgroup analysis of trials which only included patients who received ketamine for longer than 24 h demonstrated ketamine's superiority over placebo. A more definitive result was found for ketamine at 6 months following surgery, with an overall significant decrease in the incidence of CPSP. Interestingly, at 6 months following surgery, studies in which patients had received ketamine for less than 24 h demonstrated a reduction in the incidence of CPSP compared to studies in which ketamine was given for more than 24 h. The two clinical trials which were excluded from the systematic review reported no significant differences between ketamine and placebo [81, 112]. The reason for their exclusion was due to lack of reporting of the outcomes of interest. While the use of ketamine to reduce CPSP is empirically promising, the results still remain controversial due to the wide variability in clinical settings, ketamine dose and duration, and reported outcomes. In addition, some of the positive results were obtained using clinical anaesthesia regimens which are not accepted as standard treatments [112, 113]. Overall, the available literature supports the perioperative use of ketamine to prevent CPSP.

#### *4.2.5. Intrathecal administration of morphine*

Moriyama et al. [114] studied the effect of intrathecal administration of 0.1 mg morphine in women undergoing caesarean section during surgery. No respiratory depression was reported. The study concluded that although no effect on acute pain was observed, intrathecal administration of morphine significantly decreased chronic pain after surgery by 50% at 3 months post-operatively [114].

#### *4.2.6. Multimodal analgesia*

Multimodal analgesia has become the widely accepted modality of treatment for perioperative pain. It is utilising different regimens of different classes of medications according to the type of the surgical procedure and the institute where surgery is performed [115]. The main aim of multimodal analgesia is to target several peripheral and CNS mechanisms to maximise pain reduction, reduce opioids requirements and to decrease opioid-related side effects [103, 107]. A few studies have explored the effects of multimodal analgesia on CPSP prevention. The evidence indicated positive effects at 3 months [116] and at 1 year following surgery [117]. Additional studies are required to study the effects of multimodal analgesia on different types of surgical procedures and to find out whether its preventive effects do indeed reduce the incidence and severity of CPSP.

identification of individual risk factors and the development of assessment tools before planning for any surgical procedure. There is a hope that we can develop better understanding about the genetics of pain to try to identify responsible genes and develop specific therapies for them. Future studies could be designed to be more procedure-specific to help us understand the mechanistic differences between surgical incisions and pathologies. The role of the multimodal analgesia in the prevention of CPSP should be explored further in view of the positive results of the few available studies. Advance in surgical techniques to try to minimise nerve injuries as much as possible since nerve damage plays a major role in the development of chronic postsurgical neuropathic pain is another promising area for research. Future studies in the field of CPSP should be designed in a better way to include a larger sample size, standard doses and regimens of drugs, and more consistent outcome

Is Chronic Post-Surgical Pain Preventable? http://dx.doi.org/10.5772/intechopen.79500 47

CPSP is a complex process which is not fully understood. When it occurs, it affects the patients' quality of life. Based on our current understanding of the pathophysiology, nerve injury and inflammation are the two main responsible mechanisms for the development of CPSP. Specific risk factors, which make some individuals at a higher risk than others for CPSP, have been identified. Timely identification of these individuals based on their risk profile allows us to develop appropriate interventions. Several modalities and interventions for CPSP prevention have been investigated. These include pre-emptive and perioperative interventions (**Table 1**). CPSP prevention is an important area for future research in view of the methodological prob-

measurement tools.

**6. Conclusion**

lems with the majority of available studies.

Adapted with permission from reference [125].

**Table 1.** Evidence-based strategies to reduce the risk of chronic post-surgical pain (CPSP).

#### *4.2.7. Non-steroidal anti-inflammatory drugs (NSAIDs)*

Prostaglandins are one of the inflammatory mediators activated during surgery which has a possible role in CPSP pathophysiology. NSAIDs are a group of medications which are widely used for their anti-inflammatory properties. They reduce the pain and inflammation through the inhibition of the synthesis of prostaglandins by inhibiting COX-1 and COX-2 receptors. NSAIDs can reduce secondary hyperalgesia and central sensitization [118, 119]. One study showed that Celecoxib (COX-2 inhibitor) had reduced post-operative pain, the need for post-operative opioid analgesia [120] and meanwhile did not inhibit bone healing following arthroplasty surgery [121]. In summary, the available clinical trials are heterogeneous and differ in the following: the type of drug used, follow-up time point and pain outcomes. None of these trials demonstrated a significant impact of NSAIDs on reduction in the incidence or severity of CPSP [122, 123].

#### *4.2.8. Glucocorticoids*

Glucocorticoids prevent pain by expressing anti-inflammatory properties and by preventing central sensitization [124]. Three trials studied the effects of perioperative corticosteroid on CPSP. The studies used different types of steroids Dexamethasone, Methylprednisolone and Hydrocortisone. A Cochrane review included these clinical trials. The results were inconclusive, and the heterogeneity precluded any possible meta-analysis. The heterogeneity was due to variations in drugs used, follow-up time intervals and the measured pain outcomes [82].

#### **5. Future directions**

CPSP remains as a challenging clinical problem. There are several areas which are promising and can be explored further in the future. Investigators could focus more on the better identification of individual risk factors and the development of assessment tools before planning for any surgical procedure. There is a hope that we can develop better understanding about the genetics of pain to try to identify responsible genes and develop specific therapies for them. Future studies could be designed to be more procedure-specific to help us understand the mechanistic differences between surgical incisions and pathologies. The role of the multimodal analgesia in the prevention of CPSP should be explored further in view of the positive results of the few available studies. Advance in surgical techniques to try to minimise nerve injuries as much as possible since nerve damage plays a major role in the development of chronic postsurgical neuropathic pain is another promising area for research. Future studies in the field of CPSP should be designed in a better way to include a larger sample size, standard doses and regimens of drugs, and more consistent outcome measurement tools.
