**4.4 Effects on other organ systems**

Opioids are the most efficient of all pain analgesics drugs for attenuating the stress response associated with pain, laryngoscopy and airway manipulation. The plasma concentration of stress hormones (cortisol, catecholamines, vasopressin, aldosterone and growth factor) increases during trauma, anaesthesia or surgery. This produce increased myocardial work, tissue catabolism and hyperglycaemia – effects associated with increased morbidity and mortality. Opioids reduce nociception inhibiting the pituitary-adrenal axis, decreasing central sympathetic outflow and influencing centrally mediated neuroendocrine response. Fentanyl and its congeners are the most efficacious in this action (**Table 7**).


#### **Table 7.**

*Opioid effects on major organ system [6].*

#### **4.5 Side effects**

Side effects can be observed from minors to the most concerning ones and are individual and age depending beyond of disease extension, presence of organ

**247**

in this regard [6].

*Analgesics*

*DOI: http://dx.doi.org/10.5772/intechopen.94319*

phylaxis has been reported.

central and peripheral mechanisms.

nitroglycerine and glucagon.

dysfunction, concurrent administration of certain drugs, route of administration and prior of opioid exposure. Some side effects induced by the opioids are induced by the activation of the opioid receptors either peripherally or centrally, or even in both areas. Serious allergic reactions to opioids are extremely rare, although ana-

At equianalgesic doses, all opioids produce equivalent degrees of respiratory depression through reducing the sensitivity to CO2 of the breathing drive. The extreme ages, elderly and neonates are at the highest risk. Tolerance arises rapidly to this effect, and with chronic opioid exposure the risk of major respiratory depression is reduced. Apnoea may occur in conscious patients, but this is rare, and is usually associated with other signs of CNS depression. In such a condition, apnoeic patients can be instructed to breath as voluntary control of ventilation remains intact. Sleep or the concomitant use of other CNS depressants (except clonidine) potentiates this risk. Opioid-induce depression of airway reflexes is usually regarded as an advantage side effect for the practitioner in some condition like airway manipulation. Although at the same time the mucociliary function depression can be detrimental. All opioids have an antitussive activity at less than analgesic doses, working via

The incidence of nausea after opioids use is reported to be between 10 and 60%, and this is markedly increased in pain-free and ambulatory patients (via opioid sensitisation of the vestibular nucleus). This reactivity is based on individual variability, but tolerance develops rapidly [6]. Switch to oral administration and

Constipation remains the most common side effect of chronic opioid treatment, and toxic megacolon may occur in patients with ulcerative colitis [6]. Tolerance, in this situation develops very slowly, as well as other smooth muscle effects. Loperamide is a synthetic agent, does not cross the blood brain barrier, used as an antimotility drug. All opioids are reported to increase bile duct pressure, with a spasmogenic action cause contraction of the sphincter of Oddi with effects on doses dependent activity [6]. Pethidine also, produces smooth muscle contraction via a direct action. Opioids effects on the biliary tract can be reversed by naloxone,

Other effects on the smooth muscle target the genitourinary system, often leading to urinary retention and urgency. This effect is predominant in elderly and when administered neuraxially. This later feature explains a centrally mediated

There are some others centrally mediated opioids effects. Some of these are of no clinical benefit and usually unpleasant. Often, opioids may trigger pruritus with various ranges of severity, with mechanism of action not fully discovered. The pruritus predominantly affects nose, face and chest being independent of histamine release. Substituting opioids agents will decrease the incidence. Studies has shown that low dose of naloxone will alleviate this effect. Muscle rigidity is triggered at or just after the loss of consciousness and may manifest from hoarseness in mild cases to impossibility of ventilate in severe situations. It can be minimised by co-administration of induction agents and benzodiazepines. In anaesthetic practice may be prevented by pre-treatment priming with small doses of muscle relaxants. This side effect was reported to be with a higher incidence on concomitant use of nitrous oxide [6]. It is seen more commonly with Fentanyl and its congeners than with morphine and the risk is dose depended. In emergency situation of impossibil-

Opioids agents decrease thermoregulation thresholds, except pethidine, which is a unique in its ability to reduce shivering. Tramadol also has proved to be efficacious

mechanism of action via receptors located at the sacral spinal cord.

ity of ventilation can be reversed by administration of naloxone.

substituting one opioid to another may reduce the incidence of nausea.

#### *Analgesics DOI: http://dx.doi.org/10.5772/intechopen.94319*

*Pain Management - Practices, Novel Therapies and Bioactives*

Mean arterial pressure

Cardiovascular Heart rate Sinus bradycardia via central vagal stimulation

bradycardia)

depressant)

Excitability Decreased myocardial contractility

Respiratory Mechanics Decrease in rate, tidal volume and minute ventilation at equianalgesic doses

Control Increased apnoeic threshold

Biliary tree Increase bile duct pressure

Vascular system No effect on SVR (unless histamine release)

central sympathetic outflow) Myocardium No effect on contractility (except for pethidine which is a

> No effect on metabolic rate Possible ischemic preconditioning

Increased refractory period Increased VF threshold

Decrease CO2 sensitivity

Airway reflexes Decrease airway reflexes with improve tolerance to ETT

Decrease mucociliary action

stool and constipation Decrease gastric acid

Nausea and vomiting

decrease in GFR (predominates)

Vesicular sphincter contraction

Genitourinary Kidney Antidiuresis as a result of decrease in renal blood flow and

Bladder Increased bladder and urethral tone

opioid

Immunity Immune system Decrease immunoglobulin production (uncertain significance)

Side effects can be observed from minors to the most concerning ones and are individual and age depending beyond of disease extension, presence of organ

Occasionally sinus arrest exacerbated by concomitant vagal

Mild venodilation with a decrease in preload (due to decrease of

Usually no effect or a slight decrease (unless significant

Greater decrease if associated with histamine release

Increase pauses, irregular breathing and apnoea

Antitussive through central and peripheral actions

Increase tone of pyloric, ileocecal and anal sphincters

Sphincter Oddi contraction (little clinical significance)

Decrease vasopressin release in response to osmotic triggers

Reactivation of herpes simplex virus 2–5 days after neuraxial

Brief cough in up to 50% with pethidine bolus

Decrease carotid body chemoreception and hypoxic drive Voluntary control of respiration remains intact No effect on hypoxic pulmonary vasoconstriction

Decrease peristalsis and secretions and increase tone causing dry

Decrease gastric emptying with increase antral tone and decrease lower oesophageal sphincter tone promoting high aspiration risk

excitation (e.g. laryngoscopy) and Beta-blockers

**System Effect**

Gastrointestinal Stomach and

*Opioid effects on major organ system [6].*

bowel

Chemoreceptor trigger zone

**246**

**Table 7.**

**4.5 Side effects**

dysfunction, concurrent administration of certain drugs, route of administration and prior of opioid exposure. Some side effects induced by the opioids are induced by the activation of the opioid receptors either peripherally or centrally, or even in both areas. Serious allergic reactions to opioids are extremely rare, although anaphylaxis has been reported.

At equianalgesic doses, all opioids produce equivalent degrees of respiratory depression through reducing the sensitivity to CO2 of the breathing drive. The extreme ages, elderly and neonates are at the highest risk. Tolerance arises rapidly to this effect, and with chronic opioid exposure the risk of major respiratory depression is reduced. Apnoea may occur in conscious patients, but this is rare, and is usually associated with other signs of CNS depression. In such a condition, apnoeic patients can be instructed to breath as voluntary control of ventilation remains intact. Sleep or the concomitant use of other CNS depressants (except clonidine) potentiates this risk.

Opioid-induce depression of airway reflexes is usually regarded as an advantage side effect for the practitioner in some condition like airway manipulation. Although at the same time the mucociliary function depression can be detrimental. All opioids have an antitussive activity at less than analgesic doses, working via central and peripheral mechanisms.

The incidence of nausea after opioids use is reported to be between 10 and 60%, and this is markedly increased in pain-free and ambulatory patients (via opioid sensitisation of the vestibular nucleus). This reactivity is based on individual variability, but tolerance develops rapidly [6]. Switch to oral administration and substituting one opioid to another may reduce the incidence of nausea.

Constipation remains the most common side effect of chronic opioid treatment, and toxic megacolon may occur in patients with ulcerative colitis [6]. Tolerance, in this situation develops very slowly, as well as other smooth muscle effects. Loperamide is a synthetic agent, does not cross the blood brain barrier, used as an antimotility drug. All opioids are reported to increase bile duct pressure, with a spasmogenic action cause contraction of the sphincter of Oddi with effects on doses dependent activity [6]. Pethidine also, produces smooth muscle contraction via a direct action. Opioids effects on the biliary tract can be reversed by naloxone, nitroglycerine and glucagon.

Other effects on the smooth muscle target the genitourinary system, often leading to urinary retention and urgency. This effect is predominant in elderly and when administered neuraxially. This later feature explains a centrally mediated mechanism of action via receptors located at the sacral spinal cord.

There are some others centrally mediated opioids effects. Some of these are of no clinical benefit and usually unpleasant. Often, opioids may trigger pruritus with various ranges of severity, with mechanism of action not fully discovered. The pruritus predominantly affects nose, face and chest being independent of histamine release. Substituting opioids agents will decrease the incidence. Studies has shown that low dose of naloxone will alleviate this effect. Muscle rigidity is triggered at or just after the loss of consciousness and may manifest from hoarseness in mild cases to impossibility of ventilate in severe situations. It can be minimised by co-administration of induction agents and benzodiazepines. In anaesthetic practice may be prevented by pre-treatment priming with small doses of muscle relaxants. This side effect was reported to be with a higher incidence on concomitant use of nitrous oxide [6]. It is seen more commonly with Fentanyl and its congeners than with morphine and the risk is dose depended. In emergency situation of impossibility of ventilation can be reversed by administration of naloxone.

Opioids agents decrease thermoregulation thresholds, except pethidine, which is a unique in its ability to reduce shivering. Tramadol also has proved to be efficacious in this regard [6].

Histamine release and associated hypotension are variable in incidence and severity, and are with decreased incidence where is a slow IV administration and ameliorated by intravascular fluid loading. This effect is less with fentanyl and its subclass agents, except pethidine. The histamine release may be localised or generalised, often causing facial flushing and variable itch [6].

#### *4.5.1 Opioid-specific effects*

Pethidine has been described as a unique agent because of its non-opioid effects. It has a local anaesthetic effect of equivalent potency to cocaine and it has a quinidine-like effect on cardiac muscle to reduce cardiac irritability and arrhythmias [6]. Pethidine overdose produce a complex syndrome characterised by a cardiovascular collapse, seizures, hyperreflexia, mydriasis in addition to a respiratory depression [6].

The use of phenylpiperidines family (except remifentanil) in anaesthesia has been associated with postoperative respiratory depression after high doses, due secondary peaks in plasma levels, possible from the opioids release from the body stores. This action is responsible for the increase in peripheral perfusion and postoperative shivering.

#### **4.6 Pharmacokinetics**

#### *4.6.1 Administrations*

The choice of route of administration depends on the opioid being utilised, pain severity, the need for agent titration, potential side effects and contraindications to a particular route. The way of administration may activate the onset of peak analgesia and the side effects. For example, respiratory depression may be triggered 7 minutes after an IV dose of morphine, but not until 30 minutes after IM or 6–10 hours after a spinal administration.

There are various degree and length of pain relief effect conferred by certain routes. Spinal administration may produce a greater quality and potentially a longer duration of analgesia, with a lower incident of supraspinal effects. However, an increased incidence of specific side effects (nausea, itching, urinary retention) occurs.

No opioid agonist demonstrates dose-dependent pharmacokinetics. First pass metabolism of orally administrated opioids is made in the liver and the digestive tract wall (up to 50%). Opioids given IM or SC have 100% bioavailability, but peak plasma concentration may be variable up to fivefold influenced by body temperature, site of injection and hemodynamic status. IV administration results in a much restricted rage of plasma concentration [6].

The lung exerts an important first-pass effect on highly lipid-soluble opioids. Prior administration of other lipophilic amines, such propranolol decreases pulmonary uptake, by saturating biding sites [6].

#### *4.6.2 Elimination*

Opioids mainly sustain a liver metabolism with a renal excretion of the more hydrophilic metabolites. A few metabolites also take the biliary excretion route. Some amounts of the more hydrophilic agents may be excreted unchanged in the urine. Liver blood flow is the main factor influencing the plasma clearance for most opioids, because of their high hepatic extraction ratio [6].

**249**

*Analgesics*

morphine [6].

*DOI: http://dx.doi.org/10.5772/intechopen.94319*

levels of transformed norpethidine [6].

physiological states as stated in **Table 8**.

**4.7 Opioid drug interaction**

*Morphine*. The biotransformation of morphine is unique among opioids agents. Glucuronidation is responsible for 60–80% of its metabolism, and is primarily undergone in the liver with production of high quantity morphine-3-glucoronide (M3G) and only 10% of morphine-6-glucoronide (M6G). The remainder undergoes sulphation (important feature in neonates where glucuronidation metabolism is immature), 5% is demethylated to normorphine, a small amount is converted to codeine, and 10% is excreted in the urine [6, 29]. In healthy subjects up to 10% of glucuronidation occurs in extrahepatic sites, such kidney and intestine. The excretion of the morphine metabolites is directly influenced by the creatinine clearance. 90% of conjugated morphine is excreted in the urine and 10% is excreted in bile, sweat and breast milk. M6G is 2–4 time more potent than morphine and has a longer elimination half-life [29]. Despite being more hydrophilic than morphine, M6G cross the blood-brain barrier, with a longer action due to slower elimination from this site. There is also an entero-hepatic recirculation of morphine and its

*Diamorphine*. Diamorphine is inactive and needs deacetylation in the CSF, liver, and plasma to its final metabolites 6-monoacetylmorphine and morphine. These active metabolites are more hydrophilic, and their ensuing metabolism is as for

*Codeine*. Codeine is suffering a hepatic metabolization to mainly codeine conjugates

*Pethidine*. Pethidine metabolism mainly involves hydrolysis to pethidinic acid, with small amount being freely excreted through urine (5%) of the prodrug – although this may be increased up to 25% with urinary acidification (pH < 5) [6]. One third of the metabolism takes the route to N-demethylation to norpethidine, which is finally hydrolysed to norpethidinic acid. Enzyme induction triggered by chronic pethidine use (sometimes also by carbamazepine therapy) induces high

*Fentanyl and sufentanyl*. The high lipid solubility of these agents is responsible for their large volume of distribution, which causes rapid and continued peripheral tissue uptake, limiting initial liver metabolism. This is leading to a greater variability in plasma concentration (13-fold range in fentanyl) during the elimination phase, particularly with fluctuations in muscles blood flow that may be responsible of the secondary peaks in plasma concentration after large doses. Fentanyl, sufentanyl and alfentanyl have a small unchanged renal excretion, being mainly metabolised in the

and norcodeine, with some urinary excretion of free codeine. Up to 10% of a dose is also metabolised to morphine. This biotransformation is responsible for analgesia produced by codeine. Due to genetic polymorphism, up to 8% of western Europeans are deficient of the enzyme implicated in the liver metabolism. These patients require higher doses, and they may still not experience effective pain relief. Furthermore, the

variability may produce dangerous high morphine levels in breast milk [30].

liver. These inactive metabolites are taking the urinary route for excretion.

*4.6.3 Patient factors influencing opioid pharmacokinetics and pharmacodynamics*

The pharmacokinetics and dynamics of opioids may be altered in a number of

This class of pain killers have limited but important interactions with other drugs. Their action is synergistically with other CNS depressant on the level of consciousness. Barbiturates, benzodiazepines and propofol produce effects on the loss of

metabolites, particularly under the chronic oral administration [29].

#### *Analgesics DOI: http://dx.doi.org/10.5772/intechopen.94319*

*Pain Management - Practices, Novel Therapies and Bioactives*

alised, often causing facial flushing and variable itch [6].

*4.5.1 Opioid-specific effects*

respiratory depression [6].

postoperative shivering.

**4.6 Pharmacokinetics**

6–10 hours after a spinal administration.

restricted rage of plasma concentration [6].

opioids, because of their high hepatic extraction ratio [6].

uptake, by saturating biding sites [6].

*4.6.1 Administrations*

tion) occurs.

*4.6.2 Elimination*

Histamine release and associated hypotension are variable in incidence and severity, and are with decreased incidence where is a slow IV administration and ameliorated by intravascular fluid loading. This effect is less with fentanyl and its subclass agents, except pethidine. The histamine release may be localised or gener-

Pethidine has been described as a unique agent because of its non-opioid effects. It has a local anaesthetic effect of equivalent potency to cocaine and it has a quinidine-like effect on cardiac muscle to reduce cardiac irritability and arrhythmias [6]. Pethidine overdose produce a complex syndrome characterised by a cardiovascular collapse, seizures, hyperreflexia, mydriasis in addition to a

The use of phenylpiperidines family (except remifentanil) in anaesthesia has been associated with postoperative respiratory depression after high doses, due secondary peaks in plasma levels, possible from the opioids release from the body stores. This action is responsible for the increase in peripheral perfusion and

The choice of route of administration depends on the opioid being utilised, pain severity, the need for agent titration, potential side effects and contraindications to a particular route. The way of administration may activate the onset of peak analgesia and the side effects. For example, respiratory depression may be triggered 7 minutes after an IV dose of morphine, but not until 30 minutes after IM or

There are various degree and length of pain relief effect conferred by certain routes. Spinal administration may produce a greater quality and potentially a longer duration of analgesia, with a lower incident of supraspinal effects. However, an increased incidence of specific side effects (nausea, itching, urinary reten-

No opioid agonist demonstrates dose-dependent pharmacokinetics. First pass metabolism of orally administrated opioids is made in the liver and the digestive tract wall (up to 50%). Opioids given IM or SC have 100% bioavailability, but peak plasma concentration may be variable up to fivefold influenced by body temperature, site of injection and hemodynamic status. IV administration results in a much

The lung exerts an important first-pass effect on highly lipid-soluble opioids. Prior

administration of other lipophilic amines, such propranolol decreases pulmonary

Opioids mainly sustain a liver metabolism with a renal excretion of the more hydrophilic metabolites. A few metabolites also take the biliary excretion route. Some amounts of the more hydrophilic agents may be excreted unchanged in the urine. Liver blood flow is the main factor influencing the plasma clearance for most

**248**

*Morphine*. The biotransformation of morphine is unique among opioids agents. Glucuronidation is responsible for 60–80% of its metabolism, and is primarily undergone in the liver with production of high quantity morphine-3-glucoronide (M3G) and only 10% of morphine-6-glucoronide (M6G). The remainder undergoes sulphation (important feature in neonates where glucuronidation metabolism is immature), 5% is demethylated to normorphine, a small amount is converted to codeine, and 10% is excreted in the urine [6, 29]. In healthy subjects up to 10% of glucuronidation occurs in extrahepatic sites, such kidney and intestine. The excretion of the morphine metabolites is directly influenced by the creatinine clearance. 90% of conjugated morphine is excreted in the urine and 10% is excreted in bile, sweat and breast milk. M6G is 2–4 time more potent than morphine and has a longer elimination half-life [29]. Despite being more hydrophilic than morphine, M6G cross the blood-brain barrier, with a longer action due to slower elimination from this site. There is also an entero-hepatic recirculation of morphine and its metabolites, particularly under the chronic oral administration [29].

*Diamorphine*. Diamorphine is inactive and needs deacetylation in the CSF, liver, and plasma to its final metabolites 6-monoacetylmorphine and morphine. These active metabolites are more hydrophilic, and their ensuing metabolism is as for morphine [6].

*Codeine*. Codeine is suffering a hepatic metabolization to mainly codeine conjugates and norcodeine, with some urinary excretion of free codeine. Up to 10% of a dose is also metabolised to morphine. This biotransformation is responsible for analgesia produced by codeine. Due to genetic polymorphism, up to 8% of western Europeans are deficient of the enzyme implicated in the liver metabolism. These patients require higher doses, and they may still not experience effective pain relief. Furthermore, the variability may produce dangerous high morphine levels in breast milk [30].

*Pethidine*. Pethidine metabolism mainly involves hydrolysis to pethidinic acid, with small amount being freely excreted through urine (5%) of the prodrug – although this may be increased up to 25% with urinary acidification (pH < 5) [6]. One third of the metabolism takes the route to N-demethylation to norpethidine, which is finally hydrolysed to norpethidinic acid. Enzyme induction triggered by chronic pethidine use (sometimes also by carbamazepine therapy) induces high levels of transformed norpethidine [6].

*Fentanyl and sufentanyl*. The high lipid solubility of these agents is responsible for their large volume of distribution, which causes rapid and continued peripheral tissue uptake, limiting initial liver metabolism. This is leading to a greater variability in plasma concentration (13-fold range in fentanyl) during the elimination phase, particularly with fluctuations in muscles blood flow that may be responsible of the secondary peaks in plasma concentration after large doses. Fentanyl, sufentanyl and alfentanyl have a small unchanged renal excretion, being mainly metabolised in the liver. These inactive metabolites are taking the urinary route for excretion.

#### *4.6.3 Patient factors influencing opioid pharmacokinetics and pharmacodynamics*

The pharmacokinetics and dynamics of opioids may be altered in a number of physiological states as stated in **Table 8**.

#### **4.7 Opioid drug interaction**

This class of pain killers have limited but important interactions with other drugs. Their action is synergistically with other CNS depressant on the level of consciousness. Barbiturates, benzodiazepines and propofol produce effects on the loss of


#### **Table 8.**

*Factors influencing opioid pharmacokinetics and pharmacodynamics.*

consciousness with a synergic action from the opioids side and also increase the risk of cardiovascular depression. With anaesthetic use, opioids may decrease the concentration of volatile agents by up to 50% while ensuring amnesia and immobility, with the preservation of hemodynamic stability at low inhaled concentrations (≤1 MAC) [6].

The use of opioids (particularly pethidine and tramadol) with monoamine oxidase inhibitors (MAOI) may lead to serious and potentially fatal consequences as excitatory syndrome (type I) [2, 6]. This is complex syndrome characterised by excitatory phenomena including agitation, fever, rigidity, seizures and coma. This is triggered by the excessive CNS serotonin activity, since both MAOI and pethidine block serotonin reuptake. Rarely also can arise an inhibitory syndrome (type II) characterised by respiratory depression, coma and hypotension, which is the result of MAOI inhibition of hepatic microsomal enzymes leading to a pethidine accumulation.

A similar excitatory syndrome (serotoninergic) is found during the combination of tramadol and serotonin-noradrenaline reuptake inhibitors (SNRIs) [6].

Morphine has been recommended as the opioid of choice for use in these patients.

#### **4.8 Opioid antagonists**

The main opioid antagonist currently used in practice is naloxone.

Naloxone is an N-allyl derivate of oxymorphone. It is pure opioid antagonist, without an intrinsic pharmacological activity. It has a high affinity for miu opioid receptors but also blocks other receptors. Naloxone reverses the respiratory depression and analgesia of opioids but also precipitates the withdrawal syndrome in opioids addicts. Naloxone could also block the action of endogenous opioids. IV administration of 200–400 mcg of naloxone will reverse the respiratory depression,

**251**

*Analgesics*

**4.9 Tramadol**

system effects [31].

skin rashes.

relieves it

• E - empower patients

**6. Pharmacological intervention**

*DOI: http://dx.doi.org/10.5772/intechopen.94319*

because and major first pass metabolism [6].

but incremental titration (1.5–3 mcg/kg) is referable in order to minimise the reversal of the analgesic effects of the opioids. Naloxone's action time is roughly 30 minutes, so further doses may be considered to avoid the return of respiratory depression effects of any agonist agent that outlasts the effect of naloxone. Naloxone is also efficient in releasing the pruritus and urinary retention of the intrathecal and epidural opioids. Naloxone has very small oral availability, only 2%,

Tramadol is included in the opioids class of drugs, with unique and complex mode of action, only part of which is mediated through opioid receptors. Tramadol is an analogue of codeine and acts as a weak agonist at all types of opioid receptors, with some preference for the miu receptors. It has 10% of the potency of morphine. Tramadol blocks the reuptake of noradrenaline and 5-HT (serotonin) and facilitate the release of the later. By its effects, influences nociceptive transmission activating the descending inhibitory pathways in the CNS. Therefore, Naloxone only partially reverses the analgesic effects of tramadol. Effects on alfa2-adrenergic, NMDA and benzodiazepine receptors may be due to indirect effects secondary noradrenergic

Tramadol is recommended in the treatment of moderate to severe pain. It is well absorbed when given orally, with a bioavailability of 68% and only 20% protein bound. Tramadol is predominantly metabolised in the liver by demethylation and conjugation, with 90% being excreted in the urine. The elimination half-life is 4–6 hours. His metabolites have longer half-life (up to 9 hours) and 2–4 times greater analgesic potency than tramadol and precautions should be taken in hepatic and renal failure. Tramadol exhibits small risk for respiratory depression when compared with equianalgesic doses of morphine. Also, cardiovascular effects are minimal. There is a low potency for abuse and physical dependence, but still reported. Tramadol's known side effects include: dizziness, nausea, sedation, dry mouth, sweating and

Concomitant use of MAOIs is contraindicated and co-administration with

• B - believe the patient's/resident's and family's reports of pain and what

• D - deliver interventions in a timely, logical and coordinated fashion

incidents of patient abuse, clinicians are encouraged to carefully assess their

As a result of a nationwide effort to reduce unnecessary opioid use and reduce

carbamazepine may decrease the concentration and effect of tramadol.

**5. General pain management principles**

• C - choose appropriate pain control options

• A - ask about pain regularly

#### *Analgesics DOI: http://dx.doi.org/10.5772/intechopen.94319*

but incremental titration (1.5–3 mcg/kg) is referable in order to minimise the reversal of the analgesic effects of the opioids. Naloxone's action time is roughly 30 minutes, so further doses may be considered to avoid the return of respiratory depression effects of any agonist agent that outlasts the effect of naloxone. Naloxone is also efficient in releasing the pruritus and urinary retention of the intrathecal and epidural opioids. Naloxone has very small oral availability, only 2%, because and major first pass metabolism [6].
