Student Forum Opioid-Induced Pruritus Jessica L. Benson, Hope E. Campbell, Cory N. Phillips Opioid analgesics are commonly used medications for the treatment of acute and chronic pain syndromes associated with multiple disease states. However, their use is often limited by adverse effects. Opioid-induced pruritus (OIP) is one of the most common adverse effects, affecting patients on oral and neuraxial opioids. Although not life-threatening, pruritus is an unpleasant side effect potentially contributing to patient discomfort, decreased quality of life, and noncompliance. The occurrence of pruritus varies with the type of opioid, dose, and method of administration. Pharmacists can make interventions that will optimize control of, or reduce the incidence of, OIP. An understanding of the receptors, mechanisms, incidence, and pharmacological therapies available to manage OIP is required knowledge for practitioners caring for patients who use opioids.
Introduction Opioid analgesics are useful agents for managing acute and chronic pain, but their use is often limited by adverse effects, including sedation, pruritus, nausea, respiratory depression, hypotension, and constipation.1 Opioidinduced pruritus (OIP) is one of the most common adverse effects, affecting 2% to 10% of patients on oral opioids and up to 100% of patients receiving neuraxial (epidural and intrathecal) opioids.1,2 It is an unpleasant side effect leading to patient discomfort, decreased quality of life, and discontinuation of medication. The occurrence of pruritus varies with the type of opioid, dose, and method of administration. Pharmacists are in a key position to make recommendations to limit the incidence and symptoms of OIP and ensure patient compliance with opioid therapy. The purpose of this article is to review the current understanding of the mechanisms, incidence, and the pharmacological therapies available to manage OIP.
Mechanism of Opioid-Induced Pruritus Key words: Adverse effect, Analgesic, Opioid, Pain,
Pruritus, Receptors. Abbreviations: D2 = Dopamine receptor 2, GABA = Gamma-aminobutyric acid, IV = Intravenous, mcg = Microgram, NSAID = Nonsteroidal anti-inflammatory drug, OIP = Opioid-induced pruritus, 5-HT2/5-HT3 = Serotonin or 5-hydroxytryptamine. Consult Pharm 2015;30:221-7.
The mechanism of OIP is still unclear, but appears to have both peripheral- and central-acting pathways.2 Peripherally induced pruritus is seen with opioid agonists (morphine, methadone) secondary to histamine release from mast cells, resulting in local itching and hives.2 Fentanyl and oxymorphone are less likely to produce histamine release, but they are still linked to pruritus, suggesting that another mechanism may be involved. Centrally mediated pruritus has been documented in several animal studies, linking the prevention of pruritus with the use of opioid-receptor antagonists.3 Decreased pruritus with opioid antagonists indicate that histamine release is not the sole cause for OIP and that activation of the central mu-opioid receptors is likely a contributing factor.3 Recent research involving neuraxial OIP suggests mu-opioid receptors are responsible for the centrally mediated response.2 Probable mechanisms of centrally mediated pruritus include direct binding to opioid receptors in the spinal cord and brain, changes in neurotransmission of these receptors, and interaction with serotonin or 5-hydroxytryptamine (5-HT3) receptors. The end result is activation of the medullary dorsal horn
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Student Forum within the trigeminal nerve and antagonism of inhibitory transmitters, such as gamma-aminobutyric acid (GABA).4 There is a high concentration of opioid receptors located within the trigeminal nerve and spinal cord, leading to itching of the face with neuraxial administration. In these cases, pretreatment with naloxone, a mu-receptor antagonist, is more effective in preventing pruritus compared with antihistamines. Serotonin, dopamine 2 (D2) receptors, prostaglandins, and spinal inhibitory pathways may also contribute to OIP, but lack credible evidence.5 Understanding these mechanisms will aid in the selection of appropriate agents.
Pruritus Incidence Among Different Opioids Opioids have subtle differences in binding to the mu, kappa, and sigma receptors; the clinical effects can vary from one agent to another.1 The prevalence of pruritus depends on the method of administration, the opioid used, and dosage. Approximately 2% to 10% of patients on chronic opioids will experience pruritus, and the risk significantly increases when opioids are given epidurally or intrathecally.2 Oral formulations have a lower incidence of pruritus compared with injectable formulations while extended-release formulations have a higher incidence because of prolonged activation of the opioid receptors.2,4 Pruritus related to transdermal patches, such as buprenorphine and fentanyl, ranges between 3% and 15% and is primarily a localized reaction. Injectable formulations such as morphine, buprenorphine, fentanyl, hydromorphone, methadone, meperidine, and oxymorphone have an incidence of 10% to 50% in patients receiving intravenous (IV) opioids and 20% to 100% of those receiving epidural or intrathecal opioids.4 The most susceptible groups are women in labor (60% to 100%) and patients who have received major orthopedic surgery (30% to 60%). The highest prevalence (up to 100%) is associated with intrathecal morphine.2 Intrathecal administration rapidly reaches peak concentration in the cerebrospinal fluid, resulting in the highest incidence of central-acting pruritus. Epidural injections have a delay in peak concentration, resulting in less-rapid development of pruritus. For
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example, there is a 10- to 20-minute delay with fentanyl and a one-to-four hour delay with morphine.4 Lipid soluble opioids, like fentanyl, have a shorter duration of pruritus and respond to decreases in dosage.2 In most cases, higher doses of opioids correlate with a higher incidence of pruritus.
Management of OpioidInduced Pruritus Treatment of opioid-induced pruritus, especially neuraxial pruritus, remains a challenge. Prevention may be the key by using the lowest effective doses of opioids and using prophylactic therapy. Strategies to minimize OIP include opioid rotation, dose reduction, changing the route of administration, and symptomatic management.1 Dose reductions or changing to an opioid with less histaminereleasing properties (hydromorphone, oxymorphone, and fentanyl) can occasionally provide relief, but does not reliably relieve pruritus.1 Nondrug treatments, such as cool compresses or moisturizers, may be beneficial for certain patients.1 Table 1 lists various pharmacologic treatments with differing mechanisms that have been studied for the prevention and treatment of OIP. These medications include pure opioid-receptor antagonists, mixed opioidreceptor agonist/antagonists, serotonin 5-HT3 antagonists, dopamine D2-receptor antagonists, antihistamines, and nonsteroidal anti-inflammatory drugs (NSAIDs), among others.7 Antihistamines are often used as first-line treatment, even though the role of histamine in OIP is controversial.2 Antihistamines have little or no effect on centrally induced pruritus, but are effective for the peripherally induced pruritus of morphine and methadone. First-generation antihistamines (diphenhydramine, hydroxyzine) may decrease the sensation of pruritus through sedation.4 Recent evidence indicates the dominant pathway is mureceptor-mediated rather than histamine-mediated. The use of opioid antagonists (naloxone and naltrexone) in the prevention of OIP is limited as a result of the potential reversal of analgesic activity.7 A meta-analysis revealed one in four patients receiving prophylactic naloxone would not experience pruritus. This low response
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Table 1. Summary of Treatment Options and Their Strengths and Weaknesses Drug
Dosing
Naloxone
Mu-opioid-receptor • Potent antipruritic effects Continuous antagonist infusion: • Rapid onset: 2 to 5 minutes 0.25-1 mcg/kg/hr • Most reliable and cost- Synthetic derivative effective form of treatment Doses > 2 mcg/ of oxymorphone • May be used as a rescue kg/h may reverse treatment the analgesic • After a single dose of effects epidural morphine there was a 55% response to the initial dose of naloxone and 80% response after the second dose
• Short half-life of 1 hr does not produce lasting relief of pruritus • Not effective after intrathecal opioid administration • Identical response to propofol after epidural morphine. 55% reduction in both groups • May result in significant increase in pain because of reversal of analgesia
Naltrexone
9 mg orally
Mu-opioid-receptor • Potent antipruritic effects antagonist • Longer half-life of 4 to 5 hrs Epidural: initial • Twice the potency of dose of 0.167-0.3 Analogue of naloxone5 naloxone5 mcg/kg/hr
• Only found to be effective in preventing pruritus with 6 mg or 9 mg doses • Not available in doses < 50 mg in tablet form • May result in significant increase in pain. Doses greater than 9 mg significantly reduced pain control
Mechanism
Strengths
Continuous infusion: initial dose of 0.25-1 mcg/kg/hr Nalbuphine
IM: 1 to 5 mg Epidural: 3-4 mg
Mixed mu-opioidreceptor agonist/ antagonist
• Effectively prevents and treats opioid-induced pruritus without reduction in pain control • Superior to propofol and ondansetron • Superior to propofol (83% vs 61%) in intrathecal morphine-induced pruritus • Superior to ondansetron in intrathecal morphine- induced pruritus, but not in pediatric patients
Serotonin (5-HT3) receptor antagonist
• May be effective as • Efficacy is controversial prophylactic treatment • Intrathecal morphine-induced • Reduction in pruritus related pruritus (34% vs. 66% in to epidural morphine vs. placebo) placebo (70% vs. 30%) • Less effective after neuraxial lipid-soluble opioids injection • Only showed efficacy on perinasal itching
Continuous infusion: 2.5 mg ⁄ hr
Ondansetron
4-8 mg IV
Weaknesses
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• Causes increase in drowsiness
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Student Forum Table 1. Summary of Treatment Options and Their Strengths and Weaknesses (continued) Drug
Dosing
Mechanism
Strengths
Weaknesses
Dolasetron
12.5 mg IV
Serotonin (5-HT3) receptor antagonist
•May be considered as a treatment alternative
• Efficacy is controversial
Promethazine 50 mg IV
• Ineffective in the treatment of H1 antagonist with • Recommended for anticholinergic peripherally induced pruritus neuraxial opioid-induced pruritus activity
Droperidol
Dopamine (D2) receptor antagonist with weak anti-5HT3 activity
• Good alternative to opioid- • Optimal dosing is unknown and is less effective than receptor antagonists • Data suggest it is superior to mu-antagonists propofol and promethazine • Success after hip replacement
IV: 1.25-2.5 mg Epidural: 1.25-5 mg
Propofol
10-20 mg IV
Depression of nerve transmission, possibly by potentiating the GABA-A receptor
• Less effective compared with • May be effective as a nalbuphine prophylactic measure for intrathecal-associated pruritus • Success rate of 80% in relieving pruritus induced by epidural morphine for 3 to 6 hours when given as bolus injection, with the added advantage of reducing postoperative pain
Mirtazapine
30 mg
Selective inhibition of serotonin (5-HT2/5-HT3) receptor, H1 antagonist, activation of muopioid receptors
• Limited data • May reduce intrathecal- associated pruritus • Shown to decrease the onset, severity, and duration of pruritus • Acts both centrally and peripherally • Has a longer duration of action compared with serotonin inhibitors
Gabapentin
1,200 mg orally
Anticonvulsant, a structural analog of GABA
• May reduce intrathecal- associated pruritus • Preoperative 1,200 mg shown to decrease the onset, severity, and duration of pruritus
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• Limited data • Preoperative 600 mg did not significantly reduce intrathecal morphine-induced pruritus
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Table 1. Summary of Treatment Options and Their Strengths and Weaknesses (continued) Drug
Dosing
Mechanism
Strengths
Diclofenac
100 mg rectally
Cyclooxygenase inhibition
• Shown to reduce the severity • Limited data of morphine-induced pruritus postoperatively
Diphenhydramine
25 to 50 mg orally every 4 to 6 hrs
Hydroxyzine
25 to 100 mg orally at bedtime1
H1 antagonist with • Effective for methadone- and anticholinergic morphine-induced pruritus activity • Sedative effects may decrease the perception of pruritus
• Only control peripherally generated opioid-induced pruritus • Not recommended for neuraxial- induced pruritus • Increased risk of oversedation and increased respiratory depression
Cetirizine
10 mg orally once daily
H1 antagonist
• Limited data • Only control peripherally generated opioid-induced pruritus
Fexofenadine 60 mg orally twice per day Loratadine
Weaknesses
10 mg orally once daily1
Abbreviations: D2= Dopamine receptor 2, GABA = Gamma-aminobutyric acid, hr = Hour, H1 = Histamine receptor 1, IM = Intramuscular, IV = Intravenous, kg = Kilogram, mcg = Microgram, 5-HT2/5-HT3 = Serotonin or 5-hydroxytryptamine. Source: References 1-5, 7, 8.
is likely linked to high study doses of naloxone, which reversed the analgesic effects; therefore, doses should not exceed 2 mcg/kg/hr.8 The most effective study dose of naloxone is 0.25-1 mcg/kg/h continuous IV infusion. Continuous infusion is necessary because of the extremely short half-life of naloxone (one hour).4 Studies show naltrexone has a dose-dependent effect, with superior efficacy at 9 mg, but this must be balanced with the associated decrease in pain control. Nalbuphine is a mixed opioid receptor agonist/antagonist and is superior to propofol and ondansetron in reducing OIP. Nalbuphine may be preferred over pure opioid antagonists because it does not decrease pain control. Limitations, however, include lack of efficacy in pediatric patients and increased drowsiness.2,4
Droperidol, a dopamine D2 receptor antagonist with weak 5-HT3 inhibition, may be an alternative. It was found to be superior to propofol and promethazine in one study. Other dopamine antagonists, such as metoclopramide, however, have not been proven effective.4 The use of 5-HT3 receptor antagonists (ondansetron, dolasetron) produced conflicting data.2 A systematic review of 15 randomized controlled trials found prophylactic treatment with an IV bolus of 5-HT3 receptor antagonist significantly decreased the incidence and intensity of pruritus after neuraxial opioid administration, specifically with morphine.6 This was not always the case, however, in other investigations.2 Other potential treatments include NSAIDs, propofol, mirtazapine, and gabapentin. The mechanism of
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Student Forum antipruritic effects of NSAIDs is unknown, but may be linked to inhibition of cyclooxygenase and prostaglandin formation. Studies indicate that tenoxicam and diclofenac at a rectal dose of 100 mg reduce pruritus in patients receiving neuraxial opioids, but lornoxicam and celecoxib did not.4 Propofol decreases nerve transmission and possibly potentiates the GABA-A receptor, producing an antipruritic effect. Studies indicate it is most effective in prevention of pruritus, though inferior to nalbuphine.4 Mirtazapine is an antidepressant studied for the prevention of intrathecal morphine-induced pruritus. It selectively blocks 5-HT2 and 5-HT3 receptors, has strong antihistamine effects, reduces the perception of pruritus through the cerebral cortex, and is thought to activate kappa-opioid receptors.4 Compared with 5-HT3 receptor antagonists, it has a quicker onset, faster peak concentration (within two hours), and has a long elimination half-life (20-40 h). When used as a preventative, it delayed the onset, decreased the incidence and severity, and shortened the overall duration of pruritus.4 Gabapentin is an anticonvulsant, a structural analog of GABA, shown to be effective in many chronic pruritic conditions. It may exert its antipruritic effects through central reduction of itch perception, reduced excitability of spinal and supraspinal neurons, and spinal-supraspinal inhibition of serotonergic circuits. Unfortunately, the effectiveness of gabapentin as a prophylactic treatment option is inconclusive.
Conclusion Opioids are often implicated in causing pruritus. As a result of OIP, patients may discontinue their opioid medication, leading to a loss of beneficial effects, such as analgesia. A clear understanding regarding the mechanism of OIP would facilitate a more educated approach to prevention or treatment of OIP. Unfortunately, the mechanism by which
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OIP occurs is still limited. Several treatment options for OIP have been proposed, but none are reliably effective. Antihistamines remain the first-line treatment for peripherally mediated pruritus as seen with morphine and methadone, while opioid-receptor antagonists, such as naloxone, have the largest amount of evidence to support reversal of centrally mediated pruritus. Risk of analgesia reversal is the greatest concern associated with using opioid antagonists. Evaluation of the choice of opioid, dose, and route of administration should be a part of the strategy to prevent OIP. Treatment options to manage OIP should be evaluated against host factors such as organ function, comorbidities, patient preference, and medication-related factors such as cost, available dosage forms, pharmacokinetic and pharmacodynamic properties, and risk of analgesia reversal. More studies are required to better elucidate the mechanism and identification of more effective treatment options for OIP.
Jessica L. Benson PharmD, is a pharmacist at Walgreens, Nashville,Tennessee. At the time of this writing she was a pharmacy student, Belmont University College of Pharmacy, Nashville. Hope E. Campbell, PharmD, BCPS is assistant professor of pharmacy practice, Belmont University College of Pharmacy. At the time of this writing Cory N. Phillips, PharmD was a pharmacy student, Belmont University College of Pharmacy. For correspondence: Hope E. Campbell, PharmD, BCPS, Belmont University College of Pharmacy, 1900 Belmont Boulevard, #330 McWorther Hall, Nashville, TN 37212-3757; Phone: 615-364-0116; Fax: 615-460-6537; E-mail: [email protected]. Disclosure: No funding was received for the development of this manuscript. The authors have no potential conflicts of interest. © 2015 American Society of Consultant Pharmacists, Inc. All rights reserved. Doi:10.4140/TCP.n.2015.221.
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References 1. Swegle JM, Logemann C. Management of common opioid-induced adverse effects. Am Fam Physician 2006;74:1347-54. 2. Reich A, Szepietowski JC. Opioid-induced pruritus: an update. Clin Exp Derm 2009;35:2-6. 3. Ko MC, Song MS, Edwards T et al. The role of central mu opioid receptors in opioid-induced itch in primates. J Pharmacol Exp Ther 2004;310:169. 4. Kumar K, Singh SI. Neuraxial opioid-induced pruritus: an update. J Anaesthesiol Clin Pharmacol 2013;29:303-7. 5. Ganesh A, Maxwell LG. Pathophysiology and management of opioid-induced pruritus. Drugs 2007;67:2323-33.
6. Bonnet MP, Marret E, Josserand J et al. Effect of prophylactic 5-HT3 receptor antagonists on pruritus induced by neuraxial opioids: a quantitative systematic review. Br J Anaesth 2008;101:311-9. 7. Miller JL, Hagemann TM. Use of pure opioid antagonists for management of opioid-induced pruritus. Am J Health Syst Pharm 2011;68:1419-25. 8. Kjellberg F, Tramer MR. Pharmacological control of opioidinduced pruritus: a quantitative systematic review of randomized trials. Euro J Anaesthesiol 2001;1:346-57. 9. Kam P, Tan K. Pruritus: itching for a cause and relief? Anaesthesia 1996;51:1133-8.
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Introduction Opioid analgesics are useful agents for managing acute and chronic pain, but their use is often limited by adverse effects, including sedation, pruritus, nausea, respiratory depression, hypotension, and constipation.1 Opioidinduced pruritus (OIP) is one of the most common adverse effects, affecting 2% to 10% of patients on oral opioids and up to 100% of patients receiving neuraxial (epidural and intrathecal) opioids.1,2 It is an unpleasant side effect leading to patient discomfort, decreased quality of life, and discontinuation of medication. The occurrence of pruritus varies with the type of opioid, dose, and method of administration. Pharmacists are in a key position to make recommendations to limit the incidence and symptoms of OIP and ensure patient compliance with opioid therapy. The purpose of this article is to review the current understanding of the mechanisms, incidence, and the pharmacological therapies available to manage OIP.
Mechanism of Opioid-Induced Pruritus Key words: Adverse effect, Analgesic, Opioid, Pain,
Pruritus, Receptors. Abbreviations: D2 = Dopamine receptor 2, GABA = Gamma-aminobutyric acid, IV = Intravenous, mcg = Microgram, NSAID = Nonsteroidal anti-inflammatory drug, OIP = Opioid-induced pruritus, 5-HT2/5-HT3 = Serotonin or 5-hydroxytryptamine. Consult Pharm 2015;30:221-7.
The mechanism of OIP is still unclear, but appears to have both peripheral- and central-acting pathways.2 Peripherally induced pruritus is seen with opioid agonists (morphine, methadone) secondary to histamine release from mast cells, resulting in local itching and hives.2 Fentanyl and oxymorphone are less likely to produce histamine release, but they are still linked to pruritus, suggesting that another mechanism may be involved. Centrally mediated pruritus has been documented in several animal studies, linking the prevention of pruritus with the use of opioid-receptor antagonists.3 Decreased pruritus with opioid antagonists indicate that histamine release is not the sole cause for OIP and that activation of the central mu-opioid receptors is likely a contributing factor.3 Recent research involving neuraxial OIP suggests mu-opioid receptors are responsible for the centrally mediated response.2 Probable mechanisms of centrally mediated pruritus include direct binding to opioid receptors in the spinal cord and brain, changes in neurotransmission of these receptors, and interaction with serotonin or 5-hydroxytryptamine (5-HT3) receptors. The end result is activation of the medullary dorsal horn
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Student Forum within the trigeminal nerve and antagonism of inhibitory transmitters, such as gamma-aminobutyric acid (GABA).4 There is a high concentration of opioid receptors located within the trigeminal nerve and spinal cord, leading to itching of the face with neuraxial administration. In these cases, pretreatment with naloxone, a mu-receptor antagonist, is more effective in preventing pruritus compared with antihistamines. Serotonin, dopamine 2 (D2) receptors, prostaglandins, and spinal inhibitory pathways may also contribute to OIP, but lack credible evidence.5 Understanding these mechanisms will aid in the selection of appropriate agents.
Pruritus Incidence Among Different Opioids Opioids have subtle differences in binding to the mu, kappa, and sigma receptors; the clinical effects can vary from one agent to another.1 The prevalence of pruritus depends on the method of administration, the opioid used, and dosage. Approximately 2% to 10% of patients on chronic opioids will experience pruritus, and the risk significantly increases when opioids are given epidurally or intrathecally.2 Oral formulations have a lower incidence of pruritus compared with injectable formulations while extended-release formulations have a higher incidence because of prolonged activation of the opioid receptors.2,4 Pruritus related to transdermal patches, such as buprenorphine and fentanyl, ranges between 3% and 15% and is primarily a localized reaction. Injectable formulations such as morphine, buprenorphine, fentanyl, hydromorphone, methadone, meperidine, and oxymorphone have an incidence of 10% to 50% in patients receiving intravenous (IV) opioids and 20% to 100% of those receiving epidural or intrathecal opioids.4 The most susceptible groups are women in labor (60% to 100%) and patients who have received major orthopedic surgery (30% to 60%). The highest prevalence (up to 100%) is associated with intrathecal morphine.2 Intrathecal administration rapidly reaches peak concentration in the cerebrospinal fluid, resulting in the highest incidence of central-acting pruritus. Epidural injections have a delay in peak concentration, resulting in less-rapid development of pruritus. For
222
example, there is a 10- to 20-minute delay with fentanyl and a one-to-four hour delay with morphine.4 Lipid soluble opioids, like fentanyl, have a shorter duration of pruritus and respond to decreases in dosage.2 In most cases, higher doses of opioids correlate with a higher incidence of pruritus.
Management of OpioidInduced Pruritus Treatment of opioid-induced pruritus, especially neuraxial pruritus, remains a challenge. Prevention may be the key by using the lowest effective doses of opioids and using prophylactic therapy. Strategies to minimize OIP include opioid rotation, dose reduction, changing the route of administration, and symptomatic management.1 Dose reductions or changing to an opioid with less histaminereleasing properties (hydromorphone, oxymorphone, and fentanyl) can occasionally provide relief, but does not reliably relieve pruritus.1 Nondrug treatments, such as cool compresses or moisturizers, may be beneficial for certain patients.1 Table 1 lists various pharmacologic treatments with differing mechanisms that have been studied for the prevention and treatment of OIP. These medications include pure opioid-receptor antagonists, mixed opioidreceptor agonist/antagonists, serotonin 5-HT3 antagonists, dopamine D2-receptor antagonists, antihistamines, and nonsteroidal anti-inflammatory drugs (NSAIDs), among others.7 Antihistamines are often used as first-line treatment, even though the role of histamine in OIP is controversial.2 Antihistamines have little or no effect on centrally induced pruritus, but are effective for the peripherally induced pruritus of morphine and methadone. First-generation antihistamines (diphenhydramine, hydroxyzine) may decrease the sensation of pruritus through sedation.4 Recent evidence indicates the dominant pathway is mureceptor-mediated rather than histamine-mediated. The use of opioid antagonists (naloxone and naltrexone) in the prevention of OIP is limited as a result of the potential reversal of analgesic activity.7 A meta-analysis revealed one in four patients receiving prophylactic naloxone would not experience pruritus. This low response
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Opioid-Induced Pruritus
Table 1. Summary of Treatment Options and Their Strengths and Weaknesses Drug
Dosing
Naloxone
Mu-opioid-receptor • Potent antipruritic effects Continuous antagonist infusion: • Rapid onset: 2 to 5 minutes 0.25-1 mcg/kg/hr • Most reliable and cost- Synthetic derivative effective form of treatment Doses > 2 mcg/ of oxymorphone • May be used as a rescue kg/h may reverse treatment the analgesic • After a single dose of effects epidural morphine there was a 55% response to the initial dose of naloxone and 80% response after the second dose
• Short half-life of 1 hr does not produce lasting relief of pruritus • Not effective after intrathecal opioid administration • Identical response to propofol after epidural morphine. 55% reduction in both groups • May result in significant increase in pain because of reversal of analgesia
Naltrexone
9 mg orally
Mu-opioid-receptor • Potent antipruritic effects antagonist • Longer half-life of 4 to 5 hrs Epidural: initial • Twice the potency of dose of 0.167-0.3 Analogue of naloxone5 naloxone5 mcg/kg/hr
• Only found to be effective in preventing pruritus with 6 mg or 9 mg doses • Not available in doses < 50 mg in tablet form • May result in significant increase in pain. Doses greater than 9 mg significantly reduced pain control
Mechanism
Strengths
Continuous infusion: initial dose of 0.25-1 mcg/kg/hr Nalbuphine
IM: 1 to 5 mg Epidural: 3-4 mg
Mixed mu-opioidreceptor agonist/ antagonist
• Effectively prevents and treats opioid-induced pruritus without reduction in pain control • Superior to propofol and ondansetron • Superior to propofol (83% vs 61%) in intrathecal morphine-induced pruritus • Superior to ondansetron in intrathecal morphine- induced pruritus, but not in pediatric patients
Serotonin (5-HT3) receptor antagonist
• May be effective as • Efficacy is controversial prophylactic treatment • Intrathecal morphine-induced • Reduction in pruritus related pruritus (34% vs. 66% in to epidural morphine vs. placebo) placebo (70% vs. 30%) • Less effective after neuraxial lipid-soluble opioids injection • Only showed efficacy on perinasal itching
Continuous infusion: 2.5 mg ⁄ hr
Ondansetron
4-8 mg IV
Weaknesses
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• Causes increase in drowsiness
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Student Forum Table 1. Summary of Treatment Options and Their Strengths and Weaknesses (continued) Drug
Dosing
Mechanism
Strengths
Weaknesses
Dolasetron
12.5 mg IV
Serotonin (5-HT3) receptor antagonist
•May be considered as a treatment alternative
• Efficacy is controversial
Promethazine 50 mg IV
• Ineffective in the treatment of H1 antagonist with • Recommended for anticholinergic peripherally induced pruritus neuraxial opioid-induced pruritus activity
Droperidol
Dopamine (D2) receptor antagonist with weak anti-5HT3 activity
• Good alternative to opioid- • Optimal dosing is unknown and is less effective than receptor antagonists • Data suggest it is superior to mu-antagonists propofol and promethazine • Success after hip replacement
IV: 1.25-2.5 mg Epidural: 1.25-5 mg
Propofol
10-20 mg IV
Depression of nerve transmission, possibly by potentiating the GABA-A receptor
• Less effective compared with • May be effective as a nalbuphine prophylactic measure for intrathecal-associated pruritus • Success rate of 80% in relieving pruritus induced by epidural morphine for 3 to 6 hours when given as bolus injection, with the added advantage of reducing postoperative pain
Mirtazapine
30 mg
Selective inhibition of serotonin (5-HT2/5-HT3) receptor, H1 antagonist, activation of muopioid receptors
• Limited data • May reduce intrathecal- associated pruritus • Shown to decrease the onset, severity, and duration of pruritus • Acts both centrally and peripherally • Has a longer duration of action compared with serotonin inhibitors
Gabapentin
1,200 mg orally
Anticonvulsant, a structural analog of GABA
• May reduce intrathecal- associated pruritus • Preoperative 1,200 mg shown to decrease the onset, severity, and duration of pruritus
224
• Limited data • Preoperative 600 mg did not significantly reduce intrathecal morphine-induced pruritus
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Opioid-Induced Pruritus
Table 1. Summary of Treatment Options and Their Strengths and Weaknesses (continued) Drug
Dosing
Mechanism
Strengths
Diclofenac
100 mg rectally
Cyclooxygenase inhibition
• Shown to reduce the severity • Limited data of morphine-induced pruritus postoperatively
Diphenhydramine
25 to 50 mg orally every 4 to 6 hrs
Hydroxyzine
25 to 100 mg orally at bedtime1
H1 antagonist with • Effective for methadone- and anticholinergic morphine-induced pruritus activity • Sedative effects may decrease the perception of pruritus
• Only control peripherally generated opioid-induced pruritus • Not recommended for neuraxial- induced pruritus • Increased risk of oversedation and increased respiratory depression
Cetirizine
10 mg orally once daily
H1 antagonist
• Limited data • Only control peripherally generated opioid-induced pruritus
Fexofenadine 60 mg orally twice per day Loratadine
Weaknesses
10 mg orally once daily1
Abbreviations: D2= Dopamine receptor 2, GABA = Gamma-aminobutyric acid, hr = Hour, H1 = Histamine receptor 1, IM = Intramuscular, IV = Intravenous, kg = Kilogram, mcg = Microgram, 5-HT2/5-HT3 = Serotonin or 5-hydroxytryptamine. Source: References 1-5, 7, 8.
is likely linked to high study doses of naloxone, which reversed the analgesic effects; therefore, doses should not exceed 2 mcg/kg/hr.8 The most effective study dose of naloxone is 0.25-1 mcg/kg/h continuous IV infusion. Continuous infusion is necessary because of the extremely short half-life of naloxone (one hour).4 Studies show naltrexone has a dose-dependent effect, with superior efficacy at 9 mg, but this must be balanced with the associated decrease in pain control. Nalbuphine is a mixed opioid receptor agonist/antagonist and is superior to propofol and ondansetron in reducing OIP. Nalbuphine may be preferred over pure opioid antagonists because it does not decrease pain control. Limitations, however, include lack of efficacy in pediatric patients and increased drowsiness.2,4
Droperidol, a dopamine D2 receptor antagonist with weak 5-HT3 inhibition, may be an alternative. It was found to be superior to propofol and promethazine in one study. Other dopamine antagonists, such as metoclopramide, however, have not been proven effective.4 The use of 5-HT3 receptor antagonists (ondansetron, dolasetron) produced conflicting data.2 A systematic review of 15 randomized controlled trials found prophylactic treatment with an IV bolus of 5-HT3 receptor antagonist significantly decreased the incidence and intensity of pruritus after neuraxial opioid administration, specifically with morphine.6 This was not always the case, however, in other investigations.2 Other potential treatments include NSAIDs, propofol, mirtazapine, and gabapentin. The mechanism of
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Student Forum antipruritic effects of NSAIDs is unknown, but may be linked to inhibition of cyclooxygenase and prostaglandin formation. Studies indicate that tenoxicam and diclofenac at a rectal dose of 100 mg reduce pruritus in patients receiving neuraxial opioids, but lornoxicam and celecoxib did not.4 Propofol decreases nerve transmission and possibly potentiates the GABA-A receptor, producing an antipruritic effect. Studies indicate it is most effective in prevention of pruritus, though inferior to nalbuphine.4 Mirtazapine is an antidepressant studied for the prevention of intrathecal morphine-induced pruritus. It selectively blocks 5-HT2 and 5-HT3 receptors, has strong antihistamine effects, reduces the perception of pruritus through the cerebral cortex, and is thought to activate kappa-opioid receptors.4 Compared with 5-HT3 receptor antagonists, it has a quicker onset, faster peak concentration (within two hours), and has a long elimination half-life (20-40 h). When used as a preventative, it delayed the onset, decreased the incidence and severity, and shortened the overall duration of pruritus.4 Gabapentin is an anticonvulsant, a structural analog of GABA, shown to be effective in many chronic pruritic conditions. It may exert its antipruritic effects through central reduction of itch perception, reduced excitability of spinal and supraspinal neurons, and spinal-supraspinal inhibition of serotonergic circuits. Unfortunately, the effectiveness of gabapentin as a prophylactic treatment option is inconclusive.
Conclusion Opioids are often implicated in causing pruritus. As a result of OIP, patients may discontinue their opioid medication, leading to a loss of beneficial effects, such as analgesia. A clear understanding regarding the mechanism of OIP would facilitate a more educated approach to prevention or treatment of OIP. Unfortunately, the mechanism by which
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OIP occurs is still limited. Several treatment options for OIP have been proposed, but none are reliably effective. Antihistamines remain the first-line treatment for peripherally mediated pruritus as seen with morphine and methadone, while opioid-receptor antagonists, such as naloxone, have the largest amount of evidence to support reversal of centrally mediated pruritus. Risk of analgesia reversal is the greatest concern associated with using opioid antagonists. Evaluation of the choice of opioid, dose, and route of administration should be a part of the strategy to prevent OIP. Treatment options to manage OIP should be evaluated against host factors such as organ function, comorbidities, patient preference, and medication-related factors such as cost, available dosage forms, pharmacokinetic and pharmacodynamic properties, and risk of analgesia reversal. More studies are required to better elucidate the mechanism and identification of more effective treatment options for OIP.
Jessica L. Benson PharmD, is a pharmacist at Walgreens, Nashville,Tennessee. At the time of this writing she was a pharmacy student, Belmont University College of Pharmacy, Nashville. Hope E. Campbell, PharmD, BCPS is assistant professor of pharmacy practice, Belmont University College of Pharmacy. At the time of this writing Cory N. Phillips, PharmD was a pharmacy student, Belmont University College of Pharmacy. For correspondence: Hope E. Campbell, PharmD, BCPS, Belmont University College of Pharmacy, 1900 Belmont Boulevard, #330 McWorther Hall, Nashville, TN 37212-3757; Phone: 615-364-0116; Fax: 615-460-6537; E-mail: [email protected]. Disclosure: No funding was received for the development of this manuscript. The authors have no potential conflicts of interest. © 2015 American Society of Consultant Pharmacists, Inc. All rights reserved. Doi:10.4140/TCP.n.2015.221.
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References 1. Swegle JM, Logemann C. Management of common opioid-induced adverse effects. Am Fam Physician 2006;74:1347-54. 2. Reich A, Szepietowski JC. Opioid-induced pruritus: an update. Clin Exp Derm 2009;35:2-6. 3. Ko MC, Song MS, Edwards T et al. The role of central mu opioid receptors in opioid-induced itch in primates. J Pharmacol Exp Ther 2004;310:169. 4. Kumar K, Singh SI. Neuraxial opioid-induced pruritus: an update. J Anaesthesiol Clin Pharmacol 2013;29:303-7. 5. Ganesh A, Maxwell LG. Pathophysiology and management of opioid-induced pruritus. Drugs 2007;67:2323-33.
6. Bonnet MP, Marret E, Josserand J et al. Effect of prophylactic 5-HT3 receptor antagonists on pruritus induced by neuraxial opioids: a quantitative systematic review. Br J Anaesth 2008;101:311-9. 7. Miller JL, Hagemann TM. Use of pure opioid antagonists for management of opioid-induced pruritus. Am J Health Syst Pharm 2011;68:1419-25. 8. Kjellberg F, Tramer MR. Pharmacological control of opioidinduced pruritus: a quantitative systematic review of randomized trials. Euro J Anaesthesiol 2001;1:346-57. 9. Kam P, Tan K. Pruritus: itching for a cause and relief? Anaesthesia 1996;51:1133-8.
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