Methylnaltrexone for Acute Opioid-induced Constipation
Methylnaltrexone for Acute Opioid-induced Constipation
Background: Methylnaltrexone has been shown to be effective for treating opioid-induced constipation (OIC) in chronic settings, but its effects on acute OIC have not been studied.
Objective: To assess safety and efficacy of subcutaneous methylnaltrexone in patients with acute OIC after orthopedic procedures.
Design: Double-blind, randomized, parallel-group, placebo-controlled, hypothesis-generating phase 2 study.
SETTING: Sixteen US hospitals and rehabilitation facilities.
Patients: Adult patients with acute OIC after orthopedic surgical procedure, expected to require opioids for at least 7 days postrandomization.
Interventions: Patients received once-daily subcutaneous methylnaltrexone 12 mg or placebo for up to 4 or 7 days.
Measurements: All endpoints were exploratory and included the percentage of patients achieving laxation within 2 and 4 hours of first dose and time to laxation.
Results: Thirty-three patients received at least 1 dose of study drug (methylnaltrexone, n = 18; placebo, n = 15). Within 2 and 4 hours, significantly more patients receiving methylnaltrexone achieved laxation (2 hours: 33.3% vs 0%, P = 0.021; 4 hours: 38.9% vs 6.7%, P = 0.046) compared with placebo. Time to laxation was significantly shorter with methylnaltrexone (median = 15.8 hours) versus placebo (median = 50.9 hours), P = 0.0197. The most common adverse events related to the gastrointestinal tract. Pain scores remained stable and were similar to those of placebo, and signs and symptoms of opioid withdrawal did not emerge in patients receiving methylnaltrexone.
Conclusions: Methylnaltrexone was generally well tolerated and was active in inducing laxation in this study of patients experiencing acute OIC following orthopedic surgery. Journal of Hospital Medicine 2012. © 2011 Society of Hospital Medicine.
The management of postoperative pain is essential to perioperative care, and adequate postoperative analgesia has been associated with several key clinical benefits, including fewer postoperative complications, earlier patient ambulation, reduced costs due to shorter hospital stays, and improved rehabilitation. While opioids have long been central to postoperative analgesia, they have been associated with various adverse effects, including sedation, dizziness, nausea, vomiting, constipation, dependence, tolerance, and respiratory depression. Constipation, one of the most common adverse effects resulting from opioid therapy, can be debilitating. Indeed, opioid effects on gut motility can occur even after a single dose. The consequences of opioid-induced constipation (OIC) may be severe enough to warrant a dosage reduction of the opioid; however, this may lead to compromised analgesia, which can hinder recovery. Thus, effective treatment of OIC is an important clinical consideration in patients undergoing pain management with opioids. Unfortunately, laxatives and other treatment strategies can have unpredictable or suboptimal results for many patients with OIC; therefore, other options are needed for the treatment of OIC.
Opioid receptor agonists cause constipation by adversely altering many aspects of intestinal function, including fluid dynamics, gastric emptying, propulsive motor activity, and transit time. Opioid receptors are widely distributed in the central nervous system and throughout the intestinal system. The mechanism of OIC may have both peripherally and centrally mediated components. Nonselective opioid receptor antagonists block the undesired effects on the gut, but because they cross the blood-brain barrier, they also interfere with analgesia and may lead to symptoms of withdrawal. Methylnaltrexone is a selective, peripherally acting mu-opioid receptor antagonist, formed by the addition of a methyl group to the amine ring of the mu-opioid receptor antagonist naltrexone. The resulting quarternary amine has greater polarity, lower lipid solubility, and restricted ability to cross the blood-brain barrier. Thus, methylnaltrexone was designed to decrease the peripheral adverse effects of opioids without interfering with centrally mediated analgesia.
Investigations of methylnaltrexone effects in healthy volunteers showed that methylnaltrexone attenuated morphine-induced delays in gastric emptying and oral-cecal transit without affecting analgesia. Further studies of methylnaltrexone for the treatment of constipation due to methadone use demonstrated rapid laxation response. Two randomized, double-blind, placebo-controlled studies of methylnaltrexone in 288 patients with advanced illness and OIC showed that methylnaltrexone rapidly induced laxation without compromising analgesia. Methylnaltrexone is currently approved for the treatment of OIC in patients with advanced illness who are receiving palliative care, when response to laxative therapy has not been sufficient.
Recently, the use of methylnaltrexone for the treatment of OIC in patients with chronic, nonmalignant pain was assessed in a randomized, double-blind, placebo-controlled trial of more than 400 patients. Investigators found that methylnaltrexone induced laxation and was generally well tolerated (Blonsky et al., 28th Annual Scientific Meeting of the American Pain Society, May 7–9, 2009, San Diego, CA; Duerden et al., 29th Annual Scientific Meeting of the American Pain Society, May 6–10, 2010, Baltimore, MD), supporting the safety and efficacy of methylnaltrexone in the setting of OIC resulting from chronic opioid treatment. The present study aimed to assess the activity of methylnaltrexone in patients receiving mu-agonist opioid analgesics during rehabilitation, following an orthopedic surgical procedure, who were experiencing acute OIC.
Abstract and Introduction
Abstract
Background: Methylnaltrexone has been shown to be effective for treating opioid-induced constipation (OIC) in chronic settings, but its effects on acute OIC have not been studied.
Objective: To assess safety and efficacy of subcutaneous methylnaltrexone in patients with acute OIC after orthopedic procedures.
Design: Double-blind, randomized, parallel-group, placebo-controlled, hypothesis-generating phase 2 study.
SETTING: Sixteen US hospitals and rehabilitation facilities.
Patients: Adult patients with acute OIC after orthopedic surgical procedure, expected to require opioids for at least 7 days postrandomization.
Interventions: Patients received once-daily subcutaneous methylnaltrexone 12 mg or placebo for up to 4 or 7 days.
Measurements: All endpoints were exploratory and included the percentage of patients achieving laxation within 2 and 4 hours of first dose and time to laxation.
Results: Thirty-three patients received at least 1 dose of study drug (methylnaltrexone, n = 18; placebo, n = 15). Within 2 and 4 hours, significantly more patients receiving methylnaltrexone achieved laxation (2 hours: 33.3% vs 0%, P = 0.021; 4 hours: 38.9% vs 6.7%, P = 0.046) compared with placebo. Time to laxation was significantly shorter with methylnaltrexone (median = 15.8 hours) versus placebo (median = 50.9 hours), P = 0.0197. The most common adverse events related to the gastrointestinal tract. Pain scores remained stable and were similar to those of placebo, and signs and symptoms of opioid withdrawal did not emerge in patients receiving methylnaltrexone.
Conclusions: Methylnaltrexone was generally well tolerated and was active in inducing laxation in this study of patients experiencing acute OIC following orthopedic surgery. Journal of Hospital Medicine 2012. © 2011 Society of Hospital Medicine.
Introduction
The management of postoperative pain is essential to perioperative care, and adequate postoperative analgesia has been associated with several key clinical benefits, including fewer postoperative complications, earlier patient ambulation, reduced costs due to shorter hospital stays, and improved rehabilitation. While opioids have long been central to postoperative analgesia, they have been associated with various adverse effects, including sedation, dizziness, nausea, vomiting, constipation, dependence, tolerance, and respiratory depression. Constipation, one of the most common adverse effects resulting from opioid therapy, can be debilitating. Indeed, opioid effects on gut motility can occur even after a single dose. The consequences of opioid-induced constipation (OIC) may be severe enough to warrant a dosage reduction of the opioid; however, this may lead to compromised analgesia, which can hinder recovery. Thus, effective treatment of OIC is an important clinical consideration in patients undergoing pain management with opioids. Unfortunately, laxatives and other treatment strategies can have unpredictable or suboptimal results for many patients with OIC; therefore, other options are needed for the treatment of OIC.
Opioid receptor agonists cause constipation by adversely altering many aspects of intestinal function, including fluid dynamics, gastric emptying, propulsive motor activity, and transit time. Opioid receptors are widely distributed in the central nervous system and throughout the intestinal system. The mechanism of OIC may have both peripherally and centrally mediated components. Nonselective opioid receptor antagonists block the undesired effects on the gut, but because they cross the blood-brain barrier, they also interfere with analgesia and may lead to symptoms of withdrawal. Methylnaltrexone is a selective, peripherally acting mu-opioid receptor antagonist, formed by the addition of a methyl group to the amine ring of the mu-opioid receptor antagonist naltrexone. The resulting quarternary amine has greater polarity, lower lipid solubility, and restricted ability to cross the blood-brain barrier. Thus, methylnaltrexone was designed to decrease the peripheral adverse effects of opioids without interfering with centrally mediated analgesia.
Investigations of methylnaltrexone effects in healthy volunteers showed that methylnaltrexone attenuated morphine-induced delays in gastric emptying and oral-cecal transit without affecting analgesia. Further studies of methylnaltrexone for the treatment of constipation due to methadone use demonstrated rapid laxation response. Two randomized, double-blind, placebo-controlled studies of methylnaltrexone in 288 patients with advanced illness and OIC showed that methylnaltrexone rapidly induced laxation without compromising analgesia. Methylnaltrexone is currently approved for the treatment of OIC in patients with advanced illness who are receiving palliative care, when response to laxative therapy has not been sufficient.
Recently, the use of methylnaltrexone for the treatment of OIC in patients with chronic, nonmalignant pain was assessed in a randomized, double-blind, placebo-controlled trial of more than 400 patients. Investigators found that methylnaltrexone induced laxation and was generally well tolerated (Blonsky et al., 28th Annual Scientific Meeting of the American Pain Society, May 7–9, 2009, San Diego, CA; Duerden et al., 29th Annual Scientific Meeting of the American Pain Society, May 6–10, 2010, Baltimore, MD), supporting the safety and efficacy of methylnaltrexone in the setting of OIC resulting from chronic opioid treatment. The present study aimed to assess the activity of methylnaltrexone in patients receiving mu-agonist opioid analgesics during rehabilitation, following an orthopedic surgical procedure, who were experiencing acute OIC.
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