Randomized, Double-Blind Trial of Oral Methylnaltrexone for the Treatment of Opioid-Induced Constipation in Patients with Chronic Noncancer Pain

Pain Pract. 2017 Jul;17(6):820-828. doi: 10.1111/papr.12535. Epub 2017 Feb 10.

Abstract

Background: Subcutaneous methylnaltrexone, a peripherally acting μ-opioid receptor antagonist, improves opioid-induced constipation (OIC) in patients with chronic noncancer pain. An oral methylnaltrexone formulation has been developed.

Methods: In this phase 3, double-blind trial, adults with chronic noncancer pain receiving opioid doses of ≥ 50 mg/day oral morphine equivalents with OIC were randomly assigned to oral methylnaltrexone (150, 300, or 450 mg) or placebo once daily (QD) for 4 weeks followed by as-needed dosing for 8 weeks. Patients who had ≥ 3 rescue-free bowel movements (RFBMs)/week, with an increase of ≥ 1 RFBM/week from baseline for ≥ 3 of 4 weeks during the QD period, were responders.

Results: Overall, 803 patients were included in the analyses. A significantly greater percentage of patients had an increase in mean percentage of dosing days resulting in an RFBM within 4 hours of dosing during weeks 1 through 4 (QD period; primary endpoint) with methylnaltrexone (300 mg/day [24.6%; P = 0.002] and 450 mg/day [27.4%; P < 0.0001]) vs. placebo (18.2%). The percentage of responders (49.3% for 300 mg [P = 0.03] and 51.5% for 450 mg [P = 0.005] vs. 38.3% with placebo) and change from baseline in mean number of weekly RFBMs (difference vs. placebo, 0.5 for 300 mg [P = 0.03] and 0.5 for 450 mg [P = 0.02]) was significantly greater with methylnaltrexone 300 and 450 mg/day vs. placebo during the QD period. All dosages of oral methylnaltrexone were well tolerated.

Conclusions: Oral methylnaltrexone was efficacious and well tolerated for OIC in patients with chronic noncancer pain, particularly the 450-mg dose.

Keywords: Relistor; methylnaltrexone; noncancer pain; opioid-induced constipation; oral; μ-opioid receptor antagonist.

Publication types

  • Clinical Trial, Phase III
  • Multicenter Study
  • Randomized Controlled Trial

MeSH terms

  • Administration, Oral
  • Adult
  • Aged
  • Analgesics, Opioid / adverse effects*
  • Analgesics, Opioid / therapeutic use
  • Chronic Pain / drug therapy*
  • Chronic Pain / epidemiology
  • Constipation / chemically induced*
  • Constipation / drug therapy*
  • Constipation / epidemiology
  • Double-Blind Method
  • Female
  • Humans
  • Injections, Subcutaneous
  • Male
  • Middle Aged
  • Naltrexone / administration & dosage
  • Naltrexone / analogs & derivatives*
  • Narcotic Antagonists / administration & dosage*
  • Quaternary Ammonium Compounds / administration & dosage
  • Receptors, Opioid, mu / antagonists & inhibitors
  • Treatment Outcome

Substances

  • Analgesics, Opioid
  • Narcotic Antagonists
  • Quaternary Ammonium Compounds
  • Receptors, Opioid, mu
  • methylnaltrexone
  • Naltrexone