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

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.