Oral methylnaltrexone is efficacious and well tolerated for the treatment of opioid-induced constipation in patients with chronic noncancer pain receiving concomitant methadone

摘要

Purpose: To evaluate the safety and efficacy of oral methylnaltrexone for opioid-induced constipation (OIC). Patients and methods: This was a post hoc analysis of patients receiving methadone in a randomized, double-blind, placebo-controlled, Phase 3 trial. The trial included adults with chronic noncancer pain for ≥2 months receiving opioid doses ≥50 mg/day of oral morphine equivalents for ≥14 days and with a history of OIC. Patients were assigned to oral methylnaltrexone (150, 300, or 450 mg) or placebo once daily (QD) for 4 weeks followed by 8 weeks as needed. Percentage of dosing days that resulted in a rescue-free bowel movement (RFBM) within 4 hours of dosing was assessed during QD dosing (primary efficacy endpoint). Other endpoints included percentage of responders (ie, ≥3 RFBMs/week, with an increase of ≥1 RFBM/week from baseline for ≥3 of the 4 weeks) during QD dosing and change in weekly number of RFBMs. Adverse events were assessed. Results: Concomitant methadone was reported in 120 patients (oral methylnaltrexone: 150 mg [n=33], 300 mg [n=30], and 450 mg [n=31]; placebo [n=26]). Oral methylnaltrexone-treated patients had significant increases in mean percentage of dosing days with RFBMs within 4 hours of dosing during weeks 1–4 with 300 mg (33.6%; P 0.01) and 450 mg (38.2%; P 0.001) vs placebo; improvements with 150 mg (20.0%) vs placebo (15.1%) did not reach statistical significance. The percentage of responders was greater vs placebo, but not significant, for the higher doses during the QD period (150 mg [39.4%], 300 mg [60.0%], 450 mg [67.7%], and placebo [38.5%]). Change from baseline in the mean number of weekly RFBMs (weeks 1–4) was significantly greater with oral methylnaltrexone 450 mg vs placebo (least-squares mean difference vs placebo, 1.2; P =0.04); no significant differences were found for 300 or 150 mg. Oral methylnaltrexone was well tolerated at all doses; few patients discontinued treatment. Conclusion: Oral methylnaltrexone, particularly 450 mg, was efficacious and safe for treating OIC in these patients.