Subcutaneous methylnaltrexone for the treatment of opioid-induced constipation in patients with chronic non-malignant pain

Abstract

Long-term use of opioid analgesics for the treatment of chronic pain may be complicated by dose-limiting side effects, most commonly opioid-induced constipation (OIC). Methylnaltrexone, a selective peripherally acting μ-opioid receptor antagonist, decreases the peripheral side effects of opioids without affecting centrally mediated analgesia. The purpose of this double-blind, randomized, placebo-controlled phase 3 study was to determine if subcutaneous methylnaltrexone alleviates OIC in patients with chronic non-malignant pain. This study included 469 patients on stable doses of opioids with <3 rescue-free bowel movements (RFBMs)/week. Patients were randomized to one of two different regimens of methylnaltrexone bromide or placebo for 4 weeks. Use of routine laxatives was not permitted; however, “rescue” laxative use was standardized and allowed if needed. Co-primary endpoints were rescue-free laxation response within 4 hours of first dose and rescue-free laxation response within 4 hours after all active doses. Methylnaltrexone demonstrated a 34.2% response rate within 4 hours compared with 9.9% for placebo (p<0.001). Methylnaltrexone also maintained a consistent response rate of 28.9% and 30.2% for the first and second dose regimens, respectively, within 4 hours of dose compared with 9.4% and 9.3% for placebo (p<0.001) for the 4-week period. Time to first bowel movement was significantly shorter for patients receiving active treatment than placebo (p<0.001), with 46% in the methylnaltrexone group having an RFBM within 24 hours vs 25.3% placebo. Methylnaltrexone patients showed improvements in straining, stool consistency, and completeness of evacuation compared with placebo. Methylnaltrexone treatment groups also had significantly less need for rescue laxative use (p<0.001 vs placebo). The most common AEs with frequency notably different from placebo were abdominal pain, dizziness, vomiting, nausea and diarrhea. The results of this study will help determine the safety and efficacy of subcutaneous methylnaltrexone in providing rapid and reliable laxation in patients with chronic non-malignant pain and OIC. (Supported by a grant from Wyeth Research, Collegeville, PA.)