Methylnaltrexone Is Effective in the Treatment of Opioid‐Induced Constipation in Patients with Advanced Illness and Postoperative Ileus without Affecting Analgesia

Background:

Methylnaltrexone, a quaternary derivative of naltrexone, is being developed for the treatment of opioid‐induced constipation in patients with advanced illness and postoperative ileus. GI transit, slowed by morphine, is reversed by intravenous, subcutaneous, or oral methylnaltrexone. In previous studies involving opioid users on chronic methadone maintenance treated with intravenous or oral methylnaltrexone laxated within minutes or hours of injection, respectively, without any incidences of withdrawal.

Methods:

Safety and efficacy of methylnaltrexone in patients with advanced illness and opioid‐induced constipation were examined in 2 randomized, placebo‐controlled phase 3 trials. In study 301, 154 patients received a single dose of subcutaneous methylnaltrexone (0.15 or 0.3 mg/kg) or placebo. In study 302, 134 patients received either subcutaneous methylnaltrexone 0.15 mg or placebo QOD for 2 weeks. Utility of methylnaltrexone in the treatment of postoperative ileus was studied in a double‐blind, randomized, placebo‐controlled phase 2 trial in which 65 patients undergoing segmental colectomies via laparotomy received within 90 minutes postsurgery, either intravenous methylnaltrexone 0.3 mg/kg every 6 hours or placebo, until 24 hours after GI recovery, discharge from the hospital, or for a maximum of 7 days. A signed and dated IRB‐approved informed consent form was obtained for all patients, and the institutional review board of each center approved the study.

Results:

The 2 phase 3 trials showed that subcutaneous methylnaltrexone at a single dose or QOD resulted in laxation within 4 hours of the first injection in 61.7% and 48.4% of methylnaltrexone‐treated patients, respectively, versus 13.5% and 15.5% of placebo patients with advanced illness and opioid‐induced constipation (P < .0001). Most of the responders laxated within 1 hour. There were no significant side effects, evidence of withdrawal, or clinically meaningful changes in analgesia. The phase 2 trial with intravenous methylnaltrexone showed significant decreases in the time to first laxation, by 20 hours (P = .038), and in eligibility for hospital discharge, by 33 hours (P = .049) compared with placebo.

Conclusions:

Our studies showed that subcutaneous and intravenous methylnaltrexone rapidly induced laxation in advanced‐illness patients with opioid‐induced constipation and accelerated bowel recovery in postsurgical patients, respectively. Combined with its favorable side effect profile, methylnaltrexone appears to have an important role in the management of opioid‐induced bowel dysfunction.

Author Disclosure:

J. Thomas, Progenics Pharmaceuticals, Inc., consulting fees or other remuneration (payment); R. K. Portenoy, Progenics Pharmaceuticals, Inc., consulting fees or other remuneration (payment); S. Karver, Progenics Pharmaceuticals, Inc., consulting fees or other remuneration (payment); R. Israel, Progenics Pharmaceuticals, Inc., employment (full or part‐time).