Phase III Trial Demonstrates Efficacy of Methylnaltrexone for Use in Advanced-Illness Patients With Opioid-Induced Constipation

Wyeth Pharmaceuticals, a division of Wyeth, and Progenics Pharmaceuticals, Inc. recently announced the publication of results from a pivotal phase III trial of methylnaltrexone bromide (Relistor) subcutaneous injection in the New England Journal of Medicine. Methylnaltrexone is a newly approved therapy for the treatment of opioid-induced constipation (OIC) in patients with advanced illness who are receiving palliative care, when response to laxative therapy has not been sufficient.

The clinical study showed that significantly more OIC patients with advanced illness experienced bowel movements (laxation) within 4 hours of receiving their first dose of subcutaneous methylnaltrexone than patients receiving placebo, without the use of a rescue laxative (48% vs 15%; P < .001). The study also demonstrated that methylnaltrexone did not impair the ability of opioids to provide pain relief, and the drug was generally well tolerated.

Novel Mechanism
"Effectively managing pain is critical for patients with advanced illness," says Jay Thomas, md, phd, a lead author of the study and Clinical Medical Director of The San Diego Hospice and the Institute for Palliative Medicine. "However, the side effects associated with many pain medications can represent a significant barrier to providing good pain management for those patients. The data published in NEJM are particularly exciting because not only do they demonstrate that Relistor has the potential to relieve OIC effectively, but that it does so without interfering with much-needed pain relief."

Methylnaltrexone, administered via subcutaneous injection, is a peripherally acting muopioid receptor antagonist that counteracts the constipating effects of opioid pain medications in the gastrointestinal tract without impacting opioid-mediated analgesic effects on the central nervous system.

Study Design and Results
The double-blind, randomized, placebo-controlled phase III trial examined the efficacy and safety of subcutaneous methylnaltrexone in relieving OIC in patients with an advanced illness. Coprimary endpoints were the proportion of patients with a rescue-free bowel movement within 4 hours of the first dose, and the proportion of patients with rescue-free bowel movements occurring within 4 hours of at least two of the first four doses, both compared to placebo. Patients who completed the 2-week, placebo-controlled trial were eligible to enter a subsequent 3-month, open-label extension study. Patients in the extension study received methylnaltrexone as needed, not more frequently than once daily, for up to 3 months.

In the double-blind phase of the study, 48% of patients experienced a bowel movement within 4 hours of receiving the first dose of methylnaltrexone (0.15 mg/kg), more than three times the rate seen in patients treated with placebo (15%; P < .001). Half of the methylnaltrexone patients who responded within 4 hours did so within 30 minutes. Additionally, more patients receiving methylnaltrexone (52%) experienced a bowel movement within 4 hours of receiving at least two of the first four doses than those receiving placebo (8%; P < .001). The response rates remained consistent throughout the extension study. Overall safety data from the studies showed that methylnaltrexone was generally well tolerated. The most frequently reported adverse events were abdominal pain and flatulence.