Methylnaltrexone for Opioid‐lnduced Constipation During Rehabilitation Following Orthopedic Procedures: A Double‐Blind, Randomized Clinical Study

Background:

Methylnaltrexone, a quaternary derivative of naltrexone, is a peripheral mu‐opioid receptor antagonist recently approved 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 aim of this study was to assess the efficacy of subcutaneous (SC) methylnaltrexone in inducing laxation in patients with acute OIC during rehabilitation following orthopedic surgical procedures.

Methods:

This double‐blind, randomized, parallel‐group, placebo‐controlled phase 2 trial was conducted in 20 U.S. hospitals and rehabilitation facilities, Adults who had undergone orthopedic surgery, were constipated because of opioid use, and were expected to require opioid analgesics for at least 7 days after randomization were included. Patients were randomized and treated with SC methylnaltrexone or placebo once daily for up to 4 days. All end points were exploratory and included laxation response within 4 hours of the first dose of study drug and median time to first laxation.

Results:

A total of 37 patients were randomized, 33 of whom made up the modified intent‐to‐treat population receiving SC methylnaltrexone 12 mg (n = 18) or placebo (n = 15), The proportion of patients with laxation response within 4 hours of the first dose of study drug was 38.9% in the methylnaltrexone group versus 6.7% in the placebo group (P = 0.046). Median time to first laxation was 15.8 hours in the methylnaltrexone group versus 50.9 hours in the placebo group (P = 0.0197), In methylnaltrexone‐treated patients who achieved laxation within 4 hours of the first dose, median time to laxation was less than 1 hour. Adverse events occurred in 33.3% of patients in the methylnaltrexone group and 26.7% in the placebo group. No serious adverse events were reported.

Conclusions:

In this hypothesis‐generating study of OIC patients following orthopedic procedures, the percentage of patients in the methylnaltrex one group who achieved laxation within 4 hours of dosing was nearly 6‐fold greater than that in the placebo group. In addition, the methylnaltrexone group experienced median time to laxation more than 1 day earlier than did the placebo group, and methylnaltrexone was generally well tolerated. Methylnaltrexone may be useful in the setting of acute OIC following orthopedic procedures.

Author Disclosure:

L. Anissian, Louisiana State University Health Sciences Center, study investigator; K. Vincent, University of Florida, study investigator; H. Schwartz, Moss Rehabilitation Research Institute, study investigator; J. Carpenito, Progenies Pharmaceuticals, employee of Progenies; D. Penenberg, Progenies Pharmaceuticals, employee of Progenies; T. Ramakrishna, Progenies Pharmaceuticals, employee of Progenies.