Thomas, J., Karver, S., Cooney, G.A., Chamberlain, B.H., Watt, C.K., Slatkin, N.E., . . . Israel, R.J. (2008). Methylnaltrexone for opioid-induced constipation in advanced illness. New England Journal of Medicine, 358, 2332-2343.doi: 10.1056/NEJMoa0707377
To examine the safety and efficacy of subcutaneous methylnaltrexone for treating opioid-induced constipation in patients with advanced illness.
Patients were randomly assigned to receive either methylnaltrexone 0.15 mg/kg or placebo subcutaneously every other day for two weeks. Patients were permitted to continue their baseline laxatives and could use rescue laxatives. By day 8, the study drug dose (methylnaltrexone or placebo) could be doubled if patients had fewer than three rescue-free bowel movements. Patients in both groups who completed the two-week study were eligible to enter an open-label extension phase. During the extension trial, methylnaltrexone 0.15 mg/kg was offered as needed every 24 hours for up to three months. Subsequent doses could be increased to 0.3 mg/kg if there was no defecation.
The study has clinical applicability for the end-of-life and palliative phases of care.
This was a two-week, double-blind, randomized, placebo-controlled phase III study with a subsequent three-month, open-label extension phase.
Efficacy Analysis: Double-Blind Phase
Pain Scores and Opioid Withdrawal
Methylnaltrexone as administered in this study was effective in inducing laxation in patients with advanced illness and opioid-induced constipation, without compromising analgesia or triggering withdrawal symptoms.
Calculations showed that a total of 130 patients (65 in each group) would allow detection of a difference of 30% to 35% in the proportion of patients having a laxation response. However, only 106 patients (52 in the methylnaltrexone group and 54 in the placebo group) completed the study.
Subcutaneous methylnaltrexone seems effective in treating constipation in patients with advanced illness and opioid-induced constipation without compromising analgesia or causing withdrawal symptoms. In this study, more than 50% of patients had a diagnosis of cancer; therefore, conclusions can likely be extended to patients with cancer. In addition, patients in this study were receiving a median opioid dose of approximately 100 mg of oral morphine equivalent. Many patients with cancer receive a larger dose; therefore, further study with increased doses of morphine equivalent is warranted.