A single dose of methylnaltrexone relieved opioid-induced constipation three times more often than did placebo in a phase III clinical trial of 133 terminally ill patients, investigators have reported.
The treatment did not interfere with analgesia or cause opioid withdrawal, according to Dr. Jay Thomas of San Diego Hospice and the Institute for Palliative Medicine, San Diego, and his associates.
Since opioid-induced constipation is primarily mediated by peripheral opioid receptors, the researchers hypothesized that selective blockade of these receptors “might relieve constipation without compromising the centrally mediated effects of opioid analgesia or precipitating withdrawal.” Methylnaltrexone, produced by N-methylation of the opioid antagonist naltrexone, has a limited ability to cross the blood-brain barrier and thus acts primarily in the periphery.
Dr. Thomas and his associates compared subcutaneous injections of methylnaltrexone with placebo in a double-blind trial at 27 U.S. and Canadian nursing homes, hospices, and palliative care centers.
The 133 patients (median age 71 years) were taking a median opioid dose of 100 mg of oral morphine equivalent and had constipation that failed to respond to a median of two classes of laxative therapy (N. Engl. J. Med. 2008;358:2332–43).
Patients were randomly assigned to receive injections of methylnaltrexone (62 subjects) or placebo (71 subjects) on alternate days for 2 weeks. The study was supported by Progenics Pharmaceuticals Inc.
Within 4 hours of receiving the first dose, 48% of subjects in the methylnaltrexone group defecated, compared with 15% in the placebo group. Over the course of the trial, the proportion of patients who defecated three or more times per week was significantly higher with methylnaltrexone (68%) than with placebo (45%).
In addition, the median time to defecation after the first dose was 6.3 hours with methylnaltrexone, compared with more than 48 hours in the placebo group. Most responders were able to defecate within 1 hour of the injection, and half were able to do so within 30 minutes–a significantly more predictable onset of action than is typically seen with standard laxative treatments, the investigators noted.
Moreover, “more patients in the methylnaltrexone group than in the placebo group had reductions in the difficulty of laxation and distress associated with constipation,” Dr. Thomas and his associates said.
In a subjective assessment, the majority of patients given methylnaltrexone reported that their bowel status had improved with therapy, while the majority of those given placebo reported that their bowel status was unchanged.
At the conclusion of the double-blind phase of the trial, 89 patients opted to receive methylnaltrexone for up to 3 months in an open-label extension of the study. The drug's efficacy persisted throughout this phase of the study, the investigators said.
Mild or moderate abdominal pain and flatulence were the most common adverse events reported. The rates of both adverse events and treatment discontinuation were similarly low in both groups.
Approximately half of patients did not respond to the first dose of methylnaltrexone. It is possible that in at least some of these cases, constipation may have been a result of causes other than opioid use. These include “immobility, decreased oral intake, a low-fiber diet, metabolic and endocrine imbalances, neurologic disorders, concomitant drug side effects, inadequate toileting arrangements, sedation, depression, and advanced age,” Dr. Thomas and his associates noted.
Progenics Pharmaceuticals is collaborating with Wyeth Pharmaceuticals in submitting to the Food and Drug Administration subcutaneous methylnaltrexone for treating opioid-induced constipation in patients receiving palliative care. Dr. Thomas disclosed that he has received consulting and lecture fees, and served on advisory boards for Wyeth Pharmaceuticals.
Most responders were able to defecate within 1 hour of the injection of methylnaltrexone. DR. THOMAS