Subcutaneous Methylnaltrexone for the Treatment of Opioid-Induced Constipation in Patients with Advanced Illness: A Double-Blind, Randomized, Parallel Group, Dose-Ranging Study

Abstract

Methylnaltrexone, a peripherally-acting quaternary opioid antagonist, is an investigational treatment for opioid-induced constipation in patients with advanced illness. This randomized, parallel-group, repeated dose, dose-ranging trial included a double-blind phase for one week followed by an open-label phase for a maximum of three weeks. Opioid-treated patients with advanced illness who met criteria for opioid-induced constipation despite laxative therapy were potentially eligible. Double-blind treatment occurred on Days 1, 3, and 5; open-label therapy could be administered as often as every other day. The initial dose range of 1mg, 5mg, or 12.5mg was extended by adding a 20mg group during the study while still maintaining the double blind; the initial open-label dose of 5mg could be titrated. The primary outcome was a laxation response within four hours after the first dose. Thirty-three patients received at least one dose of methylnaltrexone. Only one of 10 patients (10%) who received the 1mg dose experienced laxation within four hours of dosing. The median time to laxation was >48 hours for the 1mg dose group, compared to 1.26 hours for all patients receiving >or=5mg (P=0.0003). There was no apparent dose-response above 5mg. Most adverse events were related to the gastrointestinal system, were mild, and did not lead to discontinuation. In conclusion, methylnaltrexone relieved opioid-induced constipation at doses >or=5mg in patients with advanced illness, and did not reduce analgesia or cause opioid withdrawal symptoms.

Methylnaltrexone or laxatives for the Management of Opioid-induced Constipation among Palliative Patients on Opioid Therapy: Evidencebased Review

“…Opinions of respected authorities/Consensus panels Thomas et al [17] To evaluate the safety and efficacy of methyl naltrexone 0.15 mg/kg subcutaneously every other day for two weeks.…”

“…The impact of constipation on patients' quality of life is important, especially for cancer patients [17]. Whose quality of life is already significantly impaired by the illness itself, constipation has been deemed by cancer patients to be an even greater source of discomfort than the pain they suffered.…”

The medical treatment of cancer pain

“…senna plus docusate), although a recent study has demonstrated the efficacy of senna alone (35). Once constipation occurs, stimulant or osmotic laxatives should be early administered: when response to common laxatives is unsatisfactory and constipation is clearly related to opioid treatment, methylnaltrexone, an opioid antagonist that works on the receptors of the gastrointestinal tract, can be subcutaneously administered as a rescue therapy (36,37). Although many drugs administered in cancer patients can be responsible of sedation, this symptom is generally attributed to opioid therapy.…”

Emerging drugs for cancer-related pain

“…Different controlled studies have shown that methylnaltrexone promptly and predictably induced laxation in cancer patients with opioid-induced constipation. Bowel movements were observed in about half of patients within 4 h of administration, independent of age and opioid doses [30,36].…”