Subcutaneous methylnaltrexone for the treatment of opioid-induced constipation in patients with advanced illness: a double-blind, randomized, parallel group, dose-ranging study

J Pain Symptom Manage. 2008 May;35(5):458-68. doi: 10.1016/j.jpainsymman.2007.12.005.

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.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acquired Immunodeficiency Syndrome / complications
  • Adult
  • Aged
  • Aged, 80 and over
  • Analgesics, Opioid / adverse effects*
  • Diarrhea / chemically induced*
  • Diarrhea / drug therapy*
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Female
  • Humans
  • Injections, Subcutaneous
  • Male
  • Middle Aged
  • Naltrexone / administration & dosage
  • Naltrexone / adverse effects
  • Naltrexone / analogs & derivatives*
  • Naltrexone / therapeutic use
  • Narcotic Antagonists / administration & dosage
  • Narcotic Antagonists / adverse effects
  • Narcotic Antagonists / therapeutic use*
  • Neoplasms / complications
  • Pain / drug therapy
  • Pain / etiology
  • Pain Measurement
  • Quaternary Ammonium Compounds / administration & dosage
  • Quaternary Ammonium Compounds / adverse effects
  • Quaternary Ammonium Compounds / therapeutic use
  • Terminal Care

Substances

  • Analgesics, Opioid
  • Narcotic Antagonists
  • Quaternary Ammonium Compounds
  • methylnaltrexone
  • Naltrexone