Methylnaltrexone for opioid-induced constipation in advanced illness.
BACKGROUND
Constipation is a distressing side effect of opioid treatment. As a quaternary amine, methylnaltrexone, a mu-opioid-receptor antagonist, has restricted ability to cross the blood-brain barrier. We investigated the safety and efficacy of subcutaneous methylnaltrexone for treating opioid-induced constipation in patients with advanced illness.


METHODS
A total of 133 patients who had received opioids for 2 or more weeks and who had received stable doses of opioids and laxatives for 3 or more days without relief of opioid-induced constipation were randomly assigned to receive subcutaneous methylnaltrexone (at a dose of 0.15 mg per kilogram of body weight) or placebo every other day for 2 weeks. Coprimary outcomes were laxation (defecation) within 4 hours after the first dose of the study drug and laxation within 4 hours after two or more of the first four doses. Patients who completed this phase were eligible to enter a 3-month, open-label extension trial.


RESULTS
In the methylnaltrexone group, 48% of patients had laxation within 4 hours after the first study dose, as compared with 15% in the placebo group, and 52% had laxation without the use of a rescue laxative within 4 hours after two or more of the first four doses, as compared with 8% in the placebo group (P<0.001 for both comparisons). The response rate remained consistent throughout the extension trial. The median time to laxation was significantly shorter in the methylnaltrexone group than in the placebo group. Evidence of withdrawal mediated by central nervous system opioid receptors or changes in pain scores was not observed. Abdominal pain and flatulence were the most common adverse events.


CONCLUSIONS
Subcutaneous methylnaltrexone rapidly induced laxation in patients with advanced illness and opioid-induced constipation. Treatment did not appear to affect central analgesia or precipitate opioid withdrawal. (Clinical Trials.gov number, NCT00402038 [ClinicalTrials.gov].).
Thomas
Jay
J
San Diego Hospice and the Institute for Palliative Medicine, San Diego, CA 92103, USA. jthomas@sdhospice.org
Karver
Sloan
S
Cooney
Gail Austin
GA
Chamberlain
Bruce H
BH
Watt
Charles Kevin
CK
Slatkin
Neal E
NE
Stambler
Nancy
N
Kremer
Alton B
AB
Israel
Robert J
RJ
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000701:Analgesics, Opioid / Q000009:adverse effects*; D003248:Constipation / Q000139:chemically induced / Q000188:drug therapy*; D003672:Defecation / Q000187:drug effects; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007279:Injections, Subcutaneous; D054368:Laxatives / Q000009:adverse effects / Q000627:therapeutic use*; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D009271:Naltrexone / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D009292:Narcotic Antagonists / Q000009:adverse effects / Q000627:therapeutic use*; D000644:Quaternary Ammonium Compounds / Q000009:adverse effects / Q000627:therapeutic use; D019452:Terminally Ill
D000701:Analgesics, Opioid; D054368:Laxatives; D009292:Narcotic Antagonists; D000644:Quaternary Ammonium Compounds; C032257:methylnaltrexone; D009271:Naltrexone