NEJM article - I assume that's why they were quiet on the details:
Volume 358:2332-2343 May 29, 2008 Number 22
Methylnaltrexone for Opioid-Induced Constipation in Advanced Illness
Jay Thomas, M.D., Ph.D., Sloan Karver, M.D., Gail Austin Cooney, M.D., Bruce H. Chamberlain, M.D., Charles Kevin Watt, D.O., Neal E. Slatkin, M.D., Nancy Stambler, M.S., Alton B. Kremer, M.D., Ph.D., and Robert J. Israel, M.D.
Commentary
- Editorial
by Berde, C.
ABSTRACT
Background Constipation is a distressing side effect of opioid treatment. As a quaternary amine, methylnaltrexone, a µ-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] .)
Source Information
From San Diego Hospice and the Institute for Palliative Medicine, San Diego, CA (J.T.); Gulfside Regional Hospice, New Port Richey, FL (S.K.); Hospice of Palm Beach County, West Palm Beach, FL (G.A.C.); Palliative Consulting, Orem, UT (B.H.C.); Research Center of the Ozarks, Everton, MO (C.K.W.); City of Hope National Medical Center, Duarte, CA (N.E.S.); and Progenics Pharmaceuticals, Tarrytown, NY (N.S., A.B.K., R.J.I.).
Drs. Thomas and Karver contributed equally to this article.
And from the Editorial:
... Several types of pharmacologic agents have been used to treat opioid-induced constipation, including osmotic or lubricant laxatives, stimulant laxatives (orally and rectally), and prokinetics. The effects of such therapies are nonspecific and generally unpredictable, often generating diarrhea or cramps. Furthermore, many patients do not respond to such therapies, so new, more specific, pathophysiologically based treatments are needed.7
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Methylnaltrexone was at least three times as effective as placebo in producing laxation within 4 hours after the initial dose, and its effectiveness appeared to be undiminished throughout the 2-week double-blind trial, as well as during the 3-month open-label extension. Methylnaltrexone appeared to be safe in this small group of patients, although a larger number of patients will be needed in future studies to detect uncommon adverse events. No episodes of generalized opioid withdrawal or a form of gut hypermotility known as "gut withdrawal syndrome" were observed, and there was no evidence of antagonism of analgesia.
Although methylnaltrexone was significantly more effective than placebo, it was somewhat disappointing that in both phases of the study, the drug produced rescue-free laxation in only about half the patients. There may be several reasons for this failure rate. First, although all the patients were receiving opioids, the predominant causes of constipation among the patients who did not have a response to the drug could have been the effects of other drugs or disease processes unrelated to actions mediated by opioid receptors. Second, although constipation is commonly regarded as a peripheral side effect of opioids, central actions of opioids contribute as well. For example, opioids can reduce the motility of both the small and large intestines through direct actions in the spinal dorsal horn. Future studies in a larger number of patients may help to delineate predictors of the success or failure of methylnaltrexone in specific subgroups of patients and may guide decisions about increasing or decreasing the dose for various patients.
Practical and ethical constraints pose unique challenges for clinical trials involving patients in hospice or palliative care. Collaboration among 27 palliative care centers was required to generate this study, with 133 patients included in the efficacy analysis. Such patients have diverse and medically complex conditions, and it may be difficult to distinguish adverse events caused by a study drug from those caused by the patient's underlying disease or a variety of other coadministered drugs. Thomas et al. should be commended for performing a useful real-world study to benefit this vulnerable group of patients and potentially other patients who need better approaches to the treatment or prevention of opioid side effects. |
