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].).

Methylnaltrexone, a peripherally acting mu-opioid receptor antagonist with restricted ability to cross the blood-brain barrier, reverses opioid-induced constipation (OIC) without affecting analgesia. A double-blind study in patients with advanced illness and OIC demonstrated that methylnaltrexone significantly induced laxation within four hours after the first dose compared with placebo. In this study, patients with advanced illness and OIC on stable doses of opioids and laxatives were randomized to methylnaltrexone 0.15mg/kg (n=62) or placebo (n=71) subcutaneously every other day for two weeks. Laxation was assessed daily. Constipation distress, bowel status change, pain, laxative use, and opioid withdrawal symptoms were assessed weekly using standardized scales. Additional analyses to further characterize response to methylnaltrexone revealed that among patients with a bowel movement within four hours following the first dose, the median time to response was 0.5 hours for methylnaltrexone. Response rates among methylnaltrexone-treated patients who had responded to all previous doses were 57%-100% for doses two to seven. Among methylnaltrexone-treated patients who did not respond to the first or to the first two consecutive doses, 35% and 26% responded to the second and third dose, respectively. Higher percentages of patients and clinicians rated bowel status as improved in the methylnaltrexone than the placebo group. Fewer methylnaltrexone than placebo patients reported use of common laxative types, particularly enemas, during the study. Subcutaneous methylnaltrexone promptly and predictably induced laxation, improved constipation distress, and was associated with less laxative use in patients with advanced illness and OIC.

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Aim: To evaluate methylnaltrexone for opioid-induced constipation in patients with and without cancer. Methods: This post hoc analysis comprises two Phase III, multicenter, double-blind, randomized studies of advanced-illness patients who received methylnaltrexone subcutaneous injection or placebo. Results: Significantly more patients treated with methylnaltrexone than placebo experienced laxation within 4 (cancer = 55.5 vs 15.5%; noncancer = 55.6 vs 12.8%) and 24 (cancer = 64.7 vs 29.8%; noncancer = 64.4 vs 30.8%) h after the first dose (p < 0.01 vs placebo). Regardless of cancer status, methylnaltrexone reduced median time to laxation and improved constipation relief without impacting opioid analgesia or withdrawal symptoms. Conclusion: Methylnaltrexone provided significant improvements in opioid-induced constipation over placebo in advanced-illness patients with and without cancer. Clinical trial registration numbers: study 301: NCT00401362; study 302: NCT00402038.