Webster LR, Brenner D, Israel RJ, et al. Reductions in All-Cause Mortality Associated with the Use of Methylnaltrexone for Opioid-Induced Bowel Disorders: A Pooled Analysis. Pain Med. 2022 Sep 14. pii: 6697894. doi: 10.1093/pm/pnac136. (Original study)

OBJECTIVE: Preclinical and clinical studies suggest that activation of the µ-opioid receptor may reduce overall survival and increase the risk for all-cause mortality in patients with cancer and noncancer pain. Methylnaltrexone, a selective, peripherally acting µ-opioid receptor antagonist, has demonstrated efficacy for the treatment of opioid-induced constipation. This retrospective analysis of 12 randomized, double-blind, placebo-controlled studies of methylnaltrexone evaluated the treatment of opioid-induced bowel disorders in patients with advanced illness or noncancer pain.

METHODS: The risk of all-cause mortality within 30 days after the last dose of study medication during the double-blind phase was compared between methylnaltrexone and placebo groups. The data were further stratified by cancer vs noncancer, age, gender, and acute vs chronic diagnoses.

RESULTS: Pooled data included 2526 methylnaltrexone-treated patients of which 33 died, and 1192 placebo-treated patients of which 35 died. The mortality rate was 17.8 deaths/100 person-years of exposure in the methylnaltrexone group and 49.5 deaths/100 person-years of exposure for the placebo group. The all-cause mortality risk was significantly lower among patients receiving methylnaltrexone compared with placebo (hazard ratio: 0.399, 95% confidence interval: 0.25, 0.64; P = 0.0002), corresponding to a 60% risk reduction. Significant risk reductions were observed for those receiving methylnaltrexone who had cancer or chronic diagnoses. Methylnaltrexone-treated patients had a significantly reduced mortality risk compared with placebo regardless of age or gender.

CONCLUSIONS: Methylnaltrexone reduced all-cause mortality vs placebo treatment across multiple trials, suggesting methylnaltrexone may confer survival benefits in patients with opioid-induced bowel disorders taking opioids for cancer-related or chronic noncancer pain.

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Comments from MORE raters

Physician rater

Interesting data but hypothesis-generating.

Physician rater

Interesting but post hoc and done in response to findings seen in the studies that are driving the pooled result. The conclusions are exaggerated: "...clinically significant reduction in all-cause mortality among patients receiving MNTX for treatment of OIC, with consistent effects observed in patients with cancer or chronic diagnoses, independent of age and gender." Total number of deaths is small and driven by previously noted post-hoc results from cancer trials.

Physician rater

This is a thought-provoking hypothesis. The study, however, shows correlation, not causality. Definitely worth more investigation.

Physician rater

This post-hoc analysis of RCTs demonstrates a significant (60%) mortality reduction in patients with opioid-induced bowel disorders receiving opioids + methylnaltrexone in versus opioids + placebo. µ-opioid receptor (MOR) stimulation is associated with tumor progression and increased mortality, and MOR antagonists like methylnaltrexone may antagonize that. A prospective randomized trial to study this would be justified.
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