47 - Reductions in All-Cause Mortality Associated With the Use of Methylnaltrexone for Opioid-Induced Bowel Disorders: A Pooled Analysis
Lynn R. Webster1, Darren Brenner2, Robert J. Israel3, Nancy Stambler4, Neal E. Slatkin5
1PRA Health Sciences, Salt Lake City, UT, USA. 2Northwestern University Feinberg School of Medicine, Chicago, IL, USA. 3Bausch Health US, LLC, Bridgewater, NJ, USA. 4Progenics Pharmaceuticals, Inc, New York, NY, USA. 5Salix Pharmaceuticals, Bridgewater, NJ, USA
Purpose Opioids are often associated with the development of delays in gastrointestinal motility and associated conditions. Preclinical and clinical studies have suggested 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.1-4 Methylnaltrexone, a peripherally acting μ-opioid receptor antagonist, has demonstrated efficacy for the treatment of bowel disorders.5,6 This analysis evaluated if all-cause mortality was impacted by methylnaltrexone use. Methods A retrospective analysis of 12 phase 2 to 4 randomized, double-blind, placebo-controlled studies of methylnaltrexone for the treatment of opioid-induced bowel disorders in patients with advanced illness or noncancer pain was conducted. The risk of all-cause mortality, defined as the number of patients who died within 30 days after the last dose of study medication during the double-blind phase of each study, was compared between methylnaltrexone and placebo groups. The data were also stratified by cancer vs noncancer, age, gender, and acute vs chronic diagnosis. Results The analysis was based on 2526 patients who received methylnaltrexone and 1192 patients who received placebo, from which there were 33 deaths in the methylnaltrexone group and 35 deaths in the placebo group. Based on the number of deaths in each group, 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 (hazard ratio 0.399; 95% confidence interval 0.25–0.64; P=0.0002) compared with patients receiving placebo, corresponding to a 60% reduction in risk. Significant risk reductions were observed for those receiving methylnaltrexone who had cancer (hazard ratio 0.470; 95% confidence interval 0.27–0.83, P=0.009) or chronic illness (hazard ratio 0.315; 95% confidence interval 0.19–0.54, P<0.0001). Methylnaltrexone-treated patients had a significantly reduced mortality risk compared with placebo regardless of age or gender. Conclusions A substantial reduction in all-cause mortality was observed among methylnaltrexone-treated patients pooled from phase 2–4 studies. Significant reductions were also observed for those receiving methylnaltrexone regardless of age or gender and who had cancer or a chronic illness. We hypothesize that methylnaltrexone μ-opioid receptor antagonism may provide protective benefit against the additional mortality risk associated with opioid treatment in patients with chronic illnesses. References 1. Janku F, et al. Treatment with methylnaltrexone is associated with increased survival in patients with advanced cancer. Ann Oncol. 2016;27(11):2032-2038. 2. Zylla D, et al. Opioid requirement, opioid receptor expression, and clinical outcomes in patients with advanced prostate cancer. Cancer. 2013;119(23):4103-4110. 3. Ray WA, et al. Prescription of long-acting opioids and mortality in patients with chronic noncancer pain. JAMA. 2016;315(22):2415-2423. 4. Lennon FE, et al. The mu opioid receptor promotes opioid and growth factor-induced proliferation, migration and epithelial mesenchymal transition in human lung cancer. PLoS One. 2014;9(3):e91577. 5. Thomas J, et al. Methylnaltrexone for opioid-induced constipation in advanced illness. N Engl J Med. 2008;328(22):2332-2343. 6. Rauck R, et al. Randomized, double-blind trial of oral methylnaltrexone for the treatment of opioid-induced constipation in patients with chronic noncancer pain. Pain Pract. 2017;17(6):820-828.