Subcutaneous Methylnaltrexone as Treatment for Opioid-Induced Constipation in Patients with Advanced Cancer and Noncancer Illnesses: A Post Hoc Analysis of Two Clinical Trials

Eric D Shah,1 Bruce H Chamberlain,2 Michelle Rhiner,3 Neil E Slatkin,4,5 Nancy Stambler,6 Robert J Israel7 1Section of Gastroenterology and Hepatology, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA; 2Genesis Healthcare, Davenport, IA, USA; 3Department of Family Medicine, Loma Linda University Health, Loma Linda, CA, USA; 4School of Medicine, University of California Riverside, Riverside, CA, USA; 5Medical Affairs, Salix Pharmaceuticals, Bridgewater, NJ, USA; 6Clinical Research, Progenics Pharmaceuticals, Inc., A Subsidiary of Lantheus Holdings, Inc, New York, NY, USA; 7Clinical and Medical Affairs, Bausch Health US, LLC, Bridgewater, NJ, USACorrespondence: Eric D Shah, Section of Gastroenterology and Hepatology, Dartmouth-Hitchcock Medical Center, 1 Medical Center Drive, Lebanon, NH, 03766, USA, Tel +1 603-650-5261, Email eric.d.shah@hitchcock.orgPurpose: To evaluate the efficacy and safety of subcutaneous (SC) methylnaltrexone for opioid-induced constipation (OIC) in patients with and without active cancer.Patients and Methods: We analyzed two randomized, double-blind, placebo-controlled, Phase 3/4 trials (NCT00402038, NCT00672477). Patients received SC methylnaltrexone (study 302, 0.15 mg/kg; study 4000, 8 mg or 12 mg based on body weight) or placebo every other day for 2 weeks. Patients were stratified by cancer status. Primary efficacy endpoints included proportion of patients achieving rescue-free laxation (RFL); secondary endpoints included time to RFL, pain intensity scores, and safety/tolerability. Trial results were evaluated separately.Results: The safety population (patients receiving ≥ 1 study drug dose) included 364 patients (study 302, n=134; study 4000, n=230). Study 302 had 78 patients with active cancer (methylnaltrexone, n=37; placebo, n=41) and 56 without cancer (methylnaltrexone, n=26; placebo, n=30); study 4000 had 152 patients with active cancer (methylnaltrexone, n=79; placebo, n=73) and 78 without cancer (methylnaltrexone, n=37; placebo, n=41). A significantly greater proportion of patients treated with methylnaltrexone achieved a laxation response within 4 hours after at least 2 of the first 4 doses versus placebo, dosed by body weight (cancer, 54.1% [methylnaltrexone] vs 7.3% [placebo], P< 0.0001; noncancer, 48.0% vs 10.0%; P< 0.005) or given as a weight-adjusted fixed dose (cancer, 59.5% vs 6.8%; noncancer, 70.3% vs 14.6%; P< 0.0001 each). With fixed-dose methylnaltrexone, average time to RFL for patients with and without cancer was < 1 hour of the first dose; with methylnaltrexone dosed by body weight, the first RFL occurred in < 4 and < 7 hours of treatment in patients with and without cancer, respectively. No significant differences were found in pain scores. SC methylnaltrexone was well tolerated at all doses in all patient cohorts.Conclusion: SC methylnaltrexone was efficacious in inducing rapid RFL and safe among patients with and without active cancer suffering from OIC.Keywords: methylnaltrexone, opioid-induced constipation, μ-opioid receptor antagonist, cancer, chronic pain