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; Bruce H Chamberlain; Michelle Rhiner; Neil E Slatkin; Nancy Stambler; Robert J Israel

doi:10.2147/JPR.S366460

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

J Pain Res. 2023 Feb 10:16:395-406. doi: 10.2147/JPR.S366460. eCollection 2023.

Authors

Eric D Shah¹, Bruce H Chamberlain², Michelle Rhiner³, Neil E Slatkin^{4

5}, Nancy Stambler⁶, Robert J Israel⁷

Affiliations

¹ Section of Gastroenterology and Hepatology, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA.
² Genesis Healthcare, Davenport, IA, USA.
³ Department of Family Medicine, Loma Linda University Health, Loma Linda, CA, USA.
⁴ School of Medicine, University of California Riverside, Riverside, CA, USA.
⁵ Medical Affairs, Salix Pharmaceuticals, Bridgewater, NJ, USA.
⁶ Clinical Research, Progenics Pharmaceuticals, Inc., A Subsidiary of Lantheus Holdings, Inc, New York, NY, USA.
⁷ Clinical and Medical Affairs, Bausch Health US, LLC, Bridgewater, NJ, USA.

Abstract

Purpose: 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: cancer; chronic pain; methylnaltrexone; opioid-induced constipation; µ-opioid receptor antagonist.