Lubiprostone for Treatment of Opioid-induced Constipation: Analysis of Influencing Factors

Abstract

Introduction: Opioid-induced constipation (OIC) frequently results from chronic opioid treatment. Lubiprostone (LUB) efficacy was evaluated in 3 similar phase 3, randomized, double-blind, placebocontrolled, 12-week studies in chronic, non-cancer pain patients with OIC (<3 spontaneous bowel movements [SBMs]/week) at baseline. Two studies enrolled methadone users: 1 met the primary endpoint of change from baseline (CFB) in SBM frequency at Week 8, the other did not. Despite similar design, mean morphine equivalent daily dose (MEDD) of methadone in LUB-treated subjects in the latter study was 32% higher than in the successful study. Unknown at the time of these studies, methadone dosedependently inhibits the ClC-2-mediated secretory effect of LUB (Cuppoletti et al., Cell Biochem Biophys 2013;66:53-63). Methods: Post-hoc sensitivity analyses were used to evaluate the impact of high-dose methadone on CFB in SBM frequency at Week 8 in the intent-to-treat (ITT) population excluding all subjects taking methadone, and separately, excluding subjects taking high-dose (≥200 mg MEDD) methadone. A final sensitivity analysis used a median group replacement simulation for this endpoint. In this analysis, group median values for non-methadone patients and patients taking <200 mg MEDD methadone replaced Week 8 CFB values of methadone and high-dose methadone patients, respectively. Results: Excluding methadone-treated subjects from analysis resulted in clearly improved observed treatment effects in favor of LUB in both studies (Table). Though the second study did not achieve statistical significance in this analysis, clinical effect size was similar across the studies and thus the results were corroborative. In the replacement simulation, highly statistically and clinically significant improvements were observed for both trials for all simulations (p≤0.001). Adverse events were generally mild to moderate, and primarily gastrointestinal. Conclusion: LUB appears effective and well-tolerated in OIC patients with chronic, non-cancer pain taking non-methadone-type opioids. Disclosure - Ms. Losch-Beridon - Employee and holder of stock options: Sucampo Pharma Americas, LLC; Dr. Lichtlen - Consultant to Sucampo; Mr. Wang - Employee of Sucampo Pharma Americas, LLC. This research was supported by an industry grant from Sucampo Pharma Americas, LLC; Takeda Pharmaceuticals International, Inc.Table 1: Methadone Sensitivity Analyses: Change From Baseline, SBM Frequency, Week 8