Lubiprostone Effectively Relieves Opioid-induced Constipation in Patients Using Non-diphenylheptane Opioids for Non-cancer Pain: Pooled Analysis of Three Randomized Controlled Trials

Abstract

Purpose: Oral lubiprostone (24 mcg twice daily [BID]) is approved to treat opioid-induced constipation (OIC) in adults with chronic non-cancer pain, but effectiveness has not been established in OIC patients taking diphenylheptane opioids (e.g., methadone). In two well-controlled studies of lubiprostone in OIC, a dose-dependent decrease in the efficacy of lubiprostone was observed in those patients using diphenylheptane opioids; a third, similarly designed, well-controlled study was also conducted in which patients taking diphenylheptanes were excluded. In this analysis, efficacy and safety data from the non-diphenylheptane population from the three individual trials were pooled and analyzed. Methods: Data were pooled from three multicenter, 12-week, double-blind, randomized, placebocontrolled trials in patients ≥18 years old with OIC due to use of opioids for chronic non-cancer pain. Patients were randomized to receive either lubiprostone 24 mcg (n=572) or placebo (n=568), which were self-administered BID. Changes from baseline (CFB) in weekly spontaneous bowel movement (SBM) frequency at week 8, week 12, and overall were analyzed. Median time-to-first SBM and overall CFBs in specific symptoms of OIC (constipation severity, straining, stool consistency, abdominal bloating, and abdominal discomfort) were also analyzed. Results: Demographic characteristics were consistent across the three trials. In the pooled analysis, mean CFB in SBM frequency at week 8 was significantly increased in the lubiprostone group vs the placebo group (CFB=3.1 vs 2.5 SBMs/week, respectively; p=0.006). Mean CFBs in SBM frequency were also signifi cantly improved for lubiprostone vs placebo at week 12 (CFB=3.2 vs 2.7 SBMs/week, respectively; p=0.040) and overall (CFB=3.0 vs 2.3 SBMs/week, respectively; p<0.001). The median time-to-first SBM was significantly shorter with lubiprostone vs placebo (28.5 h vs 40.0 h, respectively; p<0.001). Statistically significant improvements in constipation severity, straining, stool consistency, abdominal bloating, and abdominal discomfort were also reported with lubiprostone vs placebo (p≤0.015). Overall, lubiprostone was well tolerated; no clinically meaningful safety differences were observed. Conclusion: Pooled analysis of phase 3 trials confirmed the overall benefits of lubiprostone therapy in patients with OIC resulting from chronic treatment with non-diphenylheptane opioids, as demonstrated by statistically significant improvements in SBM frequency, time-to-first SBM, and OIC-related symptoms. This research was funded by Sucampo Pharma Americas, LLC, Bethesda, MD, and Takeda Pharmaceuticals International, Inc., Deerfield, IL. Disclosure - Shadreck Mareya is an employee of Sucampo Pharma Americas, LLC. Douglas A. Drossman has been a consultant and received research funding from Takeda Pharmaceuticals North America, Inc., and has been a consultant for Sucampo Pharmaceuticals, Inc. Taryn Joswick is an employee of Sucampo Pharma Americas, LLC. Gayle Dolecek is an employee of Sucampo Pharma Americas, LLC. Yijun Sun is an employee of Sucampo Pharma Americas, LLC. Ryuji Ueno is a Director of Sucampo AG, is an employee of Sucampo Pharma Americas, LLC, and is a shareholder of Sucampo Pharmaceuticals, Inc. This research was supported by an industry grant from Sucampo Pharma Americas, LLC; Takeda Pharmaceuticals International, Inc.