Impact of Methadone Dose and Baseline Bowel Movement Frequency on Efficacy of Lubiprostone for Opioid-Induced Constipation

Abstract

Introduction: Opioid-induced constipation (OIC) is a frequent side-effect of opioids due to disruption of GI electrolyte and fluid secretion by opioid receptor binding. Lubiprostone (LUB) induces fluid secretion via activation of ClC-2 chloride channels in intestinal epithelium, bypassing these antisecretory effects. LUB efficacy was evaluated in 2 identically designed, randomized, placebo (PBO)-controlled 12-week, phase 3 studies in subjects with chronic, non-cancer pain and documented OIC. Study 0631 met the primary efficacy endpoint, Study 0632 did not. Demographic and baseline characteristics were comparable, but 0632 had more subjects with ≥3 spontaneous bowel movements (SBMs) per week at baseline and a 32% higher mean morphine-equivalent daily dose (MEDD) for subjects taking methadone. Methadone dose-dependently attenuates the ClC-2-mediated secretory effect of LUB (Cuppoletti et al., Cell Biochem Biophys 2013;66:53-63). We assessed the impact of baseline SBM frequency and methadone use on LUB efficacy. Methods: Post-hoc sensitivity analyses examined overall change from baseline (CFB) in SBM frequency in subjects with <3 SBMs per week at baseline taking only non-methadone-type opioids. Regression analysis evaluated the relationship between methadone MEDD and overall SBM frequency. Results: For the protocol-specified intent-to-treat population, overall mean CFB in SBM frequency for LUB vs. PBO was significantly greater for 0631 (2.7 vs 2.1; P=0.0047), but not for 0632 (2.6 vs 2.3; P=0.2242). When the 0632 population is adjusted to include only subjects with <3 SBMs per week at baseline, the p-value decreases to p=0.1401 (2.7 vs. 2.4 SBMs per week for LUB vs. PBO). Removal of subjects taking methadone from the 0632 analysis results in near statistical significance (2.8 vs. 2.3 SBMs per week for LUB vs. PBO; p=0.0548), showing the substantial impact of methadone use. Despite the smaller population, overall CFB in SBM frequency for only subjects with <3 SBMs per week at baseline and taking non-methadone opioids was statistically significant for LUB vs. PBO in both studies 0631 (2.9 vs. 2.3 SBMs per week, p=0.0086) and 0632 (2.9 vs. 2.4 SBMs per week, p=0.0479). Regression analysis also showed a MEDD-dependent trend in the methadone effect on LUB efficacy. In both studies, adverse events for LUB were mild to moderate and mainly GI-related. Conclusion: Overall, LUB significantly increases overall SBM frequency in subjects with <3 SBMs at baseline; efficacy is decreased by high-dose methadone. LUB is well tolerated in OIC subjects. These results are consistent with those of a separate randomized, PBO-controlled study of LUB efficacy that excluded methadone subjects. Disclosure - Dr.Cryer - Consultant: Sucampo Pharma Americas LLC; Dr. Lichtlen - Consultant: Sucampo AG; Mr. Wang - Employee: Sucampo Pharma Americas, LLC; Ms. Losch-Beridon: Employee and Stockholder: Sucampo Pharma Americas, LLC. This research was supported by an industry grant from Sucampo Pharma Americas, LLC; Takeda Pharmaceuticals International, Inc.