Background: Methylnaltrexone (MNTX) is a peripherally acting µ-opioid receptor antagonist indicated for opioid-induced constipation (OIC). We evaluated whether baseline use of laxatives, including stimulants, osmotic agents, stool softeners, or combinations thereof affects the efficacy and safety of MNTX.
Methods: This post hoc analysis included pooled data from 2 multicenter, randomized, double-blind, placebo (PBO)-controlled, institutional review board–approved clinical studies in adult patients with OIC and advanced illness. Study 302 (NCT00402038) compared subcutaneous (SC) MNTX 0.15 mg/kg versus PBO and study 4000 (NCT00672477) compared body weight‒based SC MNTX 8 mg (38–< 62 kg) or 12 mg (≥62 kg) versus PBO. Patients were stratified according to baseline laxative regimen (stimulant laxative, stool softener, and/or osmotic laxatives), which were permitted to continue during the studies. Efficacy endpoints included the proportion of patients with rescue-free laxation (RFL) within 4 or 24 hours of ≥2 of the first 4 doses and median time to RFL. Treatment group comparisons were performed using Chi square tests. Treatment-emergent adverse events (TEAEs) were summarized by patient subgroup.
Results: The pooled population included 358 patients (MNTX, 175; PBO, 183). More than 98% of patients in both treatment groups were receiving a laxative regimen at baseline, and the distribution of laxative use was similar in patients treated with MNTX and PBO (stimulants only, 20.6% and 17.5%; osmotic agents only, 12.0% and 8.2%; stool softener only, 6.3% and 7.1%; stimulants + osmotic agents, 13.1% and 19.7%; stimulants + stool softeners, 22.9% and 29.5%; osmotic agents + stool softeners, 2.3% and 2.2%; stimulants + osmotic agents + stool softeners, 21.1% and 14.8%; no laxatives, 1.7% and 1.1%). Patients receiving MNTX were more likely to have an RFL within 4 or 24 hours of ≥2 of the first 4 doses, regardless of baseline laxative regimen; treatment differences were significant (P< 0.05) in every subgroup except the no laxatives group for the 4-hour interval, and in the stimulants, stool softeners, stimulants + osmotic agents, and stimulants + stool softeners groups for the 24-hour interval (Figure 1). Overall, most patients reported TEAEs (MNTX, 80.0%; PBO, 69.4%), which were more frequent with MNTX vs PBO in all subgroups except the stimulants + stool softeners and osmotic agents + stool softeners groups. Consistent with prior reports, the most common TEAEs were gastrointestinal in nature, and no new or unusual safety signals were observed in any subgroup.
Conclusions: In patients with advanced illness and OIC refractory to conventional laxative treatments, MNTX significantly increased the proportion of patients with RFL, regardless of baseline laxative regimen.