58 - Cumulative Laxation Response With Methylnaltrexone: Implications for Hospitalized Patients With Advanced Illness and Opioid-Induced Constipation

¹Loma Linda University Medical Center, Loma Linda, CA, USA. ²University of California Riverside, School of Medicine, Riverside, CA, USA. ³Salix Pharmaceuticals, Bridgewater, NJ, USA. ⁴Progenics Pharmaceuticals, New York, NY, USA. ⁵Bausch Health US, LLC, Bridgewater, NJ, USA

Purpose
Hospitalized patients with advanced illness often encounter constipation when receiving opioid treatment for pain. Methylnaltrexone (MNTX) is a peripherally acting μ-opioid receptor antagonist used to treat opioid-induced constipation (OIC), which does not affect opioid central analgesia. This post hoc analysis evaluated cumulative laxation response rates with repeated doses of MNTX in adults with advanced illness and laxative refractory OIC who had varying levels of baseline functional status.
Methods
Data were pooled from 2 randomized, double-blind, placebo-controlled studies. Patients received subcutaneous MNTX 0.15 mg/kg or placebo (study 302; NCT00402038) or subcutaneous MNTX 8 mg (38–<62 kg), 12 mg (≥62 kg), or placebo (study 4000; NCT00672477) every other day for 2 weeks. Baseline assessments included demographics and patient characteristics (eg, primary diagnosis, functional status, laxative use). Endpoints were rescue-free laxation (RFL) within 4 or 24 hours after the first dose, cumulative laxation rates after the first and second doses, and after the first, second, and third doses. RFL response rates were also analyzed when patients were stratified by baseline functional status (assessed by the World Health Organization [WHO] or the Eastern Cooperative Oncology Group [ECOG] performance status scales). Other endpoints included time to RFL, pain intensity, and treatment-emergent adverse events.
Results
The analysis included 364 patients (MNTX=179; placebo=185). The median age was 66 years in each group. Approximately 52% were women; 94% were white. The primary diagnosis was cancer (63.4%), followed by cardiovascular disorders (11.3%) and pulmonary disease (7.4%), among others. Cumulative RFL responses with MNTX increased from 62.4% within 4 hours of the first dose to 80.9% within 4 hours of the third dose compared with 16.8% and 35.1%, respectively, with placebo. Cumulative RFL responses among MNTX-treated patients with baseline WHO/ECOG performance status of >2 at baseline increased from 59.0% within 4 hours after the first dose to 81.0% within 4 hours of the third dose compared with 12.4% and 32.4%, respectively, with placebo. Similar findings were observed among patients with baseline WHO/ECOG performance status of ≤2. Median time to RFL was significantly shorter with MNTX than with placebo, at the 4- and 24-hour time points following initial dosing (4 hours: 1.11 vs >4 hours; 24 hours: 1.11 vs 23.58 hours; P<0.0001 for both comparisons). Similar results from the Kaplan-Meier analysis were observed when patients were stratified by baseline WHO/ECOG performance status. Regardless of baseline WHO/ECOG status, no significant differences vs placebo were observed in current and worst pain intensity scores. Treatment-emergent adverse events were mostly gastrointestinal in nature (ie, nausea, abdominal pain, flatulence).
Conclusions
In a diverse population of laxative-treated advanced-illness patients with OIC, MNTX significantly improved RFL responses 4 hours after the first dose vs placebo; the cumulative response continued after the second and third doses and was maintained regardless of baseline WHO/ECOG status, indicating that MNTX efficacy was not impacted by functional performance status. Opioid analgesia was maintained, and side effects were generally reflective of effective laxation. These findings have implications for hospitalized advanced-illness patients with OIC.