Background: Opioid analgesia is an important treatment modality for patients with chronic pain, including pain attributed to cancer- and noncancer-related illness. Unfortunately, an estimated 40%–80% of opioid users experience opioid-induced constipation (OIC). Methylnaltrexone (MNTX) is indicated for the treatment of OIC. In clinical trials, the most common adverse events (AEs) were gastrointestinal (GI) in nature. This post hoc analysis assessed the incidence of AEs, including GI AEs, across 7 doses of MNTX versus placebo (PBO) in patients with and without cancer to inform possible associations between effective laxation and AEs.
Methods: Data were pooled from 2 multicenter, double-blind, randomized, PBO-controlled clinical trials of subcutaneous (SC) MNTX in adults with OIC and advanced illness. Study 302 (NCT00402038) compared SC MNTX 0.15 mg/kg (adjustable to ≥0.30 mg/kg beginning on day 9) versus PBO every other day for 14 days. Study 4000 (NCT00672477) compared SC MNTX (8 mg for patients ≥38 to < 62 kg; 12 mg for patients ≥62 kg) versus PBO every other day for 14 days. AEs occurring within 24 hours following each dose were reported. A responder analysis was also performed that looked at AEs occurring within 24 hours following each dose in patients who had a rescue-free laxation response within 4 hours of the respective dose.
Results: The full cohort included 179 patients who received MNTX (cancer, n=116; noncancer, n=63) and 185 patients who received PBO (cancer, n=114; noncancer, n=71). The proportion of MNTX-treated patients with an AE in the full, cancer, and noncancer cohorts decreased from dose 1 (26.3%, 30.2%, 19.0%) to dose 7 (10.2%, 10.4%, 9.8%); slight reductions were also observed in the PBO group from dose 1 (14.6%, 14.9%, 14.0%) to dose 7 (12.2%, 12.3%, 12.0%). Consistent with previous observations, the most common AEs were GI in nature, which reduced in MNTX-treated patients from dose 1 (20.7%, 25.0%, 12.7%) to dose 7 (7.4%, 7.5%, 7.3%), and in PBO-treated patients from dose 1 (8.1%, 8.8%, 7.0%) to dose 7 (4.1%, 5.5%, 2.0%). Responding patients at each dose were more likely to have AEs than nonresponders, regardless of treatment, and the incidence of AEs was similar among responding patients at each dose treated with MNTX or PBO (eg, dose 1: 31.5% and 25.8%, 35.1% and 29.4%, 24.3% and 21.4% in the full, cancer, and noncancer cohorts).
Conclusions: The incidence of AEs with MNTX in patients with advanced illness improves with repeat dosing. The association of observed AEs and treatment response suggests laxation response as a potential factor driving AE experiences with MNTX.