Background: Hospitalized patients with advanced illness often encounter constipation when receiving treatment for pain. Methylnaltrexone (MNTX, Relistor®) 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 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 of laxative-treated patients with advanced illness. Both studies received appropriate Institutional Review Board approval. Patients received subcutaneous (SC) MNTX 0.15 mg/kg or placebo (study 302) or SC MNTX 8 mg (38–<62 kg), 12 mg (≥62 kg), or placebo (study 4000) every other day for 2 weeks. Baseline assessments included demographics (eg, age, gender, race) and other characteristics (eg, opioid morphine equivalent, 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 patient functional status (assessed by the World Health Organization [WHO] or the Eastern Cooperative Oncology Group [ECOG] performance status scales). Additional endpoints included time to RFL, pain intensity, and treatment-emergent adverse events (TEAEs).
Results: The pooled 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. Median baseline opioid morphine equivalent (mg/day) was greater in patients receiving MNTX (156 mg, range 0–4427 mg) vs placebo (130 mg, range, 0–10,160). MNTX treatment significantly improved RFL response 4 hours after the first dose, cumulative second dose, and cumulative third dose, each P<0.0001 vs placebo (Figure 1). Similar findings were observed when patients were stratified by baseline ECOG/WHO functional status (Figure 2). MNTX significantly reduced the median time to RFL at the 4 and 24 hour time points vs placebo (each P<0.0001). Regardless of baseline ECOG/WHO status, no significant differences relative to placebo were observed in current and worst pain intensity scores. TEAEs 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 compared with placebo; the cumulative response continued after the second and third doses and was maintained regardless of baseline ECOG/WHO status, indicating that MNTX efficacy was not impacted by varying degrees of 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.
