Safety of oral methylnaltrexone in patients with opioid-induced constipation and chronic noncancer pain: results from a phase 3, randomized, controlled trial
Authors: Richard Rauck, MD, The Center for Clinical Research, Winston-Salem, NC
Neal E. Slatkin, MD, University of California Riverside, Riverside, CA; Salix Pharmaceuticals, Bridgewater, NJ
Nancy Stambler, DrPH, Progenics Pharmaceuticals, Inc., New York, NY
Robert J. Israel, MD, Salix Pharmaceuticals, Bridgewater, NJ
Introduction: An oral formulation of methylnaltrexone, a selective peripheral µ-opioid receptor antagonist, was approved in July 2016 for opioid induced constipation (OIC) in patients with chronic noncancer pain. This analysis describes the safety of oral methylnaltrexone in a randomized, placebo-controlled trial conducted in patients with chronic noncancer pain with OIC.
Materials and Methods: This phase 3, double-blind, placebo-controlled trial included patients with chronic noncancer pain for ≥2 months, receiving ≥50 mg/d of oral morphine equivalents for ≥14 days, and experiencing OIC (confirmed during a 14-day screening and defined by <3 rescue-free bowel movements [RFBMs] per week, on average, associated with ≥1 of the following: ≥25% of RFBMs categorized as type 1 or type 2 on the Bristol Stool Form Scale, straining during ≥25% of RFBMs, or ≥25% of RFBMs with a sensation of incomplete evacuation). Following local IRB approval and informed consent, patients were randomly assigned to receive oral methylnaltrexone 150 mg, 300 mg, or 450 mg or placebo once daily for 4 weeks; for the next 8 weeks, oral methylnaltrexone or placebo was used as needed. Double-blinding was maintained throughout the study.
Results: A total of 803 patients received ≥1 dose of study medication (oral methylnaltrexone 150 mg, n=201; 300 mg, n=201; 450 mg, n=200; placebo, n=201). Approximately 10% of patients discontinued treatment during the 4-week once-daily dosing period (150 mg, 8.5%; 300 mg, 9.0%; 450 mg, 12.5%; placebo, 10.4%); during the 8-week “as-needed” dosing period, ~13% of patients discontinued treatment (150 mg, 9.6%; 300 mg, 13.8%; 450 mg, 12.4%; placebo, 14.4%). Demographic and baseline characteristics were similar among treatment groups. Treatment-emergent adverse events (TEAEs) were reported in 58.2%, 59.7%, 59.0%, and 63.2% of patients who received 150 mg, 300 mg, 450 mg, and placebo, respectively; severe TEAEs were reported in 8.5%, 8.0%, 8.5%, and 9.0%; and serious TEAEs were reported in 2.5%, 3.0%, 2.0%, and 4.0%. The most common TEAEs were abdominal pain (150 mg, 5.5%; 300 mg, 8.0%; 450 mg, 10.5%; placebo, 8.5%), nausea (6.5%, 8.0%, 6.0%, 9.0%), and diarrhea (3.5%, 6.5%, 8.0%, 3.5%); the most common drug-related TEAEs were abdominal pain (4.0%; 5.5%; 9.0%; 5.0%), nausea (3.5%, 5.5%, 5.5%, 4.0%), and flatulence (4.5%, 3.5%, 5.0%, 3.0%). Serious TEAEs reported in ≥2 patients were dyspnea (150 mg, n=1; placebo, n=2), noncardiac chest pain (placebo, n=2), chest pain (300 mg, n=2), and suicidal ideation (150 mg, n=1; 300 mg, n=1). TEAEs led to discontinuation in 3.4% of patients (150 mg, 1.0%; 300 mg, 4.5%; 450 mg, 3.5%; placebo, 4.5%). TEAEs resulting in discontinuation in ≥2 patients were diarrhea (300 mg, n=2; 450 mg, n=1; placebo, n=1), abdominal pain (300 mg, n=1; 450 mg, n=1), and dyspnea (150 mg, n=1; 450 mg, n=1).
Discussion: Our data demonstrated that once-daily oral methylnaltrexone was well tolerated, with few discontinuations due to TEAEs, in this study of patients with OIC and chronic noncancer pain. Oral methylnaltrexone provides a viable alternative to subcutaneous methylnaltrexone, particularly among patients requiring long-term treatment of OIC or who have difficulty with administration by subcutaneous injection.