Analgesia maintenance with oral methylnaltrexone in patients with opioid-induced constipation and chronic noncancer pain in 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: In July 2016, oral methylnaltrexone was approved for the treatment of opioid induced constipation (OIC) in chronic noncancer pain patients. This analysis assessed the potential impact of oral methylnaltrexone, a peripherally acting µ-opioid receptor antagonist, on opioid analgesia in a randomized, controlled trial.
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, followed by 8 weeks of oral methylnaltrexone or placebo taken as needed. Double-blinding was maintained during the study. Opioid use was recorded daily. On days 1, 14, 28, 42, 56, and 84, changes in Numerical Rating of Pain Intensity Scale scores (where 0 = no pain and 10 = worst possible pain) and opioid withdrawal (based on the Objective Opioid Withdrawal Scale [OOWS] and the Subjective Opioid Withdrawal Scale [SOWS]) were evaluated.
Results: Overall, 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). Demographics were similar among treatment groups. At baseline, the main condition requiring opioid use was back pain, reported by 65.7%, 67.7%, 67.5%, and 72.1% of patients in the 150-mg, 300-mg, 450-mg, and placebo groups, respectively. Pain intensity scores were similar among groups at baseline (mean scores, 6.15–6.38) and remained stable through the 4-week once-daily period (mean scores on day 28, 6.13–6.49) and the 8-week as-needed period (mean scores on day 84, 6.21–6.45). Patients in all groups had a median exposure of 83 d; ranges were similar among groups (150 mg, 1–94 d; 300 mg, 1–91 d; 450 mg, 1–99 d; placebo, 3–91 d). Mean changes from baseline in the OOWS score were minimal in all groups (ranged from −0.14 to 0.06); similar results were obtained when abdominal cramping was excluded from the analysis (−0.16 to 0.07). Abdominal cramping might be a confounding factor because it is associated with both constipation and the mechanism of action of methylnaltrexone. Mean changes from baseline in the SOWS score were also minimal in all groups (−4.73 to −0.06), and similar results were obtained when abdominal cramping was excluded (−4.45 to −0.16).
Discussion: Once-daily oral methylnaltrexone did not interfere with opioid analgesia and was not associated with opioid withdrawal signs or symptoms in this trial. These data support methylnaltrexone as an option for OIC treatment, without potential concerns about compromising pain management strategies in patients with chronic noncancer pain.