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Oral methylnaltrexone is efficacious and well tolerated for the treatment of opioid-induced constipation in patients with chronic noncancer pain receiving concomitant methadone

Authors Webster LR, Israel RJ

Received 22 December 2017

Accepted for publication 21 September 2018

Published 23 October 2018 Volume 2018:11 Pages 2509—2516


Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 4

Editor who approved publication: Dr E Alfonso Romero-Sandoval

Lynn R Webster,1 Robert J Israel2

1Scientific Affairs, PRA Health Sciences, Salt Lake City, UT, USA; 2Clinical and Medical Affairs, Salix Pharmaceuticals, Bridgewater, NJ, USA

Purpose: To evaluate the safety and efficacy of oral methylnaltrexone for opioid-induced constipation (OIC).
Patients and methods: This was a post hoc analysis of patients receiving methadone in a randomized, double-blind, placebo-controlled, Phase 3 trial. The trial included adults with chronic noncancer pain for ≥2 months receiving opioid doses ≥50 mg/day of oral morphine equivalents for ≥14 days and with a history of OIC. Patients were assigned to oral methylnaltrexone (150, 300, or 450 mg) or placebo once daily (QD) for 4 weeks followed by 8 weeks as needed. Percentage of dosing days that resulted in a rescue-free bowel movement (RFBM) within 4 hours of dosing was assessed during QD dosing (primary efficacy endpoint). Other endpoints included percentage of responders (ie, ≥3 RFBMs/week, with an increase of ≥1 RFBM/week from baseline for ≥3 of the 4 weeks) during QD dosing and change in weekly number of RFBMs. Adverse events were assessed.
Results: Concomitant methadone was reported in 120 patients (oral methylnaltrexone: 150 mg [n=33], 300 mg [n=30], and 450 mg [n=31]; placebo [n=26]). Oral methylnaltrexone-treated patients had significant increases in mean percentage of dosing days with RFBMs within 4 hours of dosing during weeks 1–4 with 300 mg (33.6%; P<0.01) and 450 mg (38.2%; P<0.001) vs placebo; improvements with 150 mg (20.0%) vs placebo (15.1%) did not reach statistical significance. The percentage of responders was greater vs placebo, but not significant, for the higher doses during the QD period (150 mg [39.4%], 300 mg [60.0%], 450 mg [67.7%], and placebo [38.5%]). Change from baseline in the mean number of weekly RFBMs (weeks 1–4) was significantly greater with oral methylnaltrexone 450 mg vs placebo (least-squares mean difference vs placebo, 1.2; P=0.04); no significant differences were found for 300 or 150 mg. Oral methylnaltrexone was well tolerated at all doses; few patients discontinued treatment.
Conclusion: Oral methylnaltrexone, particularly 450 mg, was efficacious and safe for treating OIC in these patients.

Keywords: methylnaltrexone, methadone, opioid-induced constipation, µ-opioid receptor antagonist, chronic pain

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