Analysis of opioid-mediated analgesia in Phase III studies of methylnaltrexone for opioid-induced constipation in patients with chronic noncancer pain
Authors Webster LR, Brenner DM, Barrett AC, Paterson C, Bortey E, Forbes WP
Received 8 May 2015
Accepted for publication 24 August 2015
Published 30 October 2015 Volume 2015:8 Pages 771—780
Checked for plagiarism Yes
Review by Single-blind
Peer reviewers approved by Dr Kerui Gong
Peer reviewer comments 5
Editor who approved publication: Professor Michael Schatman
Lynn R Webster,1 Darren M Brenner,2 Andrew C Barrett,3 Craig Paterson,3 Enoch Bortey,3 William P Forbes3
1PRA Health Sciences, Salt Lake City, UT, 2Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, 3Salix, a Division of Valeant Pharmaceuticals North America LLC, Bridgewater, NJ, USA
Background: Subcutaneous methylnaltrexone is efficacious and well tolerated for opioid-induced constipation (OIC) but may theoretically disrupt opioid-mediated analgesia.
Methods: Opioid use, pain intensity, and opioid withdrawal (Objective Opioid Withdrawal Scale [OOWS] and Subjective Opiate Withdrawal Scale [SOWS] scores) were reported in a randomized, double-blind trial with an open-label extension (RCT) and an open-label trial (OLT) evaluating safety in adults with chronic noncancer pain. In the RCT, patients taking ≥50 mg of oral morphine equivalents daily with <3 rescue-free bowel movements weekly received methylnaltrexone 12 mg once daily (n=150), every other day (n=148), or placebo (n=162) for 4 weeks, followed by open-label methylnaltrexone 12 mg (as needed [prn]; n=364) for 8 weeks. In the OLT, patients (n=1,034) on stable opioid doses with OIC received methylnaltrexone 12 mg prn for up to 48 weeks.
Results: Minimal fluctuations of median morphine equivalent dose from baseline (BL) were observed in the RCT double-blind period (BL, 154.8–161.0 mg/d; range, 137.1–168.0 mg/d), RCT open-label period (BL, 156.3–174.6; range, 144.0–180.0) and OLT (BL, 120 mg/d; range, 117.3–121.1 mg/d). No significant change from BL in pain intensity score occurred in any group at weeks 2 or 4 (both P≥0.1) of the RCT double-blind period, and scores remained stable during the open-label period and in the OLT (mean change, —0.2 to 0.1). Changes from BL in OOWS and SOWS scores during the double-blind period were not significantly impacted by methylnaltrexone exposure at weeks 2 or 4 (P>0.05 for all).
Conclusion: Methylnaltrexone did not affect opioid-mediated analgesia in patients with chronic noncancer pain and OIC.
Keywords: Relistor, mu-opioid receptor, antagonist, opioids, tolerance, withdrawal
Corrigendum for this paper has been published.
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