title: Analysis of opioid-mediated analgesia in Phase III studies of methylnaltrexone for opioid-induced constipation in patients with chronic noncancer pain.
abstract: 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 methyl naltrexone 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).
  
  
  CONCLUSIONS
  Methylnaltrexone did not affect opioid-mediated analgesia in patients with chronic noncancer pain and OIC.
authors.affiliation: PRA Health Sciences, Salt Lake City, UT, USA.
authors.forename: Lynn R
authors.initials: LR
authors.lastname: Webster
authors.affiliation: Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Darren M
authors.initials: DM
authors.lastname: Brenner
authors.affiliation: Salix, a Division of Valeant Pharmaceuticals North America LLC, Bridgewater, NJ, USA.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Barrett
authors.affiliation: Salix, a Division of Valeant Pharmaceuticals North America LLC, Bridgewater, NJ, USA.
authors.forename: Craig
authors.initials: C
authors.lastname: Paterson
authors.affiliation: Salix, a Division of Valeant Pharmaceuticals North America LLC, Bridgewater, NJ, USA.
authors.forename: Enoch
authors.initials: E
authors.lastname: Bortey
authors.affiliation: Salix, a Division of Valeant Pharmaceuticals North America LLC, Bridgewater, NJ, USA.
authors.forename: William P
authors.initials: WP
authors.lastname: Forbes
keywords: Relistor; antagonist; mu-opioid receptor; opioids; tolerance; withdrawal