title: Naloxegol for opioid-induced constipation in patients with noncancer pain.
abstract: BACKGROUND
  Opioid-induced constipation is common and debilitating. We investigated the efficacy and safety of naloxegol, an oral, peripherally acting, μ-opioid receptor antagonist, for the treatment of opioid-induced constipation.
  
  
  METHODS
  In two identical phase 3, double-blind studies (study 04, 652 participants; study 05, 700 participants), outpatients with noncancer pain and opioid-induced constipation were randomly assigned to receive a daily dose of 12.5 or 25 mg of naloxegol or placebo. The primary end point was the 12-week response rate (≥3 spontaneous bowel movements per week and an increase from baseline of ≥1 spontaneous bowel movements for ≥9 of 12 weeks and for ≥3 of the final 4 weeks) in the intention-to-treat population. The key secondary end points were the response rate in the subpopulation of patients with an inadequate response to laxatives before enrollment, time to first postdose spontaneous bowel movement, and mean number of days per week with one or more spontaneous bowel movements.
  
  
  RESULTS
  Response rates were significantly higher with 25 mg of naloxegol than with placebo (intention-to-treat population: study 04, 44.4% vs. 29.4%, P=0.001; study 05, 39.7% vs. 29.3%, P=0.02; patients with an inadequate response to laxatives: study 04, 48.7% vs. 28.8%, P=0.002; study 05, 46.8% vs. 31.4%, P=0.01); in study 04, response rates were also higher in the group treated with 12.5 mg of naloxegol (intention-to-treat population, 40.8% vs. 29.4%, P=0.02; patients with an inadequate response to laxatives, 42.6% vs. 28.8%, P=0.03). A shorter time to the first postdose spontaneous bowel movement and a higher mean number of days per week with one or more spontaneous bowel movements were observed with 25 mg of naloxegol versus placebo in both studies (P<0.001) and with 12.5 mg of naloxegol in study 04 (P<0.001). Pain scores and daily opioid dose were similar among the three groups. Adverse events (primarily gastrointestinal) occurred most frequently in the groups treated with 25 mg of naloxegol.
  
  
  CONCLUSIONS
  Treatment with naloxegol, as compared with placebo, resulted in a significantly higher rate of treatment response, without reducing opioid-mediated analgesia. (Funded by AstraZeneca; KODIAC-04 and KODIAC-05 ClinicalTrials.gov numbers, NCT01309841 and NCT01323790, respectively.).
authors.affiliation: From the Department of Internal Medicine, University of Michigan Health System, Ann Arbor (W.D.C.); PRA International, Salt Lake City (L.W.); AstraZeneca Pharmaceuticals, Wilmington, DE (M.S., J.L., P.N.B.); and the Translational Research Center for Gastrointestinal Disorders (TARGID), University of Leuven, Leuven, Belgium (J.T.).
authors.forename: William D
authors.initials: WD
authors.lastname: Chey
authors.forename: Lynn
authors.initials: L
authors.lastname: Webster
authors.forename: Mark
authors.initials: M
authors.lastname: Sostek
authors.forename: Jaakko
authors.initials: J
authors.lastname: Lappalainen
authors.forename: Peter N
authors.initials: PN
authors.lastname: Barker
authors.forename: Jan
authors.initials: J
authors.lastname: Tack
mesh_terms: D000328:Adult; D000701:Analgesics, Opioid / Q000009:adverse effects*; D003248:Constipation / Q000139:chemically induced / Q000188:drug therapy*; D003672:Defecation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009019:Morphinans / Q000008:administration & dosage* / Q000009:adverse effects; D009292:Narcotic Antagonists / Q000008:administration & dosage* / Q000009:adverse effects; D010146:Pain / Q000188:drug therapy; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000009:adverse effects; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors*
chemical_list: D000701:Analgesics, Opioid; D009019:Morphinans; D009292:Narcotic Antagonists; D017450:Receptors, Opioid, mu; D011092:Polyethylene Glycols; C000589308:naloxegol