A phase 2, double-blind, randomized, placebo-controlled, dose-escalation study to evaluate the efficacy, safety, and tolerability of naloxegol in patients with opioid-induced constipation

Pain. 2013 Sep;154(9):1542-1550. doi: 10.1016/j.pain.2013.04.024. Epub 2013 Apr 16.


Naloxegol (previously known as NKTR-118) is a peripherally acting μ-opioid receptor antagonist engineered using polymer conjugate technology in development as an oral, once-daily agent for the treatment of opioid-induced constipation (OIC). Eligible patients with OIC (n=207), defined as <3 spontaneous bowel movements (SBMs) per week with accompanying symptoms, on a stable opioid regimen of 30-1000 mg/day morphine equivalents for ≥ 2 weeks were randomized to receive 4 weeks of double-blind placebo or naloxegol (5, 25, or 50mg) once daily in sequential cohorts after a 1-week placebo run-in. The primary end point, median change from baseline in SBMs per week after week 1 of drug administration, was statistically significant for the 25- and 50-mg naloxegol cohorts vs placebo (2.9 vs 1.0 [P=0.0020] and 3.3 vs 0.5 [P=0.0001], respectively). The increase in SBMs vs placebo was maintained over 4 weeks for naloxegol 25mg (3.0 vs 0.8 [P=0.0022]) and 50mg (3.5 vs 1.0 [P<0.0001]). Naloxegol was generally well tolerated across all dosages. The most frequent adverse events (AEs) were abdominal pain, diarrhea, and nausea. Most AEs at 5 and 25mg/day were mild and transient. Similar AEs occurred with increased frequency and severity in the 50-mg cohort. There was no evidence of a statistically significant increase from baseline in pain, opioid use for the 25- and 50-mg cohorts, or centrally mediated opioid withdrawal signs and/or symptoms with naloxegol. These data demonstrate that once-daily oral naloxegol improves the frequency of SBMs compared with placebo and is generally well tolerated in this population of patients with OIC.

Keywords: Constipation; NKTR-118; Naloxegol; Naloxol; Naloxone; Opioid.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Analgesics, Opioid / adverse effects
  • Cohort Studies
  • Constipation / chemically induced
  • Constipation / drug therapy*
  • Constipation / psychology
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Female
  • Humans
  • International Cooperation
  • Male
  • Middle Aged
  • Naloxone / administration & dosage*
  • Narcotic Antagonists / administration & dosage*
  • Quality of Life
  • Surveys and Questionnaires
  • Time Factors


  • Analgesics, Opioid
  • Narcotic Antagonists
  • Naloxone