Randomised clinical trial: the long-term safety and tolerability of naloxegol in patients with pain and opioid-induced constipation

Aliment Pharmacol Ther. 2014 Oct;40(7):771-9. doi: 10.1111/apt.12899. Epub 2014 Aug 12.

Abstract

Background: Opioid-induced constipation (OIC) is a common adverse effect of opioid therapy.

Aim: To evaluate the long-term safety and tolerability of naloxegol, an oral, peripherally acting μ-opioid receptor antagonist (PAMORA), in patients with noncancer pain and OIC.

Methods: A 52-week, multicenter, open-label, randomised, parallel-group phase 3 study was conducted in out-patients taking 30-1000 morphine-equivalent units per day for ≥4 weeks. Patients were randomised 2:1 to receive naloxegol 25 mg/day or usual-care (UC; investigator-chosen laxative regimen) treatment for OIC.

Results: The safety set comprised 804 patients (naloxegol, n = 534; UC, n = 270). Mean exposure duration was 268 days with naloxegol and 297 days with UC. Frequency of adverse events (AEs) was 81.8% with naloxegol and 72.2% with UC. Treatment-emergent AEs occurring more frequently for naloxegol vs. UC were abdominal pain (17.8% vs. 3.3%), diarrhoea (12.9% vs. 5.9%), nausea (9.4% vs. 4.1%), headache (9.0% vs. 4.8%), flatulence (6.9% vs. 1.1%) and upper abdominal pain (5.1% vs. 1.1%). Most naloxegol-emergent gastrointestinal AEs occurred early, resolving during or after naloxegol discontinuation and were mild or moderate in severity; 11 patients discontinued due to diarrhoea and nine patients owing to abdominal pain. Pain scores and mean daily opioid doses remained stable throughout the study; no attributable opioid withdrawal AEs were observed. Two patients in each group had an adjudicated major adverse cardiovascular event unrelated to study drug; no AEs were reported nor adjudicated as bowel perforations.

Conclusion: In patients with noncancer pain and opioid-induced constipation, naloxegol 25 mg/day up to 52 weeks was generally safe and well tolerated.

Trial registration: ClinicalTrials.gov NCT01336205.

Publication types

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

MeSH terms

  • Adult
  • Aged
  • Analgesics, Opioid / adverse effects
  • Constipation / chemically induced
  • Constipation / drug therapy*
  • Female
  • Humans
  • Laxatives / adverse effects
  • Laxatives / therapeutic use*
  • Male
  • Middle Aged
  • Morphinans / adverse effects
  • Morphinans / therapeutic use*
  • Morphine / adverse effects
  • Narcotic Antagonists / adverse effects
  • Narcotic Antagonists / therapeutic use*
  • Pain / drug therapy*
  • Polyethylene Glycols / adverse effects
  • Polyethylene Glycols / therapeutic use*

Substances

  • Analgesics, Opioid
  • Laxatives
  • Morphinans
  • Narcotic Antagonists
  • Polyethylene Glycols
  • naloxegol
  • Morphine

Associated data

  • ClinicalTrials.gov/NCT01336205