title: Randomised clinical trial: the long-term safety and tolerability of naloxegol in patients with pain and opioid-induced constipation.
abstract: BACKGROUND
  Opioid-induced constipation (OIC) is a common adverse effect of opioid therapy.
  
  
  OBJECTIVE
  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.
  
  
  CONCLUSIONS
  In patients with noncancer pain and opioid-induced constipation, naloxegol 25 mg/day up to 52 weeks was generally safe and well tolerated.
authors.affiliation: PRA Health Sciences, Salt Lake City, UT, USA.
authors.forename: L
authors.initials: L
authors.lastname: Webster
authors.forename: W D
authors.initials: WD
authors.lastname: Chey
authors.forename: J
authors.initials: J
authors.lastname: Tack
authors.forename: J
authors.initials: J
authors.lastname: Lappalainen
authors.forename: U
authors.initials: U
authors.lastname: Diva
authors.forename: M
authors.initials: M
authors.lastname: Sostek
mesh_terms: D000328:Adult; D000368:Aged; D000701:Analgesics, Opioid / Q000009:adverse effects; D003248:Constipation / Q000139:chemically induced / Q000188:drug therapy*; D005260:Female; D006801:Humans; D054368:Laxatives / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009019:Morphinans / Q000009:adverse effects / Q000627:therapeutic use*; D009020:Morphine / Q000009:adverse effects; D009292:Narcotic Antagonists / Q000009:adverse effects / Q000627:therapeutic use*; D010146:Pain / Q000188:drug therapy*; D011092:Polyethylene Glycols / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D000701:Analgesics, Opioid; D054368:Laxatives; D009019:Morphinans; D009292:Narcotic Antagonists; D011092:Polyethylene Glycols; C000589308:naloxegol; D009020:Morphine