title: 6β-naltrexol, a peripherally selective opioid antagonist that inhibits morphine-induced slowing of gastrointestinal transit: an exploratory study.
abstract: OBJECTIVE
  Opioid-induced constipation is a frequent side effect of opioid pain therapy due to opioid effects on the enteric nervous system, including gastric emptying and fluid absorption. The current exploratory studies were conducted to determine whether the neutral opioid antagonist 6β-naltrexol, the primary metabolite of naltrexone, could selectively inhibit gastrointestinal opioid effects in human subjects.
  
  
  METHODS
  Volunteers participated in a randomized, double-blind, placebo-controlled, five-way crossover study under an Exploratory Investigational New Drug application.
  
  
  METHODS
  6β-Naltrexol has been reported to act as a neutral antagonist with peripheral selectivity in opioid-naïve and opioid-dependent systems in vitro and in vivo.
  
  
  METHODS
  Ten healthy, opioid-naïve male volunteers were enrolled in the study.
  
  
  METHODS
  Oral-cecal transit time was measured using the lactulose-hydrogen breath test. For central nervous system effects, analgesia was evaluated using a cold pressor test, and pupil size was measured. Blood samples were collected over 36 hours for pharmacokinetic analyses.
  
  
  RESULTS
  The mean terminal plasma elimination half-life of 6β-naltrexol was 11.1±2.4 hours. 6β-Naltrexol potently blocked morphine-induced slowing of gastrointestinal transit, with a median effective dose (ED(50) ) of ~3 mg. In contrast, no effect was observed with 6β-naltrexol doses up to 20 mg on morphine-induced analgesia or pupil constriction. Intravenous 6β-naltrexol infusion over 30 minutes was well-tolerated up to the highest dose tested.
  
  
  CONCLUSIONS
  6β-Naltrexol acts as a potent, peripherally selective opioid antagonist. The compound was well-tolerated in this study and may have clinical potential in the therapy of peripheral opioid effects such as opioid-induced constipation.
authors: AIKO Biotechnology Inc., 2 Union Street, Portland, ME 04101, USA. jyancey@aikobiotech.com
authors: Janet
authors: J
authors: Yancey-Wrona
authors: Brian
authors: B
authors: Dallaire
authors: Edward
authors: E
authors: Bilsky
authors: Brad
authors: B
authors: Bath
authors: John
authors: J
authors: Burkart
authors: Lynn
authors: L
authors: Webster
authors: Dan
authors: D
authors: Magiera
authors: Xiaoxia
authors: X
authors: Yang
authors: Mitch
authors: M
authors: Phelps
authors: Wolfgang
authors: W
authors: Sadee
mesh_terms: D000328:Adult; D000818:Animals; D001944:Breath Tests; D003248:Constipation / Q000139:chemically induced*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005772:Gastrointestinal Transit / Q000187:drug effects*; D006801:Humans; D008297:Male; D015877:Miosis / Q000139:chemically induced; D009020:Morphine / Q000009:adverse effects*; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000493:pharmacokinetics / Q000494:pharmacology*; D010146:Pain / Q000188:drug therapy*; D010147:Pain Measurement; D010865:Pilot Projects; D010919:Placebos; D055815:Young Adult
chemical_list: D009292:Narcotic Antagonists; D010919:Placebos; C010410:6 beta-hydroxynaltrexone; D009271:Naltrexone; D009020:Morphine