• Opioid;
  • Antagonist;
  • Opioid-Induced Constipation;
  • Neutral Antagonist;
  • 6β-Naltrexol


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.

Design.  Volunteers participated in a randomized, double-blind, placebo-controlled, five-way crossover study under an Exploratory Investigational New Drug application.

Interventions.  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.

Subjects.  Ten healthy, opioid-naïve male volunteers were enrolled in the study.

Outcome Measures.  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 (ED50) 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.