6ß-naltrexol, a peripherally selective opioid antagonist that inhibits morphine-induced slowing of gastrointestinal transit: an exploratory study.

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 6ß-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: 6ß-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 6ß-naltrexol was 11.1±2.4 hours. 6ß-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 6ß-naltrexol doses up to 20 mg on morphine-induced analgesia or pupil constriction. Intravenous 6ß-naltrexol infusion over 30 minutes was well-tolerated up to the highest dose tested. CONCLUSIONS: 6ß-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.

6beta-naltrexol preferentially antagonizes opioid effects on gastrointestinal transit compared to antinociception in mice.

AIMS: The current studies were designed to compare the in vivo potencies of the opioid antagonists 6beta-naltrexol and naltrexone in blocking the effects of the opioid agonist hydrocodone following intravenous (i.v.) or oral (p.o.) administration. MAIN METHODS: Adult male CD-1 mice were used for all experiments. The 55 degrees C tail-flick assay was used to assess the CNS antinociceptive activity of hydrocodone, and a charcoal meal gastrointestinal transit assay was used to assess the peripheral effects of hydrocodone. Graded antagonist dose-response curves for i.v. and p.o. 6beta-naltrexol and naltrexone were generated to determine ID(50) antagonist potency estimates against fixed doses of hydrocodone. KEY FINDINGS: Both antagonists produced dose-related blockade of hydrocodone-induced antinociception and inhibition of gastrointestinal transit. Naltrexone was between 5- and 13-fold more potent than 6beta-naltrexol in blocking a CNS effect of hydrocodone, whereas the drugs were nearly equipotent in blocking inhibition of gastrointestinal transit. Co-administration studies indicated an approximate 10-fold greater potency of 6beta-naltrexol for antagonism of hydrocodone-induced inhibition of gastrointestinal transit versus antinociception, whereas naltrexone blocked both effects with near equal potency. 6beta-naltrexol produced a longer duration of antagonist blockade and had a slower time to peak effect compared to naltrexone. SIGNIFICANCE: The pharmacology of 6beta-naltrexol differentiates it from currently available opioid antagonists. This includes an intermediate selectivity for peripheral versus central opioid receptors, a long duration of action, and neutral antagonist qualities in opioid exposed systems. These properties render it a drug candidate for a co-formulation product with opioid analgesics to reduce peripheral opioid side effects and limit abuse potential.