Enadoline, a selective kappa opioid agonist: comparison with butorphanol and hydromorphone in humans

Rationale: The availability of the highly selective and specific kappa opioid agonist enadoline provides an opportunity to explore the function of kappa receptors in humans and their potential utility as a target for substance abuse pharmacotherapy development. Objectives: The purpose of this study was to characterize the pharmacodynamic effects of enadoline, a selective kappa agonist, and to compare it with butorphanol, a mixed mu/kappa agonist, and hydromorphone, a mu agonist, in humans. Methods: Pilot evaluation (n=3) served to establish intramuscular doses of enadoline (20, 40, 80, and 160 mug/70 kg), butorphanol (1.5, 3, 6, and 12 mg/70 kg), and hydromorphone (1.5, 3, and 6 mg/70 kg) of comparable activity. These acute doses were examined under double-blind, placebo-controlled and constrained randomized conditions with a minimum of 72 h between tests in volunteers with polysubstance abuse histories (n=6). Physiological and subject- and observer-rated measures were collected 30 min before and for 4 h after administration. Results: Enadoline significantly increased measures of sedation, confusion and dizziness, produced visual distortions and feelings of depersonalization, and increased urinary output. The highest dose (160 mug/70 kg) was not tolerated and led to psychotomimetic effects. Hydromorphone produced prototypic mu opioid effects including respiratory depression, miosis, and euphoria. Butorphanol was most similar to hydromorphone and shared few effects with enadoline. Conclusions: These results are discussed with respect to the potential use and safety of kappa agonists for clinical indications.