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

Rationale: The availability of the highly selective and specific kappa opio id agonist enadoline provides an opportunity to explore the function of kap pa receptors in humans and their potential utility as a target for substanc e abuse pharmacotherapy development. Objectives: The purpose of this study was to characterize the pharmacodynamic effects of enadoline, a selective k appa 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 exami ned under double-blind, placebo-controlled and constrained randomized condi tions with a minimum of 72 h between tests in volunteers with polysubstance abuse histories (n=6). Physiological and subject- and observer-rated measu res were collected 30 min before and for 4 h after administration. Results: Enadoline significantly increased measures of sedation, confusion and dizz iness, produced visual distortions and feelings of depersonalization, and i ncreased urinary output. The highest dose (160 mug/70 kg) was not tolerated and led to psychotomimetic effects. Hydromorphone produced prototypic mu o pioid effects including respiratory depression, miosis, and euphoria. Butor phanol was most similar to hydromorphone and shared few effects with enadol ine. Conclusions: These results are discussed with respect to the potential use and safety of kappa agonists for clinical indications.