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


OBJECTIVE
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 microg/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 microg/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.
Walsh
S L
SL
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21224, USA. swalsh@jhmi.edu
Strain
E C
EC
Abreu
M E
ME
Bigelow
G E
GE
D000328:Adult; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000704:Analysis of Variance; D001572:Benzofurans / Q000494:pharmacology* / Q000627:therapeutic use; D002077:Butorphanol / Q000494:pharmacology*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006556:Heroin Dependence / Q000188:drug therapy; D006801:Humans; D004091:Hydromorphone / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D010865:Pilot Projects; D011759:Pyrrolidines / Q000494:pharmacology* / Q000627:therapeutic use; D017473:Receptors, Opioid, kappa / Q000819:agonists* / Q000502:physiology
D000701:Analgesics, Opioid; D001572:Benzofurans; D018696:Neuroprotective Agents; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; C067110:enadoline; D004091:Hydromorphone; D002077:Butorphanol