Safety of oral dronabinol during opioid withdrawal in humans.
BACKGROUND
Opioid dependence remains a significant public health problem worldwide with only three FDA-approved treatments, all targeting the mu-opioid receptor. Dronabinol, a cannabinoid (CB) 1 receptor agonist, is currently under investigation as a novel opioid withdrawal treatment. This study reports on safety outcomes of dronabinol among adults in opioid withdrawal.


METHODS
Twelve adults physically dependent on short-acting opioids participated in this 5-week within-subject, randomized, double blind, placebo-controlled inpatient study. Volunteers were maintained on oral oxycodone 30 mg qid. Double-blind placebo substitutions occurred for 21 h before each of 7 experimental sessions in order to produce opioid withdrawal. A single oral test dose was administered each session (placebo, oxycodone 30 and 60 mg, dronabinol 5, 10, 20, and 30 mg [decreased from 40 mg]). Heart rate, blood pressure, respiratory outcomes and pupil diameter were assessed repeatedly.


RESULTS
Dronabinol 40 mg produced sustained sinus tachycardia accompanied by anxiety and panic necessitating dose reduction to 30 mg. Sinus tachycardia and anxiety also occurred in one volunteer after dronabinol 20mg. Compared to placebo, dronabinol 20 and 30 mg produced significant increases in heart rate beginning 1h after drug administration that lasted approximately 2h (p<0.05). Dronabinol 5 and 10mg produced placebo-like effects. Oxycodone produced prototypic mu-opioid agonist effects (e.g., miosis).


CONCLUSIONS
Dronabinol 20mg and higher increased heart rate among healthy adults at rest who were in a state of opioid withdrawal, raising concern about its safety. These results have important implications for future dosing strategies and may limit the utility of dronabinol as a treatment for opioid withdrawal.
University of Kentucky College of Medicine (UK COM), Center on Drug and Alcohol Research, 845 Angliana Ave., Lexington, KY 40508, United States. Electronic address: crystal.jicha@uky.edu.
Crystal J
CJ
Jicha
University of Kentucky College of Medicine (UK COM), Center on Drug and Alcohol Research, 845 Angliana Ave., Lexington, KY 40508, United States; UK COM, Department of Behavioral Science, Lexington, KY 40536, United States; UK COM, Department of Psychiatry, Lexington, KY 40509, United States. Electronic address: michelle.lofwall@uky.edu.
Michelle R
MR
Lofwall
UK COM, Department of Behavioral Science, Lexington, KY 40536, United States. Electronic address: pnuzz2@uky.edu.
Paul A
PA
Nuzzo
University of Kentucky College of Medicine (UK COM), Center on Drug and Alcohol Research, 845 Angliana Ave., Lexington, KY 40508, United States; UK COM, Department of Behavioral Science, Lexington, KY 40536, United States. Electronic address: babalonis@uky.edu.
Shanna
S
Babalonis
UK COM, Department of Cardiology, Gill Heart Institute, Lexington, KY 40536, United States. Electronic address: samy-claude.elayi@uky.edu.
Samy Claude
SC
Elayi
University of Kentucky College of Medicine (UK COM), Center on Drug and Alcohol Research, 845 Angliana Ave., Lexington, KY 40508, United States; UK COM, Department of Behavioral Science, Lexington, KY 40536, United States; UK COM, Department of Psychiatry, Lexington, KY 40509, United States. Electronic address: sharon.walsh@uky.edu.
Sharon L
SL
Walsh
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000701:Analgesics, Opioid / Q000008:administration & dosage; D001794:Blood Pressure / Q000187:drug effects; D063386:Cannabinoid Receptor Agonists / Q000008:administration & dosage / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D013759:Dronabinol / Q000008:administration & dosage / Q000009:adverse effects*; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D009293:Opioid-Related Disorders / Q000188:drug therapy*; D010098:Oxycodone / Q000008:administration & dosage; D011680:Pupil / Q000187:drug effects; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy*; D013616:Tachycardia, Sinus / Q000139:chemically induced; D016896:Treatment Outcome; D055815:Young Adult
D000701:Analgesics, Opioid; D063386:Cannabinoid Receptor Agonists; D013759:Dronabinol; D010098:Oxycodone
Dronabinol; Opioid dependence; Opioid withdrawal; Safety; Treatment