Safety of oral dronabinol during opioid withdrawal in humans

Abstract

BackgroundOpioid 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. MethodsTwelve 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 30mgqid. Double-blind placebo substitutions occurred for 21h 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 60mg, dronabinol 5, 10, 20, and 30mg [decreased from 40mg]). Heart rate, blood pressure, respiratory outcomes and pupil diameter were assessed repeatedly. ResultsDronabinol 40mg produced sustained sinus tachycardia accompanied by anxiety and panic necessitating dose reduction to 30mg. Sinus tachycardia and anxiety also occurred in one volunteer after dronabinol 20mg. Compared to placebo, dronabinol 20 and 30mg 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). ConclusionDronabinol 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.