Safety of oral dronabinol during opioid withdrawal in humans

Abstract

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).

Conclusion: 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.

Keywords: Dronabinol; Opioid dependence; Opioid withdrawal; Safety; Treatment.

Figure 1. Physiologic time course data for heart rate, blood pressure and pupil diameter

Time action curves for heart rate, systolic and diastolic blood pressure, and pupil diameter are shown as mean data (n=12 for placebo, oxycodone 30 and 60mg, and dronabinol 5, 10, and 20, but n=9 for dronabinol 30 mg). B indicates baseline. Data from dronabinol dose conditions and placebo are shown in the left figures while the placebo and positive oxycodone control condition are shown in the right figures. Error bars are omitted for clarity; however, Table 1 shows the standard errors for each dose condition for these outcomes and illustrates the magnitude of variability in peak effects. Black symbols indicate a significant difference from placebo (p<0.05). Data from subjects 1 (S1) and 2 (S2), the only two volunteers (in gray) who received dronabinol 40 mg, are also displayed in the left figures (these data were not included in the analyses but are shown here for illustrative purposes). There was a significant main effect of dose (F_(6,63)=14.3, p<0.0001) and dose x time interaction for heart rate (F_(150,1575)=2.0, p<0.0001) as well as for pupil diameter (main effect of dose: F_(6,63)=15.2, p<0.0001; dose x time interaction: F_{(144, 1508)}=2.2, p<0.0001). A significant effect of dose was found for systolic and diastolic blood pressure (SBP: F_(6,63)=4.7, p=0.001; DBP: F_(6,63)=5.3, p<0.0001).