Within-subject, double-blinded, randomized, and placebo-controlled evaluation of the combined effects of the cannabinoid dronabinol and the opioid hydromorphone in a human laboratory pain model.
This Phase II study evaluated analgesia, abuse liability, and cognitive performance of hydromorphone and oral delta-9-tetrahydrocannabinol (THC dronabinol) using a within-subject, double-blind, randomized, placebo-controlled, human laboratory trial. Healthy adults (N 29) with no history of drug use disorder received combinations of placebo, hydromorphone (4 mg oral), and dronabinol (2.5 mg, 5.0 mg, 10 mg oral). Primary outcomes were quantitative sensory testing (QST) measures of acute (thermal, pressure pain thermal, punctate probe temporal summation cold pressor conditioned pain modulation) and chronic pain (capsaicin 10% topical cream with thermal rekindling), measures of drug abuse liability, cognitive functioning, and adverse events. Subgroup analyses were conducted within opioid-responders (endorsed >20 on a Drug Effect visual analog scale during the hydromorphone-only condition) and nonresponders. A consistent dose-effect relationship of dronabinol on hydromorphone across all measures was not observed. Analgesia only improved in the hydromorphone dronabinol 2.5 mg condition. Hydromorphone dronabinol 2.5 mg showed the lowest and hydromorphonedronabinol 5 mg showed the highest risk for abuse. Hydromorphonedronabinol 10 mg produced a high rate of dysphoric effects, and hydromorphonedronabinol 5 mg and hydromorphone dronabinol 10 mg produced AEs. Subgroup analyses showed subjective effects and abuse risk was increased among opioid responders and largely absent among nonresponders. Overall, only hydromorphonedronabinol 2.5 mg modestly enhanced hydromorphone-based analgesia and hydromorphone dronabinol 5 mg and 10 mg increased risk for abuse and AEs. These data can help inform opioid-sparing efforts in clinical pain populations. Demonstration that potential opioid effects varied as a function of participant opioid sensitivity (e.g., responder status) is a novel finding that warrants additional research.