Authors: Hamilton KR et al.
Anesthesiology December 31, 2025
Summary
This double-blind, randomized, placebo-controlled, within-subject crossover trial evaluated the acute analgesic effects and drug-related outcomes of dronabinol, hydromorphone, and their combination in adults with knee osteoarthritis. Twenty-one participants with a mean age of 63 years received four oral dosing conditions across separate sessions: placebo, hydromorphone alone, dronabinol alone, and hydromorphone combined with dronabinol. Pain outcomes, quantitative sensory testing measures, physical and cognitive performance, subjective drug effects, and adverse events were assessed over a four-hour post-dosing period.
Hydromorphone produced modest analgesic effects on select experimentally induced pain measures, including improved pressure pain thresholds and reduced mechanical temporal summation compared with placebo. In contrast, dronabinol alone did not demonstrate significant analgesic benefit across experimental or clinical pain measures. Neither drug, alone or in combination, resulted in meaningful reductions in clinical knee pain severity or improvements in most experimental pain outcomes, including thermal pain thresholds, cold pressor tolerance, conditioned pain modulation, or measures of central sensitization.
Importantly, combining hydromorphone with dronabinol did not enhance analgesia beyond hydromorphone alone. The combination was associated with greater cognitive impairment, including slower working memory reaction times, and higher subjective drug effects such as feeling “high,” greater overall drug effects, and increased nausea compared with hydromorphone alone. Hydromorphone impaired working memory accuracy, while dronabinol produced higher subjective intoxication ratings than hydromorphone. There were no significant differences among conditions in physical functioning, fine motor performance, drug liking, or adverse event frequency or severity.
Overall, opioid and cannabinoid medications failed to produce robust analgesia for experimentally induced or clinical pain in patients with knee osteoarthritis, and there was no evidence of synergistic analgesic benefit from combining these agents.
What You Should Know
This controlled human trial found no clinically meaningful analgesic advantage to combining a cannabinoid with an opioid for knee osteoarthritis pain. While hydromorphone showed limited effects on select experimental pain measures, these did not translate into improved clinical pain, and combination therapy increased cognitive and subjective drug effects without added benefit.
Key Points
• Hydromorphone produced limited analgesia on select experimental pain measures only.
• Dronabinol alone did not demonstrate meaningful analgesic effects.
• No opioid–cannabinoid synergistic analgesia was observed.
• Combination therapy increased cognitive impairment and subjective drug effects without improving pain outcomes.
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