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

Abstract

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 hydromorphone+dronabinol 5 mg showed the highest risk for abuse. Hydromorphone+dronabinol 10 mg produced a high rate of dysphoric effects, and hydromorphone+dronabinol 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 hydromorphone+dronabinol 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.

Opioid-sparing effect of cannabinoids for analgesia: an updated systematic review and meta-analysis of preclinical and clinical studies

“…Five laboratory-based studies in healthy volunteers ( n = 82) examined pain responses with co-administered opioids and cannabinoids using double-blind within-patient study designs (Table 2a ). Four studies examined oral dronabinol (2.5–20 mg) [ 59 – 62 ] and one examined smoked cannabis [ 63 ]. Inconsistent outcomes were observed; two studies found evidence of increased pain, two found some measures of decreased pain, and one study found effects of cannabinoids on pain “unpleasantness” but not pain ratings.…”

“…This was in contrast to the analgesic effect observed on pain threshold and tolerance with a cold pressor test when smoked cannabis was administered with 5 mg oxycodone compared oxycodone or cannabis alone, although effects were not found on measure of outcomes of pain intensity or bothersomeness [ 63 ]. Dunn et al [ 62 ] demonstrated analgesic effects from dronabinol 2.5 mg when co-administered with hydromorphone on thermal pain measures, but not with higher doses of dronabinol, or on other measures of pain. Roberts et al [ 60 ] found that the co-administration of dronabinol and morphine resulted in reduced pain “unpleasantness” compared to either drug alone.…”

“…A limited number of controlled studies demonstrated benefits of combining cannabinoids with opioids for analgesia. Experimental pain studies found cannabinoids improved [ 62 , 63 ] and worsened [ 61 ] analgesia. These effects were not dose dependent, with significant effects seen with lower but not higher doses of delta-9-THC.…”

Do We Have Structure, Process and Outcomes to Support Cannabis as Supportive Therapy in Cancer?

“…The 10 mg dronabinol dose with hydromorphone produced hyperalgesia. The” drug liking” effect relative to hydromorphone alone increased with dronabinol 5 in 10 mg. 76 In a similar manner, cannabis tolerant individuals experienced analgesia from experimental pain at the with 1.29% vaporized THC THC dose which did not increase with 3.5% vaporized cannabis. The “like drug effect” and “desire for more of this drug” increased with the dose.…”

Medicinal Cannabis and Central Nervous System Disorders

“…A clinical trial utilizing healthy participants with no prior indication of pathological pain had observed that orally administered THC (dronabinol, 5 mg) was not able enhance the analgesic effects of oxycodone in coadministrations and reported an increase in both abuse and impairment related effects associated with opioid use ( Babalonis et al, 2019 ). A similar study in healthy subjects also reported that THC (dronabinol, max 10 mg) had no consistent dose-effect relationship with the opioid agonist hydromorphone in measures of both acute and chronic pain, though significant analgesia in acute pain with hydropmorphone and 2.5 mg dronabinol compared to placebo was observed ( Dunn et al, 2021 ). Additionally, a clinical trial utilizing healthy cannabis smokers found that the combination of oxycodone (2.5 mg) and cannabis (cigarettes, 5.6% THC) was not able to provide analgesia in measures of acute pain and increased abuse-related subjective effects but did increase pain thresholds and tolerance ( Cooper et al, 2018 ).…”