Small knee-surgery trial found no significant opioid reduction in main…

Cannabidiol (CBD) is a non-intoxicating phytocannabinoid with limited clinical evidence of its analgesic and opioid sparing effects. In the United States, the oral cannabidiol solution, Epidiolex®, is FDA-approved for intractable seizures. We conducted an off-label pilot randomized trial to evaluate its perioperative effects in patients undergoing bilateral total knee arthroplasty (BTKA). After IRB-approval and trial registration (NCT04749628), 36 patients were randomized to receive four perioperative doses of placebo (n=12), 400mg (n=12) or 800mg (n=12) oral CBD with standardized anesthesia and multimodal analgesia. The primary outcome was cumulative 72-hour opioid consumption (MME). Secondary outcomes included pain scores, adjunct analgesic use, inflammatory markers (IL-6), sleep, mood (HADS), safety, and pharmacokinetics. Dunnett's test showed no significant differences in 72-hour opioid consumption versus placebo (400mg: 144 vs 209 MME, p=0.10; 800mg: 203.2 vs 209 MME, p=0.98), although post hoc testing demonstrated lower opioid use with 400mg CBD compared with placebo (p=0.04). The 400mg group also had lower pain scores and fewer rescue analgesic requirements, but greater NSAID use. The 800mg group showed no opioid-sparing effect and had greater adverse event burden. CBD groups reported improved subjective sleep domains, while anxiety and depression scores were higher, particularly at 800mg. IL-6 levels were higher in CBD groups. Pharmacokinetic analyses confirmed measurable, dose-dependent exposure with substantial interindividual variability. These pilot data suggest a potential therapeutic signal at moderate dosing but not at higher doses. Larger trials are needed to confirm efficacy and define optimal dosing. PERSPECTIVE: Among BTKA patients, 400mg cannabidiol reduced opioid use and pain while remaining tolerable, whereas higher dosing increased side effects, supporting further evaluation of CBD analgesia.