An opioid-withholding human laboratory paradigm during opioid agonist treatment for opioid use disorder and chronic pain: Phase- and dose-dependent effects of cannabidiol

Even during opioid agonist treatment (OAT) for opioid use disorder (OUD), chronic pain remains common and unrelieved, as opioids impair endogenous pain modulation. Cannabidiol (CBD) may represent a non-opioid adjunct, but its effects among persons with co-occurring OUD and chronic pain receiving OAT are unknown. We conducted a randomized, double-blind, placebo-controlled crossover study evaluating acute oral CBD (400, 800, 1200 mg) effects on pain modulation, craving, and cognition among 23 participants (11 female) with co-occurring OUD and chronic pain receiving methadone (mean dose 85.7; SD: 29.7 mg/day). An opioid withholding model assessed CBD effects during two phases: Pre-OAT (delayed methadone dosing) and Post-OAT (following methadone administration). Primary outcomes included conditioned pain modulation (CPM; descending inhibition) and temporal summation of pain (TSP; ascending facilitation) assessed via quantitative sensory testing. Secondary outcomes included heat pain threshold and tolerance, and exploratory outcomes included cue-induced craving and cognitive performance. Pre-OAT, CBD was associated with a significant linear dose-response for enhanced descending pain inhibition (p = 0.034; d'=0.34 at 800 mg, d'=0.59 at 1200 mg). Post-OAT, CBD 1200 mg was associated with significant reduction of heat pain threshold relative to placebo (d'=-0.63, p = 0.017). CBD showed no significant effects on opioid craving. Cognitive performance was preserved across doses and CBD demonstrated a favorable safety profile. Among persons with co-occurring OUD and chronic pain receiving OAT, CBD demonstrated phase-dependent effects on pain modulation-dose-dependent enhanced descending inhibition Pre-OAT but worsened pain sensitivity Post-OAT at higher doses. These findings highlight OAT timing as a critical consideration for CBD-based pain interventions.