An opioid-withholding human laboratory paradigm during opioid agonist treatment for opioid use disorder and chronic pain: Phase- and dose-dependent effects of cannabidiol
Gabriel P A Costa 1 2, Mehmet Sofuoglu 1 2 3, Peggy Compton 4, Mohini Ranganathan 1 3, Brian Pittman 1, Joao P De Aquino 5 6 7
- 1Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
- 2Clinical Neuroscience Research Unit (CNRU), Connecticut Mental Health Center (CMHC), New Haven, CT, USA.
- 3VA Connecticut Healthcare System, West Haven, CT, USA.
- 4Department of Family and Community Health, University of Pennsylvania School of Nursing, Philadelphia, PA, USA.
- 5Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA. joao.deaquino@yale.edu.
- 6Clinical Neuroscience Research Unit (CNRU), Connecticut Mental Health Center (CMHC), New Haven, CT, USA. joao.deaquino@yale.edu.
- 7VA Connecticut Healthcare System, West Haven, CT, USA. joao.deaquino@yale.edu.
Affiliationer
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
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