Dronabinol and Epidiolex to Manage Uncontrolled Residual Symptoms of Buprenorphine Initiation Trial

OUD and opioid overdose death rates remain shockingly high in the United States fueled by high potency opioids like fentanyl. Buprenorphine is an evidence-based therapy for OUD that reduces mortality, improves OUD outcomes, and is increasingly available. Three-month buprenorphine retention halves all-cause mortality; however, only 40-60% of POUD are retained in buprenorphine treatment for 3 or more months. Further, POUD who use fentanyl report protracted opioid withdrawal symptoms including anxiety, pain, insomnia, and opioid cravings, even months after reaching maximum doses of buprenorphine. Nearly 50% of POUD who use fentanyl return to use within 3 months.12 To improve success of buprenorphine treatment, new strategies for starting buprenorphine have emerged, such as low-dose initiation with ongoing opioid agonists, however, few interventions exist to improve treatment after starting buprenorphine, and those that exist are non-pharmacologic. Alpha-2-agonists (e.g., clonidine) reduce some withdrawal symptoms but can only be given for a short time without cardiac side effects. Pharmacologic adjuncts to buprenorphine are desperately needed to improve OUD outcomes in the fentanyl era.

Cannabis, the two key ingredients of which are THC and CBD, reduces opioid withdrawal in observational studies and thus has biologic plausibility for improving buprenorphine treatment retention. In two randomized trials, THC improved acute opioid withdrawal symptoms (e.g., muscle aches, muscle tension, and flu-like prodrome) a common driver of ongoing opioid use. THC is also effective in reducing acute and chronic pain in POUD another driver of ongoing use; however, patients receiving THC alone may experience adverse effects, such as panic, anxiety, and poor cognition. Co-administration with CBD may counteract these effects and maximize THC's benefits. In pre-clinical and clinical trials CBD reduces anxiety, pain, cue-induced opioid cravings, and attentional bias to drug-induced cues. When THC and CBD are co-administered, patients experience improved analgesic effects and reduced adverse effects. The overarching hypothesis of this study is that adjunctive dronabinol + Epidiolex improves buprenorphine retention and opioid use in POUD through reducing opioid withdrawal (including cravings, and pain).

The investigator team has developed an innovative 12-week pilot randomized trial of dronabinol + Epidiolex (versus placebo) as an adjunct to buprenorphine for OUD outcomes. 40 POUD participants within 21 days of buprenorphine initiation who are continuing either to use illicit opioids or to experience opioid withdrawal symptoms will be enrolled. Participants will be randomized to one of two arms as described in this registration. Study visits will occur at enrollment, and weeks 1, 2, 4, 8, and 12.

There are two overarching Aims in this study.

Aim 1: To determine the effectiveness and safety of 8- weeks of dronabinol + Epidiolex (vs. placebo) as an adjunct to buprenorphine in improving retention in OUD treatment and reducing opioid use. Hypothesis 1a: The dronabinol + Epidiolex (vs. placebo) group will have better 12-week retention in OUD treatment. Hypothesis 1b: The dronabinol + Epidiolex (vs. placebo) group will report less illicit opioid use. Hypothesis 2: The dronabinol + Epidiolex (vs. placebo) group will have no difference in significant adverse events or treatment limiting adverse events.

Aim 2: To explore the mechanism by which cannabinoids may improve OUD outcomes after buprenorphine initiation in POUD. The investigator team will explore how dronabinol + Epidiolex use are associated with change in opioid withdrawal symptoms, opioid cravings, and pain and whether these changes are associated with OUD outcomes. Hypothesis 3: The dronabinol + Epidiolex (vs. placebo) group will have fewer withdrawal symptoms, opioid cravings and pain, which will mediate the impact of cannabinoids on OUD outcomes.

• Retention in OUD Treatment [Time frame: Baseline and ~1-week, 2-weeks, 4-weeks, and 8-weeks following initiation of intervention]
• Opioid Use - Self Reported [Time frame: Baseline and ~1-week, 2-weeks, 4-weeks, 8-weeks, and 12 weeks following initiation of intervention]
• Opioid Use - Urine Toxicology [Time frame: Baseline and ~2-weeks, 4-weeks, 8-weeks, and 12 weeks following initiation of intervention]
• Opioid Use Disorder Symptoms - Subjective Opiate Withdrawal Scale [Time frame: Baseline and ~4-weeks, 8-weeks, and 12 weeks following initiation of intervention]
• Opioid Use Disorder Symptoms - Opiate Craving Scale [Time frame: Baseline and ~4-weeks, 8-weeks, and 12 weeks following initiation of intervention]
• Pain Severity [Time frame: Baseline and ~1-week, 2-weeks, 4-weeks, 8-weeks, and 12 weeks following initiation of intervention]
• Pain Interference [Time frame: Baseline and ~1-week, 2-weeks, 4-weeks, 8-weeks, and 12 weeks following initiation of intervention]
• Panic Symptoms [Time frame: Baseline and ~1-week, 2-weeks, 4-weeks, 8-weeks, and 12 weeks following initiation of intervention]
• Anxiety Symptoms [Time frame: Baseline and ~4-weeks, 8-weeks, and 12 weeks following initiation of intervention]
• Cognitive Function [Time frame: Baseline and ~1-week, 2-weeks, 4-weeks, 8-weeks, and 12 weeks following initiation of intervention]