This is a clinical trial to characterize the safety and pharmacokinetics of using extended-release buprenorphine (XR-BUP) as a novel low-dose buprenorphine induction strategy. Individuals with a diagnosis of Opioid Use Disorder (OUD) (n=30) will be admitted to an inpatient unit to complete study procedures over the course of 3 days. Participants will receive fentanyl to prevent the emergence of withdrawal. Each participant will then receive a single injection of XR-BUP after which study staff will monitor for any precipitated withdrawal.

The approach is to conduct a single ascending dose trial in a controlled human laboratory setting with individuals with a diagnosis of OUD (n=30) actively using illicit fentanyl. After obtaining informed consent and establishing eligibility, 10 participants will be scheduled for an inpatient visit lasting 3 days, 2 nights and receive XR-BUP when not yet experiencing any opioid withdrawal. Participants will receive fentanyl to prevent the emergence of withdrawal, and on the following morning, receive XR-BUP 16mg in single-blind fashion. If at least 90% successfully complete induction (success defined as experiencing no precipitated withdrawal) with the 16mg dose, then we will proceed with 10 more participants to receive the 24mg dose. If at least 90% successfully complete induction the 24mg dose, then we will proceed with 10 more participants to the 32mg dose. Timed blood samples will be collected in heparinized Vacutainer tubes via a catheter in the antecubital vein at baseline, and at 0.5, 1, 2, 4, 6, 8, 12, and 24 hours after the XR-BUP injection.

Inclusion Criteria:

• English speaking adults aged 18 and above.
• diagnosis of opioid use disorder.
• Self-reporting use of illicit opioids in >21 days in the prior 30 days.
• Provide urine toxicology testing positive for fentanyl at baseline.

Exclusion Criteria:

• Seeking medication treatment for opioid use disorder with sublingual buprenorphine or methadone.
• Received buprenorphine or methadone treatment in prior 30 days.
• Current diagnosis of alcohol or sedative/hypnotic use disorder.
• Positive urine drug screen for benzodiazepines, alcohol and or methadone.
• Physical dependence on alcohol or sedative/hypnotics.
• Psychotic disorder, active suicidality or homicidally or any psychiatric condition that impair ability to provide informed consent.
• Have a history or diagnosis of Intracranial mass/bleed, seizure disorder, liver cirrhosis, renal failure, obstructive lung disease, hyperthyroidism, narrow-angle glaucoma, valvular heart disease, cardiac arrhythmias, heart failure.
• Recent (within 6 months) head trauma, stroke, or myocardial infarction
• Requiring treatment with opioids for acute or chronic pain.
• History of hypersensitivity or allergy to buprenorphine or fentanyl.
• Pregnant or breastfeeding.
• Liver function test greater than 3 times upper normal limit.
• Receiving medications that are strong or moderate CYP34A inducers or inhibitors (including but not limited to ketoconazole, itraconazole, clarithromycin, fluconazole, erythromycin), in the past 30 days.

Only the participant will be masked.