The goal of this clinical trial is to learn if buprenorphine can be started for opioid use disorder with fentanyl use without requiring or precipitating opioid withdrawal. To be eligible, participants must have moderate or severe opioid use disorder and must have fentanyl detected on a urine drug test.

Participants will be admitted to a monitored research unit for the trial. They will be randomized to start buprenorphine with either standard initiation or with a new approach called rapid outpatient low-dose initiation (ROLDI).

For standard initiation, participants will be instructed to arrive to the unit with at least 8 hours since last fentanyl use. Once they have at least moderately severe opioid withdrawal (Clinical Opiate Withdrawal Scale [COWS] 11 or higher), participants will receive 2 mg, 2 mg, 4 mg, and then 8 mg sublingual buprenorphine, with doses every 2 hours. They will then continue 8 mg twice daily (or up to three times daily). This is the current standard of care.

For ROLDI, participants will not be required to have a period abstinence, they will have no or minimal withdrawal (COWS 4 or less) when starting buprenorphine, and participants will take 0.5, 0.5, 0.5, 0.5, 2, 16 mg with doses scheduled every 2 hours. They will then continue 8mg twice daily (or up to three times daily).

The main aim of this clinical trial is to assess whether ROLDI is safe, feasible, acceptable to patients, and worthwhile to study in a larger trial. The secondary aim is to describe fentanyl and norfentanyl pharmacokinetics (that is to say, fentanyl and norfentanyl concentration in blood and urine) during early abstinence to understand why some people using fentanyl develop precipitated withdrawal with standard initiation.

Inclusion Criteria:

• Ages 18 or older
• Male, female, transgender, or non-binary
• DSM-5 criteria for opioid use disorder, moderate to severe
• Fentanyl positive on urine drug test
• Able to provide written informed consent in English prior to any study-related procedure

Exclusion Criteria:

• Pregnancy or actively lactating
• Previously documented hypersensitivity or allergy to buprenorphine or naloxone
• DSM-5 criteria for substance use disorder other than opioid use disorder (e.g., cannabis, cocaine, alcohol)
• Current benzodiazepine use
• Urine drug testing at screening positive for buprenorphine and/or methadone
• AST and/or ALT >3x upper limit of normal or total bilirubin >1.5x upper limit of normal
• eGFR <30 mL/min
• Use of CYP3A4-metabolized agents such as azole antifungals, macrolides, and protease inhibitors
• High risk of severe medetomidine withdrawal based on drug urine testing for medetomidine, prior withdrawal syndrome requiring intensive care unit admission, and/or patient-reported severe nausea/vomiting during early withdrawal, at the discretion of the study physicians.
• Significant medical symptoms (e.g. severe respiratory insufficiency), psychiatric symptoms, or dementia that, in the opinion of the investigators, would preclude compliance with the protocol, cooperation in the study, obtaining informed consent, or ability to safely participate in the study
• Pending legal action that could prohibit participation and/or compliance in study procedures