The goal of this clinical trial is to compare buprenorphine formulations (sublingual buprenorphine versus long-acting injectable buprenorphine) for treating opioid use disorder among individuals who use fentanyl and/or other high potency synthetic opioids. Individuals aged 18-65 will be eligible for enrollment. The main questions it aims to answer are:

Are there differences in frequency of drug use after individuals start treatment with sublingual buprenorphine compared to injectable buprenorphine?

Are there differences in rates of sustained relapse after individuals start treatment with sublingual buprenorphine compared to injectable buprenorphine?

Investigators also seek to understand and explore:

How factors like body fat, body weight, and quantity of fentanyl use before treatment influence treatment outcomes.

How blood levels of buprenorphine and its metabolite norbuprenorphine early on in treatment may influence treatment outcomes.

How factors like craving and opioid withdrawal symptoms influence treatment outcomes.

Participants will:

Complete a brief overnight hospital stay in an inpatient research unit. This hospital stay will enable participants to start treatment with either sublingual buprenorphine or injectable buprenorphine.

Provide blood and urine samples while on the inpatient unit and at follow up.

Complete in-person follow up visits at 1-, 2-, 3- and 4-weeks after leaving the hospital to measure drug use, craving, withdrawal, quality of life, and physical health.

Inclusion Criteria:

• Aged 18 to 65
• Voluntarily seeking treatment for opioid use disorder (OUD)
• Consistent use of fentanyl or other high potency synthetic opioids
• Meets DSM-5 criteria for OUD with at least moderate severity
• Able to provide written informed consent in English and willing to comply with study procedures

Exclusion Criteria:

• Meets DSM-5 criteria for another substance use disorder as the primary diagnosis
• Has an active, unmanaged psychiatric condition that would make participation hazardous (e.g., acute, psychosis, current suicidality, current manic episode)
• Has an active, unmanaged medical condition that would make participation hazardous or preclude use of buprenorphine or ancillary medications for withdrawal (e.g., unmanaged hypertension, unmanaged diabetes, clinically significant abnormality on ECG, acute hepatitis)
• Buprenorphine or methadone treatment in the past 30 days
• Known allergy, hypersensitivity or intolerance to buprenorphine
• Pregnancy, lactation, or unwillingness to use adequate contraceptive methods
• Current physiological dependence on sedative-hypnotics or alcohol that would require medically supervised detoxification
• Liver function tests > 2x the upper limit of normal
• Use of medications or herbal products with known CYP3A4 inhibition or induction properties in the past 30 days

According to NIDA's policy for data management and sharing, de-identified data will be deposited into the NAHDAP repository.

De-identified data will be made available no later than when the primary outcome paper is published or when the award ends. The data will be stored in the repository for at least 10 years after the funding period ends.

Once released to the repository, the investigator will not control data access.