This study is a multisite double-blind, double-dummy, randomized clinical trial enrolling ED patients with untreated moderate to severe opioid use disorder (OUD) to compare Standard Dose Induction (SDI) and High Dose Induction (HDI) on rates of participation in OUD treatment within 10 days post randomization, and opioid withdrawal symptoms, opioid craving, and use of illicit and non-prescribed drugs.

This study will recruit, train, and provide resources to approximately 4 ED systems throughout the U.S. to recruit ED patients presenting with OUD not receiving medications for opioid use disorder (MOUD) as part of an RCT to compare SDI (Zubsolv 5.7/1.4 mg buprenorphine/naloxone* plus 2 placebo tablets) with HDI (three Zubsolv 5.7/1.4 mg* buprenorphine/naloxone tablets) to evaluate rate of participation in OUD treatment within 10 days post-randomization and differences in outcomes of tolerability, opioid withdrawal symptoms, craving, and use of illicit drugs.

Inclusion Criteria:

All patients enrolled into the study must:

1. Be 18-65 years of age.
2. Be treated in the ED during study screening hours.
3. Meet DSM-5 diagnostic criteria for moderate to severe OUD.
4. Have a Clinical Opiate Withdrawal Scale (COWS) score of ≥8 at enrollment (including 2 objective signs of withdrawal at enrollment).
5. Have a urine toxicology test that is positive for opioids.
6. Be able to speak English sufficiently to understand the study procedures and provide written informed consent to participate in the study.

Exclusion Criteria:

All patients enrolled into the study must not:

1. Have a medical or psychiatric condition that requires hospitalization at the time of index ED visit.
2. Have a known hypersensitivity reaction to buprenorphine/naloxone
3. Be actively suicidal or severely cognitively impaired precluding informed consent.
4. Require ongoing prescription for opioid analgesics.
5. Have a physical exam or reported history consistent with severe liver failure
6. Have a positive urine test for methadone and reported use in the past 72 hours
7. Be a prisoner or in police custody at the time of index ED visit.
8. Be unwilling to follow study procedures (e.g., unwilling to provide permission to contact referral provider/program or unavailable for the follow-up assessments)
9. Have prior enrollment in the current study.
10. Receiving MOUD treatment within the past 7 days.
11. Be pregnant as determined by human gonadotropin (hCG) testing at the index ED visit
12. Have a respiratory rate <8 or oxygen saturation <93%
13. Be a participant in any other clinical trial in which medications are being delivered or the use of an investigational drug or device within the last 30 days

In line with the National Institutes of Health Helping to End Addiction Long-term (NIH HEAL) Initiative Public Access and Data Sharing Policy, publications and underlying primary data will be made available to the public.

Data will be made available after 1) the primary paper has been accepted for publication, or 2) the data is locked for more than 18 months, whichever comes first.

De-identified scientific data generated from this study will be available to the public in the NIDA data repository, per NIDA CTN policy and the Data Management and Sharing Plan for this study.

This study is a multi-site double-blind, double-dummy randomized clinical trial. Only the DSC staff overseeing the random assignment schedule, a few designated CCC staff, and the central research staff preparing the study medication will be unblinded; all other study personnel and participants will remain blinded to treatment arm until the nationwide completion of the trial and the database is formally locked. Detailed information on the study procedures regarding the double-blinding will be contained in a standalone Blinding Management Plan and Study Site Blinding Plan. A DSMB will review study data throughout the course of the trial in a blinded fashion (e.g., masked treatment assignments), however they can request to be unblinded at any time.