Comparing Outpatient Treatment Retention Among Individuals Using Fentanyl Randomized to Low-dose and Direct-to-inject Buprenorphine Initiation

• Injectable buprenorphine (Drug), also known as Direct-to-inject, Brixadi, Sublocade, Long-acting injectable buprenorphine: Starting dose (8-32mg) of long-acting injectable buprenorphine (Brixadi or Sublocade) on day 1, followed by monthly maintenance doses (e.g., 128mg Brixadi or 300mg Sublocade)
• Sublingual Buprenorphine (SUBOXONE, Zubsolv, or generic tablets) (Drug), also known as Low-dose buprenorphine initiation, Suboxone, Buprenorphine blister packs: Starting dose (0.5mg) of sublingual buprenorphine tablets in blister packs (Brixadi or Sublocade) on day 1, followed by 0.5-1.0mg daily increases in week 1 and maintenance dosing based on shared decision-making with provider

Primary outcomes

• Continuous retention in outpatient buprenorphine treatment by day 90 [90 days]: Receiving continuous treatment with buprenorphine sublingual prescriptions or injections administrations during the 90 days of follow up post-randomization as intended-to-treat. A period without buprenorphine treatment ≥8 days will be considered treatment discontinuation. Number of days of continuous treatment with the site clinician prescribing sublingual or injectable buprenorphine treatment during the 90 days post-randomization among RCT participants
• Self-reported protocol satisfaction at day 7 [7 days]: Patient-reported satisfaction with buprenorphine initiation protocol measured by Likert-scale satisfaction survey administered on day 7 follow-up visit

Secondary outcomes

• Per protocol and as-treated retention in outpatient buprenorphine treatment at day 90 [90 days]: Similar to the primary intention to treat analysis, though we will be analyzing data and individuals based on actual protocol received and treated, rather than assigned treatment at randomization
• Successful buprenorphine initiation within first 7 days [7 days]: Defined as successfully completing buprenorphine initiation. For LDI treatment arm, this means self-reported completion of initiation "blister pack" during Days 1-6 at clinical follow up and pick up of buprenorphine refill based on prescription data. For DTI, this means administration of initial weekly BRIXADI injection and subsequent monthly BRIXADI or SUBLOCADE buprenorphine injection within 7 days of the initial weekly injection.
• Fentanyl use during days 1-7 determiend by urinary drug screen [7 days]: Concurrent fentanyl use during days 1-7 following buprenorphine initiation, determined by urinary drug screen at day 7 follow-up visit.
• Fentanyl use during days 8-30 determined by urinary drug screen [30 days]: Concurrent fentanyl use during days 8-30 following buprenorphine initiation, determined by urinary drug screen at day 30 follow-up visit.
• Fentanyl use during days 31-90 determined by urinary drug screen [90 days]: Concurrent fentanyl use during days 31-90 following buprenorphine initiation, determined by urinary drug screen at day 90 follow-up visit.
• Self-reported concurrent fentanyl use during days 1-7 [7 days]: Concurrent fentanyl use during days 1-7 following buprenorphine initiation, determined by self-reported Timeline Follow Back survey at day 7 follow-up visit.
• Self-reported concurrent fentanyl use during days 8-30 [30 days]: Concurrent fentanyl use during days 8-30 following buprenorphine initiation, determined by self-reported Timeline Follow Back survey at day 30 follow-up visit.
• Self-reported concurrent fentanyl use during days 31-90 [90 days]: Concurrent fentanyl use during days 31-90 following buprenorphine initiation, determined by self-reported Timeline Follow Back survey at day 90 follow-up visit.
• Self-reported number of days of fentanyl use in first 7 days [7 days]: Number of days of concurrent fentanyl use during days 1-7 following buprenorphine initiation, determined by self-reported Timeline Follow Back survey at day 7 follow-up visit.
• Self-reported number of days of concurrent fentanyl use during first 30 days [30 days]: Number of days of concurrent fentanyl use during days 8-30 following buprenorphine initiation, determined by self-reported Timeline Follow Back survey at day 30 follow-up visit.
• Self-reported number of days of concurrent fentanyl use during days 31-90 [90 days]: Number of days of concurrent fentanyl use during days 31-90 following buprenorphine initiation, determined by self-reported Timeline Follow Back survey at day 90 follow-up visit.
• Baseline withdrawal symptoms, measured with COWS [0 days]: At baseline, a Clinical Opioid Withdrawal Score (COWS) survey will be administered and confirmed with the prescribing clinician.
• Standardized self-reported daily withdrawal symptom severity over days 1-7 by SOWS [7 days]: During each of the first 7 days, participants will rate the severity of withdrawal symptoms using standardized Likert-type response scales in a daily diary. Items will be adapted from the validated Subjective Opioid Withdrawal Scale \[SOWS\] (from 0-4, with 0 being not at all and 4 being extreme) to assess for subjective withdrawal symptoms to minimize participant burden while ensuring reliable data capture.
• Standardized self-reported peak withdrawal symptom severity during days 1-7 by SOWS [7 days]: During each of the first 7 days, participants will rate the severity of withdrawal symptoms using standardized Likert-type response scales in a daily diary. Items will be adapted from the validated Subjective Opioid Withdrawal Scale \[SOWS\] (from 0-4, with 0 being not at all and 4 being extreme) to assess for subjective withdrawal symptoms to minimize participant burden while ensuring reliable data capture. We will calculate peak withdrawal symptoms during the 7-day period.
• Standardized self-reported daily craving symptom severity over days 1-7 by VAS [7 days]: During each of the first 7 days, participants will rate the severity of craving symptoms using standardized Likert-type response scales in a daily diary. Items will be adapted from the validated Visual Analog Scale \[VAS\] (from 0-100, with 0 being none at all and 100 being strongest craving ever) to assess for subjective craving symptoms to minimize participant burden while ensuring reliable data capture.
• Standardized self-reported peak craving symptom severity during days 1-7 by VAS [7 days]: During each of the first 7 days, participants will rate the severity of craving symptoms using standardized Likert-type response scales in a daily diary. Items will be adapted from the validated Visual Analog Scale \[VAS\] (from 0-100, with 0 being none at all and 100 being strongest craving ever) to assess for subjective craving symptoms to minimize participant burden while ensuring reliable data capture. We will calculate the peak craving severity during the first 7 days.

Other outcomes

• Overall number of adverse events in each arm within 30 days, and by relatedness to study intervention [30 days]: Number of adverse events within 30 days, coded by body system and MedDRA classification. All adverse events reported by participants or identified through clinical documentation will be recorded and categorized by severity, duration, and relationship to the study intervention.
• Number of serious adverse events in each arm in 30 days, and by relatedness to the study intervention [30 days]: Number of serious adverse events within 30 days, coded by body system and MedDRA classification. All adverse events reported by participants or identified through clinical documentation will be recorded and categorized by severity, duration, and relationship to the study intervention.
• Number of ED visits and hospital admissions in each arm in 30 days, and by relatedness to study intervention [30 days]: Number of emergency department visits and hospital admissions within 30 days, coded by body system and MedDRA classification. All adverse events reported by participants or identified through clinical documentation will be recorded and categorized by severity, duration, and relationship to the study intervention.
• Number of fatal opioid overdose events occurring during the 90-day follow-up period, by study arm [90 days]: Documented deaths due to opioid overdose during the 90-day follow-up period will be identified through the EHR and, if available, linkage to external death records.
• Treatment Fidelity and Protocol Adherence [90 days]: Study staff will track whether the assigned LDI or DTI protocol was delivered as intended, including any deviations from the dosing schedule or logistical challenges encountered

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Age ≥ 18 years of age at Visit 1.
* Documentation of an OUD diagnosis as evidenced by meeting two or more of the DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, 5th Edition) Criteria for Opioid Use Disorder
* Self-reported daily use of fentanyl ≥ 5 out of the past 7 days at baseline,
* Fentanyl-positive urine drug screening at baseline,
* Interest in stopping or reducing fentanyl use,
* Publicly insured through San Francisco Medicaid or Medicare and therefore able receive buprenorphine prescription dispensing through Community Behavioral Health Services (CBHS) Pharmacy

Exclusion Criteria:

* Currently nursing, pregnant, or anticipating pregnancy in the next 6 months
* Methadone-positive urine drug screening at baseline
* Buprenorphine-positive urine drug screening at baseline
* Be unable to provide any locator or contact information at least one contact in addition to themselves
* Any pending legal action that could prevent participation in study activities
* Presence of a condition or abnormality that, in the opinion of the Investigator, would compromise the safety of the patient or the quality of the data (e.g., acute psychosis), or cognitive impairment (e.g., dementia)

• Noel M, Abbs E, Suen L, Samuel L, Dobbins S, Geier M, Soran CS. The Howard Street Method: A Community Pharmacy-led Low Dose Overlap Buprenorphine Initiation Protocol for Individuals Using Fentanyl. J Addict Med. 2023 Jul-Aug 01;17(4):e255-e261. doi: 10.1097/ADM.0000000000001154. Epub 2023 Feb 17. PMID 37579105
• Rosenwohl-Mack S, Suen LW, Logan AA, Peterson D, Snyder HR. Outpatient Initiation of 7-Day Injectable Buprenorphine: A Direct-to-Inject Case Series. Subst Use Addctn J. 2025 Oct;46(4):1064-1069. doi: 10.1177/29767342251330412. Epub 2025 Apr 4. PMID 40183345

• Leslie W Suen, MD, Principal investigator, University of California, San Francisco

NIH grants: K23DA060329