PROJECT ABSTRACT Synthetic opioids including fentanyl and its analogs have flooded the unregulated drug market in the United States and are responsible for nearly three quarters of the nation’s fatal drug overdoses. Concurrently increased challenges of buprenorphine initiation and maintenance treatment in patients with fentanyl use including risk of precipitated withdrawal and inadequate control of withdrawal and cravings at standard doses are being reported. Buprenorphine research and clinical protocols were based on heroin using populations. There are no updated standardized buprenorphine maintenance dosing protocols for patients using fentanyl. Data from our own clinical practice and other buprenorphine maintenance providers suggests higher daily doses of buprenorphine (24 mg) are well-tolerated, safe, and better control cravings in populations with a history of fentanyl use, yet this strategy has neither been tested prospectively or retrospectively in a randomized controlled trial (RCT) nor compared to standard dosing to assess treatment outcomes in populations using fentanyl. Treating opioid use disorder (OUD) with buprenorphine decreases mortality by 50% and confers other personal health and social benefits. Return to use rates for patients on buprenorphine treatment are high; a recent study reported rates greater than 50 % within 3 months of treatment initiation. Additionally, It has been estimated that 40% of patients on medications for opioid use (MOUD) continue non-prescribed opioid use during treatment, yet we lack understanding of how or why ongoing fentanyl use occurs during buprenorphine therapy, the effects of treatment outcomes, and the impact of buprenorphine dose on fentanyl use practices. For this reason, we will first conduct a quantitative and qualitative mixed method study (UG3) to evaluate if there is an association between daily dose of prescribed buprenorphine and occurrence of non-fatal and fatal overdose and determine the optimal high buprenorphine maintenance treatment dose to use in the subsequent RTC. After successful completion of the UG3, we will conduct a RCT (UH3) in 250 patients with a history of non-prescribed fentanyl use to compare efficacy of standard vs. high dose maintenance buprenorphine protocols. Participants will be actively followed via surveys and UDS assessments at clinic appointments for 1, 3 and 6 months. Passive surveillance will continue throughout the study period to evaluate treatment retention on buprenorphine, non-fatal and fatal overdose at 1 month, 6 months, and 12 month intervals using administrative database linking of state-wide PDMP, ME, EMS, and ED datasets. This study will provide novel data on optimal buprenorphine dosing efficacy in patients with fentanyl use to inform best practices for clinical treatment of OUD.

PROJECT NARRATIVE Overdose deaths are driven by illicit fentanyl use in the United States, yet there has been no systematic study or updated standardized buprenorphine protocols for patients using fentanyl. We will first conduct a quantitative and qualitative mixed method study (UG3) to determine the optimal high buprenorphine treatment dose then conduct a randomized controlled trial (UH3) to compare the efficacy of standard vs. high dose buprenorphine protocols among patients with a history of non-prescribed fentanyl use. This study will provide novel data on optimal buprenorphine dosing efficacy in patients with fentanyl use to inform best practices for clinical treatment of opioid use disorder.