PROJECT SUMMARY Opioid use disorder (OUD) involving fentanyl is a major public health problem. OUD treatment with buprenorphine reduces all-cause mortality and drug-related morbidity and can be started by licensed prescribers in any outpatient or inpatient setting. For individuals using fentanyl, the process of starting buprenorphine is increasingly complicated by precipitated withdrawal. Withdrawal during initiation of buprenorphine deters some individuals from starting treatment and has been associated with treatment drop- out and relapse among those who do start. The goal of this project is to test the preliminary efficacy, safety, feasibility, and acceptability of a novel approach to initiating buprenorphine treatment for OUD that can be used in outpatient setting without requiring or precipitating opioid withdrawal. We will recruit 60 subjects with untreated OUD and recent fentanyl use through the University of Pennsylvania's Center for the Studies of Addiction. Subjects will be randomized to one of two arms: standard initiation, in which subjects will start buprenorphine after >8 hours of abstinence once they develop moderate opioid withdrawal with Clinical Opiate Withdrawal Scale (COWS) at least 11; or a novel low-dose (“micro-dose”) approach, which is started with COWS<4 and where buprenorphine doses are escalated over 10 hours, without ongoing use of full-agonist opioids. We will compare success rates with each approach, with “success” defined as reaching a total-daily dose of 8 mg buprenorphine without an increase of >6 in COWS from baseline and without early termination for any reason. Findings from this study will be used to support an R01 application to test this novel approach to initiating buprenorphine in real-world, outpatient settings with a larger sample of individuals with untreated OUD. This methodology has broad applications for increasing access to office-based treatment for OUD.