Summary This UG3/UH3 is based on the need to identify optimal induction strategies for buprenorphine (BUP) in patients’ with untreated opioid use disorder (OUD). Prior BUP induction studies and guidelines including those from the Substance Abuse and Mental Health Services Administration, the American Society of Addiction Medicine and the American College of Emergency Medicine differ with regard to BUP dosing for treatment induction. Furthermore, existing guidelines were developed before the proliferation of fentanyl in the illicit drug supply. Recently, reports have raised concerns that patients with OUD using fentanyl have more difficulty with BUP induction with more worsening/precipitated withdrawal events. These concerns have led to a proliferation of BUP induction strategies that range from low–and-slow “micro-dosing” to rapid “supra-therapeutic” BUP dosing. This proposal aims to determine whether standard buprenorphine induction results in more worsening/precipitated withdrawal events in fentanyls-positive users than other opioid-dependent patients and to examine the safety, tolerability, acceptability and clinical effectiveness of a single high dose BUP induction strategy in Emergency Department (ED) patients with untreated OUD. UG3 specific aims. Aim 1a. First we will develop and manualized escalating high dose BUP induction protocols that can be delivered with high fidelity in the ED. 1b. Then we will evaluate the safety and tolerability of escalating initial BUP dose in three 10-person cohorts (16mg, 24mg, 32mg) of fentanyl positive ED patients with untreated OUD meeting criteria for ED initiated BUP. 1c. We will collect data on patient centered and operational outcomes including patient satisfaction, need for rescue BUP doses and ancillary medications. Aim 2. Perform a pilot multicenter RCT of high versus standard BUP induction at four sites with well-established ED BUP initiation programs to prove feasibility and validate patient satisfaction. 2a. Compare the optimal high dose induction strategy from Aim 1 to a “standard” ED induction strategy in 80 (20 per site) fentanyl positive ED patients meeting criteria for ED initiated BUP randomized 1:1. 2b. Assess the primary composite outcome of precipitated/worsening withdrawal in each study arm. 2c. Compare secondary patient centered and operational outcomes in each study arm. UH3 specific aims. Aim 1a. In a multicenter RCT performed at the four UG3 sites, compare high versus standard dose BUP induction randomized 1:1 on the primary composite outcome of worsening/precipitated withdrawal in 708 patients. Aim 2a. Compare high-dose BUP induction to standard BUP induction on the clinical efficacy outcome of engagement in comprehensive addiction treatment at 7-days post BUP induction. 2b. Compare patient centered and implementation outcomes between study arms.