Project Summary Buprenorphine reduces overdose mortality by up to 70%, making it one of the most critical interventions to combat the opioid overdose crisis. With the increasing prevalence of illicit fentanyl, patients with opioid use disorder (OUD) attempting to initiate buprenorphine now routinely report experiencing buprenorphine precipitated opioid withdrawal (BPOW) despite waiting for withdrawal symptoms to first emerge. In response, clinicians today are increasingly recommending a novel strategy called “micro-dosing” or “low-dose” buprenorphine induction (LDBI), where a dose significantly lower than SL buprenorphine (SL-BUP) 4mg is administered before the emergence of any withdrawal symptoms. The requirements for a successful LDBI appear to be the sufficiently low initial dose, the up-titration of the SL-BUP dose over several days, and continuation of the full agonist opioid during the induction. However, in the emergency department (ED) or outpatient settings where individuals with OUD routinely seek care, the slow up-titration over several days and the continuation of the full agonist are difficult to implement. As such, research is urgently needed for buprenorphine induction strategies that can be easily and safely implemented in the ED or outpatient settings. One possible solution is to utilize extended-release buprenorphine (XR-BUP). The “standard” approach to initiating XR-BUP is to administer the first injection after 7 days of SL-BUP. However, XR-BUP is increasingly used in a “rapid” induction protocol, where XR-BUP is given one hour after the successful administration of even a single dose of SL-BUP. Furthermore, an ongoing NIDA-funded trial is demonstrating that XR-BUP can be “directly” initiated without first administering SL-BUP at all, where XR-BUP is administered after the emergence of opioid withdrawal. However, due to the slow rise in the serum buprenorphine levels, XR-BUP may function as a LDBI strategy on its own, allowing for XR-BUP to be administered before waiting for opioid withdrawal to emerge, without using any SL-BUP or concurrent full agonists opioids. If successful, this strategy could facilitate buprenorphine initiation in the ED and outpatient settings. Unfortunately, no prior research has evaluated whether this novel LDBI strategy using XR-BUP is safe. To fill this need, we propose to conduct a double-blind, randomized trial in an inpatient setting with individuals with OUD (n=30). Participants will be randomized to receive XR-BUP 16mg (n=10), 24mg (n=10) or 32mg (n=10) and remain in a controlled inpatient setting for 5 days. The primary aim is to determine the safety of using XR-BUP as a LDBI strategy. The secondary aim is to conduct pharmacokinetic analyses of buprenorphine, norbuprenorphine and metabolites. If successful, this research could facilitate the development of a safe approach to initiating buprenorphine treatment without the need to wait for the emergence of opioid withdrawal, require the need for...