Project Summary Abstract 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 precipitated withdrawal despite waiting for withdrawal symptoms to first emerge. In response, clinicians and patients alike are increasingly recommending a novel strategy called “micro-dosing” or “low-dose” buprenorphine induction, where a dose significantly lower than the typical 4mg is administered. With this strategy, precipitated withdrawal does not occur despite buprenorphine is administered before the emergence of withdrawal symptoms. A variety of low-dose induction protocols have been reported—some use low dose (≤0.5mg) SL buprenorphine, while others initially use transdermal (Butrans®) or buccal (Belbulca®) formulations. Regardless of the specific approach, the requirements for a successful low-dose induction appear to be the low initial dose, the slow up-titration of the buprenorphine, and continuation of the full agonist opioid during the induction. However, these approaches can be problematic—low-dose SL buprenorphine requires the medication to be cut which is often prohibited in inpatient settings; transdermal and buccal formulations are costly and often not on formulary; and their use violates US federal laws that prohibit them to be prescribed to outpatients seeking treatment for OUD. Therefore, there is an urgent need to research strategies for buprenorphine low-dose inductions that avoid having to cut the medication, or use prohibited and costly formulations. To meet this need, we propose to study the safety and feasibility of utilizing orally (PO) administered buprenorphine. Buprenorphine undergoes extensive first-pass effect when taken PO, hence the bioavailability is estimated to be significantly less than the SL route of 30-50%. As such, using the existing SL dose formulations (e.g. 8mg) via the oral route may allow low-dose induction without having to split the medication. However, research on the safety and feasibility of PO buprenorphine is largely absent. We therefore propose to conduct a two-phased study: in the first phase, we will conduct a randomized cross-over trial with healthy human volunteers to receive low-dose SL and PO buprenorphine to determine the pharmacokinetic parameters. The results will inform the dose needed for a successful low-dose induction using PO buprenorphine. In the second phase, we will conduct a pilot feasibility trial among individuals with OUD to undergo a low-dose induction using PO buprenorphine in a controlled laboratory setting. Given the importance of buprenorphine in improving clinical outcomes for individuals with OUD and preventing overdose deaths, research that aims to identify safe approaches to treatment initiation are urgently needed. Results from this stud...