PROJECT SUMMARY Opioid overdose deaths remain at crisis levels; however, increasing availability of effective medications for opioid use disorder (MOUD) are one reason for optimism. Unfortunately, MOUD are underutilized. Real-world data have identified low MOUD retention rates in contrast with higher retention rates observed in randomized controlled trials (RCTs). While comparative effectiveness RCTs found that buprenorphine-naloxone and extended-release naltrexone have similar retention and illicit opioid use, observational studies identify lower rates of fatal opioid overdose and improved retention with buprenorphine-naloxone. While RCTs are considered the gold standard for studying causal relationships, external generalizability is limited, and RCTs have limited power to study relatively rare outcomes such as fatal or nonfatal opioid overdose. The Massachusetts Public Health Data warehouse (PHD) is a novel near population-level database linking more than 20 state-based datasets at the individual level. The PHD offers an unparalleled ability to study a breadth and depth of opioid-related exposures and outcomes, including opioid overdose. The current proposal seeks to use PHD to emulate target comparative effectiveness trials of a rapidly expanding array of buprenorphine and naltrexone formulations. We will examine MOUD initiation following opioid detoxification, a common treatment entry point for individuals at high-risk for subsequent opioid overdose. To advance understanding of the differences between observational studies and RCTs we will directly compare effect estimates of treatment retention from an emulated trial in PHD with a reanalysis of the target X:BOT RCT that compared sublingual buprenorphine-naloxone and extended-release naltrexone. Using the PHD, we will examine additional outcomes, including fatal and nonfatal opioid overdose. We will leverage the emulated trial framework developed to study additional high priority comparative effectiveness questions. We will compare outcomes from initiation of sublingual buprenorphine-naloxone versus buprenorphine extended-release formulations following opioid detoxification. Finally, while long-term MOUD treatment is the standard of care, many patients prefer to stop treatment. We will assess the impact of tapering sublingual buprenorphine-naloxone after 3 or 6 months of treatment compared with continued use. The findings of these comparative effectiveness analyses will inform policy and practice on the coverage and use of an expanding array of MOUD formulations.