PUBLIC HEALTH ABSTRACT Approximately 36% of the more than 9 million patients in the US who misused opioid prescriptions in 2019 obtained them through receipt of prescribed medications. Most (>90%) Americans live <5 miles of a community pharmacy—a high potential but under-developed service setting for engagement of patients regarding risky opioid use. The most common tool available to pharmacists for monitoring opioid use among patients is PDMPs. PDMP output data is limited in its clinical utility and does not provide robust decision support. Our team previously identified clinically meaningful risk thresholds and validated the PDMP based Narcotic Score (NS) metric. The NS metric has strong potential to serve as a universal prescription opioid risk screener and entry-point to evidence-based care. This study will implement NS metric thresholds into an existing Clinical Decision Support (CDS) platform and adapt the platform for confirmatory screening and intervention delivery. This study will also assess the impact of the CDS tool on patients as well as examine implementation barriers and facilitators for large-scale rollout. Specifically, this project will conduct a type-1 implementation mixed methods study using a 2-arm parallel group clustered randomized design (randomized by pharmacy, stratified by zip code poverty level). The CDS tool will be evaluated within a division of a large- scale retail pharmacy chain (n=50 CDS pharmacies/n=50 usual care pharmacies). This design includes a 6- month enrollment phase and a 6-month follow up phase. Outcome measures will be drawn from administrative data and include: risky opioid medication use measured by the NS metric as the primary outcome—with secondary outcomes including fatal overdose measured by death certificate data, buprenorphine uptake, and quality of opioid medication care. The primary hypothesis is those within moderate or high NS metric groups will be more likely to reduce risk status to low or moderate-risk following intervention exposure compared to usual care. We will also conduct qualitative interviews with key pharmacy chain (N=15) and PDMP (N=15) leaders to assess facilitators and barriers of CDS adoption and continued utilization. This study establishes a CDS platform for future large-scale community pharmacy-based opioid treatment service delivery and research.