Project Summary Effectively treating pain while safely prescribing opioid pain medicines is a public health priority. The CDC opioid prescribing guidelines are an evidence-based approach to decreasing unnecessary opioid exposures, high-risk opioid use and abuse. The 2016 version produced modest improvements, but were sometimes misapplied for unsafe opioid tapering; highlighting the challenges of implementation and changing provider behavior. With guideline updates expected soon, there is a need for prospective trials to identify strategies to efficiently and effectively deliver CDC guideline recommended practices while documenting their impact on patient centered outcomes (e.g., pain control, morbidity and mortality). Clinical decision support (CDS) is a promising implementation strategy to both operationalize evidence-based practices and maximize the value of routinely collected data. We will use electronic health record (EHR) embedded CDS to modify clinical behavior toward CDC guideline-concordant recommendations. We propose a hybrid effectiveness-implementation trial using accepted implementation science frameworks PRISM (Practical, Robust Implementation and Sustainability Model) and RE-AIM (Reach, Effectiveness, Adoption, Implementation and Maintenance) to consider the multilevel contextual factors that influence implementation success. By developing a data-driven learning health system with the ability to evaluate patient outcomes through linkages to Prescription Drug Monitoring Program, insurance claims and death data, this project will evaluate: (1) The effectiveness of CDC guideline-concordant prescribing by describing the association between guideline concordant actions and patient outcomes. (2) The user-centered design of EHR based CDS to facilitate CDC guideline concordant actions and promote non-opioid approaches to pain management. (3) The evaluation of the implementation and effectiveness of CDS strategies to deliver guideline- concordant care in a pragmatic cluster randomized trial in a large, integrated health system. We will systematically assess key implementation outcomes and then evaluate the effectiveness of CDS on patient outcomes (vs usual care). This pragmatic research will address the need to link provider prescribing actions to individual patient outcomes. Using established implementation science approaches to evaluate CDS as an implementation strategy is innovative and important. Our results will provide robust data to document the effectiveness of CDC guideline concordant prescribing and evaluate an emerging, scalable implementation strategy using existing data to decrease morbidity and mortality from the opioid crisis.