The purpose of this funding is to advance and evaluate comprehensive state-level interventions for preventing prescription drug misuse, abuse, and overdose. Interventions of interest address patient and prescriber behaviors that drive the prescription drug overdose epidemic, particularly the misuse and inappropriate prescribing of opioid pain relievers. Specifically, awardees will perform activities that support at least two of the following complementary key prevention strategies to prevent prescription drug misuse, diversion, and overdose: enhancing and maximizing prescription drug monitoring programs (PDMPs); improving and evaluating state health insurance mechanisms to prevent prescription drug misuse, diversion, and overdose (e.g., via Medicaid or workersÂ’ compensation); and evaluating state-level laws, policies, and regulations (e.g., legislation regulating pain clinics, or supporting clinical practice guidelines). The primary outcomes of interest may vary by strategy. They might include programmatic outcomes (e.g., mandatory PDMP registration and use, enrollment in patient review and restriction programs), behavior change (e.g., decrease prescribing inconsistent with clinical guidelines, decreased doctor shopping), and/or health-related outcomes (e.g., decrease in emergency department visits due to misuse or abuse of controlled prescription drugs, decreased drug overdose death rate). State-level engagement is critical to the success of this FOA given the concentration of the authority to address the use and misuse of prescription drugs within state government. Multi-sector collaboration with partners that have shared authority over this issue is also needed (e.g., law enforcement, boards of pharmacy, medical boards, mental health and substance abuse services, medical centers, lead state agencies for Medicaid programs.) Applicants are therefore required to submit letters of support from state-level governmental entities and other partners depending on the strategies they pursue under their work plan.