ABSTRACT: BACKGROUND:While the rise in opioid analgesic prescribing and overdose deaths was multifactorial, financial relationships between opioid drug manufacturers and physicians may be one important factor. METHODS:Using national data from 2013 to 2015, we conducted a retrospective cohort study linking the Open Payments database and Medicare Part D drug utilization data. We created two cohorts of physicians, those receiving opioid-related payments in 2014 and 2015, but not in 2013, and those receiving opioid-related payments in 2015 but not in 2013 and 2014. Our main outcome measures were expenditures on filled prescriptions, daily doses filled, and expenditures per daily dose. For each cohort, we created a comparison group that did not receive an opioid-related payment in any year and was matched on state, specialty, and baseline opioid expenditures. We used a difference-in-differences analysis with linear generalized estimating equations regression models. RESULTS:We identified 6,322 physicians who received opioid-related payments in 2014 and 2015, but not in 2013; they received a mean total of $251. Relative to comparison group physicians, they had a significantly larger increase in mean opioid expenditures ($6,171; 95% CI: 4,997 to 7,346), daily doses dispensed (1,574; 95%CI: 1,330 to 1,818) and mean expenditures per daily dose ($0.38; 95% CI: 0.29 to 0.47). We identified 8,669 physicians who received opioid-related payments in 2015, but not in 2013 or 2014; they received a mean total of $40. Relative to comparison physicians, they also had a larger increase in mean opioid expenditures ($1,031; 95% CI: 603 to 1,460), daily doses dispensed (557; 95% CI: 417 to 697), and expenditures per daily dose ($0.06; 95% CI: 0.002 to 0.13). CONCLUSIONS:Our findings add to the growing public policy concern that payments from opioid drug manufacturers can influence physician prescribing. Interventions are needed to reduce such promotional activities or to mitigate their influence.