In this issue of JAMA, Xie and colleagues report findings from an evaluation of adverse outcomes following initial prescriptions for tramadol or codeine among residents of Catalonia, Spain. Using 10 years of linked primary care and pharmacy claims data, the investigators used propensity score matching to assemble a cohort of 368 960 individuals who received an initial prescription for either tramadol or codeine. Initial receipt of a tramadol prescription, compared with codeine, was associated with a significantly higher 1-year cumulative incidence of all-cause mortality (absolute rate difference [ARD], 7.37 [95% CI, 6.09-8.78] per 1000 person-years), cardiovascular events (ARD, 1.36 [95% CI, 0.45-2.36] per 1000 person-years), and fractures (ARD, 4.10 [95% CI, 3.02-5.29] per 1000 person-years) but no significant difference in risk of falls, delirium, constipation, opioid abuse/dependence, or sleep disorders. The study findings were robust to several sensitivity analyses, including a dose-response analysis that demonstrated higher effect sizes with higher quantities of tramadol dispensed.