Tramadol versus codeine and the short-term risk of cardiovascular events in patients with non-cancer pain: A population-based cohort study

Aims The effect of tramadol on the cardiovascular system is largely unknown. There is concern that, with its multimodal mechanism of action to increase serotonin and norepinephrine levels in the body, it could increase the risk of arterial ischaemia and cardiovascular events. We aimed to compare the short-term risk of cardiovascular events with the use of tramadol to that of codeine among patients with non-cancer pain. Methods We conducted a retrospective population-based cohort study using data from the Clinical Practice Research Datalink (CPRD) with new users of tramadol or codeine from April 1998 to March 2017. Exposure was defined using an approach analogous to an intention-to-treat, with a maximum follow-up of 30 days. The primary endpoint was myocardial infarction, and secondary endpoints were unstable angina, ischaemic stroke, coronary revascularization, cardiovascular death and all-cause mortality. Hazard ratios (HRs) were estimated using Cox proportional hazards models, adjusted for high-dimensional propensity score. Results The final cohort included 123 394 tramadol users and 914 333 codeine users. When tramadol was compared to codeine, the adjusted hazard ratio (HR) of myocardial infarction was 1.00 (95% CI 0.81-1.24). There was also no evidence of elevated risks of unstable angina (0.92; 95% CI 0.67-1.27), ischaemic stroke (0.98; 95% CI 0.82-1.17), coronary revascularization (0.97; 95% CI 0.69-1.38), cardiovascular death (1.07; 95% CI 0.93-1.23) or all-cause mortality (1.03; 95% CI 0.94-1.14) when tramadol was compared to codeine. Conclusions Short-term use of tramadol, compared with codeine, was not associated with an increased risk of cardiac events among patients with non-cancer pain.