All-Cause Mortality Associated with Tramadol Use: A Case-Crossover Study

Introduction Although the mortality risk associated with tramadol use in children has triggered the revision of tramadol drug labeling, the mortality risk in adults has not been thoroughly explored. Objective The objective of this study was to evaluate whether tramadol use is associated with mortality in various risk groups. Methods This was a case-crossover study addressing the period of 2004–2013, using data from the National Sample Cohort (National Health Insurance Service, South Korea). Patients who were prescribed tramadol at least once prior to their death were included. A 30-day hazard (case) period (with a 10-day washout period) was adopted and matched to three control periods. Logistic regression was used to estimate adjusted odds ratios (aORs) and their 95% confidence intervals (CIs). Adjustments were made for time-variant factors (co-medications, surgeries, and acute respiratory conditions). Results A total of 19,443 individuals were identified, with a small number of young individuals (n = 33, 0.2%). Tramadol use was associated with an increased mortality risk (aOR 1.77, 95% CI 1.67–1.87). Advanced age (> 75 years) (aOR 2.61, 95% CI 2.28–2.99) and renal (aOR 2.90, 95% CI 1.67–1.87) and hepatic (aOR 2.09, 95% CI 1.62–2.68) diseases were associated with the highest risks. Conclusion Overall, there was an increased mortality risk associated with tramadol in the adult population. However, as residual confounding cannot be completely removed in large observational studies, this must be carefully interpreted in the decision-making regarding patient care.