Association between tramadol use and seizures: A nationwide case-case-time-control study

Sohee Park, Hyesung Lee, Ju Hwan Kim, Ha-Lim Jeon, Ju-Young Shin

Research output: Contribution to journalArticlepeer-review


PURPOSE: Tramadol may lower the seizure threshold; however, there is no conclusive evidence to confirm this. This study aimed to determine whether the use of tramadol is associated with the occurrence of seizures.

METHODS: We conducted a case-case-time-control (CCTC) study by identifying patients who had received tramadol and seizure diagnosis in a nationwide healthcare database in South Korea between 2003 and 2015. Each case was matched for age and sex to one future case to adjust for time trends in exposure without selection bias from the use of an external control group. The use of tramadol was assessed during a risk period of 1-30 days, and two reference periods, 61-90 days and 91-120 days, preceding the first diagnosis of seizures. We calculated the adjusted odds ratio (aOR) by dividing the OR in cases (case-crossover) by the OR in future cases (control-crossover). We performed a dose-response analysis using the average daily dose.

RESULTS: We identified 2523 incident cases with matched future cases (mean age, 45.4 years; 50% men). The aOR for seizure with tramadol use was 0.94 (95% confidence interval [CI], 0.98-1.43) in the CCTC analysis, with a case-crossover OR of 1.19 (0.98-1.43) and control-crossover OR of 1.27 (1.03-1.56). The dose-response analysis showed a similar trend in the main analysis: a low-dose aOR of 0.80 (0.50-1.28) and a high-dose aOR of 0.92 (0.41-2.11).

CONCLUSION: We could not identify a significant association between transient use of tramadol and incidence of seizures in clinical practice.

Original languageEnglish
Pages (from-to)614-622
Number of pages9
JournalPharmacoepidemiology and Drug Safety
Issue number6
Early online date9 Feb 2022
Publication statusPublished - 2 May 2022

Bibliographical note

© 2022 John Wiley & Sons Ltd.


  • Analgesics, Opioid/adverse effects
  • Case-Control Studies
  • Cross-Over Studies
  • Female
  • Humans
  • Male
  • Middle Aged
  • Odds Ratio
  • Seizures/chemically induced
  • Tramadol/adverse effects


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