Drug Safety

pp 1–12 | Cite as

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

  • Sohyun Jeong
  • Ha Jin Tchoe
  • Junqing Li
  • Ju-Young ShinEmail author
Original Research Article



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.


The objective of this study was to evaluate whether tramadol use is associated with mortality in various risk groups.


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).


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.


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.


Compliance with Ethical Standards

Conflict of interest

Sohyun Jeong, Ha Jin Tchoe, Junqing Li, and Ju-Young Shin have no conflicts of interest that are directly relevant to the content of this study.


This research was supported by a Grant from the Korean Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (Grant no.: NHCR-HC17C0020).

Ethical approval

This study was approved by the institutional review board of the Sungkyunkwan University in South Korea (SKKU-IRB-2016-10-013). All personal identifying information of patients was anonymous; therefore, informed consent was waived by the institutional review board for this study.

Transparency declaration

The guarantors affirm that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

Data sharing

No additional data available.

Supplementary material

40264_2018_786_MOESM1_ESM.pdf (16 kb)
Supplementary material 1 (PDF 15 kb)
40264_2018_786_MOESM2_ESM.pdf (179 kb)
Supplementary material 2 (PDF 178 kb)
40264_2018_786_MOESM3_ESM.pdf (167 kb)
Supplementary material 3 (PDF 166 kb)


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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.School of PharmacySungkyunkwan UniversitySuwonSouth Korea

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