Causes, Nature and Toxicology of Tramadol-Associated Deaths Reported in the Peer-Reviewed Literature: A Systematic Review of Case Studies and Case Series

Drugs & Therapy Perspectives (2021)Cite this article

Abstract

Background

Despite the increased reporting of tramadol poisoning, the nature and toxicology of tramadol-associated deaths have not been adequately subjected to systematic evaluation. This study aims to investigate the causes, nature and toxicology of tramadol-associated deaths by systematically reviewing the case studies and case series published in peer-reviewed journals.

Methods

Scopus, Embase, Medline and Google Scholar were searched from inception until 30 May 2020 to identify the case studies and case series published in English that reported tramadol-associated deaths. Data on number of deaths, routes of administration, toxicological data and any concomitant drug usage were extracted. The Joanna Briggs Institute’s quality assessment tool was used to assess the quality of included studies.

Results

The initial searches identified 451 articles. Of these, 12 studies (eight case studies and four case series) were considered in the review, which represented a total of 181 deaths, with UK (n = 127) and Sweden (n = 17) reporting most deaths. Intentional suicide was the cause of tramadol poisoning in 54 of the 181 cases. Data on routes of administration were often missing; however, the most common related was the oral route (15.5%). Mixed drug toxicity was among the causes of reported deaths (n = 127, 70.2%), where in most cases, individuals were receiving other central nervous system depressants, especially benzodiazepines. However, tramadol, as the sole cause of death, was reported in eight cases. The mean level of blood tramadol for the deaths was 10.6 µg/mL.

Conclusion

The unintentional nature of many tramadol deaths has been reported, and it is important to consider that the drug can be acquired through illicit means. Healthcare practitioners need to build a strong understanding about tramadol’s possible toxicity and should exercise caution when a patient is to use tramadol in combination with other drugs.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

39,95 €

Tax calculation will be finalised during checkout.

Fig. 1

References

  1. 1.

    WHO. World Health Organization Expert Committee on Drug Dependence: thirty-sixth report. World Health Organization, Geneva, 2015.

  2. 2.

    Goeringer KE, Logan BK, Christian GD. Identification of tramadol and its metabolites in blood from drug-related deaths and drug-impaired drivers. J Anal Toxicol. 1997;21(7):529–37.

    CAS  Article  Google Scholar 

  3. 3.

    Gibson TP. Pharmacokinetics, efficacy, and safety of analgesia with a focus on tramadol HCl. Am J Med. 1996;101:S47–53.

    Article  Google Scholar 

  4. 4.

    Elsing B, Blaschke G. Achiral and chiral high-performance liquid chromatographic determination of tramadol and its major metabolites in urine after oral administration of racemic tramadol. J Chromatogr B Analyt Technol Biomed Life Sci. 1993;612(2):223–30.

    CAS  Article  Google Scholar 

  5. 5.

    Hennies H, Friderichs E, Schneider J. Receptor binding, analgesic and antitussive potency of tramadol and other selected opioids. Drug Res. 1988;38(7):877–80.

    CAS  Google Scholar 

  6. 6.

    Lee CR, McTavish D, Sorkin EM. Tramadol. Drugs. 1993;46(2):313–40.

    CAS  Article  Google Scholar 

  7. 7.

    Driessen B, Reimann W, Giertz H. Effects of the central analgesic tramadol on the uptake and release of noradrenaline and dopamine in vitro. Br J Pharmacol. 1993;108(3):806–11.

    CAS  Article  Google Scholar 

  8. 8.

    Sansone RA, Sansone LA. Tramadol: seizures, serotonin syndrome, and coadministered antidepressants. Psychiatry (Edgmont). 2009;6(4):17.

    Google Scholar 

  9. 9.

    Randall C, Crane J. Tramadol deaths in Northern Ireland: a review of cases from 1996 to 2012. J Forensic Leg Med. 2014;23:32–6.

    CAS  Article  Google Scholar 

  10. 10.

    Jeong S, Tchoe HJ, Li J, et al. All-cause mortality associated with tramadol use: a case-crossover study. Drugs Saf. 2019;42(6):785–96.

    CAS  Article  Google Scholar 

  11. 11.

    Barbera N, Fisichella M, Bosco A, et al. A suicidal poisoning due to tramadol. A metabolic approach to death investigation. J Forensic Leg Med. 2013;20(5):555–8.

    Article  Google Scholar 

  12. 12.

    Lintz W, Barth H, Osterloh G, et al. Bioavailability of enteral tramadol formulations. 1st communication: capsules. Arzneimittelforschung. 1986;36(8):1278–83.

    CAS  PubMed  Google Scholar 

  13. 13.

    Liao S, Hill J, Nayak R. Pharmacokinetics of tramadol following single and multiple oral doses in man. Pharm Res. 1992;9(Suppl):308.

    Google Scholar 

  14. 14.

    Bamigbade T, Langford R. Tramadol hydrochloride: an overview of current use. Hospital medicine (London, England: 1998). 1998;59(5):373–6.

    CAS  Google Scholar 

  15. 15.

    Clarot F, Goulle JP, Vaz E, et al. Fatal overdoses of tramadol: is benzodiazepine a risk factor of lethality? Forensic Sci Int. 2003;134(1):57–61.

    CAS  Article  Google Scholar 

  16. 16.

    Michaud K, Augsburger M, Romain N, et al. Fatal overdose of tramadol and alprazolam. Forensic Sci Int. 1999;105(3):185–9.

    CAS  Article  Google Scholar 

  17. 17.

    Ellenhorn MJ, Barceloux D. Diagnosis and treatment of human poisoning. Med Toxicol. 1997;1997:609–10.

    Google Scholar 

  18. 18.

    Shadnia S, Soltaninejad K, Heydari K, et al. Tramadol intoxication: a review of 114 cases. Hum Exp Toxicol. 2008;27(3):201–5.

    CAS  Article  Google Scholar 

  19. 19.

    Musshoff F, Madea B, Stuber F, Stamer UM. Enantiomeric determination of tramadol and O-desmethyltramadol by liquid chromatography-mass spectrometry and application to postoperative patients receiving tramadol. J Anal Toxicol. 2006;30(7):463–7.

    CAS  Article  Google Scholar 

  20. 20.

    Eichelbaum M, Evert B. Influence of pharmacogenetics on drug disposition and response. Clin Exp Pharmacol Physiol. 1996;23(10–11):983–5.

    CAS  Article  Google Scholar 

  21. 21.

    Bertilsson L, Dahl ML, Dalén P, et al. Molecular genetics of CYP2D6: clinical relevance with focus on psychotropic drugs. Br J Clin Pharmacol. 2002;53(2):111–22.

    CAS  Article  Google Scholar 

  22. 22.

    De Backer B, Renardy F, Denooz R, et al. Quantification in postmortem blood and identification in urine of tramadol and its two main metabolites in two cases of lethal tramadol intoxication. J Anal Toxicol. 2010;34(9):599–604.

    Article  Google Scholar 

  23. 23.

    Loughrey MB, Loughrey CM, Johnston S, et al. Fatal hepatic failure following accidental tramadol overdose. Forensic Sci Int. 2003;134(2–3):232–3.

    CAS  Article  Google Scholar 

  24. 24.

    Murphy E. Acute pain management pharmacology for the patient with concurrent renal or hepatic disease. Anaesth Intensive Care. 2005;33(3):311–22.

    CAS  Article  Google Scholar 

  25. 25.

    Leppert W. Tramadol as an analgesic for mild to moderate cancer pain. Pharmacol rep. 2009;61(6):978–92.

    CAS  Article  Google Scholar 

  26. 26.

    Hernández LG, van Steeg H, Luijten M, et al. Mechanisms of non-genotoxic carcinogens and importance of a weight of evidence approach. Mutat Res Rev Mutat Res. 2009;682(2–3):94–109.

    Article  Google Scholar 

  27. 27.

    PSNC. Pharmaceutical Services Negotiating Committee, Controlled Drug changes to the legal classification of Tramadol 2014. https://psnc.org.uk/halton-st-helens-and-knowsley-lpc/wp-content/uploads/sites/45/2014/05/Controlled-Drug-changes-to-the-legal-classification-of-Tramadol-28-5-14-2.pdf. Accessed 5 July 2020

  28. 28.

    ACMD. Advisory council on the misuse of drugs consideration of tramadol. London: ACMD; 2013.

    Google Scholar 

  29. 29.

    Tashakori A, Afshari R. Tramadol overdose as a cause of serotonin syndrome: a case series. Clin Toxicol. 2010;48(4):337–41.

    CAS  Article  Google Scholar 

  30. 30.

    Gioia S, Lancia M, Bacci M, et al. Two fatal intoxications due to tramadol alone: autopsy case reports and review of the literature. Am J Forensic Med Pathol. 2017;38(4):345–8.

    Article  Google Scholar 

  31. 31.

    Pang W-W, Mok MS, Huang S, et al. Intraoperative loading attenuates nausea and vomiting of tramadol patient-controlled analgesia. Can J Anaesth. 2000;47(10):968.

    CAS  Article  Google Scholar 

  32. 32.

    Slanař O, Nobilis M, Kvetina J, et al. Miotic action of tramadol is determined by CYP2D6 genotype. Physiol Res. 2007;56(1):129–36.

    Article  Google Scholar 

  33. 33.

    Preston KL, Jasinski DR, Testa M. Abuse potential and pharmacological comparison of tramadol and morphine. Drug Alcohol Depend. 1991;27(1):7–17.

    CAS  Article  Google Scholar 

  34. 34.

    Joannabriggs-webdev.org. Critical Appraisal Tools—JBI. (n.d.).

  35. 35.

    Musshoff F, Madea B. Fatality due to ingestion of tramadol alone. Forensic Sci Int. 2001;116(2–3):197–9.

    CAS  Article  Google Scholar 

  36. 36.

    De Decker K, Cordonnier J, Jacobs W, et al. Fatal intoxication due to tramadol alone. Case report and review of the literature. Forensic Sci Int. 2008;175(1):79–82.

    Article  Google Scholar 

  37. 37.

    Tjäderborn M, Jönsson AK, Hägg S, et al. Fatal unintentional intoxications with tramadol during 1995–2005. Forensic Sci Int. 2007;173(2–3):107–11.

    Article  Google Scholar 

  38. 38.

    Oertel R, Pietsch J, Arenz N, et al. Distribution of metoprolol, tramadol, and midazolam in human autopsy material. J Chromatogr A. 2011;1218(30):4988–94.

    CAS  Article  Google Scholar 

  39. 39.

    Sun-Edelstein C, Tepper SJ, Shapiro RE. Drug-induced serotonin syndrome: a review. Expert Opin Drug Saf. 2008;7(5):587–96.

    CAS  Article  Google Scholar 

  40. 40.

    Costa I, Oliveira A, Guedes de Pinho P, et al. Postmortem redistribution of tramadol and O-desmethyltramadol. J Anal Toxicol. 2013;37(9):670–5.

    CAS  Article  Google Scholar 

  41. 41.

    DeJean D, Giacomini M, Vanstone M, et al. Patient experiences of depression and anxiety with chronic disease: a systematic review and qualitative meta-synthesis. Ont Health Technol Assess Ser. 2013;13(16):1–33.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Affiliations

  1. School of Pharmacy, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK

    Saud Alrashdi, Vibhu Paudyal & Ejaz Cheema

  2. Public Security, Ministry of Interior, Riyadh, Saudi Arabia

    Saud Alrashdi

  3. Department of Pharmacy Practice, Faculty of Pharmacy, International Islamic University Malaysia, Kuantan, Pahang, Malaysia

    Mohamed Hassan Elnaem

  4. Quality Use of Medicines Research Group, Faculty of Pharmacy, International Islamic University Malaysia, Kuantan, Pahang, Malaysia

    Mohamed Hassan Elnaem

Authors
  1. Saud Alrashdi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Vibhu Paudyal
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mohamed Hassan Elnaem
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ejaz Cheema
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ejaz Cheema.

Ethics declarations

Funding

Not applicable.

Conflict of interest

The authors declare that they have no conflict of interest.

Ethics approval and consent to participate

This work did not require ethics approval and consent to participate.

Consent for publication

Not applicable.

Availability of data and materials

All data have been provided within the manuscript

Author contributions

EC developed the research question. SA conducted the searches and extracted the data. Both EC and SA analysed the data and did the quality assessment. EC, SA, VP and MHN contributed to the preparation of the manuscript.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Alrashdi, S., Paudyal, V., Elnaem, M.H. et al. Causes, Nature and Toxicology of Tramadol-Associated Deaths Reported in the Peer-Reviewed Literature: A Systematic Review of Case Studies and Case Series. Drugs Ther Perspect (2021). https://doi.org/10.1007/s40267-021-00859-6

Download citation