Skip to main content

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

Abstract

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.

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

Fig. 1
Fig. 2

References

  1. 1.

    World Health Organization. Tramadol—update review report (agenda item 6.1). Geneva: World Health Organization; 2014.

    Google Scholar 

  2. 2.

    Scott LJ, Perry CM. Tramadol: a review of its use in perioperative pain. Drugs. 2000;60(1):139–76.

    CAS  PubMed  Article  Google Scholar 

  3. 3.

    Miranda H, Pinardi G. Antinociception, tolerance, and physical dependence comparison between morphine and tramadol. Pharmacol Biochem Behav. 1998;61:357–60.

    CAS  PubMed  Article  Google Scholar 

  4. 4.

    Murano T, Yamamoto H, Endo N, Kudo Y, Okada N, Masuda Y, et al. Studies on dependence on tramadol in rats. Arzneimittelforschung. 1978;28:152–8.

    CAS  PubMed  Google Scholar 

  5. 5.

    Cami J, Lamas X, Farre M. Acute effects of tramadol in methadone-maintained volunteers. Drugs. 1994;47(Suppl 1):39–43.

    CAS  PubMed  Article  Google Scholar 

  6. 6.

    Jasinski D, Preston K, Sullivan J, Testa M. Abuse potential of oral tramadol. NIDA Res Monogr. 1993;132:103.

    Google Scholar 

  7. 7.

    Richter W, Barth H, Flohe L, Giertz H. Clinical investigation on the development of dependence during oral therapy with tramadol. Arzneimittelforschung. 1985;35:1742–4.

    CAS  PubMed  Google Scholar 

  8. 8.

    Raffa R, Buschmann H, Christoph T, Eichenbaum G, Englberger W, Flores C, et al. Mechanistic and functional differentiation of tapentadol and tramadol. Expert Opin Pharmacother. 2012;13(10):1437–49.

    CAS  PubMed  Article  Google Scholar 

  9. 9.

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

    CAS  PubMed  Google Scholar 

  10. 10.

    Sansone RA, Sansone LA. Tramadol: seizures, serotonin syndrome, and coadministered antidepressants. Psychiatry (Edgmont). 2009;6(4):17–21.

    Google Scholar 

  11. 11.

    Keskinbora K, Aydinli I. An atypical opioid analgesic: tramadol. Agri. 2006;18(1):5–19.

    PubMed  Google Scholar 

  12. 12.

    Duehmke RM, Derry S, Wiffen PJ, Bell RF, Aldington D, Moore RA. Tramadol for neuropathic pain in adults. Cochrane Database Syst Rev. 2017;6:CD003726. https://doi.org/10.1002/14651858.CD003726.pub4.

    PubMed  Article  Google Scholar 

  13. 13.

    Cepeda MS, Camargo F, Zea C, Valencia L. Tramadol for osteoarthritis. Cochrane Database Syst Rev. 2006;3:CD005522.

    Google Scholar 

  14. 14.

    Ho ML, Chung CY, Wang CC, Lin HY, Hsu NC, Chang CS. Efficacy and safety of tramadol/acetaminophen in the treatment of breakthrough pain in cancer patients. Saudi Med J. 2010;31(12):1315–9.

    PubMed  Google Scholar 

  15. 15.

    US Food and Drug Administration. FDA Drug Safety Communication: FDA restricts use of prescription codeine pain and cough medicines and tramadol pain medicines in children; recommends against use in breastfeeding women. Washington, DC: FDA; 2017. https://www.fda.gov/Drugs/DrugSafety/ucm549679.htm. Accessed 25 Apr 2018.

  16. 16.

    Orliaguet G, Hamza J, Couloigner V, Denoyelle F, Loriot M, Broly F, et al. A case of respiratory depression in a child with ultrarapid CYP2D6 metabolism after tramadol. Pediatrics. 2015;135:e753–5.

    PubMed  Article  Google Scholar 

  17. 17.

    European Medicines Agency. Annex I. Scientific conclusions and grounds for the variation to the terms of the Marketing Authorisation(s). UK: European Medicines Agency; 2018. https://www.ema.europa.eu/documents/psusa/tramadol-cmdh-scientific-conclusions-groundsvariation-amendments-product-information-timetable/00003002/201705_en.pdf. Accessed 5 Oct 2018.

  18. 18.

    Druginfo. Tramadol HCl. Basic information. Osong: Ministry of Food and Drug Safety; 2018. http://drug.mfds.go.kr/html/bxsDrugChange.jsp?scItemSeq=198300327. Accessed 11 Oct 2018.

  19. 19.

    Handley S, Flanagan R. Drugs and other chemicals involved in fatal poisoning in England and Wales during 2000–2011. Clin Toxicol (Phila). 2014;52(1):1–12.

    CAS  Article  Google Scholar 

  20. 20.

    Office for National Statistics. Deaths related to drug poisoning in England and Wales. 2012. http://www.ons.gov.uk/ons/rel/subnational-health3/deaths-related-to-drugpoisoning/2012/index.html. Accessed 18 Aug 2018.

  21. 21.

    Lee M-J. Korea Biomedical Review. Misuse, abuse of tramadol-based painkillers need factual survey; 2017. http://www.koreabiomed.com/news/articleView.html?idxno=1715. Accessed 18 Aug 2018.

  22. 22.

    Harrigan TM. Schedules of controlled substances: placement of tramadol into Schedule IV. Springfield: Drug Enforcement Administration/Department of Justice; 2014. https://www.deadiversion.usdoj.gov/fed_regs/rules/2014/fr0702.htm. Accessed 11 Oct 2018.

  23. 23.

    Schneider DM. Clinical inquiries. What is the addiction risk associated with tramadol? J Fam Pract. 2005;54(1):5–6.

    Google Scholar 

  24. 24.

    Jung Y-S, Kim D-K, Kim M-K, Kim H-J, Cha I-H, Han M-Y, et al. Comparison of tramadol/acetaminophen and codeine/acetaminophen/ibuprofen in onset of analgesia and analgesic efficacy for postoperative acute pain. J Korean Oral Maxillofac Surg. 2004;30:143–9.

    Google Scholar 

  25. 25.

    Kim J, Kim Y-H, Lee Y, Seong W-K, Hong S-I, Jang C-G, et al. Dependence potential of tramadol: behavioral pharmacology in rodents. Biomol Ther (Seoul). 2014;22(6):558–62.

    Article  CAS  Google Scholar 

  26. 26.

    National Association of Boards of Pharmacy. Tennessee News: tramadol and carisoprodol now classified Schedule IV. Mount Prospect: National Association of Boards of Pharmacy; 2011. https://archive.is/20130222125410/http://www.nabp.net/news/tennessee-news-tramadol-and-carisoprodol-now-classified-schedule-iv. Accessed 18 Aug 2018.

  27. 27.

    Drug Enforcement Administration. TRAMADOL (trade names: Ultram®, Ultracet®). Office of Diversion Control: Springfield, VA 22152, Drug and Chemical Evaluation Section; 2011.

  28. 28.

    Daubin C, Quentin C, Goullé J, Guillotin D, Lehoux P, Lepage O, et al. Refractory shock and asystole related to tramadol overdose. Clin Toxicol. 2007;45(8):961–4.

    Article  Google Scholar 

  29. 29.

    Gnanadesigan N, Espinoza R, Smith R, Israel M, Reuben D. Interaction of serotonergic antidepressants and opioid analgesics: is serotonin syndrome going undetected? J Am Med Direct Assoc. 2005;6(4):265–9.

    Article  Google Scholar 

  30. 30.

    Jovanović-Cupić V, Martinović Z, Nesić N. Seizures associated with intoxication and abuse of tramadol. Clin Toxicol (Phila). 2006;44(2):143–6.

    Article  Google Scholar 

  31. 31.

    Abadie D, Durrieu G, Roussin A, Montastruc JL. Réseau Français des Centres Régionaux de Pharmacovigilance. “Serious” adverse drug reactions with tramadol: a 2010–2011 pharmacovigilance survey in France [in French]. Thérapie. 2013;68(2):77–84.

    PubMed  Google Scholar 

  32. 32.

    Robb G, Loe E, Maharaj A, Hamblin R, Seddon M. Medication-related patient harm in New Zealand hospitals. N Z Med J. 2017;130(1460):21–32.

    PubMed  Google Scholar 

  33. 33.

    Garrett P. Tramadol overdose and serotonin syndrome manifesting as acute right heart dysfunction. Anaesth Intensive Care. 2004;32(4):575–7.

    CAS  PubMed  Article  Google Scholar 

  34. 34.

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

    CAS  PubMed  Article  Google Scholar 

  35. 35.

    Moore K, Cina S, Jones R, Selby D, Levine B, Smith M. Tissue distribution of tramadol and metabolites in an overdose fatality. Am J Forensic Med Pathol. 1999;20(1):98–100.

    CAS  PubMed  Article  Google Scholar 

  36. 36.

    Barsotti C, Mycyk M, Reyes J. Withdrawal syndrome from tramadol hydrochloride. Am J Emerg Med. 2003;21(1):87–8.

    PubMed  Article  Google Scholar 

  37. 37.

    Freye E, Levy J. Acute abstinence syndrome following abrupt cessation of long-term use of tramadol (Ultram): a case study. Eur J Pain. 2000;43(3):307–11.

    Article  Google Scholar 

  38. 38.

    Ojha R, Bhatia S. Tramadol dependence in a patient with no previous substance history. Prim Care Companion. J Clin Psychiatry. 2010;12(1):PCC.09100779.

    Google Scholar 

  39. 39.

    Soyka M, Backmund M, Hasemann S. Tramadol use and dependence in chronic noncancer pain patients. Pharmacopsychiatry. 2004;37(4):191–2.

    CAS  PubMed  Article  Google Scholar 

  40. 40.

    Woody G, Senay E, Geller A, Adams E, Inciardi J, Schnoll S, et al. An independent assessment of MEDWatch reporting for abuse/dependence and withdrawal from Ultram (tramadol hydrochloride). Drug Alcohol Depend. 2003;72(2):163–8.

    CAS  PubMed  Article  Google Scholar 

  41. 41.

    Madea B. Sudden death, especially in infancy—improvement of diagnoses by biochemistry, immunohistochemistry and molecular pathology. Legal Med (Tokyo). 2009;11:S36–42.

    Article  Google Scholar 

  42. 42.

    Klingmann A, Skopp G, Pedal I, Pötsch L, Aderjan R. Distribution of morphine and morphine glucuronides in body tissue and fluids–postmortem findings in brief survival. Arch Kriminol. 2000;206(1–2):38–49.

    CAS  PubMed  Google Scholar 

  43. 43.

    Oertel R, Pietsch J, Arenz N, Zeitz S, Goltz L, Kirch W. Distribution of metoprolol, tramadol, and midazolam in human autopsy material. J Chromatogr A. 2011;1218(30):4988–94.

    CAS  PubMed  Article  Google Scholar 

  44. 44.

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

    CAS  PubMed  Article  Google Scholar 

  45. 45.

    Wiebe T, Watterson J. Analysis of tramadol and O-desmethyltramadol in decomposed skeletal tissues following acute and repeated tramadol exposure by gas chromatography mass spectrometry. Forensic Sci Int. 2014;242:261–5.

    CAS  PubMed  Article  Google Scholar 

  46. 46.

    Maclure M. The case-crossover design: a method for studying transient effects on the risk of acute events. Am J Epidemiol. 1991;133(2):144–53.

    CAS  PubMed  Article  Google Scholar 

  47. 47.

    Lee J, Lee J, Park S. Cohort Profile: The National Health Insurance Service-National Sample Cohort (NHIS-NSC), South Korea. Int J Epidemiol. 2017;46(2):e15. https://doi.org/10.1093/ije/dyv319.

    PubMed  Article  Google Scholar 

  48. 48.

    WHO Collaborating Center for Drug Statistics Methodology. ATC/DDD index: tramadol. 2017. https://www.whocc.no/atc_ddd_index/?code=N02AX02. Accessed 18 Aug 2018

  49. 49.

    Fournier J-P, Azoulay L, Yin H, Montastruc J-L, Suissa S. Tramadol use and the risk of hospitalization for hypoglycemia in patients with noncancer pain. JAMA Intern Med. 2015;175(2):186–93.

    PubMed  Article  Google Scholar 

  50. 50.

    Fournier JP, Yin H, Nessim SJ, Montastruc JL, Azoulay L. Tramadol for noncancer pain and the risk of hyponatremia. Am J Med. 2015;128(4):418–25.e5. https://doi.org/10.1016/j.amjmed.2014.10.046.

    CAS  PubMed  Article  Google Scholar 

  51. 51.

    Söderberg K, Laflamme L, Möller J. Newly initiated opioid treatment and the risk of fall-related injuries. A nationwide, register-based, case-crossover study in Sweden. CNS Drugs. 2013;27(2):155–61.

    PubMed  Article  CAS  Google Scholar 

  52. 52.

    Möller J, Laflamme L, Söderberg Löfdal K. CYP2D6-inhibiting drugs and the increased risk of fall-related injuries due to newly initiated opioid treatment—a Swedish, register-based case-crossover study. Basic Clin Pharmacol Toxicol. 2014;116(2):134–9.

    PubMed  Article  CAS  Google Scholar 

  53. 53.

    Jann M, Kennedy W, Lopez G. Benzodiazepines: a major component in unintentional prescription drug overdoses with opioid analgesics. J Pharm Pract. 2014;27(1):5–16.

    PubMed  Article  Google Scholar 

  54. 54.

    Substance Abuse and Mental Health Services Administration (SAMHSA). The TEDS Report: admissions reporting benzodiazepine and narcotic pain reliever abuse at treatment entry. Rockville: Center for Behavioral Health Statistics and Quality; 2012.

    Google Scholar 

  55. 55.

    Liston HL, Markowitz JS. Opioid drug–drug interactions: a review. J Pharm Pract. 1988;11(5):325–41.

    Article  Google Scholar 

  56. 56.

    Healthcare Bigdata Hub. Lab/surgery statistics. Wonju: Health Insurance Review and Assessment Service; 2018. http://opendata.hira.or.kr/op/opc/olapDiagBhvInfo.do. Accessed 22 Oct 2018.

  57. 57.

    ICD10Data.com. The web’s free 2018 ICD-10-CM/PCS medical coding reference; 2018. https://www.icd10data.com/. Accessed 30 June 2017.

  58. 58.

    Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40(5):373–83.

    CAS  Article  Google Scholar 

  59. 59.

    WHO Collaborating Center for Drug Statistics Methodology. DDD: definition and general considerations. Oslo: WHO; 2018. https://www.whocc.no/ddd/definition_and_general_considera/. Accessed 20 May 2018.

  60. 60.

    Hassanian-Moghaddam H, Farnaghi F, Rahimi M. Tramadol overdose and apnea in hospitalized children, a review of 20 cases. Res Pharm Sci. 2015;10:544–52.

    PubMed  PubMed Central  Google Scholar 

  61. 61.

    Jenco M. The Children’s Clinic. Do not use codeine, tramadol in children: FDA. AAP News; 2017. http://www.aappublications.org/news/2017/04/20/Codeine042017. Accessed 27 Dec 2018.

  62. 62.

    Bush D. The CBHSQ report: emergency department visits for adverse reactions involving the pain medication tramadol; 2015. http://www.samhsa.gov/data/sites/default/files/report_1965/ShortReport-1965.html. Accessed 12 Oct 2018.

  63. 63.

    Bourne C, Gouraud A, Daveluy A, Grandvuillemin A, Auriche P, Descotes J, et al. Tramadol and hypoglycaemia: comparison with other step 2 analgesic drugs. Br J Clin Pharmacol. 2013;75(4):1063–7.

    CAS  PubMed  Article  Google Scholar 

  64. 64.

    White M. Tramadol deaths in the United Kingdom. London: Public Health England and UK Focal Point on Drugs, Alcohol Drugs and Tobacco Division; 2016. http://www.emcdda.europa.eu/system/files/attachments/3236/Martin%20White-UKTramadol%20deaths%20in%20the%20United%20Kingdom%20EMCDDA.pdf. Accessed 21 Oct 2018.

    Google Scholar 

  65. 65.

    Crawford K. Studies show opioid deaths less likely in cancer patients, post-surgery opioid use can be reduced successfully. Alexandria: American Society of Clinical Oncology; 2018. https://www.asco.org/about-asco/press-center/news-releases/studies-show-opioid-deaths-less-likely-cancer-patients-post. Accessed 12 Oct 2018.

  66. 66.

    Nersesyan H, Slavin KV. Current aproach to cancer pain management: availability and implications of different treatment options. Ther Clin Risk Manag. 2007;3(3):381–400.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67.

    Broglio K, Cole BE. Pain management and terminal illness. In: Practical pain management. Vertical Health; 2011. https://www.practicalpainmanagement.com/resources/hospice/pain-management-terminal-illness. Accessed 12 Oct 2018.

  68. 68.

    Ortho-McNeil Pharmaceutical Inc. ULTRAM®: (tramadol hydrochloride) tablets. Full prescribing information. Raritan: Ortho-McNeil Pharmaceutical, Inc.; 2008.

    Google Scholar 

  69. 69.

    Barbosa J, Faria J, Leal S, Afonso L, Lobo J, Queirós O, et al. Acute administration of tramadol and tapentadol at effective analgesic and maximum tolerated doses causes hepato- and nephrotoxic effects in Wistar rats. Toxicology. 2017;389:118–29.

    CAS  PubMed  Article  Google Scholar 

  70. 70.

    Sera L, McPherson ML, Holmes HM. Commonly prescribed medications in a population of hospice patients. Am J Hosp Palliat Care. 2014;31(2):126–31.

    PubMed  Article  Google Scholar 

  71. 71.

    Skinner D, Epstein J, Pappagallo M. Tramadol. In: Smith HS, editor. Current therapy in pain. Philadelphia: Elsevier; 2009. p. 508–12.

    Chapter  Google Scholar 

  72. 72.

    Ryan N, Isbister G. Tramadol overdose causes seizures and respiratory depression but serotonin toxicity appears unlikely. Clin Toxicol (Phila). 2015;53(6):545–50.

    CAS  Article  Google Scholar 

  73. 73.

    Tantry TP, Kadam D, Shetty P, Adappa KK. Tramadol-induced respiratory depression in a morbidly obese patient with normal renal function. Indian J Anaesth. 2011;55(3):318–20.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  74. 74.

    Teppema L, Nieuwenhuijs D, Olievier C, Dahan A. Respiratory depression by tramadol in the cat: involvement of opioid receptors. Anesthesiology. 2003;98:420–7.

    CAS  PubMed  Article  Google Scholar 

  75. 75.

    Stamer U, Musshoff F, Kobilay M, Madea B, Hoeft A, Stüber F. Concentrations of tramadol and O-desmethyltramadol enantiomers in different CYP2D6 genotypes. Clin Pharmacol Ther. 2007;82:41–7.

    CAS  PubMed  Article  Google Scholar 

  76. 76.

    Leppert W. CYP2D6 in the metabolism of opioids for mild to moderate pain. Pharmacology. 2011;87(5–6):274–85.

    CAS  PubMed  Article  Google Scholar 

  77. 77.

    Samer C, Lorenzini K, Rollason V, Daali Y, Desmeules J. Applications of CYP450 testing in the clinical setting. Mol Diagn Ther. 2013;17(3):165–84.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  78. 78.

    Bernarda S, Nevilleb KA, Nguyenb AT, Flockhartb DA. Interethnic differences in genetic polymorphisms of CYP2D6 in the U.S. population: clinical implications. Oncologist. 2006;11(2):126–35.

    Article  Google Scholar 

  79. 79.

    Garg RK, Fulton-Kehoe D, Franklin G. Patterns of opioid use and risk of opioid overdose death among medicaid patients. Med Care. 2017;55(7):661–8.

    PubMed  Article  Google Scholar 

  80. 80.

    U.S. Department of Health and Human Services. What is the U.S. opioid epidemic? Washington, DC: U.S. Department of Health and Human Services; 2017. https://www.hhs.gov/opioids/about-the-epidemic/index.html. Accessed 11 Oct 2018.

  81. 81.

    Weinstein M, Vaupel JW, Wachter KW. Biosocial Surveys. 16. Mendelian randomization: genetic variants as instruments for strengthening causal inference in observational studies. Washington, DC: The National Academies Press; 2008.

    Google Scholar 

  82. 82.

    Hallas J, Pottegård A, Wang S, Schneeweiss S, Gagne J. Persistent user bias in case-crossover studies in pharmacoepidemiology. Am J Epidemiol. 2016;184(10):761–9. https://doi.org/10.1093/aje/kww079.

    PubMed  Article  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Ju-Young Shin.

Ethics declarations

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.

Funding

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.

Electronic supplementary material

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Jeong, S., Tchoe, H.J., Li, J. et al. All-Cause Mortality Associated with Tramadol Use: A Case-Crossover Study. Drug Saf 42, 785–796 (2019). https://doi.org/10.1007/s40264-018-00786-y

Download citation