International Journal of Legal Medicine

, Volume 125, Issue 6, pp 803–815 | Cite as

Deaths involving contraindicated and inappropriate combinations of serotonergic drugs

  • Jennifer L. PilgrimEmail author
  • Dimitri Gerostamoulos
  • Olaf H. Drummer
Original Article


In the Australian state of Victoria, all fatalities that were recorded from 2002 through to 2008 involving the use of certain serotonin active drugs (tramadol, venlafaxine, fluoxetine, sertraline, citalopram and paroxetine), were reviewed to assess the incidence of contraindicated or ill advised drug combinations. More than 1,000 were identified of which 326 cases formed the basis of this study. These cases involved contraindicated or inappropriate drug combinations that can lead to adverse drug reactions (ADRs) and subsequent fatal toxicity. Of these, 46% were drug-related, 35% were a result of natural disease and 13% were classified as external injury cases. The remaining cases were those where the cause of death (COD) was unascertained. Tramadol was the most common drug, usually detected alongside a serotonergic antidepressant (in 20% of cases). Twenty-five (8%) cases involved contraindicated drug combinations while the remainder (301 cases, 92%) involved drug combinations that are associated with adverse interactions ranging from minor to major severity. Of these 326 cases, the Coroner determined 166 cases (51%) to be acts of intentional self-harm or drug misuse, with the remainder unascertained or attributed to natural disease. Very few post-mortem reports and Coroners’ findings made mention of possible ADRs when such combinations were actually present. The majority of cases comprising contraindicated drug combinations involved the combined use of five drugs (24%) at the time of death. A combination of three to five drugs was most common in cases involving inadvisable drug combinations. Combined drug toxicity was the most common COD, with heart disease the most common co-morbidity.


Fatalities Contraindicated drugs Adverse drug reactions Tramadol Venlafaxine Fluoxetine Sertraline Citalopram Paroxetine 



We thank the National Coroners Information System and the State Coroner’s Office for their help in obtaining mortality data. We also acknowledge the assistance of pathologists, forensic technicians and toxicologists, at the Victorian Institute of Forensic Medicine. Thanks also to Dr. Steven Haas for his assistance in manuscript preparation.


  1. 1.
    Roughead EE, Lexchin J (2006) Adverse drug events: counting is not enough, action is needed. Med J Aust 184(7):315–316PubMedGoogle Scholar
  2. 2.
    Runciman WB, Roughead EE, Semple SJ, Adams RJ (2003) Adverse drug events and medication errors in Australia. Int J Qual Health Care 15(Suppl 1):i49–i59PubMedCrossRefGoogle Scholar
  3. 3.
    Bijl D (2004) The serotonin syndrome. Neth J Med 62:309–314PubMedGoogle Scholar
  4. 4.
    Birmes P, Coppin D, Schmitt L, Lauque D (2003) Serotonin syndrome: a brief review. CMAJ 168(11):1439–1442PubMedGoogle Scholar
  5. 5.
    Boyer EW, Shannon M (2005) The serotonin syndrome. N Engl J Med 352(11):1112–1120PubMedCrossRefGoogle Scholar
  6. 6.
    Sternbach H (1991) The serotonin syndrome. Am J Psychiatry 148:705–713PubMedGoogle Scholar
  7. 7.
    Emims (1996–2010) (Accessed 2009–2010)
  8. 8.
    Micromedex® healthcare series [internet database] (1974–2010) (Accessed 16 July 2010)
  9. 9.
    Tamblyn RM, McLeod PJ, Abrahamowicz M, Monette J, Gayton DC, Berkson L, Dauphinee WD, Grad RM, Huang AR, Isaac LM, Schnarch BS, Snell LS (1994) Questionable prescribing for elderly patients in Quebec. CMAJ 150(11):1801–1809PubMedGoogle Scholar
  10. 10.
    Hamilton H, Gallagher P, O’Mahony D (2009) Inappropriate prescribing and adverse drug events in older people. BMC Geriatr 9(1):5PubMedCrossRefGoogle Scholar
  11. 11.
    Jones JK, Fife D, Curkendall S, Goehring E Jr, Guo JJ, Shannon M (2001) Coprescribing and codispensing of cisapride and contraindicated drugs. JAMA 286(13):1607–1609PubMedCrossRefGoogle Scholar
  12. 12.
    Stang P, Morris L, Kempf J, Henderson S, Yood MU, Oliveria S (2007) The coprescription of contraindicated drugs with statins: continuing potential for increased risk of adverse events. Am J Ther 14(1):30–40PubMedCrossRefGoogle Scholar
  13. 13.
    Roughead EE, Anderson B, Gilbert AL (2007) Potentially inappropriate prescribing among Australian veterans and war widows/widowers. Intern Med J 37(6):402–405PubMedCrossRefGoogle Scholar
  14. 14.
    Ringland C, Mant A, McGettigan P, Mitchell P, Kelman C, Buckley N, Pearson SA (2008) Uncovering the potential risk of serotonin toxicity in Australian veterans using pharmaceutical claims data. Br J Clin Pharmacol 66(5):682–688PubMedGoogle Scholar
  15. 15.
    Pilgrim JL, Gerostamoulos D, Drummer OH (2010) Deaths involving serotonergic drugs. Forensic Sci Int 198(1–3):110–117PubMedCrossRefGoogle Scholar
  16. 16.
    Gillman PK (2005) Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity. Br J Anaesth 95(4):434–441PubMedCrossRefGoogle Scholar
  17. 17.
    Houlihan DJ (2004) Serotonin syndrome resulting from coadministration of tramadol, venlafaxine, and mirtazapine. Ann Pharmacother 38(3):411–413PubMedCrossRefGoogle Scholar
  18. 18.
    Hernandez JL, Ramos FJ, Infante J, Rebollo M, Gonzalez-Macias J (2002) Severe serotonin syndrome induced by mirtazapine monotherapy. Ann Pharmacother 36(4):641–643PubMedCrossRefGoogle Scholar
  19. 19.
    Gillman PK (2006) A review of serotonin toxicity data: implications for the mechanisms of antidepressant drug action. Biol Psychiatry 59(11):1046–1051PubMedCrossRefGoogle Scholar
  20. 20.
    Rahola JG (2001) Antidepressants: pharmacological profile and clinical consequences. Int J Psychiatry Clin Pract 5(1):19–28Google Scholar
  21. 21.
    Eap CB, Bertschy G, Powell K, Baumann P (1997) Fluvoxamine and fluoxetine do not interact in the same way with the metabolism of the enantiomers of methadone. J Clin Psychopharmacol 17(2):113–117PubMedCrossRefGoogle Scholar
  22. 22.
    Begre S, von Bardeleben U, Ladewig D, Jaquet-Rochat S, Cosendai-Savary L, Golay KP, Kosel M, Baumann P, Eap CB (2002) Paroxetine increases steady-state concentrations of (r)-methadone in CYP2D6 extensive but not poor metabolizers. J Clin Psychopharmacol 22(2):211–215PubMedCrossRefGoogle Scholar
  23. 23.
    Drummer OH (2004) Postmortem toxicology of drugs of abuse. Forensic Sci Int 142(2–3):101–113PubMedCrossRefGoogle Scholar
  24. 24.
    Drummer OH (2007) Post-mortem toxicology. Forensic Sci Int 165(2–3):199–203PubMedCrossRefGoogle Scholar
  25. 25.
    Buajordet I, Ebbesen J, Erikssen J, Brors O, Hilberg T (2001) Fatal adverse drug events: the paradox of drug treatment. J Intern Med 250(4):327–341PubMedCrossRefGoogle Scholar
  26. 26.
    Shah S, Aslam M, Avery A (2001) A survey of prescription errors in general practice. Pharm J 267:860–863Google Scholar
  27. 27.
    Gleason OC, Yates WR, Philipsen MA, Isbell MD, Pollock BG (2004) Plasma levels of citalopram in depressed patients with hepatitis C. Psychosomatics 45(1):29–33PubMedCrossRefGoogle Scholar
  28. 28.
    Henz S, Maeder MT, Huber S, Schmid M, Loher M, Fehr T (2008) Influence of drugs and comorbidity on serum potassium in 15 000 consecutive hospital admissions. Nephrol Dial Transplant 23(12):3939–3945PubMedCrossRefGoogle Scholar
  29. 29.
    Zhang M, Holman CD, Price SD, Sanfilippo FM, Preen DB, Bulsara MK (2009) Comorbidity and repeat admission to hospital for adverse drug reactions in older adults: retrospective cohort study. BMJ 338:a2752PubMedCrossRefGoogle Scholar
  30. 30.
    Mangoni A, Jackson S (2004) Age-related changes in pharmacokinetics and pharmacodynamics: basic principles and practical applications. Br J Clin Pharmacol 57:6–14PubMedCrossRefGoogle Scholar
  31. 31.
    Spinewine A, Schmader K, Barber N, Hughes C, Lapane K, Swine C, Hanlon J (2007) Appropriate prescribing in elderly people: how well can it be measured and optimised? Lancet 370:173–184PubMedCrossRefGoogle Scholar
  32. 32.
    Woodhouse K, O’Mahony M (1997) Frailty and ageing. Age Ageing 26:245–246PubMedCrossRefGoogle Scholar
  33. 33.
    Australian Bureau of Statistics (2003) Drug-induced death, Australia, 1991–2001. Canberra, AustraliaGoogle Scholar
  34. 34.
    Butzbach DM (2009) The influence of putrefaction and sample storage on post-mortem toxicology results. Forensic Sci Med Pathol 6(1):35–45PubMedCrossRefGoogle Scholar
  35. 35.
    Barnhart FE, Bonnell HJ, Rossum KM (2001) Post-mortem drug redistribution. Forensic Sci Rev 13(2):101–129Google Scholar
  36. 36.
    Clarot F, Goulle JP, Vaz E, Proust B (2003) Fatal overdoses of tramadol: is benzodiazepine a risk factor of lethality? Forensic Sci Int 134(1):57–61PubMedCrossRefGoogle Scholar
  37. 37.
    Goldberg RM, Mabee J, Chan L, Wong S (1996) Drug–drug and drug–disease interactions in the ED: analysis of a high-risk population. Am J Emerg Med 14(5):447–450PubMedCrossRefGoogle Scholar
  38. 38.
    Gnanadesigan N, Espinoza RT, Smith R, Israel M, Reuben DB (2005) Interaction of serotonergic antidepressants and opioid analgesics: is serotonin syndrome going undetected? J Am Med Dir Assoc 6(4):265–269PubMedCrossRefGoogle Scholar
  39. 39.
    Mahlberg R, Kunz D, Sasse J, Kirchheiner J (2004) Serotonin syndrome with tramadol and citalopram. Am J Psychiatry 161(6):1129PubMedCrossRefGoogle Scholar
  40. 40.
    Launiainen T, Rasanen I, Vuori E, Ojanpera I (2010) Fatal venlafaxine poisonings are associated with a high prevalence of drug interactions. Int J Legal Med. doi: 10.1007/s00414-010-0461-5
  41. 41.
    Dams R, Benijts TH, Lambert WE, Van Bocxlaer JF, Van Varenbergh D, Van Peteghem C, De Leenheer AP (2001) A fatal case of serotonin syndrome after combined moclobemide-citalopram intoxication. J Anal Toxicol 25(2):147–151PubMedGoogle Scholar
  42. 42.
    Marino MR, Langenbacher M, Ulderman HD (1996) Interaction of nefazodone and fluoxetine. Clin Pharmacol Ther 59:180CrossRefGoogle Scholar
  43. 43.
    Martinelli V, Bocchetta A, Palmas AM, Del Zompo M (1993) An interaction between carbamazepine and fluvoxamine. Br J Clin Pharmacol 36(6):615–616PubMedGoogle Scholar
  44. 44.
    Bertschy G, Vandel S, Vandel B, Allers G, Volmat R (1991) Fluvoxamine-tricyclic antidepressant interaction. An accidental finding. Eur J Clin Pharmacol 40(1):119–120PubMedCrossRefGoogle Scholar
  45. 45.
    Weschules DJ, Bain KT, Richeimer S (2008) Actual and potential drug interactions associated with methadone. Pain Med 9(3):315–344PubMedCrossRefGoogle Scholar
  46. 46.
    Cascorbi I (2003) Pharmacogenetics of cytochrome p4502d6: genetic background and clinical implication. Eur J Clin Investig 33(Suppl 2):17–22CrossRefGoogle Scholar
  47. 47.
    Gardiner SJ, Begg EJ (2006) Pharmacogenetics, drug-metabolizing enzymes, and clinical practice. Pharmacol Rev 58(3):521–590PubMedCrossRefGoogle Scholar
  48. 48.
    Kollek R, van Aken J, Feuerstein G, Schmedders M (2006) Pharmacogenetics, adverse drug reactions and public health. Community Genet 9(1):50–54PubMedCrossRefGoogle Scholar
  49. 49.
    Stipp D (2000) A DNA tragedy. Fortune 142(10):170–174, 178, 180 passimPubMedGoogle Scholar
  50. 50.
    Stamer UM, Musshoff F, Kobilay M, Madea B, Hoeft A, Stuber F (2007) Concentrations of tramadol and o-desmethyltramadol enantiomers in different cyp2d6 genotypes. Clin Pharmacol Ther 82(1):41–47PubMedCrossRefGoogle Scholar
  51. 51.
    Gasche Y, Daali Y, Fathi M, Chiappe A, Cottini S, Dayer P, Desmeules J (2004) Codeine intoxication associated with ultrarapid cyp2d6 metabolism. N Engl J Med 351(27):2827–2831PubMedCrossRefGoogle Scholar
  52. 52.
    Koski A (2005) Interpretation of postmortem toxicology results: pharmacogenetics and drug–alcohol interaction. PhD thesis, University of Helsinki, Helsinki, FinlandGoogle Scholar
  53. 53.
    Skopp G (2004) Preanalytic aspects in postmortem toxicology. Forensic Sci Int 142(2–3):75–100PubMedCrossRefGoogle Scholar
  54. 54.
    Levisky JA, Bowerman DL, Jenkins WW, Johnson DG, Karch SB (2001) Drugs in postmortem adipose tissues: evidence of antemortem deposition. Forensic Sci Int 121(3):157–160PubMedCrossRefGoogle Scholar
  55. 55.
    Madea B, Musshoff F (2004) Postmortem toxicology. Forensic Sci Int 142(2–3):71–73PubMedCrossRefGoogle Scholar
  56. 56.
    Wagner M (2003) Stability of drugs of abuse in biological specimens. MSc thesis, Columbia Pacific UniversityGoogle Scholar
  57. 57.
    Sporer KA (1995) The serotonin syndrome. Implicated drugs, pathophysiology and management. Drug Saf 13(2):94–104PubMedCrossRefGoogle Scholar
  58. 58.
    Gillman PK (2007) Tricyclic antidepressant pharmacology and therapeutic drug interactions updated. Br J Pharmacol 151(6):737–748PubMedCrossRefGoogle Scholar
  59. 59.
    Gillman PK (1999) The serotonin syndrome and its treatment. J Psychopharmacol 13(1):100–109PubMedCrossRefGoogle Scholar
  60. 60.
    Fisher AA, Davis MW (2002) Serotonin syndrome caused by selective serotonin reuptake-inhibitors–metoclopramide interaction. Ann Pharmacother 36(1):67–71PubMedCrossRefGoogle Scholar
  61. 61.
    Bush E, Miller C, Friedman I (2006) A case of serotonin syndrome and mutism associated with methadone. J Palliat Med 9(6):1257–1259PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Jennifer L. Pilgrim
    • 1
    Email author
  • Dimitri Gerostamoulos
    • 1
  • Olaf H. Drummer
    • 1
  1. 1.Department of Forensic MedicineMonash University, Victorian Institute of Forensic MedicineSouthbankAustralia

Personalised recommendations