Advertisement

Archives of Toxicology

, Volume 92, Issue 8, pp 2457–2473 | Cite as

Opioid analgesic drugs and serotonin toxicity (syndrome): mechanisms, animal models, and links to clinical effects

  • Brian A. Baldo
Review Article

Abstract

Drugs may cause serotonin toxicity by a number of different mechanisms including inhibition of serotonin uptake and metabolism, increased serotonin synthesis and release, activation of serotonin receptors, and inhibition of cytochrome P450 oxidases. Some drug interactions involving opioids can increase intrasynaptic levels of serotonin, and opioid analgesic drugs are now recognized as being involved in some cases of serotonin toxicity especially if administered in conjunction with other serotonergic medications including monoamine oxidase inhibitors, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and tricyclic antidepressants. In March 2016, the FDA issued a Drug Safety Communication concerning the association of the entire class of opioid pain medicines with serotonin toxicity. Reports of the involvement of individual opioids particularly tramadol, tapentadol, meperidine, methadone, oxycodone, fentanyl, and dextromethorphan are reviewed. While relevance to human serotonin toxicity of animal models, including many studies on rat brain synaptosomes, is questionable, important insights have recently been forthcoming from research utilizing 5-HT receptors, serotonin transporter (SERT), and knockout mice. In studies with human SERT-transfected human HEK293 cells, the synthetic opioids tramadol, meperidine, methadone, tapentadol, and dextromethorphan inhibited SERT, but fentanyl and a number of phenanthrenes including morphine and hydromorphone did not. Receptor ligand-binding assays revealed interaction of fentanyl with 5-HT1A receptors and interaction of meperidine, methadone, and fentanyl with 5-HT2A receptors. Although the opioids most often associated with serotonin toxicity in humans inhibit human SERT in vitro, fentanyl and oxycodone are not inhibitory even though their clinical involvement has been reported. This suggests some SERT-independent effects on the serotonin system in vivo. Heightened clinician awareness of the possibility of serotonin toxicity among patients taking opioids and serotonergic antidepressants is called for.

Keywords

Serotonin toxicity Serotonin syndrome Opioid analgesics Opioids and serotonin toxicity Opioids as serotonergic drugs Diagnosis of serotonin toxicity Mechanisms of serotonin toxicity Tramadol and serotonin toxicity 

Notes

Funding

No sources of funding were used to assist in the preparation of this study.

Compliance with ethical standards

Conflict of interest

The author, Brian A. Baldo, declares that he has no conflict of interest.

References

  1. Abadie D, Rousseau V, Logerot S et al (2015) Serotonin syndrome. Analysis of cases registered in the French Pharmacovigilance Database. J Clin Psychopharmacol 35:382–388PubMedGoogle Scholar
  2. Achamallah NS (1992) Visual hallucinations after combining fluoxetine and dextromethorphan. Am J Psychiatry 149:1406PubMedGoogle Scholar
  3. Alkhatib AA, Peterson KA, Tuteja AK (2010) Serotonin syndrome as a complication of fentanyl sedation during esophagogastroduodenoscopy. Dig Dis Sci 55:215–216PubMedGoogle Scholar
  4. Allawadhi S, Sung KW, Carlson LA et al (2007) Serotonin syndrome caused by interaction between citalopram and fentanyl. J Clin Pharm Ther 32:199–202Google Scholar
  5. Altman CS, Jahangiri MF (2010) Serotonin syndrome in the perioperative period. Anesth Analg 110:526–528PubMedGoogle Scholar
  6. Altman EM, Manos GH (2007) Serotonin syndrome associated with citalopram and meperidine. Psychosomatics 48:361–363PubMedGoogle Scholar
  7. Arnt J, Hyttel J (1989) Facilitation of 8-OHDPAT-induced forepaw treading of rats by the 5-HT2 agonist DOI. Eur J Pharmacol 161:45–51PubMedGoogle Scholar
  8. Atkinson TJ, Fudin J (2015) Combined fentanyl and methadone induced serotonin syndrome is called into question. Pharmacotherapy 35:e111–e114PubMedGoogle Scholar
  9. Baldo BA (2017) Editorial. Opioid analgesic drugs: Misuse, toxicity, and hypersensitivity. J Allergy Clin Immunol 5:1607–1608Google Scholar
  10. Baldo BA, Pham NH (2012) Histamine-releasing and allergenic properties of opioid analgesic drugs: resolving the two. Anaesth Intensive Care 40:216–235PubMedGoogle Scholar
  11. Baldo BA, Pham NH (2013) Drug allergy: clinical aspects, diagnosis, mechanisms, structure-activity relationships. Springer, New York, pp 303–308Google Scholar
  12. Barann M, Urban B, Stamer U et al (2006) Effects of tramadol and O-demethyl-tramadol on human 5-HT reuptake carriers and human 5-HT3A receptors: a possible mechanism for tramadol-induced early emesis. Eur J Pharmacol 531:54–58PubMedGoogle Scholar
  13. Barann M, Stamer UM, Lyutenska M et al (2015) Effects of opioids on human serotonin transporters. Naunyn Schmiedeberg’s Arch Pharmacol 388:43–49Google Scholar
  14. Bengel D, Murphy DL, Andrews AM et al (1998) Altered brain serotonin homeostasis and locomotor insensitivity to 3,4-methylenedioxymethamphetamine (“ecstasy”) in serotonin transporter-deficient mice. Mol Pharmacol 53:649–655PubMedGoogle Scholar
  15. Boyer EW, Shannon M (2005) The serotonin syndrome. N Eng J Med 352:1112–1120Google Scholar
  16. Caamano A, Din R, Eter A (2016) Serotonin syndrome induced by combined use of tramadol and escitalopram: a case report. J Med Cases 7:554–557Google Scholar
  17. Cameron C (2006) Serotonin syndrome precipitated by an over-the-counter cold remedy. Aust Prescr 29:71.  https://doi.org/10.18773/austprescr.2006.044 CrossRefGoogle Scholar
  18. Chan BS, Graudins A, Whyte IM et al (1998) Serotonin syndrome resulting from drug interactions. Med J Aust 169:523–525PubMedGoogle Scholar
  19. Chassot M, Munz T, Livio F et al (2012) Syndrome sérotoninergique: mise au point et revue des cas annoncés en Suisse. Rev Med Suisse 8:2086–2090PubMedGoogle Scholar
  20. Chen ZR, Irvine RJ, Somogyi AA et al (1991) Mu receptor binding of some commonly used opioids and their metabolites. Life Sci 48:2165–2171PubMedGoogle Scholar
  21. Chyka PA, Erdman AR, Manoguerra AS et al (2007) Dextromethorphan poisoning: an evidence-based consensus guideline for out-of-hospital management. Clin Toxicol 45:662–677Google Scholar
  22. Cicero TJ, Inciardi JA, Adams EH et al (2005) Rates of abuse of tramadol remain unchanged with the introduction of new branded and generic products: results of an abuse monitoring system, 1994–2004. Pharmacoepidemiol Drug Saf 14:851–859PubMedGoogle Scholar
  23. Clark RF, Wei EM, Anderson PO (1995) Meperidine: therapeutic use and toxicity. J Emerg Med 13:797–802PubMedGoogle Scholar
  24. Clarot F, Goullé J-P, Vaz E et al (2003) Fatal overdoses of tramadol: is benzodiazepine a risk factor for lethality? Forensic Sci Int 134:57–61PubMedGoogle Scholar
  25. Codd EE, Shank RP, Schupsky JJ et al (1995) Serotonin and norepinephrine uptake inhibiting activity of centrally acting analgesics. J Pharmacol Exp Ther 274:1263–1270PubMedGoogle Scholar
  26. Coplan JD, Gorman JM (1993) Detectable levels of fluoxetine after discontinuation. An unexpected serotonin syndrome. Am J Psychiatry 150:837PubMedGoogle Scholar
  27. Darmani NA, Ahmad B (1999) Long-term sequential determination of behavioral ontogeny of 5-HT1 And 5-HT2 receptor functions in the rat. J Pharmacol Exp Ther 288:247–253PubMedGoogle Scholar
  28. Daubin C, Quentin C, Goullé J-P et al (2007) Refractory shock and asystole related to tramadol overdose. Clin Toxicol 45:961–964Google Scholar
  29. Davis MP, Varga J, Dickersen D et al (2003) Normal-release and controlled-release oxycodone: pharmacokinetics, phamacodynamics, and controversy. Support Care Cancer 11:84–92PubMedGoogle Scholar
  30. Driessen B, Reimann W (1992) Interaction of the central analgesic, tramadol, with the uptake and release of 5-hydroxytryptamine in the rat brain in vitro. Br J Pharmacol 105:147–151PubMedPubMedCentralGoogle Scholar
  31. Driessen B, Reimann W, Giertz H (1993) Effects of the central analgesic tramadol on the uptake and release of noradrenaline and dopamine in vitro. Br J Pharmacol 108:806–811PubMedPubMedCentralGoogle Scholar
  32. Dunkley EJ, Isbister GK, Sibbritt D (2003) The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity. QJM 96:635–642PubMedGoogle Scholar
  33. Duthie DJR, Nimmo WS (1987) Adverse effects of opioid analgesic drugs. Br J Anaesth 59:61–77PubMedGoogle Scholar
  34. Egberts AC, ter Borgh J, Brodie-Meijer CC (1997) Serotonin syndrome attributed to tramadol addition to paroxetine therapy. Int Clin Psychopharmacol 12:181–182PubMedGoogle Scholar
  35. Eison AS, Wright RN (1992) 5-HT1A and 5-HT2 receptors mediate discrete behaviors in the Mongolian gerbil. Pharmacol Biochem Behav 43:131–137PubMedGoogle Scholar
  36. Evans RW, Tepper SJ, Shapiro RE et al (2010) The FDA alert on serotonin syndrome with use of triptans combined with selective serotonin-norepinephrine reuptake inhibitors: American Headache Society position paper. Headache 50:1089–1099PubMedGoogle Scholar
  37. Falls BA, Gurrera RJ (2014) Serotonin syndrome in a patient on tramadol, bupropion, trazodone, and oxycodone. Psychosomatics 55:305–309PubMedGoogle Scholar
  38. FDA Drug safety communications (2016) FDA warns about several safety issues with opioid pain medicines; requires label changes. March 22, 2016. https://www.fda.gov/downloads/Drugs/DrugSafety/UCM491302.pdf. Accessed 30 January 2018
  39. Forster EA, Cliffe IA, Bill DJ et al (1995) A pharmacological profile of the selective silent 5-HT1A receptor antagonist, WAY-100635. Eur J Pharmacol 281:81–88PubMedGoogle Scholar
  40. Fox MA, Jensen CL, Gallagher PS et al (2007) Receptor mediation of exaggerated responses to serotonin-enhancing drugs in serotonin transporter (SERT)-deficient mice. Neuropharmacol 53:643–656Google Scholar
  41. Fox MA, Jensen CL, Murphy DL (2009) Tramadol and another atypical opioid meperidine have exaggerated serotonin syndrome behavioral effects, but decreased analgesic effects, in genetically-deficient serotonin transporter (SERT) mice. Int J Neuropsychopharmacol 12:1055–1065PubMedPubMedCentralGoogle Scholar
  42. Fox MA, Panessiti MG, Moya PR et al (2013) Mutations in monoamine oxidase (MAO) genes in mice lead to hypersensitivity to serotonin-enhancing drugs: implications for drug side effects in humans. Pharmacogenomics J 13:551–557PubMedGoogle Scholar
  43. Franco DM, Ali Z, Levine B et al (2014) Case report of a fatal intoxication by Nucynta. Am J Forensic Med Pathol 35:234–236PubMedGoogle Scholar
  44. Freye E (2008) Opioids in medicine. Springer, DordrechtGoogle Scholar
  45. Ganetsky M, Babu KM, Boyer EW (2007) Serotonin syndrome in dextromethorphan ingestion responsive to propofol therapy. Pediatr Emerg Care 23:829–831PubMedGoogle Scholar
  46. Garrett PM (2004) Tramadol overdose and serotonin syndrome manifesting as acute right heart dysfunction. Anaesth Intensive Care 32:575–577PubMedGoogle Scholar
  47. Gasse C, Derby L, Vasilakis-Scaramozza C et al (2000) Incidence of first-time idiopathic seizures in users of tramadol. Pharmacotherapy 20:629–634PubMedGoogle Scholar
  48. Gayle JA, Volpi-Abadie J, Kaye AM et al (2015) Serotonin syndrome. In: Kaye AD, Kaye AM, Urman RD (eds) Essentials of pharmacology for anesthesia, pain medicine, and critical care. Springer, New York, pp 797–807Google Scholar
  49. Gillman PK (1999) The serotonin syndrome and its treatment. J Psychopharmacol 13:100–109PubMedGoogle Scholar
  50. Gillman PK (2005) Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity. Br J Anaesth 95:434–441PubMedGoogle Scholar
  51. Gillman PK (2006a) A review of serotonin toxicity data: Implications for the mechanisms of antidepressant drug action. Biol Psychiatry 59:1046–1051PubMedGoogle Scholar
  52. Gillman PK (2006b) Extracting value from case reports: lessons from serotonin toxicity. Anaesthesia 61:419–422PubMedGoogle Scholar
  53. Gillman PK (2010) Triptans, serotonin agonists, and serotonin syndrome (serotonin toxicity): a review. Headache 50:264–272PubMedGoogle Scholar
  54. Gillman PK, Whyte IM (2004) Serotonin syndrome. In: Haddad P, Dursun S, Deakin B (eds) Adverse syndromes and pschiatric drugs. Oxford University Press, Oxford, pp 37–49Google Scholar
  55. Giusti P, Buriani A, Cima L et al (1997) Effect of acute and chronic tramadol on [3H]-5-HT uptake in rat cortical synaptosomes. Br J Pharmacol 122:302–306PubMedPubMedCentralGoogle Scholar
  56. Gnanadesigan N, Espinoza RT, Smith R et al (2005) Interaction of serotonergic antidepressants and opioid analgesics: Is serotonin syndrome going undetected? J Am Med Dir Assoc 6:265–269PubMedGoogle Scholar
  57. Gollapudy S, Kumar V, Dhamee MS (2012) A case of serotonin syndrome precipitated by fentanyl and ondansetron in a patient receiving paroxetine, duloxetine, and bupropion. J Clin Anesth 24:251–252PubMedGoogle Scholar
  58. Gonzalez-Pinto A, Imaz H, De Heredia JL et al (2001) Mania and tramadol-fluoxetine combination. Am J Psychiatry 158:964–965PubMedGoogle Scholar
  59. Goodwin GM, Green AR (1985) A behavioral and biochemical study in mice and rats of putative selective agonists and antagonists for 5-HT1 and 5-HT2 receptors. Br J Pharmacol 84:743–753PubMedPubMedCentralGoogle Scholar
  60. Gressler LE, Hammond DA, Painter JT et al (2017) Serotonin syndrome in tapentadol literature: systematic review of original research. J Pain Palliat Care Pharmacother 31:228–236PubMedGoogle Scholar
  61. Guay DR (2009) Is tapentadol an advance on tramadol? Consult Pharm 24:833–840PubMedGoogle Scholar
  62. Guo S-L, Wu T-J, Liu C-C et al (2009) Meperidine-induced serotonin syndrome in a susceptible patient. Br J Anaesth 103:369–370PubMedGoogle Scholar
  63. Haberzettl R, Bert B, Fink H et al (2013) Animal models of the serotonin syndrome: a systematic review. Behav Brain Res 256:328–345PubMedGoogle Scholar
  64. Haberzettl R, Fink H, Bert B (2014) Role of 5-HT1A and 5-HT2A receptors for the murine model of the serotonin syndrome. J Pharmacol Toxicol Methods 70:129–133PubMedGoogle Scholar
  65. Herrlin K, Segerdahl M, Gustafsson LL et al (2000) Methadone, ciprofloxacin, and adverse drug reactions. Lancet 356(9247):2069–2070PubMedGoogle Scholar
  66. Hillman AD, Witenko CJ, Sultan SM et al (2015) Serotonin syndrome caused by fentanyl and methadone in a burn injury. Pharmacotherapy 35:112–117PubMedGoogle Scholar
  67. Houlihan DJ (2004) Serotonin syndrome resulting from coadministration of tramadol, venlafaxine, and mirtazapine. Ann Pharmacother 38:411–413PubMedGoogle Scholar
  68. Houmes RJ, Voets MA, Verkaaik A et al (1992) Efficacy and safety of tramadol versus morphine for moderate and severe postoperative pain with special regard to respiratory depression. Anesth Analg 74:510–514PubMedGoogle Scholar
  69. Hoyer D, Hannon JP, Martin GR (2002) Molecular, pharmacological and functional diversity of 5-HT receptors. Pharmacol Biochem Behav 71:533–554PubMedGoogle Scholar
  70. Insel TR, Roy BF, Cohen RM et al (1982) Possible development of the serotonin syndrome in man. Am J Psychol 139:954–955Google Scholar
  71. Isbister GK, Buckley NA (2005) The payhophysiology of serotonin to toxicity in animals and humans. Implications for diagnosis and treatment. Clin Neuropharmacol 28:205–214PubMedGoogle Scholar
  72. Isbister GK, Bowe SJ, Dawson A et al (2004) Relative toxicity of selective serotonin reuptake inhibitors (SSRIs) in overdose. J Toxicol Clin Toxicol 42:277–285PubMedGoogle Scholar
  73. Isbister GK, Buckley NA, Whyte IM (2007) Serotonin toxicity: a practical approach to diagnosis and treatment. Med J Aust 187:361–365PubMedGoogle Scholar
  74. Isenberg D, Wong SC, Curtis JA (2008) Serotonin syndrome triggered by a single dose of suboxone. Am J Emerg Med 26:840.e3–840.e5Google Scholar
  75. Jick H, Derby LE, Vasilakis C et al (1998) The risk of seizures associated with tramadol. Pharmacotherapy 18:607–611PubMedGoogle Scholar
  76. Joe S, Kim E, Park J et al (2017) Famotidine-induced reversal of meperidine-related serotonin syndrome—a case report. Korean J Anesthesiol 70:221–223PubMedPubMedCentralGoogle Scholar
  77. Jovanović-Čupić V, Martinović Ž, Nešić N (2006) Seizures associated with intoxication and abuse of tramadol. Clin Toxicol 44:143–146Google Scholar
  78. Kahn LH, Alderfer RJ, Graham DJ (1997) Seizures reported with tramadol. JAMA 278:1661PubMedGoogle Scholar
  79. Kalso E (2005) Oxycodone. J Pain Symptom Manage 29(5 Suppl):S47–S56PubMedGoogle Scholar
  80. Kalueff AV, Fox MA, Gallagher PS et al (2007) Hypolocomotion, anxiety and serotonin syndrome-like behavior contribute to the complex phenotype of serotonin transporter knockout mice. Genes Brain Behav 6:389–400PubMedGoogle Scholar
  81. Karamanakos PN, Panteli ES (2008) Comment on: “Dextromethorphan-induced serotonin syndrome”. Clin Toxicol 46:1101Google Scholar
  82. Karunatilake H, Buckley NA (2006) Serotonin syndrome induced by fluvoxamine and oxycodone. Ann Pharmacother 40:155–157PubMedGoogle Scholar
  83. Kerry NL, Somogyi AA, Bochner F et al (1994) The role of CYP2D6 in primary and secondary oxidative metabolism of dextromethorphan: in vitro studies using human liver microsomes. Br J Clin Pharmacol 38:243–248PubMedPubMedCentralGoogle Scholar
  84. Kesavan S, Sobala GM (1999) Serotonin syndrome with fluoxetine plus tramadol. J Roy Soc Med 92:474–475PubMedGoogle Scholar
  85. Kinoshita H, Ohkubo T, Yasuda M et al (2011) Serotonin syndrome induced by dextromethorphan (Medicon) administered at the conventional dose. Geniatr Gerontol Int 11:121–122Google Scholar
  86. Kirschner R, Donovan JW (2010) Serotonin syndrome precipitated by fentanyl during procedural sedation. J Emerg Med 38:477–480PubMedGoogle Scholar
  87. Kishimoto K, Koyama S, Akaike N (2001) Synergistic µ-opioid and 5-HT1A presynaptic inhibition of GABA release in rat periaqueductal gray neurons. Neuropharmacol 5:529–538Google Scholar
  88. Koshikawa F, Koshikawa N, Stephenson JD (1985) Effects of antidepressant drug combinations on corticol 5-HT receptors and wet dog-shakes in rats. Eur J Pharmacol 118:273–281PubMedGoogle Scholar
  89. Kung SW, Ng MH (2007) Serotonin syndrome with tramadol and dextromethorphan. Hong Kong J Emerg Med 14:48–52Google Scholar
  90. Labate A, Newton MR (2005) Tramadol and new-onset seizures. Med J Aust 182:42–43PubMedGoogle Scholar
  91. Lange-Asschenfeldt C, Weigmann H, Hiemke C et al (2002) Serotonin syndrome as a result of fluoxetine in a patient with tramadol abuse: plasma level correlated symptomatology. J Clin Psychopharmacol 22:440–441PubMedGoogle Scholar
  92. Lantz MS, Buchalter EN, Giambanco V (1998) Serotonin syndrome following the administration of tramadol with paroxetine. Int J Geriatr Psychiatry 13:343–345PubMedGoogle Scholar
  93. Larsen JJ, Hyttel J (1985) 5-HT-uptake inhibition potentiates antinociception induced by morphine, pethidine, methadone and ketobemidone in rats. Acta Pharmacol Toxicol (Copenh) 57:214–218Google Scholar
  94. Latta KS, Ginsberg B, Barkin RL (2002) Meperidine: a critical review. Am J Ther 9:53–68PubMedGoogle Scholar
  95. Lee J, Franz L, Goforth HW (2009) Serotonin syndrome in a chronic-pain patient receiving concurrent methadone, ciprofloxacin, and venlafaxine. Psychosomatics 50:638–639PubMedGoogle Scholar
  96. Levin TT, Cortes-Ladino A, Weiss M et al (2008) Life-threatening serotonin toxicity due to a citalopram-fluconazole drug interaction: case reports and discussion. Gen Hosp Psychiatry 30:372–377PubMedGoogle Scholar
  97. Levy JH (1986) Anaphylactic reactions in anesthesia and intensive care. Butterworths, BostonGoogle Scholar
  98. Mackay FJ, Dunn NR, Mann RD (1999) Antidepressants and the serotonin syndrome in general practice. Br J Gen Pract 49:871–874PubMedPubMedCentralGoogle Scholar
  99. Mahlberg R, Kunz D, Sasse J et al (2004) Serotonin syndrome with tramadol and citalopram. Am J Psychiatry 161:1129PubMedGoogle Scholar
  100. Mancano MA (2013) ISMP adverse drug reactions. Serotonin syndrome with concomitant use of tapentadol and venlafaxine. Hosp Pharm 48:542–549Google Scholar
  101. Maréchal C, Honorat R, Claudet I (2011) Serotonin syndrome induced by tramadol intoxication in an 8-month-old infant. Pediatr Neurol 44:72–74PubMedGoogle Scholar
  102. Martinez TT, Martinez DN (2008) A case of serotonin syndrome associated with methadone overdose. Proc West Pharmacol Soc 51:42–44PubMedGoogle Scholar
  103. Martin-Lazaro JF, Hayde-West J, Chatzimichael S et al (2017) A dangerous triad: Sertraline, mirtazapine and methadone. Clin Med Rev Case Rep 4:154–155Google Scholar
  104. Mason BJ, Blackburn KH (1997) Possible serotonin syndrome associated with tramadol and sertraline coadministration. Ann Pharmacother 31:175–177PubMedGoogle Scholar
  105. Mason PJ, Morris VA, Balcezak TJ (2000) Serotonin syndrome. Presentation of two cases and review of the literature. Medicine (Baltimore) 79:201–209Google Scholar
  106. Mattila MJ, Jounela AJ (1973) Effect of p-chlorophenylalanine on the interaction between phenelzine and pethidine in conscious rabbits. Biochem Pharmacol 22:1674–1676PubMedGoogle Scholar
  107. McDiarmid T, Mackler L, Schneider DM (2005) Clinical inquiries. What is the addiction risk associated with tramadol? J Fam Pract 54:72–73PubMedGoogle Scholar
  108. Mehrpour M (2005) Intravenous tramadol-induced seizure: two case reports. Iran J Pharmacol Ther 42:146–147Google Scholar
  109. Meyer D, Halfin V (1981) Toxicity secondary to meperidine in patients on monoamine oxidase inhibitors: a case report and critical review. J Clin Psychopharmacol 1:319–321PubMedGoogle Scholar
  110. Milano G, Natta WM, Bello A et al (2017) Codeine precipitating serotonin syndrome in a patient in therapy with antidepressant and triptan. Clin Psychopharmacol Neurosci 15:292–295PubMedPubMedCentralGoogle Scholar
  111. Mills KC (1997) Serotonin syndrome. A clinical update. Crit Care Clin 13:763–783PubMedGoogle Scholar
  112. Mitchell RS (1955) Fatal toxic encephalitis occurring during iproniazid therapy in pulmonary tuberculosis. Ann Intern Med 42:417–424PubMedGoogle Scholar
  113. Mittino D, Mula M, Monaco F (2004) Serotonin syndrome associated with tramadol-sertraline coadministration. Clin Neuropharmacol 27:150–151PubMedGoogle Scholar
  114. Monte AA, Chuang R, Bodmer M (2010) Dextromethorphan, chlorpheniramine and serotonin toxicity: case report and systematic literature review. Br J Clin Pharmacol 70:794–798PubMedPubMedCentralGoogle Scholar
  115. Moore KA, Cina SJ, Jones R et al (1999) Tissue distribution of tramadol and metabolites in an overdose fatality. Am J Forensic Med Pathol 20:98–100PubMedGoogle Scholar
  116. Morphine sulfate injection. Highlights of prescribing information (2016) Adverse reactions. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/204223s006lbl.pdf.Accessed 2 March 2018
  117. Mullins ME, Dribben WH (2017) Comment on tapentadol and serotonin syndrome. Hosp Pharm 52:246–247PubMedPubMedCentralGoogle Scholar
  118. Nair MK, Patel K, Starer PJ (2008) Ciprofloxacin-induced torsades de pointes in a methadone-dependent patient. Addiction 103:2062–2064PubMedGoogle Scholar
  119. Nasmyth PA, Stewart HC (1950) The release of histamine by opium alkaloids. J Physiol 111:19PGoogle Scholar
  120. Nichols DE, Nichols CD (2008) Serotonin receptors. Chem Rev 108:1614–1641PubMedGoogle Scholar
  121. Nisijima K, Yoshino T, Yui K et al (2001) Potent serotonin (5-HT)(2A) receptor antagonists completely prevent the development of hyperthermia in an animal model of the 5-HT syndrome. Brain Res 890:23–31PubMedGoogle Scholar
  122. Nisijima K, Shioda K, Yoshino T et al (2004) Memantine, an NMDA antagonist, prevents the development of hyperthermia in an animal model for serotonin syndrome. Pharmacopsychiatry 37:57–62PubMedGoogle Scholar
  123. Nucynta® ER (Tapentadol). Highlights of prescribing information (2016) Warnings and precautions. Adverse reactions. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/200533s014lbl.pdf. Accessed 2 Mar 2018
  124. Oates JA, Sjoerdsma A (1960) Neurological effects of tryptophan in patients receiving a monoamine oxidase inhibitor. Neurology 10:1076–1078PubMedGoogle Scholar
  125. Orlova Y, Rizzoli P, Loder E (2018) Association of coprescription of triptan antimigraine drugs and selective serotonin reuptake inhibitors or selective norepinephrine reuptake inhibitor antidepressants with serotonin syndrome. JAMA Neurol.  https://doi.org/10.1001/jamaneurol.2017.5144 CrossRefPubMedGoogle Scholar
  126. Otte W, Birkenhager TK, van den Broek VWV (2003) Fatal interaction between tranylcypromine and imipramine. Eur Psychiatry 18:264–265PubMedGoogle Scholar
  127. Ozkardesler S, Gurpinar T, Akan M et al (2008) A possible perianesthetic serotonin syndrome related to intrathecal fentanyl. J Clin Anesth 20:143–145PubMedGoogle Scholar
  128. Parks V, Philipp AW, Raje S et al (2012) Concomitant blockade of 5-HT1A receptor and 5-HT transporter: use of the hunter serotonin toxicity criteria in a clinical pharmacology study. Eur Neuropsychopharmacol 22:92–99PubMedGoogle Scholar
  129. Pothiawala S, Ponampalam R (2011) Tramadol overdose: a case report. Proc Singap Healthc 20:219–223Google Scholar
  130. Pöyhiä R, Vainio A, Kalso E (1993) A review of oxycodone’s clinical pharmacokinetics and pharmacodynamics. J Pain Symptom Manage 8:63–67PubMedGoogle Scholar
  131. Radomski JW, Dursun SM, Reveley MA et al (2000) An exploratory approach to the serotonin syndrome: an update of clinical phenomenology and revised diagnostic criteria. Med Hypotheses 55:218–224PubMedGoogle Scholar
  132. Raffa RB, Friderichs E, Reimann W et al (1992) Opioid and non-opioid components independently contribute to the mechanism of action of tramadol an ‘atypical’ opioid analgesic. J Pharmacol Exp Ther 260:275–285PubMedGoogle Scholar
  133. Raffa RB, Buschmann H, Christoph T et al (2012) Mechanistic and functional differentiation of tapentadol and tramadol. Expert Opin Pharmacother 13:1437–1449PubMedGoogle Scholar
  134. Ramaswamy S, Chang S, Mehta V (2015) Tapentadol—the evidence so far. Anaesthesia 70:518–522PubMedGoogle Scholar
  135. Rang ST, Field J, Irving C (2008) Serotonin toxicity caused by an interaction between fentanyl and paroxetine. Can J Anaesth 55:521–525PubMedGoogle Scholar
  136. Rastogi R, Swarm RA, Patel TA (2011) Case scenario: opioid association with serotonin syndrome. Implications to the practitioners. Anesthesiology 115:1291–1298PubMedGoogle Scholar
  137. Reich M, Lefebvre-Kuntz D (2010) Serotonergic antidepressants and opiate analgesics: a sometimes-painful association. A case report. (Article in French). Encephale 36(Suppl 2):D119–D123PubMedGoogle Scholar
  138. Richter W, Barth H, Flohé L et al (1985) Clinical investigation on the development of dependence during oral therapy with tramadol. Arzneimittelforschung 35:1742–1744PubMedGoogle Scholar
  139. Rickli A, Liakoni E, Hoener M et al (2018) Opioid-induced inhibition of the human 5-HT and noradrenaline transporters in vitro: link to clinical reports of serotonin syndrome. Br J Pharmacol 175:532–543PubMedPubMedCentralGoogle Scholar
  140. Rivers N (1970) Possible lethal reaction between Nardil and dextromethorphan. Can Med Assoc J 103:85PubMedPubMedCentralGoogle Scholar
  141. Rogers KJ, Thornton JA (1969) The interaction between monoamine oxidase inhibitors and narcotic analgesics in mice. Br J Pharm 36:470–480Google Scholar
  142. Rosebraugh CJ, Flockhart DA, Yasuda SU et al (2001) Visual hallucination and tremor induced by sertraline and oxycodone in a bone marrow transplant patient. J Clin Pharmacol 41:224–227PubMedGoogle Scholar
  143. Ruoff GE (1999) Slowing the initial titration rate of tramadol improves tolerability. Pharmacotherapy 19:88–93PubMedGoogle Scholar
  144. Russo M, Santarelli D, Isbister G (2017) Comment on “probable tapentadol-associated serotonin syndrome after overdose”. Hosp Pharm 52:248PubMedPubMedCentralGoogle Scholar
  145. Ryan NM, Isbister GK (2015) Tramadol overdose causes seizures and respiratory depression but serotonin toxicity appears unlikely. Clin Toxicol 53:545–550Google Scholar
  146. Samoy L, Shalansky K (2010) Interaction between methadone and ciprofloxacin. Can J Hosp Pharm 63:382–384PubMedPubMedCentralGoogle Scholar
  147. Schloss P, Williams DC (1998) The serotonin transporter: a primary target for antidepressant drugs. J Psychopharmacol 12:115–121PubMedGoogle Scholar
  148. Schreiber R, Brocco M, Audinot V et al (1995) (1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane)-induced head-twitches in the rat are mediated by 5-hydroxytryptamine (5-HT) 2A receptors: modulation by novel 5-HT2A/2C antagonists, D1 antagonists and 5-HT1A agonists. J Pharmacol Exp Ther 273:101–112PubMedGoogle Scholar
  149. Schug SA, Zech D, Grond S (1992) Adverse effects of systemic opioids analgesics. Drug Saf 7:200–213PubMedGoogle Scholar
  150. Schwartz AR, Pizon AF, Brooks DE (2008) Dextromethorphan-induced serotonin syndrome. Clin Toxicol 46:771–773Google Scholar
  151. Shadnia S, Soltaninejad K, Heydari K et al (2008) Tramadol intoxication: a review of 114 cases. Hum Exp Toxicol 27:201–205PubMedGoogle Scholar
  152. Shakoor M, Ayub S, Ahad A et al (2014) Transient serotonin syndrome caused by concurrent use of tramadol and selective serotonin reuptake inhibitor. Am J Case Rep 15:562–564PubMedPubMedCentralGoogle Scholar
  153. Skop BP, Finkelstein JA, Mareth TR et al (1994) The serotonin syndrome associated with paroxetine, an over-the-counter cold remedy, and vascular disease. Am J Emerg Med 12:642–644PubMedGoogle Scholar
  154. Smith LM, Peroutka SJ (1986) Differential effects of 5-hydroxytryptamine selective drugs on the 5-HT behavioral syndrome. Pharmacol Biochem Behav 24:1513–1519PubMedGoogle Scholar
  155. Soldin OP, Tonning JM (2008) Serotonin syndrome associated with triptan monotherapy. N Eng J Med 358:2185–2186Google Scholar
  156. Song H-K (2013) Serotonin syndrome with perioperative oxycodone and pregabalin. Pain Physician 16:E632–E633PubMedGoogle Scholar
  157. Spiller HA, Gorman SE, Villalobos D et al (1997) Prospective multicenter evaluation of tramadol exposure. J Toxicol Clin Toxicol 35:361–364PubMedGoogle Scholar
  158. Sternbach H (1991) The serotonin syndrome. Am J Psychiatry 148:705–713PubMedGoogle Scholar
  159. Takeshita J, Litzinger MH (2009) Serotonin syndrome associated with tramadol. Prim Care Companion J Clin Psychiatry 11:273PubMedPubMedCentralGoogle Scholar
  160. Tashakori A, Afshari R (2010) Tramadol overdose as a cause of serotonin syndrome: a case series. Clin Toxicol 48:337–341Google Scholar
  161. Taylor DC (1962) Alarming reaction to pethidine in patients on phenelzine. Lancet 280(7252):401–402Google Scholar
  162. Tissot TA (2003) Probable meperidine-induced serotonin syndrome in a patient with a history of fluoxetine use. Anesthesiology 98:1511–1512PubMedGoogle Scholar
  163. Tjäderborn M, Jönsson AK, Hägg S et al (2007) Fatal unintentional intoxications with tramadol during 1995–2005. Forensic Sci Int 173:107–111PubMedGoogle Scholar
  164. Tobias JD (1997) Seizure after overdose of tramadol. South Med J 90:826–827PubMedGoogle Scholar
  165. Tricklebank MD, Forler C, Fozard JR (1984) The involvement of subtypes of the 5-HT1 receptor and of catecholaminergic systems in the behavioral response to 8-hydroxy-2-(di-n-propylamino)tetralin in the rat. Eur J Pharmacol 106:271–282PubMedGoogle Scholar
  166. Tzschentke TM, Christoph T, Kögel B et al (2007) (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride (tapentadol HCl): a novel µ-opioid receptor agonist/norepinephrine reuptake inhibitor with broad-spectrum analgesic properties. J Pharmacol Exp Ther 323:265–276PubMedGoogle Scholar
  167. Tzschentke TM, Jahnel U, Kogel B et al (2009) Tapentadol hydrochloride: a next-generation, centrally acting analgesic with two mechanisms of action in a single molecule. Drugs Today (Barc) 45:483–496Google Scholar
  168. Ure DS, Gillies MA, James KS (2000) Safe use of remifentanil in a patient treated with the monoamine oxidase inhibitor phenelzine. Br J Anaesth 84:414–416PubMedGoogle Scholar
  169. Vadivelu N, Timchenko A, Huang Y et al (2011) Tapentadol extended-release for treatment of chronic pain: a review. J Pain Res 4:211–218PubMedPubMedCentralGoogle Scholar
  170. Verthein U, Ullman R, Lachmann A et al (2005) The effects of racemic D,L-methadone and L-methadone in substituted patients—a randomized controlled study. Drug Alcohol Depend 80:267–271PubMedGoogle Scholar
  171. Vizcaychipi MP, Walker S, Palazzo M (2007) Serotonin syndrome triggered by tramadol. Br J Anaesth 99:919PubMedGoogle Scholar
  172. Volpi-Abadie J, Kaye AM, Kaye AD (2013) Serotonin syndrome. Ochsner J 13:533–540PubMedPubMedCentralGoogle Scholar
  173. Vuori E, Henry JA, Ojanpera I et al (2003) Death following ingestion of MDMA (ecstasy) and moclobemide. Addiction 98:365–368PubMedGoogle Scholar
  174. Walczyk H, Liu CH, Alafris A et al (2016) Probable tapentadol-associated serotonin syndrome after overdose. Hosp Pharm 51:320–327PubMedPubMedCentralGoogle Scholar
  175. Walkembach J, Brűss M, Urban BW et al (2005) Interaction of metoclopramide and ergotamine with human 5-HT3A receptors and human 5-HT reuptake carriers. Br J Pharmacol 146:543–552PubMedPubMedCentralGoogle Scholar
  176. Walter C, Ball D, Duffy M et al (2012) An unusual case of serotonin syndrome with oxycodone and citalopram. Case Rep Oncol Med 2012:261787.  https://doi.org/10.1155/2012/261787 CrossRefPubMedPubMedCentralGoogle Scholar
  177. Weiner AL (1999) Meperidine as a potential cause of serotonin syndrome in the emergency department. Acad Emerg Med 6:56–58Google Scholar
  178. Werneke U, Jamshidi F, Taylor DM et al (2016) Conundrums in neurology: diagnosing serotonin syndrome—a meta-analysis of cases. BMC Neurol 16:97.  https://doi.org/10.1186/s12883-016-06161 CrossRefPubMedPubMedCentralGoogle Scholar
  179. Whyte IM (2004) Serotonin syndrome (toxicity). In: Dart RC (ed) Medical toxicology, 3rd edn., vol. 1. Lippincott Williams and Wilkens, Baltimore, pp 103–106Google Scholar
  180. Wittmann M, Schaaf T, Peters I et al (2008) The effects of fentanyl-like opioids and hydromorphone on human 5-HT3A receptors. Anesth Analg 107:107–112PubMedGoogle Scholar
  181. Yap CY, Taylor DA (1983) Involvement of 5-HT2 receptors in the wet-dog shake behavior induced by 5-hydroxytryptamine in the rat. Neuropharmacol 22:801–804Google Scholar
  182. Zanger UM, Schwab M (2013) Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Ther 138:103–141PubMedGoogle Scholar
  183. Zornberg GL, Bodkin JA, Cohen BM (1991) Severe adverse interaction between pethidine and selegilene. Lancet 337:246PubMedGoogle Scholar
  184. Zwisler ST, Enggaard TP, Noehr-Jensen L et al (2009) The hypoalgesic effect of oxycodone in human experimental pain models in relation to the CYP2D6 oxidation polymorphism. Basic Clin Pharmacol Toxicol 104:335–344PubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Molecular Immunology Unit, Department of Medicine, Kolling Institute of Medical ResearchRoyal North Shore Hospital of Sydney, University of SydneySydneyAustralia

Personalised recommendations