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

Arch Toxicol. 2018 Aug;92(8):2457-2473. doi: 10.1007/s00204-018-2244-6. Epub 2018 Jun 18.


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

Publication types

  • Review

MeSH terms

  • Analgesics, Opioid / adverse effects*
  • Animals
  • Brain / drug effects
  • Brain / metabolism
  • Drug Interactions
  • Humans
  • Models, Animal*
  • Serotonin / metabolism*
  • Serotonin Syndrome / chemically induced*
  • Serotonin Syndrome / metabolism


  • Analgesics, Opioid
  • Serotonin