Avoiding serotonin syndrome: The nature of the interaction between tramadol and selective serotonin reuptake inhibitors

Elana M. Nelson, Ann M. Philbrick

Research output: Contribution to journalReview articlepeer-review

64 Scopus citations


OBJECTIVE: To investigate the nature of the interaction between selective serotonin reuptake inhibitors (SSRIs) and tramadol to mitigate or avoid serotonin syndrome. DATA SOURCES: PubMed, Ovid MEDLINE, and International Pharmaceutical from January 1990 to August 2012 were searched. Key words used were tramadol, antidepressive agents, antidepressants, drug interactions, selective serotonin uptake inhibitors, and serotonin syndrome. STUDY SELECTION AND DATA EXTRACTION: Only English-language studies were included. No randomized controlled trials were identified. Review articles, case reports, and 1 case series that identified the scope of interaction between tramadol and SSRIs were evaluated. Review articles evaluating the role of pharmacogenetics in the use of tramadol, SSRIs, and serotonin syndrome were also reviewed. DATA SYNTHESIS: Published documentation describing the interaction between tramadol and SSRIs and its relevance to serotonin syndrome is limited to a few case reports and 1 case series. While both tramadol and SSRIs increase the amount of serotonin in the brain, the interaction is much more complicated. Tramadol is metabolized through CYP2D6 enzymes and all SSRIs are inhibitors of these enzymes. Inhibitors of CYP2D6 can increase the concentration of tramadol in the blood and thus increase its effects on serotonin in the brain, contributing to the development of serotonin syndrome. CYP2D6 poor metabolizers are at a greater risk of serotonin syndrome and an inadequate analgesic effect. CONCLUSIONS: Coadministration of tramadol and SSRIs has caused serotonin syndrome. An attempt should be made to identify individuals who are poor metabolizers of CYP2D6 and avoid this combination in those patients. When SSRIs and tramadol must be used in combination, it is critical that patients be aware of the signs and symptoms of serotonin syndrome, should they occur.

Original languageEnglish (US)
Pages (from-to)1712-1716
Number of pages5
JournalAnnals of Pharmacotherapy
Issue number12
StatePublished - Dec 2012

Bibliographical note

Copyright 2013 Elsevier B.V., All rights reserved.


  • Interaction
  • SSRI
  • Selective serotonin reuptake inhibitor
  • Serotonin syndrome
  • Tramadol


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