EBM Consult

The Incidence of Tramadol (Ultram; Ultram ER; Ultracet) Induced Serotonin Syndrome in Patients Taking SSRI Antidepressants


  • To our knowledge there is no good or convincing data about the incidence of this drug interaction resulting in patients developing serotonin syndrome.
  • The majority of literature reporting serotonin syndrome with tramadol and SSRIs are in the form of case reports which are considered insufficient to determine causality.
  • Factors contributing to this interaction include the wide spectrum of the signs and symptoms of serotonin syndrome, physicians being unaware that serotonin syndrome is a clinical diagnosis, differing diagnostic criteria, and possibly the fragmentation of care provided by the healthcare system.
  • Regardless of definitive data on the true incidence, the available evidence and warnings from regulatory agencies warrant consideration by clinicians.

Editor-in-Chief: Anthony J. Busti, MD, PharmD, FNLA, FAHA
Reviewers:  Jon D. Herrington, PharmD, BCPS, BCOP and Donald S. Nuzum, PharmD, BCACP, BC-ADM, CDE, CPP

Last Reviewed: October 2017


  • Unfortunately no one really knows the true incidence of this complication.  To our knowledge, there is no good or convincing data about the incidence of this drug interaction resulting in patients developing serotonin syndrome.  The majority of literature linking serotonin syndrome with tramadol and selective serotonin reuptake inhibitors (SSRI) are in the form of case reports which are considered insufficient to determine causality.1-7  However, having several case reports and/or case series showing similar time related occurrences of this condition can be helpful in the absence of better evidence.  One study using claims data in an Australian VA population identified 1811 (0.7%) patients who were receiving potentially life-threatening serotonergic medication combinations, most of which were an SSRI and tramadol.8  They were unable to determine if those cases resulted in the  development of serotonin syndrome. Furthermore, the mechanism for how this occurs is multifactorial.9-12 To learn more about the mechanism for tramadol induced serotonin syndrome in patients taking SSRIs ... click here

    Why is this condition difficult to assess?

    The first point about the broad spectrum of signs and symptoms is certainly a contributing factor.  In addition, the strict application of the Sternbach criteria may cause the clinician to exclude mild or subacute cases of serotonin syndrome.9,13  To complicate things further there has been such debate over the Sternbach criteria that another criteria set, called the Hunter Serotonin Toxicity Criteria, have been developed.14  The Hunter criteria have been proposed to be easier for clinicians to use. However, this may also result in an inconsistency in the diagnosis rates, depending on which criteria set a clinician uses.14 

    A third and final influencing factor (especially given the above factors) is the fragmented nature of healthcare delivery to patients.  It is not uncommon for a patient to be treated or followed by 2 or more physicians of different specialties, all of whom prescribe medications related only to their respective areas of expertise, and often without regard to medications prescribed by others.  This leaves the patient's primary care physician (if they even have one) to factor in all of these issues on top of any other comorbidities they may be trying to manage for that patient. 

    Given all of these influencing factors, it understandable why this condition may be underreported and therefore, not perceived as being a clinically significant adverse drug reaction that affects the quality of life.  This is relevant given the number of other treatment options for pain management in patients who also require serotonergic medications for another problem.  In addition, there are enough case reports and regulatory warnings about this drug interaction that clinicians should take it into consideration.15.

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    • Lecture:  What is the interaction between tramadol (Ultram) and cyclobenzaprine (Flexeril) and is it clinically relevant?



    1. Mahlberg R, Kunz D, Sasse J et al.  Serontonin syndrome with tramadol and citalopram.  Am J Psychiatry 2004;161:1129.
    2. Lange-Asschenfeldt C, Weigmann H, Hiemke C et al.  Serotonin syndrome as a result of fluoxetine in a patient with tramadol abuse: plasma level-correlated symptomatology.  J Clin Psychopharmacol  2002;22:440-1.
    3. Kesavan S, Sobala GM.  Serotonin syndrome with fluoxetine plus tramadol.  J R Soc Med  1999;92:474-5.              
    4. Gonzales-Pinto A, Imaz H, De Heredia JL et al.  Mania and tramadol-fluoxetine combination.  Am J Psychiatry  2001;158:964-5.
    5. Lantz MS, Buchalter EN, Giambanco V.  Serotonin syndrome following the administration of tramadol with paroxetine.  Int J Geriatr Psychiatry  1998;13:343-5.
    6. Egberts AC, ter Borgh J, Brodie-Meijer CC.  Serotonin syndrome attributed to tramadol addition to paroxetine therapy.  Int Clin Psychopharmacol  1997;12:181-2.      
    7. Mason BJ, Blackburn KH.  Possible serotonin syndrome associated with tramadol and sertraline coadministration.  Ann Pharmacother  1997;31:175-7.
    8. Ringland C, Mant A, McGettigan P et al.  Uncovering the potential risk of serotonin toxicity in Australian veterans using pharmaceutical claims data.  Br J Clin Pharmacol  2008;66:682-8.
    9. Boyer EW, Shannon M.  The serotonin syndrome.  N Engl J Med  2005;352:1112-20.
    10. Gnanadesigan N, Espinoza RT, Smith R et al.  Interaction of serotonergic antidepressants and opioid analgesics: is serotonin syndrome going undetected?  J Am Med Dir Assoc  2005;6:265-9.
    11. Mackay FJ, Dunn NR, Mann RD.  Antidepressants and the serotonin syndrome in general practice.  Br. J Gen Pract  1999;49:871-4.
    12. Hegerl U, Bottlender R, Gallinat J et al.  The serotonin syndrome scale: first results on validity.  Eur Arch Psychiatry Clin Neurosci  1998;248:96-103. 
    13. Sternbach H.  The serotonin syndrome.  Am J Psychiatry  1991;148:705-13. 
    14. Dunkley EJ, Isbister GK, Sibbritt D et al.  The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic rules for serotonin syndrome.  QJM  2003;96:635-42.
    15. Tramadol (Ultram ERĀ®) product package insert.  PriCara Unit of Ortho-McNeil, Inc. Raritan, NJ.  December 2007.


  • Tramadol, Ultram, SSRI, Serotonin Reuptake Inhibitor, Serotonin Syndrome, Incidence of Tramadol Induced Serotonin Syndrome, Tramadol Flexeril Interaction