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?
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
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.
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.
- Mahlberg R, Kunz D, Sasse J et al. Serontonin syndrome with tramadol and citalopram. Am J Psychiatry 2004;161:1129.
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.
- Kesavan S, Sobala GM. Serotonin syndrome with fluoxetine plus tramadol. J R Soc Med 1999;92:474-5.
- Gonzales-Pinto A, Imaz H, De Heredia JL et al. Mania and tramadol-fluoxetine combination. Am J Psychiatry 2001;158:964-5.
MS, Buchalter EN, Giambanco V. Serotonin syndrome following the
administration of tramadol with paroxetine. Int J Geriatr Psychiatry
AC, ter Borgh J, Brodie-Meijer CC. Serotonin syndrome attributed to
tramadol addition to paroxetine therapy. Int Clin Psychopharmacol
BJ, Blackburn KH. Possible serotonin syndrome associated with tramadol
and sertraline coadministration. Ann Pharmacother 1997;31:175-7.
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.
- Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005;352:1112-20.
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.
- Mackay FJ, Dunn NR, Mann RD. Antidepressants and the serotonin syndrome in general practice. Br. J Gen Pract 1999;49:871-4.
U, Bottlender R, Gallinat J et al. The serotonin syndrome scale: first
results on validity. Eur Arch Psychiatry Clin Neurosci
- Sternbach H. The serotonin syndrome. Am J Psychiatry 1991;148:705-13.
EJ, Isbister GK, Sibbritt D et al. The Hunter Serotonin Toxicity
Criteria: simple and accurate diagnostic rules for serotonin syndrome.
- Tramadol (Ultram ER®) product package insert. PriCara Unit of Ortho-McNeil, Inc. Raritan, NJ. December 2007.