Correspondence

Serotonin Syndrome Associated with Triptan Monotherapy

N Engl J Med 2008; 358:2185-2186May 15, 2008

Article

To the Editor:

Triptans are serotonin-receptor agonists used in the treatment of migraine headaches. When administered in combination with certain drugs, such as selective serotonin-reuptake inhibitors (SSRIs) and serotonin–norepinephrine reuptake inhibitors (SNRIs), triptans may precipitate the serotonin syndrome, a potentially life-threatening condition characterized by a triad of clinical manifestations — changes in mental status, autonomic hyperactivity, and neuromuscular abnormalities.1,2 The cause of the serotonin syndrome is related to altered serotonin synthesis, release, reuptake, metabolism, or receptor agonism.3 We investigated whether triptan monotherapy is associated with the serotonin syndrome by searching for such cases in the Food and Drug Administration's Adverse Event Reporting System (AERS).

We reviewed triptan adverse-event reports coded with the term “serotonin syndrome,” as well as reports containing terms other than “serotonin syndrome” that were nonetheless indicative of this syndrome (e.g., agitation, tachycardia, and tremor). Cases searched in AERS included reports for triptans marketed in the United States: almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, and zolmitriptan. We excluded cases of potentially confounding medical conditions (e.g., hyperthyroidism) and cases documenting concomitant therapy with drugs known to be associated with the serotonin syndrome (e.g., SSRIs). Twenty-seven AERS cases of the serotonin syndrome related to drug–drug interaction were associated with co-prescription of various combinations of triptans and SSRIs. Our review elicited 11 cases (mean age of the patients, 39.9 years): 3 specifically coded as serotonin syndrome and 8 coded with additional terms indicative of the triad of clinical features of the serotonin syndrome. Commonly reported symptoms among these eight cases included tremor, musculoskeletal stiffness, palpitations, flushing, hypertension, and agitation. Hospitalization as a result of the adverse event was mentioned in five cases, and two cases were coded as “life-threatening.” Anaphylactic shock could not be ruled out in one case. There were no apparent instances of overdose, except in one case that documented an intravenous overdose rather than a subcutaneous overdose. Four of the 11 cases documented an onset of symptoms within 1 hour after administration. Symptoms generally resolved over several hours either with or without supportive treatment (e.g., intravenous diphenhydramine); one case documented a return of symptoms on reintroduction of a triptan 8 months after the initial adverse event.

The serotonin syndrome is a rare but potentially serious occurrence with triptan monotherapy. Because of the spontaneous and voluntary nature of AERS reporting, the actual number of occurrences may be higher, and the risk of the serotonin syndrome among triptan users cannot be established. If symptoms of the serotonin syndrome occur, treatment should be withdrawn, and patients should seek medical attention.

Offie P. Soldin, Ph.D., M.B.A.
Georgetown University Medical Center, Washington, DC 20057
os35@georgetown.edu

for the Obstetric–Fetal Pharmacology Research Unit Network

Joseph M. Tonning, M.D., M.P.H.
Food and Drug Administration, Silver Spring, MD 20993

Supported in part by grants from the National Institute of Child Health and Human Development (5U10HD047890-03) and the Office of Research on Women's Health.

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Citing Articles (7)

Citing Articles

1. 1

   Stewart J. Tepper. (2012) Serotonin Syndrome: SSRIs, SNRIs, Triptans, and Current Clinical Practice. Headache: The Journal of Head and Face Painno-no
   CrossRef

2. 2

   Margaret F. Moloney, Lisa A. Cranwell-Bruce. (2010) Pharmacological Management of Migraine Headaches. The Nurse Practitioner 35:9, 16-22
   CrossRef

3. 3

   Randolph W. Evans, Stewart J. Tepper, Robert E. Shapiro, Christina Sun-Edelstein, Gretchen E. Tietjen. (2010) The FDA Alert on Serotonin Syndrome With Use of Triptans Combined With Selective Serotonin Reuptake Inhibitors or Selective Serotonin-Norepinephrine Reuptake Inhibitors: American Headache Society Position Paper. Headache: The Journal of Head and Face Pain 50:6, 1089-1099
   CrossRef

4. 4

   Peter J Goadsby, Till Sprenger. (2010) Current practice and future directions in the prevention and acute management of migraine. The Lancet Neurology 9:3, 285-298
   CrossRef

5. 5

   P. Ken Gillman. (2010) Triptans, Serotonin Agonists, and Serotonin Syndrome (Serotonin Toxicity): A Review. Headache: The Journal of Head and Face Pain 50:2, 264-272
   CrossRef

6. 6

   Christina Sun-Edelstein, Stewart J Tepper, Robert E Shapiro. (2008) Drug-induced serotonin syndrome: a review. Expert Opinion on Drug Safety 7:5, 587-596
   CrossRef

7. 7

   (2008) More on Serotonin Syndrome Associated with Triptan Monotherapy. New England Journal of Medicine 359:8, 870-871
   Full Text

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