Correspondence

More on Serotonin Syndrome Associated with Triptan Monotherapy

N Engl J Med 2008; 359:870-871August 21, 2008

Article

To the Editor:

The letter by Soldin and Tonning regarding the association between the serotonin syndrome and triptan monotherapy (May 15 issue)1 requires clarification. On the basis of an analysis of 27 cases from the Adverse Event Reporting System (AERS), the Food and Drug Administration (FDA) issued an alert, “Potentially Life-Threatening Serotonin Syndrome with Combined Use of SSRIs [selective serotonin reuptake inhibitors] or SNRIs [selective serotonin–norepinephrine reuptake inhibitors] and Triptan Medications.”2 After receiving a Freedom of Information Act request, the FDA provided me with data on 29 cases that they evaluated as the basis for the alert. My analysis revealed that seven of those cases met the Sternbach criteria for the serotonin syndrome and none met the stricter Hunter criteria.3

Now Soldin and Tonning report 11 cases of the serotonin syndrome associated with triptan use alone from the AERS. They do not report whether Sternbach or Hunter criteria were met. Finally, triptans alone would not seem to contribute to the serotonin syndrome.4 Triptans are agonists of 5-hydroxytryptamine (5-HT), or serotonin, receptors of type 1B (5-HT_1B), type 1D (5-HT_1D), and type 1F (5-HT_1F), whereas the serotonin syndrome is believed to be due to activation of the 5-HT type 1A (5-HT_1A) and 5-HT type 2A (5-HT_2A) receptors.5

Randolph W. Evans, M.D.
Baylor College of Medicine, Houston, TX 77004
rwevans@pol.net

Dr. Evans reports receiving consulting fees from Abbott and consulting and lecture fees from GlaxoSmithKline, Merck, Ortho-McNeil, Pfizer, and Valeant. No other potential conflict of interest relevant to this letter was reported.

5 References

1. 1

   Soldin OP, Tonning JM. Serotonin syndrome associated with triptan monotherapy. N Engl J Med 2008;358:2185-2186
   Full Text | Web of Science | Medline

2. 2

   Food and Drug Administration. Information for healthcare professionals: selective serotonin reuptake inhibitors (SSRIs), selective serotonin-norepinephrine reuptake inhibitors (SNRIs), 5-hydroxytryptamine receptor agonists (triptans). July 19, 2006. (Accessed August 1, 2008, at http://www.fda.gov/cder/drug/InfoSheets/HCP/triptansHCP.htm.)
   

3. 3

   Evans RW. The FDA alert on serotonin syndrome with combined use of SSRIs or SNRIs and triptans: an analysis of the 29 case reports. Medscape Gen Med 2007;9:48-48http://www.medscape.com/viewarticle/561741
   Medline

4. 4

   Shapiro RE, Tepper SJ. The serotonin syndrome, triptans, and the potential for drug-drug interactions. Headache 2007;47:266-269
   CrossRef | Web of Science | Medline

5. 5

   Isbister GK, Buckley NA. The pathophysiology of serotonin toxicity in animals and humans: implications for diagnosis and treatment. Clin Neuropharmacol 2005;28:205-214
   CrossRef | Web of Science | Medline

Author/Editor Response

Evans makes the point that the serotonin syndrome is due to activation of 5-HT_1A and 5-HT_2A receptors. However, six of the seven types of triptan that are marketed in the United States have at least some degree of 5-HT_1A activity.1 Of our 11 “triptan-only” cases (with no concomitant use of serotonergic drugs), 3 were specifically reported as the serotonin syndrome; the other 8 cases all met criteria documenting mental-status changes, autonomic hyperactivity, and neuromuscular abnormalities — a triad widely reported in the literature as indicative of the serotonin syndrome.2 Although various criteria exist for evaluating the serotonin syndrome, these criteria may have varying usefulness when applied to different databases. The Hunter criteria were developed at a toxicology service using a data set of overdoses in which medical staff used a preformatted form that prompted staff to evaluate specific overdose symptoms.3 The criteria can be used for adverse drug reactions but have not been validated for that purpose.4 Because the serotonin syndrome reflects a clinical spectrum (mild, moderate, or severe), such strict criteria may lack appropriate sensitivity when applied to databases containing spontaneously reported adverse drug events from the public, such as the AERS.

Offie P. Soldin, Ph.D., M.B.A.
Georgetown University Medical Center, Washington, DC 20037
os35@georgetown.edu

4 References

1. 1

   Pauwels PJ, Palmier C, Dupuis DS, Colpaert FC. Interaction of 5-HT1B/D ligands with recombinant h 5-HT1A receptors: intrinsic activity and modulation by G-protein activation state. Naunyn Schmiedebergs Arch Pharmacol 1998;357:490-499
   CrossRef | Web of Science | Medline

2. 2

   Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005;352:1112-1120[Erratum, N Engl J Med 2007;356:2437.]
   Full Text | Web of Science | Medline

3. 3

   Dunkley EJ, Isbister GK, Sibbritt D, Dawson AH, Whyte IM. The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity. QJM 2003;96:635-642
   CrossRef | Medline

4. 4

   Isbister GK, Buckley NA, Whyte IM. Serotonin toxicity: a practical approach to diagnosis and treatment. Med J Aust 2007;187:361-365
   Web of Science | Medline

Citing Articles (3)

Citing Articles

1. 1

   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

2. 2

   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

3. 3

   (2009) Current awareness: Pharmacoepidemiology and drug safety. Pharmacoepidemiology and Drug Safety 18:1, i-xiv
   CrossRef