In July 2006, the FDA issued an alert regarding a “potentially life-threatening” interaction between triptans (the most effective abortive medications for migraine) and selective serotonin reuptake inhibitors (SSRIs) or serotonin/ norepinephrine reuptake inhibitors (SNRIs). The SSRIs of concern included citalopram (Celexa, generics), fluvoxamine (Luvox, generics), escitalopram (Lexapro, generics), fluoxetine (Prozac, Sarafem, generics), paroxetine (Paxil, Pexeva, generics), and sertraline (Zoloft, generics). Also listed in the alert were the SNRIs duloxetine (Cymbalta), sibutramine (Meridia), and venlaxafine (Effexor, generics). The agency based its alert on a review of 29 cases of reported adverse effects in patients taking triptans and these antidepressants. The alert required that all patients receiving this drug combination be informed of the possibility of serotonin syndrome.1

Serotonin syndrome (now frequently called serotonin toxicity [ST]) consists of a triad of signs and symptoms, including autonomic nervous system manifestations (fever, diaphoresis, tachypnea, and tachycardia), neuromuscular changes (tremor, clonus, myoclonus, hyperreflexia, and rigidity), and altered mental status (agitation and confusion). The syndrome manifests abruptly, either at the initiation of a drug or drug-drug combination or within hours of an increase in dosage. ST is associated with numerous medications, either alone or in combination, and involves such drugs as monamine oxidase inhibitors (MAOIs), SSRIs, tricyclic antidepressants, opioids, antibiotics, OTC cough medicines, antiemetics, drugs of abuse, and herbal supplements.2 Life-threatening cases usually occur only when MAOIs are combined with SSRIs or SNRIs.

Published data indicate that 17% of women and more than 5% of men in the United States suffer from migraine.3 Migraineurs are two to four times as likely to have depression and two to five times as likely to have anxiety or panic disorder as nonmigraineurs.3 Many thousands of patients who require triptans also take SSRIs. Shapiro and Tepper estimated that 185,000 Americans were exposed to a triptan plus an SSRI during a 1-month period in 2001.4

In 12 years as a headache specialist, I have never seen a case of ST or met a colleague who has. Because most headache specialists' experience with ST mirrors mine, many were alarmed and confused by the 2006 FDA alert. A query to the FDA by Randolph W. Evans, MD, asking for the data used to justify the alert was rejected, so Evans filed a Freedom of Information Act request. In his analysis of the data, Evans reported that the quality of the information provided to the FDA was often incomplete or anecdotal and that most of the cases lacked the essential criteria to establish a diagnosis of ST. Evans concluded that there was little biologic plausibility that triptans could precipitate ST. When he asked the FDA why it had not published the 29 original case reports, he was told that FDA policy did not mandate such publication.

After an in-depth review, Evans concluded that one of the 29 cases may have been ST caused by combining a triptan and an SSRI. He also concluded that triptans might rarely precipitate ST and that the evidence does not support any change in the use of triptans with SSRIs or SNRIs.

For those of us utilizing an electronic health record (EHR), ignoring the FDA warning may be impossible. An alert may pop up warning of serotonin syndrome. Other clinicians may have their workday disrupted by pharmacists calling to alert them of the potential drug-drug interaction and warn patients that the combination may put them at risk of death.

When I petitioned the Formulary and Therapeutics Committee (FTC) at Kaiser Permanente Northwest to remove the electronic alert from our EHR, the FTC had to appeal to the software company's pharmacists. They reviewed the evidence and downgraded the level of the drug interaction, thus removing the warning from the software. While I was pleased that my appeal might allow our patients to receive the most effective migraine drugs available, I soon learned that the warning was removed from all of the software company's programs, including those sent to pharmacies, other health plans, the Veterans Administration, and hospitals worldwide.

The take-home lessons from my experience? First, PAs can now better serve patients with migraines who need both triptans and SSRIs or SNRIs. Second, some FDA alerts are subject to further scrutiny, and a PA-generated appeal can have a beneficial effect on patients and clinicians alike. JAAPA

Eric Schuman is a PA in the departments of adult and pediatric neurology, Kaiser Permanente, Portland, Oregon, and adjunct assistant professor, Oregon Health Sciences University, also in Portland.

REFERENCES

1. US Food and Drug Administration. FDA Public Health Advisory. Combined Use of 5- Hydroxytryptamine Receptor Agonists (Triptans), Selective Serotonin Reuptake Inhibitors (SSRIs) or Selective Serotonin/Norepinephrine Reuptake Inhibitors (SNRIs) May Result in Lifethreatening Serotonin Syndrome. Updated November 24, 2006. http://www.fda.gov/cder/drug/ advisory/SSRI_SS200607.htm. Accessed April 9, 2009.

2. Sun-Edelstein C, Tepper SJ, Shapiro RE. Drug-induced serotonin syndrome: a review. Expert Opin Drug Saf. 2008;7(5):587-596.

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 General Medicine. 2007;9(3):48. Medscape Web site. http://journal.medscape.com/viewarticle/561741_1. Accessed April 9, 2009.

4. Shapiro RE, Tepper SJ. Serotonin syndrome, triptans, and the potential for drug-drug interactions. Headache. 2007;47(2):266-269.