Abstract
Dear Sir I read the article, ‘Serotonin syndrome and rhabdomyolysis induced by concomitant use of triptans, fluoxetine and hypericum’ by Bonetto et al. with concern (1). Their conclusion that the patient had serotonin syndrome precipitated by the use of eletriptan was incorrect if the diagnosis was based upon meeting criteria and not conjecture. The authors do not state specifically which criteria they used for serotonin syndrome. Their patient does not meet the Hunter serotonin toxicity criteria (2). The patient fulfilled the clinical features, but did not meet the Sterbach criteria because other aetiologies were not ruled out (2). In this case, an infectious aetiology (meningoencephalitis) was not excluded by a lumbar puncture, serology or cultures.
This case may very well have been due to an enterovirus meningitis such as group B coxsackievirus, which could have caused all of the symptoms and signs including the complications of seizure, rhabdomyolysis, and renal failure (3). The elevated D-dimer level, which the authors state is not a laboratory finding of serotonin syndrome, may also have been associated with the viral disease and complications.
In 2006, the United States Food and Drug Administration (FDA) issued an alert to potentially life-threatening complications from the combined use of triptans with selective serotonin re-uptake inhibitors (SSRI) or selective norepinephrine reuptake inhibitors (SNRI) based upon 27 cases reported worldwide (4). Following a Freedom of Information Act request, the FDA provided me all of the case information on 29 cases, not just 27 as described in the alert. On analysis, seven of the cases met the Sternbach criteria and no case met the Hunter criteria (5).
The biological plausibility of the serotonin syndrome with combined use is not clear, as triptans are 5HT1B/5HT1D/5HT1F subtype receptor agonists, whereas serotonin syndrome is believed to be due to activation of the 5-HT1A and 5-HT2A receptors (6). Although the incidence of serotonin syndrome among patients on SSRI monotherapy has been estimated in the range of 0.5–0.9 cases per 1000 patient-months of treatment (7), there have been no reported cases of serotonin syndrome due to triptans taken alone (8). A prospective postmarketing safety study (9) for up to 1 year of subcutaneous sumatriptan use in 1784 migraineurs on SSRIs found no cases of serotonin syndrome. However, it is possible that additional definite cases may be reported with greater physician awareness of these potential drug interactions and serotonin syndrome.
As Bonetto et al. concur, ‘The FDA recommends that patients treated concomitantly with a triptan and an SSRI/SNRI be informed of the possibility of serotonin syndrome’. This recommendation seems premature when more than 1 million patients have been exposed to the drug combinations (8) with only seven cases meeting just one set of criteria for serotonin syndrome. Routinely advising our patients may be a poor use of time, unnecessarily alarm some patients, and may be harmful when efficacious medications are not used.