On July 19, 2006, the US Food and Drug Administration (FDA) issued an alert, “Potentially Life-Threatening Serotonin Syndrome With Combined Use of SSRIs or SNRIs and Triptan Medications.” However, the cases that were the basis for the alert were not made available. The FDA recommends that patients treated concomitantly with a triptan and a selective serotonin reuptake inhibitor (SSRI)/selective norepinephrine reuptake inhibitor (SNRI) be informed of the possibility of serotonin syndrome.
MethodsFollowing a Freedom of Information Act request, the FDA provided the 29 cases that they evaluated as the basis for the alert. I summarize the cases, rate the quality of the cases on the basis of the information provided, and then determine whether the cases fulfill the Sternbach and Hunter criteria for serotonin syndrome.
ResultsSeven cases met the Sternbach criteria but did not meet the Hunter criteria. No cases met both criteria or just the Hunter criteria.
ConclusionsTriptans when administered with SSRIs or SNRIs might rarely precipitate serotonin syndrome. The data do not support prohibiting the use of triptans with SSRIs or SNRIs. With increased physician awareness of serotonin syndrome, it is possible that additional cases may be reported.
IntroductionOn July 19, 2006, the US Food and Drug Administration (FDA) issued an alert, “Potentially Life-Threatening Serotonin Syndrome With Combined Use of SSRIs or SNRIs and Triptan Medications.[1]” (An update was issued on November 24, 2006 adding sibutramine.[2]) The FDA reported that there is the potential for life-threatening serotonin syndrome in patients taking 5-hydroxytryptamine receptor agonists (triptans) and selective serotonin reuptake inhibitors (SSRIs) or SSRIs/selective norepinephrine reuptake inhibitors (SNRIs) concomitantly (Table 1).
Table 1.List of Drug Names
“This information is based on reports of serotonin syndrome occurring in patients treated with triptans and SSRIs/SNRIs, and the biological plausibility of such a reaction in persons receiving two serotonergic medications. The FDA recommends that patients treated concomitantly with a triptan and an SSRI/SNRI be informed of the possibility of serotonin syndrome (which may be more likely to occur when starting or increasing the dose of an SSRI, SNRI, or triptan) and be carefully followed.”[1] The FDA now requires that this information be included as part of the prescribing information for triptans.
Since then, on the basis of this alert, numerous patients and their physicians have received warnings or recommendations from pharmacists to discontinue one of their medications when they are taking these combinations (information from my practice and many other physicians with whom I have spoken). Should one of the medications be discontinued?
I review the information on the number of patients who may be taking these combinations, serotonin syndrome, and the cases that the FDA reviewed to issue this alert.
Background Migraine Is Comorbid With Depression, Anxiety, Panic, and Bipolar DisorderMigraine is a very common disease in the United States, with a 1-year period prevalence among those age 12 years and older of 11.7 % (17.1% in women and 5.6% in men).[3] An additional 4.5% have probable migraine.[4] Migraine is comorbid with various psychiatric disorders.[5] Migraineurs are 2.2–4.0 times more likely to have depression. Migraine is also comorbid with generalized anxiety disorder (odds ratio [OR] 3.5–5.3), panic disorder (OR 3.7), and bipolar disorder (OR 2.9–7.3).
Therefore, it is not surprising that many migraineurs take triptans for acute headache attacks and are also taking SSRIs and SNRIs for their comorbid psychiatric disorders, which are common even when not comorbid. Extrapolating from a large pharmacy benefit coprescription data base, Shapiro and Tepper[6] estimated that more than 185,000 Americans were exposed to a triptan and an SSRI over a 1-month or greater period during 2000–2001. “Assuming that the 2000–2001 data are representative of the years 1998 to 2002, almost 1 million relevant patient-month exposures to the combination of triptans and SSRIs occurred during the period of the reporting of the FDA cases.”[6] Triptans and SNRIs are also commonly coprescribed, but I have not found any estimates of the number of patients taking both.
Serotonin SyndromeSerotonin syndrome is an adverse drug reaction that results from therapeutic single or combination medication use or overdose of medication that increases serotonin levels and stimulates central and peripheral postsynaptic serotonin receptors. In addition to the medications discussed above, others associated with serotonin syndrome include monoamine oxidase inhibitors, tricyclic antidepressants, opiate analgesics, over-the-counter cough medicines, antibiotics, weight-reduction agents, antiemetics, drugs of abuse, and herbal products. The syndrome has also been associated with the withdrawal of medications. Sixty percent of patients present within 6 hours of medication initiation, overdose, or change in dosage and 74% within 24 hours.[7]
Serotonin syndrome presents with 1 or a combination of mental status changes (with a range, including anxiety, agitation, confusion, delirium and hallucinations, drowsiness, and coma), autonomic hyperactivity in about 50% (including hyperthermia, diaphoresis, sinus tachycardia, hypertension or hypotension, flushing of the skin, diarrhea, and vomiting), and neuromuscular dysfunction (including myoclonus, hyperreflexia, muscle rigidity, tremor, and severe shivering).[8,9] The symptoms may range from diarrhea and tremor in a mild case to life-threatening complications, such as seizures, coma, rhabdomyolysis, and disseminated intravascular coagulation.
The diagnosis is one of exclusion that is based on the history of medication use, the physical examination, and the ruling out of other neurologic disorders – such as meningoencephalitis, delirium tremens, heat stroke, neuroleptic malignant syndrome, malignant hyperthermia, and anticholinergic poisoning (Table 2).
Table 2.Manifestations of Severe Serotonin Syndrome and Related Clinical Conditions
Condition MedicationHistory Time Needed for Condition to Develop Vital Signs Pupils Mucosa Skin Bowel Sounds Neuromuscular Tone Reflexes Mental Status Serotonin syndrome Proserotonergic drug < 12 hr Hypertension, tachycardia, tachypnea, hyperthermia (> 41.1°C) Mydriasis Sialorrhea Diaphoresis Hyperactive Increased, predominantly in lower extremities Hyperreflexia, clonus (unless masked by increased muscle tone) Agitation, coma Anticholinergic “toxidrome” Anticholinergic agent < 12 hr Hypertension (mild), tachycardia, tachypnea, hyperthermia (typically 38.8°C or less) Mydriasis Dry Erythema, hot, and dry to touch Decreased or absent Normal Normal Agitated delirium Neuroleptic malignant syndrome Dopamine antagonist 1–3 days Hypertension, tachycardia, tachypnea, hyperthermia (> 41.1°C) Normal Sialorrhea Pallor, diaphoresis Normal or decreased “Lead-pipe” rigidity, present in all muscle groups Bradyreflexia Stupor, alert mutism, coma Malignant hyperthermia Inhalational anesthesia 30 min to 24 hr after administration of inhalational anesthesia or succinylcholine Hypertension, tachycardia, tachypnea, hyperthermia (can be as high as 46.0°C) Normal Normal Mottled appearance, diaphoresis Decreased Rigor mortislike rigidity Hyporeflexia AgitationThe diagnosis is suggested with a sensitivity of 84% and specificity of 97% (compared with the gold standard of diagnosis by a medical toxicologist in patients who have overdosed on a serotonergic drug) by the Hunter serotonin toxicity criteria in the presence of a serotonergic agent and one of the following symptoms: spontaneous clonus, inducible clonus and agitation or diaphoresis, ocular clonus and agitation or diaphoresis, tremor and hyperreflexia, hypertonic and temperature > 38°C, and ocular clonus or inducible clonus.[10] The Hunter criteria have not been validated in patients who develop serotonin toxicity on therapeutic doses of serotonergic agents (either single agents or as a drug interaction).
To fulfill the criteria of Sternbach,[11] coincident with the addition or increase in a known serotonergic agent to an established medication regimen, at least 3 of the following clinical features are present: mental status changes (confusion, hypomania), agitation, myoclonus, hyperreflexia, diaphoresis, shivering, tremor, diarrhea, incoordination, or fever; other etiologies (eg, infectious, metabolic, substance abuse, or withdrawal) have been ruled out; and a neuroleptic had not been started or increased in dosage prior to the onset of the signs and symptoms listed above. Following an overdose of a serotonergic drug, the Sternbach criteria suggest the diagnosis with a sensitivity of 75% and a specificity of 96%.[10] Radomski and colleagues[12] have proposed another set of criteria that might better detect the range of milder to severe cases, but the criteria have not been validated. The Serotonin Syndrome Scale criteria might also better detect milder cases but has been incompletely validated.[13]
Management varies depending on the severity of symptoms and includes removal of responsible medications, supportive care, cyproheptadine (a 5-HT2A antagonist), control of agitation (with benzodiazepines, such as lorazepam), and treatment of autonomic dysfunction and hyperthermia.[14] With appropriate management, symptoms resolve within 24 hours for about 60%, but drugs with long durations of action or active metabolites may cause prolonged symptoms.[8]
There is some debate about the exact transition point between side effects of serotoninergic administration and a toxic serotonin syndrome requiring withdrawal of medication. Some patients with stable mild subacute or chronic symptoms fulfilling criteria for serotonin syndrome (such as mild tremor and hyperreflexia) might safely continue the medication with close observation.[14]
MethodsIn the July 19, 2006 alert, the FDA summarized the data that were the basis for the alert as follows:
The FDA has reviewed 27 reports of serotonin syndrome reported in association with concomitant SSRI or SNRI and triptan use. Two reports described life-threatening events and 13 reports stated that the patients required hospitalization. Some of the cases occurred in patients who had previously used concomitant SSRIs or SNRIs and triptans without experiencing serotonin syndrome. The reported signs and symptoms of serotonin syndrome were highly variable and included respiratory failure, coma, mania, hallucinations, confusion, dizziness, hyperthermia, hypertension, sweating, trembling, weakness, and ataxia. In 8 cases, recent dose increases or addition of another serotonergic drug to an SSRI/triptan or SNRI/triptan combination were temporally related to symptom onset. The median time to onset subsequent to the addition of another serotonergic drug or dose increase of a serotonergic drug was 1 day, with a range of 10 minutes to 6 days.
Specific information about the cases is not available through the FDA publication or Web site. At the end of July 2006, I submitted a Freedom of Information Act request to the FDA who provided me with their complete reports of 29 possible serotonin syndrome cases (2 more than described in the alert). Eight of the cases have been published, and the rest were submitted to the FDA through the MedWatch reporting system. The FDA did not provide me with their analysis of the cases, what criteria they used, and whether they met the criteria for serotonin syndrome.
ResultsIn Table 3, I summarize the 29 cases, rate the quality of the cases on the basis of the information provided, and then determine whether the cases fulfill the Sternbach and Hunter criteria for serotonin syndrome.
Table 3.Summary of Cases Reported by US Food and Drug Administration (FDA) Alert: Potentially Life-Threatening Serotonin Syndrome (SS) With Combined Use of SSRIs or SNRIs and Triptan Medications: the 29 Cases
Case Number/Medications Case Summary Quality of Case Information*/Meets Sternbach and Hunter Criteria 1. Sumatriptan tab sertraline 42 y.o. woman reported she received sumatriptan (Imitrex) tabs, sertraline (Zoloft), and pseudoephedrine (for sinusitis) and developed allergic reactions with flushing, hives, wheezing, closing sensation in throat, panic, chest pain, rapid pulse, arrhythmia, sensations of fainting and being on a roller coaster, feeling like death was imminent, diarrhea, uterine cramping with spotting, shivering, chattering jaw, and myoclonus. Treated in ED with diphenhydramine. Symptoms later off sumatriptan. Psychiatrist diagnosed panic disorder. Allergist diagnosed possible conversion hysteria. Primary physician diagnosed psychophysiologic reaction. ++The quality of the information substantiating many of the cases is incomplete or anecdotal (such as cases 3, 4, and 16 in which pharmaceutical representatives are passing on possible incidents). Case 12, which alleges bilateral retinal detachments only, is irrelevant. Even two of the published cases, 26 and 28, leave out important information, such as vital signs or detailed neurologic exams; therefore, the Hunter criteria cannot be used.
Of the 29 cases, 7 met the Sternbach criteria but not the Hunter criteria. No cases met both criteria or the Hunter criteria only. However, even among those who met the criteria, there are some questions. The Sternbach criteria require ruling out other disorders. Information is not provided as to whether other disorders were excluded in cases 2, 6, 8, 18, 19, and 29, but I counted them as meeting the criteria. Case 28 may very well be serotonin syndrome, but the information provided is incomplete and did not meet the criteria.
Two cases met the criteria but are excluded. Case 1 met the criteria, but symptoms of hives and wheezing are not part of serotonin syndrome. The patient's physicians diagnosed conversion disorder and the symptoms later occurred off sumatriptan. Therefore, I rated case 1 as not meeting either criteria. Case 24 met the criteria, but she was noted to have had 2 prior similar episodes associated with the use of metoclopramide and naproxen for migraine. In addition, she was taking only sumatriptan and metoclopramide but was not taking an SSRI or SNRI.
ConclusionThe FDA alert concluded:
Serotonin syndrome following concomitant SSRI or SNRI and triptan use is biologically plausible. SSRIs, SNRIs, and triptans independently increase serotonin levels. Therefore, it is expected that concomitant use of SSRIs or SNRIs and triptans would result in higher serotonin levels than the serotonin levels observed with the use of SSRIs, SNRIs, or triptans alone, potentially leading to serotonin syndrome.[1]
The biological plausibility is not entirely clear; on the basis of the biology, triptans would not seem to contribute to serotonin syndrome.[6] 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.[15]
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,[16] there have been no reported cases of serotonin syndrome due to triptans taken alone.[6] A prospective postmarketing safety study[17] for up to 1 year of subcutaneous sumatriptan use in 1784 migraineurs on SSRIs found no cases of serotonin syndrome. Of the 29 cases obtained from the FDA (Table 3), 7 met the Sternbach serotonin syndrome criteria and no cases fulfilled the Hunter criteria. It is certainly possible that additional definite cases may be reported with greater physician awareness of these potential drug interactions and serotonin syndrome.
Triptans, when administered with SSRIs or SNRIs, might rarely precipitate serotonin syndrome. Does this justify routinely advising our patients of this possibility as the FDA advisory recommends and perhaps unnecessarily alarming them? Some migraineurs might be so alarmed that they would not want to take a triptan that could be quite efficacious. Anecdotally, few physicians are currently advising patients of the possible risk. (When I asked this question to 149 family medicine physicians from throughout Texas during a lecture on migraine in July 2007, only one indicated that he did routinely advise his patients.)
Physicians should be better informed about the information behind FDA alerts and warnings. Case information should be made readily available on the FDA Web site, so that clinicians and researchers can independently evaluate the data. (In my telephone calls to the FDA, I asked why the cases were not made available with the advisory. I was told that that was not FDA policy and that if I believed the FDA policy should be changed, I should contact my congressional representative.)
The evidence does not support any change in the use of triptans with SSRIs or SNRIs. In the unlikely event that a patient does develop symptoms and signs consistent with serotonin syndrome, the syndrome should of course be appropriately treated as discussed. I fully agree with the fine print at the bottom of the FDA advisory: “This information reflects FDA's preliminary analysis of data concerning this drug. FDA is considering, but has not reached a final conclusion about this information. FDA intends to update this sheet when additional information or analyses become available.”[1]
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