The FDA Alert on Serotonin Syndrome With Combined Use of SSRIs or SNRIs and Triptans: An Analysis of the 29 Case Reports

Abstract

Background

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.

Methods

Following 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.

Results

Seven cases met the Sternbach criteria but did not meet the Hunter criteria. No cases met both criteria or just the Hunter criteria.

Conclusions

Triptans 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.

Introduction

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.[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

SSRIs and a Combination Drug Containing an SSRI	SNRIs	Triptans
Celexa (citalopram) Fluvoxamine Lexapro (escitalopram) Paxil (paroxetine) Prozac (fluoxetine) Symbyax (olanzapine/fluoxetine) Zoloft (sertraline)	Cymbalta (duloxetine) Effexor (venlafaxine) Meridia (sibutramine)*	Amerge (naratriptan) Axert (almotriptan) Frova (frovatriptan) Imitrex (sumatriptan) Maxalt and Maxalt MLT (rizatriptan) Relpax (eletriptan) Zomig and Zomig ZMG (zolmitriptan)

Taken directly from: 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 Life-threatening Serotonin Syndrome. July 19, 2006, updated November 24, 2006. Available at: http://www.fda.gov/cder/drug/advisory/SSRI_SS200607.htm Accessed August 29, 2007.

^*Sibutramine (Meridia), a drug approved for weight loss but not depression, is a SNRI and should therefore be used with caution with triptans and other serotonergic drugs.

Sibutramine label SSRIs = selective serotonin reuptake inhibitors; SNRIs = selective norepinephrine reuptake inhibitor

“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 Disorder

Migraine 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 Syndrome

Serotonin 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	Agitation

From Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med. 2005;35:1112–1120, with permission.

The 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-HT_2A 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]

Methods

In 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.

Results

In 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.	++ No No
2. Sumatriptan tab and sc fluoxetine lithium	39 y.o. woman on fluoxetine (Prozac; dose not specified) taking Imitrex tab and sc frequently. Physician-husband described patient as becoming “manic” (spending hours cleaning the car) and reported hallucinations. If not manic, she would have bouts of trembling, sweatiness, and weakness. Lithium did not help mania. Symptoms resolved off medications. Physician reported that the symptoms she suffered were similar to that of Imitrex with fenfluramine.	++ Yes No
3. Sumatriptan (unknown formulation) Unspecified SSRI	A nurse reported to a sales representative that a patient received Imitrex and an unspecified SSRI and developed SS. Age and sex not provided.	+ No No
4. Sumatriptan tab paroxetine	Physician told sales representative that a patient (unspecified sex and age) developed medically serious SS. No details provided. Imitrex and paroxetine (Paxil) continued. Symptoms resolved.	+ No No
5. sumatriptan tab venlafaxine fluoxetine buspirone	43 y.o. man reported that after increasing his venlafaxine (Effexor XR) dose to 300 mg daily, he began to experience dizziness and confusion until he reduced the dose to 150 mg daily. Taking hydrocodone with acetaminophen following knee surgery made him confused. He started retaking old prescriptions for buspirone (BuSpar) and Prozac. The patient stated he would like to receive a letter from Wyeth stating that side effects of Effexor and effects of interactions with other medications could have led to his “not being able to pull it together in court.”	+ No No
6. Sumatriptan tab fluoxetine	38 y.o. man with increase in slurred speech, diaphoresis, increased confusion, and worsening gait. Patient received dose of Imitrex while on Prozac. Possible SS.	+ Yes No
7. Zolmitriptan tab sertraline	51 y.o. man admitted with agitation, afebrile, tachycardic, leukocytosis, flushed, and diaphoretic. Patient was diagnosed as having SS as he was taking sertraline (50 mg daily) and recently restarted zolmitriptan (Zomig) (5 mg). These were both discontinued and patient's symptoms slowly began to subside.	++ No No
8. Naratriptan Methysergide Venlafaxine oxycodone tramadol	57 y.o. woman hospitalized with hallucinations, delirium, agitation, sweating, tremor, and shivering	++ Yes No
9. Naratriptan venlafaxine	Age unknown female on Effexor XR 150 mg. On naratriptan (Amerge) 1 mg half twice daily starting prior to menses. According to the patient, she experienced SS during the third day on Amerge when she developed agitation, tachycardia, hypertension, and ataxia. Treated in the ED with 1 mg of lorazepam. She discontinued the drugs. Two days later, she developed neutropenia, mononucleosis, joint pain, and stiffness. The physician stated, “Not clear if drug related or viral.”	++ No No
10. Rizatriptan sertraline	55 y.o. woman on sertraline (Zoloft) for migraine prevention. Took rizatriptan (Maxalt) for migraine with sensory aura but persistent headache. The next day, headache less intense. Took Zoloft, went back to bed, and was unable to speak. Paramedics found blood pressure of 216/160 mm Hg and her arms were moving uncontrollably. At the hospital, her temperature was 104°F ; she was diaphoretic, unconscious, and thrashing so much that she was paralyzed and intubated. A CT and MRI of the brain were normal. An EEG showed no seizure activity. A lumbar puncture produced normal CSF. West Nile and herpes cultures were negative. She was discharged at the end of the week in good health.	+++ Yes No
11. Rizatriptan paroxetine	20 y.o. woman on Maxalt10 mg 3–4 daily for 5 weeks for migraine. Started Paxil 10 mg daily 4 weeks after starting Maxalt. Six days later, increased Paxil to 20 mg daily. Later that day, took Maxalt. Five hours later, developed burning sensation over back and body, nausea, dry mouth, flushing, and generalized weakness. Increased deep tendon reflexes and bilateral ankle clonus on exam. Maxalt and Paxil were discontinued. The symptoms resolved over 24 hr.	+++ No No
12. Sumatriptan paroxetine	Patient (sex and age not specified) on Imitrex (formulation not provided) and developed bilateral retinal detachments	+ No No
13. Sumatriptan tab buspirone venlafaxine	43 y.o man on Imitrex 100 mg daily. Switched from Prozac 20 mg 3 times daily to Effexor XR 225 mg daily; after 1 week, dose increased to 300 mg daily. The next day, he reported lightheadedness, dizziness, lack of balance, flushing associated with an increase in blood pressure, a sense of invulnerability, an unusual dream, and mental confusion.	+ No No
14. Sumatriptan tab venlafaxine	65 y.o. woman on Effexor (dose unknown). At an unknown time after starting Imitrex 50 mg, the patient experienced chills, shivering, lethargy, and seizure and was hospitalized. Physician suspected SS.	+ No No
15. Sumatriptan sc paroxetine	65 y.o. woman's dose of paroxetine was increased from 40 mg to 60 mg daily. She was hospitalized with joint pain, swelling of the face, hands and feet, and difficulty breathing. She was given 2 sumatriptan sc injections for migraine. At some point that day, she developed lightheadedness, muscle pain, confusion, dizziness, difficult urination, sweating, feeling hot, and restlessness. The next day, the symptoms were resolved and she was discharged. Treatment with sumatriptan was continued and the action with paroxetine was unknown.	++ No No
16. Sumatriptan tab unspecified SSRI	Patient (sex and age not specified) on an unspecified SSRI started Imitrex 100 mg. After an unspecified period of time, the patient experienced SS according to a report by a physician via a sales representative.	+ No No
17. Sumatriptan tab fluoxetine	34 y.o. woman on fluoxetine 20 mg daily. Several hours following administration of sumatriptan 100 mg and a second dose of sumatriptan 50 mg and fluoxetine, she experienced tightness of the chest and palpitations. Treatment with sumatriptan and fluoxetine was continued. The events were reported as resolved.	++ No No
18. Rizatriptan citalopram	37 y.o. woman on citalopram 20 mg daily for 4 months. Took rizatriptan 10 mg. Had symptoms of palpitation, tachycardia, tremor, “close syncope,” vomiting, diarrhea, and hyperthermia. The patient was not hospitalized. Rizatriptan discontinued. Had been treated before without any adverse reactions.	++ Yes No
19. Sumatriptan sc paroxetine	33 y.o. woman began paroxetine 20 mg and injected sumatriptan 6 mg sc. She subsequently developed tremor, myoclonus, headache, and severe hypertension (but not hyperthermia) requiring 2 hospitalizations and prolonged treatment with lorazepam. The events resolved slowly over a 4-week period.	++ No No
20. Sumatriptan tab paroxetine	Patient (sex and age unspecified) on Imitrex tablets. At an unspecified time, the patient started Paxil at an unspecified dose. Afterward, he experienced SS. Both Paxil and Imitrex were continued. The symptoms resolved.	+ No No
21. Zolmitriptan (unknown formulation) venlafaxine meperidine	45 y.o. woman received Zomig daily (dose and formulation unknown) in addition to Effexor, clonazepam, and meperidine (Demerol). She experienced fever, headache, palpitation, neck tightness, photophobia, and SS. The patient recovered without sequelae.	+ No No
22. Sumatriptan sc sertraline lithium methysergide[18]	44 y.o. woman on the medications listed for 3 months, administered 6 mg of sumatriptan sc. One hour later, she developed weakness, severe incoordination, and abnormal jerking movements. On examination, she was dysarthric, excited, hypomanic, shivering, with dilated pupils with weakness of all limbs more pronounced on the right. She had frequent myoclonic jerking in all limbs with hemiballistic movements in the right upper extremity. She was diffusely hyperreflexic with plantar flexors. She had ataxia of limb and gait. Serum electrolytes, ECG, and MRI of the brain were normal. All symptoms resolved within 24 hr except for hyperreflexia, which resolved within 48 hr. She was discharged on methysergide and sertraline for migraine prevention. In the month following, she had 5 similar but less severe transient episodes in close temporal proximity to the symptomatic use of sumatriptan for migraine. When sertraline was discontinued, sumatriptan was effective without adverse events.	+++ Yes No
23. Sumatriptan sc Sertraline[18]	48 y.o. woman on sertraline 100 mg daily and propranolol for migraine and depression. Ten minutes after administering sumatriptan sc for the first time, she became anxious, agitated, disoriented, and diffusely weak. She could not walk without assistance. In the ED, pulse was 120 with normal blood pressure and temperature. She was anxious and easily excitable with weakness, incoordination, and hyperreflexia in all 4 limbs. ECG and EEG were normal. Improvement in her mental status, speech, and motor control began within 3 hr of symptom onset and complete recovery within 24 hr. Sertraline was discontinued. When sumatriptan was combined with nortriptyline, she had no similar events.	+++ Yes No
24. Sumatriptan sc Metoclopramide[18]	44 y.o. woman took ibuprofen and sumatriptan 6 mg sc for menstrual migraine. When the headache recurred the next day, she took sumatriptan 6 mg. Now 24 hours later, she had myoclonic jerking worse with movement with anxiety, hyperreflexia, and incoordination, which all resolved within 24 hr. An EEG after the myoclonus resolved was normal. She had 2 prior similar episodes associated with the use of metoclopramide and naproxen for migraine.	+++ No No
25. Zolmitriptan tab paroxetine[19]	25 y.o. woman with migraine and depression on paroxetine 2/day and indoramin 2/day. She took zolmitriptan 1 pill (dose not specified) for the first time and was pain-free in 1 hr. The next afternoon, she had a migraine and took 1 zolmitriptan and 1 paroxetine together. During the night, she developed diffuse sweating, hypertonia, and myoclonus of the forelimbs, which disappeared in the morning. She stopped indoramin but took another pill of paroxetine 2 days after the prior dose. She was hospitalized after she developed the same symptoms and tachycardia, hyperreflexia, diarrhea, and agitation. She returned to normal in 3 days.	+++ Yes No
26. Zolmitriptan tab Viloxazine[19]	43 y.o. woman on viloxazine [a bicyclic antidepressant] for depression. She had been taking zolmitriptan 1 per migraine without side effects for about 6 months. She then treated a migraine with 3 zolmitriptan (dose not specified) in 6 hr. She presented the following morning with asthenia, abdominal pain, nausea, diarrhea, and diffuse sweat alternating with diffuse heat. She had no myoclonus. All symptoms disappeared in 1 hr.	++ No No
27. Sumatriptan (formulation not specified) tramadol fluoxetine mirtazapine divalproex sodium[20]	43 y.o. woman on sumatriptan and tramadol for migraine and fluoxetine 60 mg/day and mirtazapine for major depression. She consumed a 1-week supply of these medications over 3 days and presented to the ED with sleeplessness, agitation, and rapid speech. She received activated charcoal and was treated for mania with divalproex sodium. By the next morning, she was confused, anxious, agitated, and flushed, with a heart rate of 124/minute. She had muscle stiffness, myoclonic jerking at rest, mydriasis, and a temperature of 37.8°C. She was treated with cyproheptadine 8 mg every 8 hr until her symptoms remitted 4 days later. When the racing thoughts recurred, the divalproex therapy was resumed and she was discharged.	+++ Yes No
sumatriptan nefazodone divalproex	One year later, she took the prescribed dose of divalproex but took a 2-week supply of nefazodone and sumatriptan in less than 1 week. In the ED, she was manic and fully oriented with marked stiffness, fever (37.38°C), tachycardia, flushing, and mydriasis.	+++ No No
28. Sumatriptan tab sertraline citalopram moclobemide[21]	33 y.o. woman took overdose of unspecified number of tablets of sumatriptan, sertraline, citalopram, moclobemide, thioridazine, and alcohol. When the ambulance arrived 1–2 hr after ingestion of the tablets, she had vomited and was fatigued but able to speak. On arrival at the hospital, she was unconscious with blood pressure 135/60 mm Hg with mydriasis. Over the next few hours, she developed muscle rigidity, trismus, fever of 42°C, and deterioration of breathing that resulted in mechanical ventilation. Blood samples indicated rhabdomyolysis and disseminated intravascular coagulation. She was treated with dantrolene, benzodiazepines, and cyproheptadine. She recovered after 9 days.	+++ No No
29. Sumatriptan suppository paroxetine[22]	65 y.o. woman on paroxetine 20 mg daily for 4 years. Several hours after receiving sumatriptan 25 mg suppository, she experienced tachycardia, agitation, hyperthermia, hypertension, and confusion. She was hospitalized and a diagnosis of SS was made. She made a full recovery within 48 hr.	+++ Yes No

^*The quality of the cases was ranked on the basis of the clinical information provided using the following scale: poor + ++ +++ ++++ excellent

ED = emergency department; SSRI = selective serotonin reuptake inhibitor; SNRI = serotonin norepinephrine reuptake inhibitor; tab = tablet; sc = subcutaneous; y.o.= year old; CT = computed tomographic scan; MRI = magnetic resonance imaging; EEG = electroencephalogram; CSF = cerebrospinal fluid; ECG = electrocardiogram

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.

Conclusion

The 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 5HT_1B/5HT_1D/5HT_1F subtype receptor agonists, whereas serotonin syndrome is believed to be due to activation of the 5-HT_1A and 5-HT_2A 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]