The fda alert on serotonin syndrome with use of triptans combined with selective serotonin reuptake inhibitors or selective serotoninnorepinephrine reuptake inhibitors: american headache society position paper

Published by Wiley Periodicals, Inc.
AHS Position Paper
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 Paperhead_16911089.1100
Randolph W. Evans, MD; Stewart J. Tepper, MD; Robert E. Shapiro, MD, PhD; Christina Sun-Edelstein, MD; Gretchen E. Tietjen, MD Background.—In 2006, a US Food and Drug Administration (FDA) alert warned about the potential life-threatening risk
of serotonin syndrome when triptans are used in combination with selective serotonin reuptake inhibitors (SSRIs) or selective
serotonin/norepinephrine reuptake inhibitors (SNRIs). This American Headache Society Position Paper further reviews the
available evidence of the potential risk of combining triptans with other serotonergic agents.

Methods.—Using the Sternbach Criteria or the Hunter Serotonin Toxicity Criteria, the 29 cases used as the basis for the
FDA alert were assessed in addition to a more recently published clinical review of 11 case reports of serotonin syndrome
resulting from monotherapy, and one report of combination serotonergic agents. Evidence was evaluated according to the
American Academy of Neurology Clinical Practice Guideline Process Manual.

Results.—Collectively, 40 case reports are available in the literature for subjects receiving either combination or mono-
therapy of serotonin agonists, all of which are limited to Class IV level of evidence. Of the 29 cases used as the basis for the FDA
alert, 10 cases actually met the Sternbach Criteria for diagnosing serotonin syndrome. No cases fulfilled the Hunter Criteria for
serotonin toxicity. One case published since the original report does not meet either criteria, and subsequently reported cases
involving triptan monotherapy include insufficient details to confirm a diagnosis of serotonin syndrome.

Recommendations.—With only Class IV evidence available in the literature and available through the FDA registration of
adverse events, inadequate data are available to determine the risk of serotonin syndrome with the addition of a triptan to
SSRIs/SNRIs or with triptan monotherapy. The currently available evidence does not support limiting the use of triptans with
SSRIs or SNRIs, or the use of triptan monotherapy, due to concerns for serotonin syndrome (Level U). However, given the
seriousness of serotonin syndrome, caution is certainly warranted and clinicians should be vigilant to serotonin toxicity
symptoms and signs to insure prompt treatment. Health care providers should report potential cases to MedWatch and consider
submitting them for publication.

From Department of Neurology, Baylor College of Medicine, Houston, TX, USA (R.W. Evans); Center for Headache and Pain,
Neurological Institute, Cleveland Clinic, Cleveland, OH, USA (S.J. Tepper); Department of Neurology, University of Vermont
College of Medicine, Burlington, VT, USA (R.E. Shapiro); Department of Clinical Neurosciences, St. Vincent’s Hospital, Mel-
bourne, Australia (C. Sun-Edelstein); Department of Neurology, University of Toledo College of Medicine, Toledo, OH, USA (G.E.

Address all correspondence to R.W. Evans, 1200 Binz #1370, Houston, TX 77004, USA.
Accepted for publication April 7, 2010.
Conflict of Interest: R. Evans: Speaker’s bureau for Accera, Astellas, GSK, Lilly, Merck, Pfizer, Teva, and Zogenix. S. Tepper:Grants/Research Support 2009-10: ATI, GSK, MAP, Merck; Consultant 2009: GSK, MAP, Merck, Nupathe, Zogenix; Speaker’sBureau 2009: GSK, Merck; Advisors Board, 2008: GSK, Merck, MAP, Nupathe, Zogenix; and owns no stock or patents in anycompany. R. Shapiro: Advisory Boards: Iroko, MAP, NuPathe, Pfizer, Zogenix. C. Sun-Edelstein has nothing to disclose. G. Tietjen:Advisory Board: MAP. Grants/Research: GSK. Owns stock in J&J.
Keys words: FDA alert, serotonin syndrome, triptan, selective serotonin reuptake inhibitor, selective serotonin/norepinephrine
reuptake inhibitor
On July 19, 2006, the United States Food and Based upon this alert, numerous patients and Drug Administration (FDA) issued an alert, “Poten- physicians have received warnings or recommenda- tially Life-Threatening Serotonin Syndrome with tions from pharmacists that at least one of the medi- Combined Use of SSRIs or SNRIs and Triptan Medi- cations (triptan or SSRI/SNRI) be discontinued.
cations.”1 (An update was issued on November 24, However, this recommendation is based on a limited 2006 adding sibutramine).2 The FDA reported that number of anecdotal clinical reports. Consequently, there is the potential for life-threatening serotonin using established criteria for diagnosing serotonin syndrome in patients taking 5-hydroxytryptamine syndrome (eg, Sternbach Criteria and Hunter Seroto- receptor agonists (triptans) and concomitantly taking nin Toxicity Criteria), an evidence-based review of selective serotonin reuptake inhibitors (SSRIs) or the published clinical reports available to date is selective serotonin/norepinephrine reuptake inhibi- clearly warranted and provided below.
As summarized in the FDA alert, the recommen- BACKGROUND
dation is based on 29 case reports of serotonin syn- Migraine Is Co-Morbid With Depression, Anxiety,
drome that occurred in patients concomitantly Panic, and Bipolar Disorder.—Migraine is a very
treated with triptans and SSRIs/SNRIs, with the common disease with a 1-year period prevalence in assumption of biological plausibility of such a reac- the USA among those age 12 years and older of tion in persons receiving 2 serotonergic medications.1 11.7% (17.1% in women and 5.6% in men).3 An addi- The FDA recommended that patients receiving a tional 4.5% have probable migraine and 2% have triptan and SSRI/SNRI medications be informed of chronic migraine.4 Epidemiological studies also show the possible risk of serotonin syndrome.1 The FDA that migraine is co-morbid (and/or coexisting) with now requires that this information be included as part various psychiatric disorders.5,6 Specifically, these of the prescribing information for triptans.
studies show that migraineurs are 2.2-4.0 times more Table 1.—Serotonergic Agents Affected by the FDA Alert
Triptans or a combination drug containing Sumavel DosePro®‡ (sumatriptan)TREXIMET®‡ (sumatriptan/naproxen sodium)Zomig® and Zomig ZMT® (zolmitriptan) †Added in updated 11/24/06 Alert.
‡New drugs since the issue of the Alert1 that carry the warning.
SNRI = serotonin/norepinephrine reuptake inhibitor; SSRI = selective serotonin reuptake inhibitor.
likely to have depression and are more likely to have severe. Autonomic hyperactivity occurs in about 50% generalized anxiety disorder (odds ratio [OR] 3.5- of patients and may include hyperthermia, diaphore- 5.3), panic disorder (OR 3.7), and bipolar disorder sis, sinus tachycardia, hypertension, hypotension, (OR 2.9-7.3). Given these statistics, it is not surprising flushing of the skin, diarrhea, mydriasis, or vomiting.
that some migraineurs who take triptans for acute The neuromuscular dysfunction can include akathi- migraine attacks also may be taking SSRIs and SNRIs sia, myoclonus, hyperreflexia, muscle rigidity, tremor, for their co-morbid psychiatric disorders.
nystagmus, and severe shivering.9,11,12 Symptoms and In an attempt to further assess the frequency of signs may range from diarrhea and tremor in mild patients who require treatment with triptans and cases to life-threatening complications such as sei- zures, coma, rhabdomyolysis, and disseminated intra- prescription information using a large national phar- macy database.7 The authors estimated that more than Sixty percent of patients with serotonin syn- 185,000 Americans were exposed to co-treatment with drome present within 6 hours of medication initia- a triptan and an SSRI for over a 1-month or greater tion, overdose, withdrawal, or change in dosage and period during 2000-2001.7 Based on this extrapolation, 74% present within 24 hours.13 As excess serotonin and assuming that the 2000-2001 data are fairly repre- levels can present with a spectrum of toxicity from sentative of the years 1998-2002, nearly 1 million rel- mild cases in which medication(s) can be continued evant patient-month exposures occurred with the with close observation, to severe and life-threatening combination of triptans and SSRIs during the period cases requiring cessation of the medication(s), of the 29 reported FDA cases. Sclar and colleagues8 depending upon the intrasynaptic concentration, further estimated that, during 2003-2004, an annual- some authors prefer the term “serotonin toxicity” to ized mean of 694,276 patients were simultaneously prescribed or continued use of a triptan along with an The diagnosis of serotonin syndrome is based upon the history of medication use, the physical Defining and Recognizing Serotonin Syndrome.—
examination, and exclusion of other neurological Serotonin syndrome is an adverse drug reaction disorders such as meningoencephalitis, delirium resulting from increased serotonin levels, which tremens, heat stroke, neuroleptic malignant syn- stimulate central and peripheral postsynaptic seroto- drome, malignant hyperthermia, and poisoning from nin receptors, in particular serotonin 5-HT2A recep- anticholinergic drugs (summarized in Table 2). The tors. Prior to the FDA alert, selected medications diagnosis is suggested with a sensitivity of 84% and associated with serotonin syndrome or toxicity have specificity of 97% (as compared to the gold standard included SSRIs, SNRIs, monoamine oxidase inhibi- of diagnosis by a medical toxicologist in patients who tors, tricyclic antidepressants, opiate analgesics, overdosed on a serotonergic drug) by the Hunter weight-reduction agents, anti-emetics, drugs of abuse, Box 1.—Hunter Serotonin Toxicity Criteria14
and herbal products.9 As an example, the incidence ofserotonin syndrome among patients on monotherapy In the presence of a serotonergic agent and one with the SSRI, nefazodone, has been estimated to be 0.4 cases per 1000 patient-months of treatment.10 Serotonin syndrome presents with 1 or more • Inducible clonus and agitation or diaphoresis clinical features including a potential triad of mental • Ocular clonus and agitation or diaphoresis status changes, dysautonomia, and neuromuscular dysfunction.9,11,12 The mental status changes are diverse and may include anxiety, agitation, confusion, • Hypertonia and temperature >38°C and delirium and hallucinations, drowsiness, seizures, and coma. Severity of these symptoms may be mild to Conditions

The Hunter criteria have not been validated in • Treat autonomic dysfunction and/or hyperther- patients who develop serotonin toxicity on therapeu- tic doses of serotonergic agents (either single agentsor as a drug interaction). Other diagnostic criteria have been proposed that might better detect the full resolve within 24 hours for about 60% of patients, but range of mild to severe cases, but are not completely drugs with long durations of action or active metabo- A second validated set of diagnostic criteria is the There is discussion regarding the exact transition point between tolerable side effects of serotonergicadministration and a toxic serotonin syndromerequiring withdrawal of medication. Some patients Box 2.—Sternbach Criteria for Serotonin
with stable mild subacute or chronic symptoms fulfill- Syndrome17
ing criteria for serotonin syndrome (such as mildtremor and hyperreflexia) might safely continue the 1. Recent addition or increase in a known sero- 2. Absence of other possible etiologies (eg, DESCRIPTION OF THE ANALYTIC
infection, substance abuse, withdrawal, etc) 3. No recent addition or increase of a neuro- Society Clinical Action Team Chair, Gretchen E.
4. At least 3 of the following symptoms: Mental Tietjen, MD, the physicians participating in this project status changes (confusion, hypomania), agi- were selected based on their expertise in the field tation, myoclonus, hyperreflexia, diaphoresis, of migraine and headache management. All partici- shivering, tremor, diarrhea, incoordination, pants had previously published on serotonin syn- drome and toxicity. A PubMed search was performedfrom inception through March, 2010, using the recog-nized search terms triptans, serotonin syndrome, andserotonin toxicity. Supplemental literature search was Following an overdose of a serotonergic drug, the done by reviewing the cited publications from selected Sternbach Criteria suggest a serotonin syndrome relevant articles. The authors identified the selected diagnosis with a sensitivity of 75% and a specificity of publications and further extrapolated and interpreted 96%.14 Despite these validated criteria, serotonin relevant published data based upon serotonin toxicity syndrome often remains underdiagnosed – perhaps because of its variable clinical manifestations and ageneral lack of awareness of the syndrome among ANALYSIS OF EVIDENCE
Concomitant Administration of Triptans and
Management of serotonin toxicity varies depend- Serotonin Agonists.—The July 19, 2006 FDA alert
ing upon the severity of symptoms. Standard The FDA has reviewed 27 reports of serotoninsyndrome reported in association with concomi- • Remove or modify responsible medications tant 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 • Control agitation (if needed [eg, benzodiaz- previously used concomitant SSRIs or SNRIs and triptans without experiencing serotonin syn- drome. The reported signs and symptoms of sero- dents; 1 case alleges only bilateral retinal detach- ments and clearly does not represent serotonin included respiratory failure, coma, mania, hallu- syndrome; and 2 of the published cases (26 and 28) cinations, confusion, dizziness, hyperthermia, failed to include important information such as vital hypertension, sweating, trembling, weakness, and signs or detailed neurological exams so the Hunter ataxia. In 8 cases, recent dose increases or addi- criteria could not be applied. Table 3 provides a tion of another serotonergic drug to an SSRI/ limited overview of several cases and their documen- tation, which illustrates the format in which the cases were reviewed and the variability in case information median time to onset subsequent to the addition of another serotonergic drug or dose increase of a Of the 29 cases, 10 met the Sternbach Criteria, serotonergic drug was 1 day, with a range of 10 and none met the Hunter Criteria.20 Even among those cases meeting the Sternbach Criteria, some This report sparked a series of further inquires questions arise with several of the cases. The Stern- into the case reports and upon further review, it was bach Criteria require exclusion of other disorders, noted that specific information about the reported which was lacking in 6 of the 29 cases (21%). For cases was not available through standard published example, Case 1 appears to meet Sternbach Criteria, resources. Therefore, R. Evans requested that a com- but the physicians diagnosed conversion disorder, and plete report of the possible serotonin syndrome cases the noted serotonin syndrome symptoms occurred (plus 2 more than described in the original alert; later, when the patient was not actually taking n = 29) be made available for public review under the sumatriptan. Moreover, this patient also had symp- Freedom of Information Act. Of the cases, 8 were toms of hives and wheezing, which while not exclu- published in the medical literature, and the other 21 sionary criteria for making the diagnosis of serotonin cases were filed with the FDA through the MedWatch syndrome, also raise consideration of other diagnoses.
reporting system. No further description of the FDA’s Therefore, Case 1 was rated as not meeting either set analytical process, diagnostic criteria used, or how its conclusions were reached have been made public Case 24 met Sternbach Criteria, but the patient regarding the 21 cases used as the basis for the was noted to have had 2 prior similar episodes asso- ciated with the use of metoclopramide and naproxen Evaluation of 29 FDA Cases Used as the Basis for
for migraine. In addition, she was taking only the FDA Serotonin Syndrome Alert.—In response to
sumatriptan and metoclopramide but was not taking the request for information on these cases, a summary of the 29 cases was published elsewhere, including an Case 28 may very well be serotonin syndrome, overall rating of the quality of the cases based upon but based on the limited information provided, does the information provided.20 Additionally, these cases not meet established diagnostic criteria for serotonin were further analyzed to determine if they met the syndrome. Subsequent to the FDA alert, Bonetto and Sternbach and/or Hunter diagnostic criteria for sero- colleagues reported what they described as a case of serotonin syndrome in a patient on eletriptan and All of the cases reviewed were case reports and fluoxetine, but this case also met neither Sternbach therefore are considered Class-IV evidence, as estab- lished by the American Academy of Neurology Clini- Triptan Monotherapy and Serotonin Syndrome.—
In a letter to the editor, Soldin and Tonning reported Edition).21 The quality of the information substanti- that triptans alone can cause serotonin syndrome ating many of the FDA cases reports is incomplete or based upon 11 clinical cases found from their search anecdotal. Specifically, for 3 cases, pharmaceutical of the FDA’s Adverse Event Reporting System.24 The representatives submitted reports of putative inci- mean age of the patients was 39.9 years, with 3 Table 3.—Summary of Selected Cases Reported by FDA Alert1
Sternbach17 Criteria
Hunter14 Criteria
Physician told sales representative that a patient (unspecified gender and age) developed medically serious serotonin syndrome. No details provided. Medications continued andsymptoms resolved.
34 y woman. 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. Events were reported as resolved.
37 y woman. Patient took rizatriptan followed with symptoms of palpitation, tachycardia, tremor, “close syncope,” vomiting, diarrhea, and hyperthermia. Patient was not hospitalized.
Rizatriptan discontinued. Patient had received medications 48 y woman. 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 emergency room, pulse was 120 with normal blood pressure and temperature. She was anxious and easily excitable withweakness, incoordination, and hyperreflexia in all 4 limbs.
EKG and EEG were normal. Improvement in her mental status, speech, and motor control began within 3 hours ofsymptom onset and complete recovery within 24 hours.
Sertraline was discontinued. When sumatriptan was combinedwith nortriptyline, she had no similar events.
25 y woman with migraine and depression. Patient took zolmitriptan for the first time and was pain free in 1 h. The next afternoon, she had a migraine and took 1 zolmitriptan and 1 paroxetine together. During the night, she developeddiffuse sweating, hypertonia and myoclonus of the forelimbs,which resolved by morning. She discontinued indoramine buttook another tablet of paroxetine 2 d after the prior dose.
Patient was hospitalized after developing same symptoms andtachycardia, hyperreflexia, diarrhea, and agitation. All 65 y woman. Several hours after receiving sumatriptan suppository, she experienced tachycardia, agitation, hyperthermia, hypertension, and confusion. She was hospitalized and a diagnosis of serotonin syndrome was made.
She made a full recovery within 48 hours.
†Quality of evidence rating: ‡ = poor; § = fair; ¶ = good; †† = excellent.
d = day(s); mo = month(s); NS = not specified; pr = rectal suppository; sc = subcutaneous; SNRI = serotonin norepinephrine-reuptake inhibitor; SS = serotonin syndrome; SSRI = selective serotonin-reuptake inhibitor; tab = tablet; y = year(s).
patients specifically coded as serotonin syndrome and Hunter Criteria. In addition, the authors commented 8 coded with additional terms indicative of the triad that symptoms in some of these cases usually resolved of clinical features of the serotonin syndrome.
over several hours either with or without supportive These authors did not provide details of the cases, treatment such as intravenous diphenhydramine.
or an analysis of whether they met the Sternbach or Since diphenhydramine is commonly used to treat cholinergic and extrapyramidal toxicity, is not a stan- should submit the case to the FDA on-line through dard treatment for serotonin syndrome, and in fact MedWatch (, by fax, may actually exacerbate serotonin syndrome via inhi- by mail, or by telephone (1-800-FDA-1088), and also bition of serotonin reuptake, assignment of the diag- consider submitting the case for publication in nosis of serotonin syndrome in some of these cases is relevant medical journals. Post-marketing surveil- lance is certainly a challenge for all medications Full publication of the details of Soldin and Ton- and various suggestions have been made for ning’s cases would be of interest and potentially clari- fying.25 Their conclusions from these 11 case reports Given that patients now routinely receive warn- arise after over 10 million patients have used triptans ings from their pharmacists when filling prescriptions worldwide since the launch of the first triptan for SSRIs, SNRIs and/or triptans, it would be prudent (sumatriptan) in 1991.26 Moreover, a prospective to avoid undue alarm by specifically discussing sero- post-marketing safety study of the use of subcutane- tonin syndrome with patients when prescribing these ous sumatriptan for up to 1 year among 12,339 medications. Compliance may also be increased by migraineurs, including 1784 also taking SSRIs, found disclosing that an elevated risk of experiencing sero- tonin syndrome with triptans is currently unproven.
Pharmacological Plausibility of Triptan Involve-
ment in Inducing Serotonin Syndrome.—Based upon
Summary.—Insufficient data are available to deter-
their pharmacology, the involvement of triptans in mine the risk of serotonin syndrome with the addition contributing to a serotonin syndrome, either alone or of a triptan to SSRIs/SNRIs or with triptan mono- in combination with other medications, seems therapy. The currently available Class IV evidence implausible.7,29 Triptans are high-affinity agonists at does not support limiting the use of triptans with 5-HT1B/5-HT1D/5-HT1F subtype receptors with lower SSRIs or SNRIs, or the use of triptan monotherapy, affinity for 5-HT1A receptors. Available evidence sup- due to concerns for serotonin syndrome. (Class IV ports a model of serotonin syndrome due to activa- evidence is based on uncontrolled studies, case series, tion of 5-HT2A receptors, with some questionable involvement of 5-HT1A receptors.19,30 Sumatriptan Conclusion.—Level U.21 Data are inadequate or
and zolmitriptan acutely decrease 5-HT synthetic rate conflicting. Given current knowledge on the risks of in several brain regions via the activation of 5-HT1 combining triptans with SSRIs/SNRIs, increased risks Sumatriptan has been shown to inhibit release of Recommendation.—None. An evidence-based rec-
serotonin from dorsal raphe nucleus in rat brain ommendation cannot be made at this time.21 slices.32,33 Zolmitriptan may also activate prejunc-tional 5-HT1B/1D autoreceptors, thereby lowering DISCUSSION
central serotonin release.34 Collectively, these studies Given the seriousness of serotonin syndrome, do not support the assertion that triptans increase caution is certainly warranted; clinicians should be vigilant to its symptoms and signs to ensure prompttreatment when an appropriate diagnosis is made.
It is possible that additional definite cases of It is not clear at this time what role, if any, triptans serotonin syndrome may be reported by improving might play in contributing to serotonin syndrome awareness of the syndrome and these risks of these with or without SSRIs or SNRIs. Of the 29 cases potential drug interactions. If a health care provider obtained from the FDA, only 10 cases actually met has seen or sees a patient with serotonin syndrome the Sternbach Criteria for diagnosing serotonin syn- due to triptans alone or in combination with SSRIs drome, and none met the Hunter Criteria.20 One case or SNRIs meeting criteria for the syndrome, they published since the original alert met neither crite- ria.22 Putative cases of serotonin syndrome involving dures. Your reliance on any information provided by this triptan monotherapy include insufficient details to Journal is solely at your own risk. AHS, the editors and confirm the diagnosis.25 This review demonstrates that publisher disclaim all warranties and accept no liabilitywhatsoever in respect of any claim for damages arising from standardized criteria are warranted for evaluating serotonin syndrome in patients using triptan mono-therapy, or using triptans in combination with drugs AHS Policy on Competing Interests: The American Head- that increase cerebral serotonin. We suggest that ache Society is committed to producing independent, infor- newly published cases use both Sternbach and mative and accurate practice parameters. The AmericanHeadache Society has formulated a comprehensive Disclo- Hunter Criteria when documenting clinical reports sure statement to curtail the potential influence of any con- flicts of interest. This AHS Position Paper was developed The July 2006 FDA alert stated: “This informa- within strict adherence to that policy statement. Conflict of tion reflects FDA’s preliminary analysis of data con- interest forms were obtained from all authors. The Ameri- cerning this drug. FDA is considering, but has not can Headache Society limits the participation of authors reached a final conclusion about this information.
with substantial conflicts of interest. Furthermore, no com-mercial participation, or funding, is allowed within the FDA intends to update this sheet when additional preparation of any Practice Parameters. The AHS information or analyses become available.” We Policies and Procedures Regarding American Headache propose that our current analyses warrant such an Society® Disclosures of Financial Relationships and Com- update. We urge the FDA to assemble an impartial peting Interests with Industry and Others can be viewed at: advisory panel to review the available evidence and to consider whether the alert, and the resulting cau-tionary language in triptan prescribing information, REFERENCES
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