Conflict of Interest: None
Concomitant Triptan and SSRI or SNRI Use: A Risk for Serotonin Syndrome
Version of Record online: 13 NOV 2007
Headache: The Journal of Head and Face Pain
Volume 48, Issue 1, pages 126–129, January 2008
How to Cite
Sclar, D. A., Robison, L. M. and Skaer, T. L. (2008), Concomitant Triptan and SSRI or SNRI Use: A Risk for Serotonin Syndrome. Headache: The Journal of Head and Face Pain, 48: 126–129. doi: 10.1111/j.1526-4610.2007.00964.x
- Issue online: 20 DEC 2007
- Version of Record online: 13 NOV 2007
- Accepted for publication July 26, 2007.
- drug–drug interaction;
- National Ambulatory Medical Care Survey;
- serotonin syndrome;
Objective.— To discern the prevalence of concomitant use of a triptan and a selective serotonin reuptake inhibitor (SSRI) or a selective serotonin/norepinephrine reuptake inhibitor (SNRI) in the USA.
Background.— In July, 2006, the US Food and Drug Administration warned patients and health-care professionals to be aware that use of a triptan in combination with an SSRI or an SNRI may result in a potentially life-threatening problem known as serotonin syndrome.
Methods.— We used weighted data from the US National Ambulatory Medical Care Survey for years 2003 and 2004 to derive national estimates of the number of office-based visits documenting concomitant use of a triptan and an SSRI or an SNRI.
Results.— During the time frame 2003-04, an annualized mean of 3,874,367 patients were prescribed a triptan, and 50,402,149 patients were prescribed an SSRI or an SNRI. An annualized mean of 694,276 patients were simultaneously prescribed or continued use of a triptan along with an SSRI or SNRI.
Conclusion.— Our study documents that 1.3% of patients prescribed a triptan or an SSRI or an SNRI were prescribed the potentially fatal combination. While this is a small fraction overall, the actual number of patients on a nationwide basis is significant (n = 694,276).
Food and Drug Administration
National Ambulatory Medical Care Survey
National Center for Health Statistics
serotonin/norepinephrine reuptake inhibitor
selective serotonin reuptake inhibitor
triptan 5-hydroxytryptamine receptor agonist
In July, 2006, the US Food and Drug Administration (FDA) warned patients and health-care professionals to be aware that use of a 5-hydroxytryptamine receptor agonist (triptan) in conjunction with an antidepressant, inclusive of a selective serotonin reuptake inhibitor (SSRI) or a selective serotonin/norepinephrine reuptake inhibitor (SNRI) may result in a potentially life-threatening problem known as serotonin syndrome.1,2 Coadministration of triptans and SSRIs or SNRIs has an additive effect on serotonin levels that can lead to serotonin syndrome. Symptoms may include restlessness, hallucinations, loss of coordination, tachycardia, rapid blood pressure changes, increased body temperature, overactive reflexes, nausea, vomiting, and diarrhea, and can range from mild to fatal.1,2
To date, there exists a paucity of data regarding the extent of concomitant use of these medications.3 The present study was designed to discern the nationwide prevalence of combined use of a triptan and an SSRI or an SNRI in the USA.
Data from the US National Ambulatory Medical Care Survey (NAMCS) for the years 2003 and 2004 were used for this analysis.4 The NAMCS is a national probability sample designed and conducted by the National Center for Health Statistics (NCHS) of the US Centers for Disease Control and Prevention. Data are collected by the US Bureau of the Census. The 3-stage probability sampling procedure, sampling variation, and estimation procedures for the NAMCS have been described in detail elsewhere.5 Briefly, the basic sampling unit is the office-based physician–patient encounter (office-based visit). The sampling frame for each year of the NAMCS is composed of physician names as documented in the files maintained by the American Medical Association and the American Osteopathic Association, and classified therein as being involved in “office-based, patient care.” Physicians who are federally employed, hospital-based, or principally engaged in teaching, research, or administration are excluded from the NAMCS, as are anesthesiologists, radiologists, and pathologists.
An initial probability sample is drawn from primary sampling units consisting of counties, groups of counties, county equivalents (ie, parishes or independent cities), or towns and townships. Second, a probability sample is drawn from practicing physicians from within each of these primary sampling units. Finally, a systematic sample of office-based visits to an individual physician during a randomly assigned 1-week reporting period is collected. The physician sample size for the time frame 2003 through 2004 was 1342 and 1269, respectively, with response rates of 66.9% and 64.7%, thereby yielding 25,288 and 25,286 completed patient records. In turn, these patient records were weighted by the NCHS based on the probability of selection, differences in response rates, and the physician specialty distribution so as to yield unbiased national estimates of office-based visits of approximately 906 million in 2003, and 910 million in 2004.
The NAMCS data collection form requested extensive information regarding patient characteristics, the specialty of the reporting physician, and prescribed pharmacotherapy. Up to 8 prescription medications were recorded for each year. Physicians were instructed to record the specific brand or generic name for all new and continued medications. Code numbers corresponding to each brand and generic name were assigned from the US National Drug Code Directory, as was the primary class of pharmacotherapy to which the medication entry belonged.6
Data from office-based visits documenting a prescription for, or continuation of a triptan (naratriptan, almotriptan malate, frovatriptan succinate, sumatriptan/sumatritan succinate, rizatriptan benzoate, eletriptan, zolmitriptan), an SSRI (fluoxetine, paroxetine, sertraline, citalopram, escitalopram, fluvoxamine), or an SNRI (duloxetine, venlafaxine, sibutramine) during 2003 or 2004, were extracted from the NAMCS. Sibutramine, a medication approved for weight loss but not depression, is an SNRI and is therefore included in this analysis. Utilizing the methodology previously employed to analyze NAMCS data,7,8 the 2 most recent survey years were collapsed into one time period, 2003-04, in order to enhance the sample size and stability of analyses. Estimates represent the annualized mean of the 2 survey years.
Data were analyzed using SAS® (Release 9.1.3, SAS Institute Inc., Cary, NC, USA). By applying the sampling weights, national estimates were derived for the annualized number of office-based visits documenting the prescribing of a triptan, the prescribing of an SSRI or an SNRI, and the combined prescribing of a triptan and an SSRI/SNRI.
During the time frame 2003-04, an annualized mean of 3,874,367 patients were prescribed a triptan, and 50,402,149 patients were prescribed an SSRI/SNRI. An annualized mean of 694,276 patients were simultaneously prescribed or continued use of a triptan along with an SSRI/SNRI (Table). The majority of these patients were female (84.1%), white (85.8%), and had a mean age of 45.1 years (±11.7). Nearly two-thirds (65.7%) of the patients were treated by a general or family practice physician.
|Prescribed a triptan† and an SSRI‡ or SNRI§||694,276 (100.0)|
|General/family practice||456,160 (65.7)|
|Internal medicine||133,196 (19.2)|
International studies have estimated an average prevalence of migraine headaches of between 9-11%.9,10 Most recently, findings from the American Migraine Prevalence and Prevention Study reported the prevalence of migraine to be 17.1% in US women and 5.6% in men.11 Given the high prevalence of migraines, increasing use of triptans for their treatment, and the rapidly increasing magnitude of SSRI/SNRI utilization, there exists the potential for an increase in combination use of these medications, and an increase in the risk for serotonin syndrome.10-13
Our study documents that 1.3% of patients prescribed a triptan or an SSRI/SNRI were prescribed the potentially fatal combination. Fortunately, this is a small fraction overall; however, the actual number of patients on a nationwide basis is significant (n = 694,276).
Previous research by Tepper et al14 found that among patients who had filled 2 or more triptan prescriptions in a 6-month period, 21% were simultaneously prescribed an SSRI. By employing the methodology used by Tepper et al,14 and thus limiting our denominator to only patients prescribed a triptan, we found that 17.9% (694,276/3,874,367) of patients were simultaneously prescribed an SSRI/SNRI.
The actual number of patients experiencing characteristics of serotonin syndrome due to the coadministration of a triptan and an SSRI/SNRI is unknown. Moreover, reports of serotonin syndrome are rare.1,2 This may be a result of practitioners being unaware of serotonin syndrome.15 In 2006, the FDA based its warning on 27 reported cases involving patients prescribed a triptan and an SSRI/SNRI. Although we were able to quantify the extent of concomitant use of a triptan and an SSRI/SNRI on a nationwide basis, limitations inherent to the NAMCS did not allow for the identification of acute adverse reactions, including characteristics of serotonin syndrome.
Based on the available empirical evidence, we suggest that physicians avoid prescribing this combination of medications if possible, and closely monitor patients who must utilize this combination for signs and symptoms of serotonin syndrome.1,2 Further research, designed to quantify the number and severity of cases of serotonin syndrome due to use of a triptan and an SSRI/SNRI, is warranted.
Acknowledgment: This study was supported by the Pharmacoeconomics and Pharmacoepidemiology Research Unit, College of Pharmacy, Washington State University.
- 1FDA Public Health Advisory. Available at: http://www.fda/gov/cder/drug/advisory/SSRI_SS200607.htm. Accessed March 26, 2007.
- 2FDA Alert. Available at: http://www.fda.gov/cder/drug/InfoSheets/HCP/triptansHCP.htm. Accessed March 26, 2007.
- 4National Center for Health Statistics: National Ambulatory Medical Care Surveys, 2003-2004. Available at: http://www.cdc.gov/nchs/about/major/ahcd/ahcd1.htm.
- 5Sampling design, sampling variance, and estimation procedures for the National Ambulatory Medical Care Survey. National Center for Health Statistics. Vital Health Stat 2. 1988;108:1-39.,
- 6Food and Drug Administration. National Drug Code Directory. Washington, DC: Public Health Service; 1995.