The FDA attached a warning of possible Serotonin Syndrome which has been in effect for about 30 years to the use of one of the 7 triptans for Migraine and concomitant use of an SSRI or SNRI drug.

Triptans are in 2021 still the best acute therapy drugs for migraine.  Migraine is present in 25% of women and 6% of men.  For women migraine is their most common medical problem and more prevalent than hypertension, diabetes, heart trouble, or arthritis.

Untreated with only over the counter drugs like supplements, NSAIDS such as Aleve or Advil, or drugs with caffeine such as Excedrin, migraine is a tremendous burden since it is disabling and one of the most frequent reasons for a visit to the Emergency Room.

Want to learn more about using Triptans for Migraine? Read my webpage article “How to Treat Migraine Headaches” on my website, www.doctordoctormigraine.com.

Many doctors and Migraine patients worry about the FDA Triptan/SSRI/SNRI warning. What to do?

Read my Mini Book on Migraine Here.

This is an article by Britt Talley Daniel MD, member of the American Academy of Neurology, the American Headache Society, migraine textbook author, podcaster, YouTube video producer, and blogger.

Serotonin syndrome.  The Triptan SSRI/SNRI warning is wrong.  Triptans involve blocking the release of a specific neurochemical—5HT-1D.  The 5HT receptor which is active in triptan/SSRI/SSNRI relationships is not a 1D receptor.  Therefore, triptans do not set off the serotonin syndrome.

SSRI refers to Selective Serotonin Receptor Inhibitor.  SNRI is covered here also and is a term that means Serotonin Norepinephrine Receptor Inhibitor.  Both of these types of medication are indicated for treating depression, anxiety, and panic disorder.  They have been included in the FDA Triptan warning.

What does the official note from the FDA on triptans say?

The FDA states on the PI, the product information sheet, for all triptans that there is a possible triptan/SSRI/SNRI conflict and the rare risk of development of serotonin syndrome in patients who take these drugs.

What have US migraine experts said about using triptans and SSRI and SNRI drugs?

In a recent review, most physician migraine experts did not recommend that triptans and SSRIs or SNRIs be discontinued unless symptoms arise.

What is Serotonin Syndrome?

The symptoms of serotonin syndrome are restlessness, hallucination, loss of coordination, tachycardia, changes in blood pressure, fever, nausea, vomiting, or diarrhea.  The risk is estimated to be less than 0.03% of patients and life-threatening events are less than 0.002%.

Who figured out the truth about using SSRI and SNRI drugs with triptans?

Dr. Randy Evans, a headache neurologist in Houston, was the man who investigated the problem and figured it out.  Dr. Randy Evans found that the FDA warning was wrong.

Triptans block the release of 5HT 1D receptors which are part of the migraine cycle, thus stopping the release of the inflammatory neurochemicals Neurokinin A, Substance P, and CGRP which cause the migraine headache.

Dr. Evans obtained information about the triptans utilizing the Freedom of Information Act and was able to find that the 5HT receptor active in triptan/SSRI/SNRI relationships was not a 1D receptor.

Because of this, there is little risk of triptans setting off the serotonin syndrome when given conjointly with SSRIs or SNRIs.

Dr. Evans and other writers wrote another article which questioned whether patients who on the basis of the FDA's warning actually had serotonin syndrome.

Has the FDA changed their report in the original triptan PI?

The FDA has never changed their original statement that there is a problem with the use of triptans causing serotonin syndrome.

Has this FDA warning been a problem in the practice of migraine in America?

Pharmacists filling prescriptions for patients taking triptans and SSRIs or SNRIs have to notify the treating doctor and this has been done millions of time across the United States.

Neurologists offices across America are frequently notified about possible triptan/SSRI/SNRI problems by their patients’ pharmacies.

This is a meaningless procedure.  Many patients with migraine have been cautiously put off by this FDA mistaken statement and have declined taking a triptan, the best drug for acute migraine treatment.  These people have suffered greatly.

If a patient asks me about it, I refer them to this webpage article and quote Dr. Evans' work, published in Headache by The American Headache Society. Dr. Evans article follows below:

Evans RW1, Tepper SJ, Shapiro RE, Sun-Edelstein C, Tietjen GE., Headache. 2010. Jun;50(6):1089-99.  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 paper.

Abstract

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 monotherapy 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.

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All the best.

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Britt Talley Daniel MD