Are triptans safe to use with Selective Serotonin Reuptake Inhibitors (SSRIs)?

From the Guidelines

Triptans can generally be used with SSRIs, but caution is warranted due to the small risk of serotonin syndrome. Most patients taking both medications together do not experience serious problems, and the combination is commonly prescribed in clinical practice 1. Specific triptans include sumatriptan (Imitrex), rizatriptan (Maxalt), zolmitriptan (Zomig), and others, while common SSRIs include fluoxetine (Prozac), sertraline (Zoloft), and escitalopram (Lexapro). When using both medications, patients should be aware of serotonin syndrome symptoms including confusion, rapid heart rate, high blood pressure, dilated pupils, muscle rigidity, and high fever. The theoretical risk occurs because both medication classes increase serotonin activity in the brain - SSRIs by blocking serotonin reuptake and triptans by activating certain serotonin receptors.

Some key points to consider when using triptans with SSRIs include:

• The risk of serotonin syndrome with combining triptans and SSRIs or SNRIs is low, but it is still a concern 1
• Patients should be aware of the symptoms of serotonin syndrome and seek medical attention immediately if they experience any of them
• Healthcare providers should evaluate individual risk factors and start with a lower triptan dose when combining with an SSRI, monitoring for any adverse effects
• The combination of triptans and SSRIs is commonly prescribed in clinical practice, and most patients do not experience serious problems 1

It's also important to note that the American College of Physicians recommends considering the use of triptans, including sumatriptan, rizatriptan, and zolmitriptan, for the treatment of acute episodic migraine headache in outpatient settings 1. However, the primary concern is the potential risk of serotonin syndrome when combining triptans with SSRIs, and this should be carefully evaluated and monitored by healthcare providers.

From the FDA Drug Label

Cases of serotonin syndrome have been reported during co-administration of triptans and SSRIs, SNRIs, TCAs, and MAO inhibitors [see Warnings and Precautions (5.7)]. There have been rare postmarketing reports of serotonin syndrome with use of an SSRI and a triptan If concomitant treatment of Prozac with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see Serotonin Syndrome under WARNINGS)

The use of triptans with SSRIs is not entirely safe due to the risk of serotonin syndrome. Although it is not contraindicated, caution is advised when co-administering these medications, particularly during treatment initiation and dose increases. Careful observation of the patient is recommended 2, 3. Key considerations include:

• Monitoring for signs of serotonin syndrome
• Careful dose titration
• Close observation during treatment initiation and dose increases

From the Research

Safety of Triptans with SSRIs

The safety of using triptans with selective serotonin reuptake inhibitors (SSRIs) has been a topic of concern due to the potential risk of serotonin syndrome.

• The US Food and Drug Administration (FDA) issued an advisory warning in 2006 about the risk of serotonin syndrome with concomitant use of triptans and SSRIs or selective norepinephrine reuptake inhibitors (SNRIs) 4.
• However, a study published in 2018 found that the risk of serotonin syndrome associated with concomitant use of triptans and SSRIs or SNRIs was low, with an incidence rate of 0.6 cases per 10,000 person-years of exposure 5.
• Another study published in 2003 noted that serotonin syndrome has been a concern with triptan use, but reports are sporadic and not clearly causative 6.
• A review published in 2010 concluded that there is neither significant clinical evidence nor theoretical reason to entertain speculation about serious serotonin syndrome from triptans and SSRIs 7.

Incidence of Serotonin Syndrome

• A study published in 2018 found that out of 47,968 unique patients prescribed triptans, 19,017 were coprescribed triptans and antidepressants, and only 2 patients were classified as having definite serotonin syndrome 5.
• The same study found that the proportion of patients with triptan prescriptions who were coprescribed an SSRI or SNRI antidepressant was relatively stable during the study period, ranging from 21% to 29% 5.
• Another study published in 2018 found that the co-prescribing of opioids with triptans or serotonergic antidepressants was common in US office-based physician visits, with 17.7 million visits resulting in the prescribing of ≥1 opioid medication with a triptan or an SSRI/SNRI 8.

Clinical Implications

• The American Headache Society Position Paper concluded that 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 4.
• However, the paper also noted that caution is certainly warranted and clinicians should be vigilant to serotonin toxicity symptoms and signs to ensure prompt treatment 4.
• Health care providers should report potential cases to MedWatch and consider submitting them for publication 4.