The Prevalence of Coprescribing an Opioid With Serotonergic Antidepressant to Treat Migraine

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Recent data shows how common combination coprescribing of opioids with a triptan or a serotonergic antidepressant was just 2 years prior to an FDA warning about the risk of serotonin syndrome from such coprescribing.

In 2016, the FDA released a safety communication that warned of the risk of serotonin syndrome from using opioids with 5-hydroxytryptamine receptor agonists (triptans) or serotonergic antidepressants. A recent study aimed to estimate the prevalence of coprescribing an opioid with a serotonergic antidepressant and/or triptan in US office-based physician visits made by all patients and those diagnosed with migraine.

The American Academy of Family Physicians and the American Headache Society have released guidelines that recommend against routine use of opiate-containing compounds for the treatment of acute migraine headache. “This recommendation is based on concerns about dependence and medication overuse headache," the authors explained.

The study, published in Drug, Healthcare and Patient Safety, collected data from the National Ambulatory Medical Care Survey for 2013 and 2014 and identified physician office visits that included the new or continued prescribing of 1 or more opioid medications with a triptan or a serotonergic antidepressant, such as selective serotonin reuptake inhibitors (SSRIs) or serotonin—norepinephrine reuptake inhibitors (SNRIs). The researchers also stratified the coprescribed opioids by agent in order to determine the proportion of coprescriptions with opioids that are posing a greater risk of serotonergic agonism.


In 2013 to 2014 there was an annualized mean of 903.6 million office-based physician visits. Of those visits, 17.7 million resulted in the prescribing of 1 or more opioid medication with a triptan or an SSRI/SNRI. Additionally, opioid—SSRI/SNRI was coprescribed in 16,044,721 visits, while opioid–triptan was coprescribed in 1,622,827 visits.

The researchers found that one-fifth of opioid coprescribing was attributable to higher-risk opioids, specifically tramadol. Also, of the 7,672,193 visits for patients diagnosed with migraine, 16.3% of them included opioid prescribing while 2% included coprescribed opioid—triptan.

“The finding that tramadol predominated among the opioid combinations observed in the present study, despite its warning label at that time, suggests that prescribers may lack awareness of the risk of excess serotonin agonism or perceive this risk to be negligible in their clinical decision making,” the authors noted. “This finding is of particular interest, as tramadol has been reportedly linked to a greater number of cases of serotonin syndrome than have other opioid agents.”

The study emphasized how this data shows how common combination prescribing was just 2 years prior to the FDA warning about the risk of serotonin syndrome from opioid—SSRI/SNRI or opioid–triptan coprescribing. Furthermore, the researchers suggest that healthcare providers consider the risks associated with opioid use, especially when coprescribing.


Molina KC, Fairman KA, Sclar DA. Concomitant use of opioid medications with triptans or serotonergic antidepressants in US office-based physician visits. Drug Healthc Patient Saf. 2018;10:37-43. doi: 10.2147/DHPS.S151073.