Thursday, 11 August, 2022
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Top medications most often linked to headache – FDA database

Monoclonal antibodies, antivirals, immunomodulators and pulmonary arterial vasodilators top the list of drugs most frequently implicated as causes of headaches in a federal side effect database to which anyone can contribute, according to a study presented at the annual meeting of the American Headache Society.

“Surprising findings included the significant number of immunosuppressants and immunomodulators present in the data,” said study lead author Brett Musialowicz, a medical student at Robert Wood Johnson Medical School, New Brunswick, New Jersey.

“Additionally, our data provide evidence suggesting that several medications belonging to these drug classes were less likely to be associated with medication-induced headaches,” raising questions about the mechanism.

Medscape reports that the researchers launched their study to better understand headache as a side effect of medication use, Musialowicz said. They analysed entries from the US Food and Drug Administration's Adverse Event Reporting System from July 2018 to March 2020 and listed the top 30 most commonly reported medications linked to headaches and their reported odds ratio (ROR).

According to a website devoted to pharmacovigilance training, ROR refers to “the odds of a certain event occurring with your medicinal product, compared with the odds of the same event occurring with all other medicinal products in the database”.

After generic and brand-name data were consolidated, the drug most frequently linked to headaches was apremilast with 8,672 reports, followed by adalimumab (5,357), tofacitinib (4,276), fingolimod (4,123), and etanercept (4,111).

These drugs treat autoimmune disorders such as psoriasis, multiple sclerosis, and Crohn’s disease.

The other drugs in the top 15 ranked by frequency are treatments for hepatitis C (four drugs), pulmonary arterial hypertension (four drugs), arthritis (one drug), and asthma (one drug).

Of the top 30 drugs most frequently linked to headaches, the pulmonary hypertension drug epoprostenol – ranked 23rd – had the highest ROR at 12.8. The next highest were the hepatitis C drugs glecaprevir and pibrentasvir, tied at 10th in the frequency analysis and both with an ROR of 9.4.

“Pulmonary arterial dilators and vasodilators are believed to cause headaches by sensitising extracranial arteries. Clinical evidence suggests there is a vascular component to some types of headache,” Musialowicz said.

“Monoclonal antibodies are suggested to cause headache by means of an immune response. Several monoclonal antibodies are in trials targeting (the calcitonin gene-related peptide) receptor, which is believed to be involved in migraine headache. These trials will help further elucidate the mechanisms of headache and potential drugs to treat these conditions.”

Dr Stewart Tepper, a neurologist at Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, who’s familiar with the study findings, discounted the research in an interview. He said any member of the public can contribute to the federal database of adverse effects (drug manufacturers are required to contribute to it), and the data say nothing about denominators.

“It’s not a reasonable way to evaluate adverse effects, to just have everyone and their uncle saying: ‘This particular drug did this to me’. It’s not in any way useful,” he said. However, he added that the database sometimes “gives you a bit of a signal so you can go back and try to get scientifically collected data.”

Study co-author and neurologist Dr Pengfei (Phil) Zhang of Robert Wood Johnson Medical School noted that the FDA created the database “for a reason”. He also noted that the researchers used a statistical analysis technique – ROR – that was invented to adjust for weaknesses in databases.

MedicalBrief was unable to access the study details at the time of going to production.


USFDA database (Open access)


Medscape article – Top Medications Most Often Linked to Headache (Open access)


See more from MedicalBrief archives:


CHIPS: Widespread misdiagnosis and mismanagement of cluster headaches


Cannabis tied to rebound headaches in chronic migraine patients – Stanford study



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