An Exploratory Study Evaluating the 30 Medications Most Commonly Associated With Headaches in the FDA Adverse Event Reporting System

Brett Musialowicz BS; Brad Kamitaki MD; Pengfei Zhang MD


Headache. 2023;63(2):299-304. 

In This Article

Abstract and Introduction


Objective: This project seeks to identify the top 30 drugs most commonly associated with headaches in the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS), as well as their respective reporting odds ratios (RORs).

Background: Headache secondary to medication use is a well-known entity. However, which medications are most likely to cause headaches on a global scale is unknown.

Methods: We extracted case identifiers, adverse events, and attributed medications for entries in the FAERS database from July 1, 2018, to March 31, 2020. Entries were split into two datasets based on whether or they contained the word "headache(s)." Non-medication words were then excluded. The medications most commonly associated with headaches were then identified.

Results: We extracted 2,673,081 entries, of which 86,086 contain the word "headache(s)." The 30 most frequently appearing medications were then ranked by ROR values with associated 95% confidence intervals. The three medications with the greatest association with headaches were selexipag (ROR 16.7, 95% CI 15.8–17.7), epoprostenol (ROR 11.7, 95% CI 10.8–12.7), and glecaprevir (ROR 8.7, 95% CI 8.3–9.2). Immunosuppressants, antivirals, as well as pulmonary hypertension medication classes were most commonly associated with headache.

Conclusion: Our study offers a potential list of the medication classes commonly associated with iatrogenic headaches.


Introduction and Literature Review

Headache is a common unwanted medication side effect.[1–3] Previous research has identified multiple drug classes and medications associated with headache including anesthetic agents, anticonvulsants, antibiotics, antimalarials, antihistamines, antiparkinsonian agents, asthmatic agents, vasodilators, gastrointestinal agents, analgesics, hormonal therapies, immunomodulators, neuropsychiatric agents, and oncologic agents.[4] Several specific medication-related iatrogenic headache types have even made it into the International Classification of Headache Disorders (ICHD-3), specifically, nitric oxide donor-induced headaches (8.1.1), phosphodiesterase inhibitor-induced headache (8.1.2), and estrogen withdrawal headache (8.3.3).[5] Although associations between headaches and certain medications are frequently reported, large-scale studies addressing which classes of medications are most likely to cause headaches are lacking in the literature. Our project seeks to address this by evaluating the U. S. Food and Drug Administration Adverse Event Reporting System (FAERS), a drug safety surveillance database for reported adverse events (AEs) in real world settings.

Using this database, we asked the following: "Which medications are most frequently reported to cause headaches?" To answer this question, we determined which medications were most frequently associated with "headache" as an AE from the FAERS and calculated their corresponding reporting odds ratios (RORs) with 95% confidence intervals. (The ROR is a measure of disproportionality used in pharmacovigilance databases and represents the odds of an AE for a specific drug against the odds of the same AE occurring with all other drug reports. For example, a medication with an ROR value of 5 indicates that the medication is five times more likely to be associated with a particular AE when compared against all other medications included across the studied database). Ultimately, such a list of medications may be useful for prescribers when managing patients with iatrogenic headaches, as well as for exploring more definitive pharmacoepidemiologic studies in the future.