Broad Range of Drug-Drug Interactions in Migraine Prevention and Treatment

Researchers conducted a narrative review of the pharmacokinetics of major classes of migraine preventives and the implications of drug-drug interactions in treatment.

A narrative review emphasized that drug-drug interactions (DDIs) should be taken into consideration when formulating a treatment plan for patients with migraine, according to findings published in Headache.

The beta-blockers propranolol and timolol have been approved by the Food and Drug Administration (FDA) for migraine prevention. Propranolol and timolol are metabolized by the liver and are likely to interact with other drugs such as antidiabetic agents, antiarrhythmics, neuroleptic medications, antiulcer medications, lipid-lowering agents, calcium channel blockers, nonsteroidal anti-inflammatory drugs (NSAIDs), ergot alkaloids, and rizatriptan, among others.

Clinicians should be mindful of the vast array of DDIs that are possible for patients taking beta-blockers, especially among patients with comorbid conditions. In addition, beta-blockers have been associated with increased risk for cardiovascular events, severe hypoglycemia among patients with diabetes, and depression among older individuals.

Two classes of antidepressants, tricyclic antidepressants and serotonin-norepinephrine reuptake inhibitors, have been approved for migraine prevention. Like beta-blockers these drugs undergo hepatic metabolism and can interact with antiarrhythmics, antiulcer medications, antihypertensives, thyroid medications, anticoagulants, antifungals, antipsychotics, and other antidepressants, among others.

Clinicians should be cautious in the cases of comorbid bipolar disorder or unipolar depression and avoid prescribing antidepressants as they are associated with increased risk for mania, hypomanic states, and psychotic symptoms.

The antiepileptic drug divalproex sodium has been approved for migraine prevention. It has been established to interact with antibiotics, enzyme-inducing medications, and other antiepileptic medications. These drugs should not be taken if the patient is considering pregnancy.

Recent studies into monoclonal antibodies have indicated these drugs may be effective for migraine prevention. In 2018, fremanezumab and galcanezumab were approved by the FDA and in 2020, eptinezumab was approved for use. These drugs are metabolized through the cytochrome P450 pathway and are likely to only interact with drugs affecting the same pathway. At this time no DDIs have been established.

The gepants, rimegepant and ubrogepant, have been approved by the FDA for acute migraine treatment. These drugs are also metabolized through the cytochrome P450 pathway and interact with antibiotics, antifungals, calcium channel blockers, antidepressants, antiarrhythmics, antiepileptic medications, and beta-blockers.

In general, although there are a wide range of available prevention options for patients with migraine, it remains challenging for clinicians to successfully manage migraine symptoms especially among patients with comorbid conditions. Even among patients without comorbidities, some preventive therapies interact with the pain-relieving drugs patients often take to manage their migraine symptoms.

The review authors concluded that clinicians should be aware of the metabolic mechanisms of prescribed medications in order to optimize patient care and avoid potentially harmful DDIs.

Disclosure: Multiple authors declared affiliations with the pharmaceutical industry. Please refer to the original article for a full list of disclosures.


Joshi S, Tepper SJ, Lucas S, Rasmussen S, Nelson R. A narrative review of the importance of pharmacokinetics and drug–drug interactions of preventive therapies in migraine management. Headache. 2021;61(6):838-853. doi:10.1111/head.14135