A Narrative Review of the Importance of Pharmacokinetics and Drug–Drug Interactions of Preventive Therapies in Migraine Management

Shivang Joshi MD, MPH, RPh; Stewart J. Tepper MD; Sylvia Lucas MD, PhD; Soeren Rasmussen MD; Rob Nelson PharmD, BCPS


Headache. 2021;61(6):838-853. 

In This Article

Abstract and Introduction


Objective: To review the pharmacokinetics of major classes of migraine preventives and the clinical implications of drug–drug interactions (DDIs) with the use of these therapies in migraine management.

Background: Preventive treatments for migraine are recommended for a large proportion of patients with frequent migraine attacks. These patients often exhibit a number of comorbidities, which may lead to the introduction of multiple concomitant therapies. Potential DDIs must be considered when using polytherapy to avoid increased risk of adverse events (AEs) or inadequate treatment of comorbid conditions.

Methods: A literature search was performed to identify pharmacokinetic properties and potential DDIs of beta-blockers, antiepileptic drugs, antidepressants, calcium channel blockers, gepants, and monoclonal antibody therapies targeting the calcitonin gene-related peptide pathway with medications that may be used for comorbid conditions.

Results: Most DDIs occur through alterations in cytochrome P450 isoenzyme activity and may be complicated by genetic polymorphism for metabolic enzymes. Additionally, drug metabolism may be altered by grapefruit juice ingestion and smoking. The use of migraine preventive therapies may exacerbate symptoms of comorbid conditions or increase the risk of AEs associated with comorbid conditions as a result of DDIs.

Conclusions: DDIs are important to consider in patients with migraine who use multiple medications. The development of migraine-specific evidence-based preventive treatments allows for tailored clinical management that reduces the risk of DDIs and associated AEs in patients with comorbidities.


Migraine is a disabling disorder requiring treatment for acute attacks and may require preventive therapy.[1] The American Headache Society guidelines recommend preventive therapy in patients with frequent disabling migraine attacks (≥4 monthly headache days), contraindication to or overuse of acute therapies, or adverse events (AEs) in response to acute therapies.[2] Approximately 39% of patients with migraine are candidates for preventive treatment; however, treatment of these patients is challenged by comorbid conditions, for example, asthma, cardiovascular disease, anxiety, depression, arthritis, sleep disorders, and chronic pain, which may require the introduction of additional therapies.[3,4] Polytherapy may result in drug–drug interactions (DDIs) that can cause decreased effectiveness or ineffectiveness of prescribed drugs or adverse drug reactions, particularly when the prescribed drug may be an inducer or inhibitor of metabolic pathways of other drugs being taken.[5]

To avoid increased risk of AEs or inadequate treatment of comorbid conditions when using polytherapy, DDIs should be considered when developing therapeutic regimens for the treatment of migraine.[6] A risk of DDIs within migraine treatment exists even in the absence of comorbid conditions because patients using migraine preventive treatment may also require acute migraine medication for breakthrough headaches.[7] Many DDIs are the result of coadministration of multiple drugs that undergo oxidative metabolism by the cytochrome P450 (CYP) enzymes, particularly the CYP3A4, CYP2D6, CYP1A2, and CYP2C isoenzymes.[8] Clinically significant drug interactions can be predicted by the type of isoenzyme involved in metabolism. Thus, an understanding of the pharmacokinetic properties of migraine preventives is central to identifying potential interactions with drugs used for treatment of comorbid conditions. With the recent US Food and Drug Administration (FDA) approval of a new class of migraine preventive medications, the monoclonal antibody-based therapies, a review of the pharmacokinetic properties of migraine preventives and their potential drug interactions is timely. Here, we review the most frequently used pharmacologic classes of migraine preventives with established or probable efficacy in migraine prevention, including beta-blockers, antiepileptic drugs, antidepressants, calcium channel blockers, and monoclonal antibodies targeting the calcitonin gene-related peptide (CGRP) pathway. In the interim, rimegepant has been approved for migraine prevention. Finally, we discuss the clinical implications of DDIs with the use of these therapies in migraine management.