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

Migraine Preventive Therapy DDIs


Propranolol, metoprolol, and timolol undergo hepatic metabolism and are, therefore, more likely to have interactions with other drugs compared with atenolol and nadolol, which are primarily excreted through the kidneys because of their relatively high hydrophilicity. Propranolol interacts with antidiabetic agents, calcium channel blockers, cimetidine, digoxin, ergot alkaloids, nonsteroidal anti-inflammatory drugs (NSAIDs), phenobarbital, hydrochlorothiazide, rifampin, rizatriptan, theophylline, and verapamil.[74,75] Interactions with ergot alkaloids, NSAIDs, and rizatriptan are important to note, as these medications are often used in combination with migraine preventives to treat acute migraine attacks. Careful clinical monitoring is required when metoprolol is coadministered with the selective serotonin reuptake inhibitor (SSRI) paroxetine; modulation of CYP2D6 by both drugs may result in bradycardia, and dose adjustment may be necessary.[76]

Antiepileptic Drugs

Divalproex sodium inhibits CYP2C9 and can decrease the clearance of drugs metabolized by CYP2C9.[77] Clearance of divalproex sodium is increased by enzyme-inducing medications, including rifampin, ritonavir, carbamazepine, lamotrigine, phenobarbital, and phenytoin, and serum concentration is increased by aspirin, fluoxetine, felbamate, isoniazide, and chlorpromazine.[19]

Topiramate is unlikely to interact with highly protein-bound drugs and does not appear to alter the metabolism of most drugs. However, it is an inducer of CYP3A4 and inhibitor of CYP2C19 and may alter the metabolism of drugs that are substrates of these enzymes (e.g., amitriptyline, cilostazol, verapamil). Topiramate displaces valproic acid from its plasma protein-binding site; however, this interaction may not be clinically significant.[78] Coadministration of topiramate decreases ethinyl estradiol levels, and dose adjustments at topiramate doses above 200 mg should be considered in patients using estrogen-containing contraceptives.[79] Topiramate also interacts with metformin, which is commonly used for type 2 diabetes. This interaction leads to a decrease in metformin clearance and an increase in its maximum plasma concentration and should be taken into consideration when topiramate is considered as a migraine treatment for patients with diabetes.[80]


Amitriptyline and venlafaxine undergo hepatic metabolism and are subject to DDIs with drugs that share the same metabolic pathway(s). Concomitant use of TCAs with SSRIs can be considered, but may result in an increased risk of tricyclic toxicity and increased anticholinergic side effects in patients who have slow CYP2D6 metabolism and subsequent elimination of the TCA can be prolonged by the concomitant SSRI.[81] Monoamine oxidase inhibitors (MAOIs), also used off label for migraine prevention,[82] increase the serotonergic effect of TCAs and may cause serotonin syndrome; therefore, this combination is not advised.[81]

Amitriptyline metabolism is decreased with coadministration of valproic acid, cimetidine, fluconazole, fluoxetine, and fluvoxamine, leading to increased risk of toxicity of amitriptyline. Coadministration of oral anticoagulants and warfarin with amitriptyline can result in decreased metabolism and possible increased absorption of the anticoagulants, potentially leading to increased hemorrhagic risk.[74] Amitriptyline metabolism is increased with coadministration of carbamazepine, leading to decreased effectiveness of amitriptyline.[74] Venlafaxine may interact with other drugs using the CYP2D6 metabolic pathway and should not be administered with MAOIs.[60]

Calcium Channel Blockers

Verapamil and amlodipine undergo metabolism by CYP3A4; therefore, they are likely to have DDIs with other drugs that share the same pathway. Furthermore, both verapamil and amlodipine modulate the activity of the P-glycoprotein transporter, which affects plasma concentrations of other commonly used drugs, such as daunorubicin and digoxin.[83,84] Verapamil can cause an increased risk of severe cardiovascular depression when administered along with beta-blockers such as propranolol.[39] Similarly, amlodipine has an increased risk of DDIs when used with atenolol or metoprolol.[85]


Gepants are mainly metabolized by CYP3A4 and are subject to DDIs with drugs sharing the same pathway.[43,44,65] Furthermore, both ubrogepant and rimegepant are substrates of P-glycoprotein and BCRP; therefore, concomitant administration of P-glycoprotein/BCRP inhibitors (e.g., verapamil, itraconazole, novobiocin) may increase the exposure of these gepants.[43,44] Coadministration of ubrogepant, rimegepant, or atogepant with oral contraceptives containing progestin and ethinyl estradiol did not lead to any observed pharmacokinetic DDIs.[43,44,86] Some examples of known DDIs are verapamil, rifampin, and ketoconazole for ubrogepant[43] and itraconazole and rifampin for rimegepant.[44]

Monoclonal Antibody Therapies

Monoclonal antibodies are not metabolized by CYP450, so drug–monoclonal antibody interactions are not likely.[87] A study of erenumab interaction with combined oral contraceptive (ethinyl estradiol/norgestrel) showed that there was no clinically relevant DDI.[88] Antibody–antibody interactions are also unlikely since clearance of immunoglobulin G is dependent on saturation of FcRn, but saturation is not likely to occur at typical therapeutic doses of monoclonal antibody.[87] No DDI information is available for mAb use with gepants.