Research Summary: A narrative review of the importance of pharmacokinetics and drug–drug interactions of preventive therapies in migraine management

Summarized by Richard Kim, MD 

Headache®: The Journal of Head and Face Pain published “A narrative review of the importance of pharmacokinetics and drug–drug interactions of preventive therapies in migraine management.”

Migraine is a disabling neurological disorder requiring acute therapy for attacks, with many patients being a candidate for preventive treatment. Many patients with migraine also have comorbid conditions that need to be addressed, such as anxiety, depression, cardiovascular disease, asthma, sleep disorders, and other chronic pain conditions, which can make treatment challenging due to potential drug-drug interactions (DDIs). Many DDIs result from the coadministration of multiple drugs that undergo metabolism by the cytochrome P450 (CYP) enzymes. The authors reviewed the literature to identify potential DDIs of the most frequently used classes of migraine preventive medications with medications that may be used for comorbid conditions.

Study Results

• Beta-blockers
  • Propranolol, metoprolol, and timolol undergo hepatic metabolism and are more likely to interact with other drugs than atenolol and nadolol.
  • Propranolol interacts with antidiabetic agents, calcium channel blockers, cimetidine, digoxin, ergot alkaloids, NSAIDs, phenobarbital, hydrochlorothiazide, rifampin, rizatriptan, theophylline, verapamil and paroxetine.
• Antiepileptics
  • Divalproex sodium:
    • Inhibits CYP2C9 and can decrease the clearance of drugs metabolized by CYP29.
    • Its clearance is increased by enzyme-inducing medications, such as rifampin, ritonavir, carbamazepine, lamotrigine and phenobarbital.
    • Serum concentration is increased by aspirin, fluoxetine, felbamate, isoniazid and chlorpromazine.
  • Topiramate:
    • Is an inducer of CYP3A4 and inhibitor of CYP2C19 and may alter the metabolism of drugs that are substrates of these enzymes, such as amitriptyline, cilostazol and verapamil.
    • Decreases ethinyl estradiol levels. Dose adjustments at topiramate doses above 200 mg should be considered in patients using estrogen-containing contraceptives.
    • Decreases metformin clearance, leading to an increase in its maximum plasma concentration.
• Antidepressants
  • Amitriptyline:
    • Undergoes hepatic metabolism.
    • Metabolism is decreased by valproic acid, cimetidine, fluconazole, fluoxetine and fluvoxamine.
    • Can decrease metabolism and increase absorption of oral anticoagulants and warfarin, potentially increasing the risk of hemorrhage.
    • Metabolism is increased by carbamazepine.
    • Concomitant use of TCAs with SSRIs can be considered, but in patients with slow CYP2D6 metabolism, there can be an increased risk of tricyclic toxicity and anticholinergic side effects.
  • Monoamine oxidase inhibitors (MAOIs) combined with TCAs may cause serotonin syndrome.
  • Venlafaxine:
    • Also undergoes hepatic metabolism.
    • May interact with other drugs metabolized by the CYP2D6 enzyme and should not be administered with MAOIs.
• Calcium channel blockers (verapamil and amlodipine):
  • Undergo metabolism by CYP3A4.
  • Both modulate the activity of the P-glycoprotein transporter, which affects plasma levels of other common drugs, such as daunorubicin and digoxin.
  • Verapamil can increase the risk of severe cardiovascular depression when administered with beta-blockers.
  • Amlodipine similarly has an increased risk of DDIs when used with atenolol or metoprolol.
• Gepants:
  • Mainly metabolized by CYP3A4.
  • Ubrogepant and rimegepant are substrates of P-glycoprotein and BCRP; therefore, administration of P-glycoprotein or BCRP inhibitors (e.g., verapamil, itraconazole, novobiocin) may increase exposure of these gepants.
• CGRP monoclonal antibody therapies (eptinezumab, erenumab, fremanezumab, galcanezumab):
  • Metabolized by the reticuloendothelial system/mononuclear phagocyte system and are not metabolized by CYP450, so drug-monoclonal antibody interactions are not likely.

Implications for Primary Care Clinicians

• Due to potential DDIs, management of migraine with preventive treatments can be challenging, especially when comorbidities are present.
• Treating each comorbid condition independently (polytherapy) may lead to greater chances of potential DDIs. Treating multiple conditions with a single medication (monotherapy) may be more difficult to fine-tune dosage and administration frequency and could lead to suboptimal treatment.
• Most DDIs occur through alterations in CYP450 isoenzyme activity, although other mechanisms for DDIs exist.
• DDIs may become more significant in patients with altered metabolism, such as renal or hepatic impairment.
• Monoclonal antibodies are not metabolized by CYP enzymes. Therefore, DDIs are not a major concern and may be a good option when incorporating them into a polytherapy regimen.

This summary is part of the First Contact – Headache in Primary Care initiative, an American Headache Society program that provides educational resources to empower healthcare professionals and improve headache and migraine care. We encourage providers in all stages of their careers to visit our homepage to access educational tools to improve patient care.