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

Clinical Implications

Despite the availability of preventive therapies for migraine, clinical management of patients with migraine is challenging when comorbidities are present. Two general approaches to treatment are treating each condition independently (polytherapy) or treating multiple conditions with a single medication (monotherapy). In the case of polytherapy, adherence is known to decrease as medication schedules become more complex.[105] While monotherapy may have better adherence rates, it is more difficult for physicians to fine-tune dosage and administration frequency than can be done with polytherapy and may not be the optimal treatment.[6]

When treating patients with migraine and comorbid conditions using polytherapy, the pharmacokinetic and pharmacodynamic properties of each drug must be considered. Changes in binding kinetics or rate of elimination with the introduction of additional medications may require dose adjustments and careful clinical monitoring. For example, TCAs or neuroleptics may lower the seizure threshold by blocking the GABA receptor and should be used with caution in patients with migraine and epilepsy.[106] Furthermore, because preventive therapies are often used in tandem with acute therapies for migraine, it is especially important to consider possible DDIs when both types of therapies are prescribed simultaneously (Table 3).

Physicians should be aware of elimination pathways of drugs used for migraine prevention and possible competitive metabolic mechanisms to optimize patient care. While there are many distinct pathways and mechanisms in which DDIs can occur, most occur through alterations in CYP450 isoenzyme activity. The combination of two drugs that are substrates of, inhibit, or induce the same CYP450 isoenzyme can alter the pharmacokinetics of one or both medications, resulting in altered plasma concentrations and potential toxicity. For example, propranolol should be used with caution in patients with migraine who take cimetidine for stomach ulcers, because cimetidine reduces oxidative drug metabolism by binding to CYP450, leading to decreased propranolol metabolism and reduced systemic clearance.[107] In addition, the propranolol–cimetidine combination has been reported to cause bradycardia.[107]

Many DDIs can be predicted based on drug metabolism and CYP isoenzyme type, and not all DDIs are clinically significant. DDIs may become significant in patients with altered metabolism, such as patients with renal or hepatic impairment. Therapeutic monoclonal antibodies are not metabolized via CYP enzymes, and DDIs are not a major concern when incorporating monoclonal antibodies into a polytherapy regimen.

The ability to predict DDIs based on drug metabolism is complicated by genetic polymorphism for metabolic enzymes. A number of drugs are known to be affected by CYP pharmacogenetics, including propranolol and TCAs. The metabolism of propranolol is affected by genetic polymorphism for CYP1A2 and CYP2D6.[55,108] For TCAs, patients who are CYP2D6 or CYP2C19 rapid metabolizers are at risk of treatment failure due to low plasma concentrations. Patients who are CYP2D6 or CYP2C19 poor metabolizers are at risk of AEs due to elevated plasma concentrations; dose adjustments or alternate therapies are recommended in these patients.[59]

The elimination pathway of a migraine preventive drug can affect patients in other ways as well. For example, topiramate has been shown to cause type 2 renal tubular acidosis, normal anion gap metabolic acidosis, and kidney stone formation. Therefore, physicians should observe for these side effects and advise patients to be vigilant about adequate hydration.[109]