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 Drug–Disease Considerations

When assessing preventive therapies for migraine, it is important to consider their interaction with drugs used to treat other conditions. For example, the use of beta-blockers has been associated with an increased risk of cardiovascular events and a higher incidence of severe hypoglycemia among patients with diabetes mellitus.[89] Furthermore, nonselective beta-blockers, such as nadolol or propranolol, may lead to a higher risk of severe symptom exacerbation among patients with chronic obstructive pulmonary disease.[90] Although a large meta-analysis did not find evidence to support an increased risk of depressive symptoms in patients receiving beta-blockers, some clinicians still remain concerned about this possibility.[91] There have also been reports of depression in elderly patients receiving lipophilic beta-blockers, which is an important consideration given the high comorbidity of migraine with depression.[92,93]

When using antiepileptic drugs for migraine, it is important to consider the patient's history with hypersensitivity to similar drugs, as some antiepileptic agents lead to high prevalence of rashes.[94]

In the case of calcium channel blockers, there are some known drug–disease interactions for verapamil that should be taken into account. Verapamil is known to cause constipation by delaying colon transit, and therefore should be used with caution in patients with constipation issues.[95] Furthermore, there have been reports of exacerbated symptoms in patients with myasthenia gravis that followed verapamil treatment.[96] Verapamil, in the high doses used to treat cluster headache, has also been associated with a risk of prolongation of the PR interval and atrioventricular block.[97] As such, when verapamil is administered with other PR-prolonging medications or to those with preexisting cardiac irregularities, ECG monitoring may be warranted.

For antidepressants, caution should be exercised when administering TCAs to patients with bipolar disorder, as they are associated with an increased risk of manic or hypomanic states.[98] In addition, venlafaxine and SSRIs are also linked to an increased incidence of mania or bipolar disorder among patients with unipolar depression.[99] Finally, TCAs and MAOIs may exacerbate psychosis symptoms in patients with unipolar disorder with psychotic features, which does not occur with SSRI monotherapy.[100] Besides the psychiatric risks, the cardiovascular risk of antidepressants should also be assessed. SSRIs are generally considered safe for cardiovascular complications, but patients with heart rate issues should nevertheless be closely monitored. On the other hand, SSNRIs and venlafaxine are highly associated with cardiovascular AEs.[101] TCAs are also known for wide cardiovascular effects that can occur in patients with or without a prior history of cardiovascular disease.[102]

Constipation-related complications have been reported with erenumab use, and patients using medication that decreases gastrointestinal motility may be at increased risk for severe constipation.[50] The incidence of constipation AEs following long-term open-label treatment with erenumab was low, and there were no cases of treatment discontinuation due to constipation;[103] however, patients using erenumab in a real-world setting should be closely monitored for severe constipation.[50] Similarly, new onset hypertension or worsening of preexisting hypertension has been reported with erenumab use, most typically with single blood pressure recordings within the first week of erenumab administration.[50] Therefore, blood pressure should be monitored in patients receiving erenumab[50] and considered for patients receiving other inhibitors of the CGRP pathway, despite lack of significant cardiovascular complications in short-term trials to date.[104]