A critical review of the neurovascular nature of migraine and the main mechanisms of action of prophylactic antimigraine medications

ABSTRACT

Introduction

Migraine involves neurovascular, functional, and anatomical alterations. Migraineurs experience an intense unilateral and pulsatile headache frequently accompanied with vomiting, nausea, photophobia, etc. Although there is no ideal preventive medication, frequency in migraine days may be partially decreased by some prophylactics, including antihypertensives, antidepressants, antiepileptics, and CGRPergic inhibitors. However, the mechanisms of action involved in antimigraine prophylaxis remain elusive.

Areas covered

This review recaps some of the main neurovascular phenomena related to migraine and currently available preventive medications. Moreover, it discusses the major mechanisms of action of the recommended prophylactic medications.

Expert opinion

In the last three years, migraine prophylaxis has evolved from nonspecific to specific antimigraine treatments. Overall, nonspecific treatments  mainly involve neural actions, whereas specific pharmacotherapy (represented by CGRP receptor antagonists and CGRPergic monoclonal antibodies) is predominantly mediated by neurovascular mechanisms that may include, among others: (i) reduction in the cortical spreading depression (CSD)–associated events; (ii) inhibition of pain sensitization; (iii) blockade of neurogenic inflammation; and/or (iv) increase in cranial vascular tone. Accordingly, the novel antimigraine prophylaxis promises to be more effective, devoid of significant adverse effects (unlike nonspecific treatments), and more beneficial for the quality of life of migraineurs.

KEYWORDS:

• Antimigraine prophylaxis
• migraine
• neurovascular axis
• propranolol

Article highlights

• Migraine is a complex neurovascular disorder that involves calcitonin gene-related peptide (CGRP) released from sensory perivascular nerves following activation of the trigeminovascular system.

• Current antimigraine pharmacotherapy can be divided into acute (abortive) and prophylactic (preventive) treatments.

• Furthermore, antimigraine drugs can be classified into specific and nonspecific. Specific drugs mainly block (directly or indirectly) the CGRPergic transmission at the peripheral and central levels, whereas nonspecific medications refer to molecules whose target was not directly related to antimigraine treatment.

• Although triptans (specific acute drugs) are the gold standard in antimigraine therapy, some patients with severe and/or high-frequency attacks require prophylactic (specific or nonspecific) treatment to reduce the frequency and severity of attacks.

• The nonspecific prophylactic treatments (i.e. some antiepileptics, antihypertensives [β-blockers], and antidepressants) mainly target the neuronal excitability of the central nervous system. However, they also seem to exert a minor indirect vascular action.

• In contrast, specific prophylactic treatments (i.e. the CGRP receptor antagonist atogepant and CGRPergic monoclonal antibodies) as well as botulinum toxin type A (injected pericranially) directly interfere with the CGRPergic transmission at the peripheral (neurovascular), rather than central, levels. In addition, some second generation (longer-acting) triptans (i.e. frovatriptan, naratriptan and zolmitriptan) have also shown efficacy in the short-term prophylactic treatment against menstrual migraine.

• In general, only the specific prophylactic treatments seem to interact with vascular function by: (i) blocking vascular CGRP receptors (e.g. atogepant and the mAb erenumab); (ii) scavenging CGRP (e.g. mAbs against CGRP including galcanezumab, fremanezumab, and eptinezumab); (iii) interfering with CGRP release (e.g. prejunctional trigeminal inhibition by the triptans); and/or (iv) producing cranial vasoconstriction (e.g. via 5-HT_1B receptors by the triptans). However, the novel prophylactic antimigraine treatments (atogepant and anti-CGRPergic mAbs) mainly involve the first two mechanisms. These novel treatments promise to be more effective and beneficial to the quality of life of migraine patients.

Acknowledgments

Figure 1 was drawn using biorender.com with license paid by the Autonomous University of Aguascalientes to BAMC.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or conflict with the subject matter or materials discussed in this manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was financially supported by: the ‘Fondo Sectorial de Investigación para la Educación’ (CONACyT, Grant No. A1-S-23631 to AGH); the SEP-Cinvestav Research Support Fund (Grant No. 50 to CMV) and the ‘Dirección General de Investigación y Posgrado’ (UAA, Grant No. PIFF21-1 to BAMC).