Introduction

Almost all migraine episodes require acute therapy. Patients with high-frequency episodic migraine (EM) and with chronic migraine (CM) should receive preventative treatment [1]. The indications for migraine prevention are manifold. It can be necessary to start prophylaxis in subjects with only 1 attack/month, e.g., if the pain cannot be controlled with acute medication [1]. With limited progress in the last decades, migraine frequency management remains often problematic. Approximately half of the patients with an indication for preventive treatment do not receive therapy for several reasons [2]. Moreover, all preventive therapies on the market have not been developed primarily for migraine and were originally licensed for other purposes. Their efficacy and tolerability are often unsatisfactory [3, 4]. In fact, ~50% of CM patients treated with current available preventive medications discontinue therapy because of poor tolerability or safety issues within half a year, and in a substantial percentage, treatment response is insufficient [2, 5].

Migraine’s pathophysiology is complex and multifactorial. However, migraine is a CNS disorder, in which activation and sensitization of the trigeminovascular system plays a pivotal role [6]. Stimulation of the trigeminal nerve system leads to the release of neuropeptides, notably calcitonin gene-related peptide (CGRP) [7]. CGRP binds to the CGRP receptor on vascular smooth muscle cells and thereby causes vasodilatation. Neurons also express the receptor, which mediates the neurotransmitter function of the peptide [6, 8].

CGRP and Its Role in Migraine Pathophysiology

CGRP was discovered 35 years ago in rats as a potent endogenous vasodilator [8, 9]. In the peripheral nervous system, it is located in unmyelinated C fibers and small myelinated Aδ fibers, both responsible for pain transmission [10]. Centrally, it is widely distributed throughout several structures, including the hypothalamus, thalamus, and cerebellum [10]. CGRP exists in 2 isoforms, α and β. αCGRP results from alternative splicing of mRNA and proteolytic processing of the calcitonin gene [9]. It consists of 37 amino acids and is particularly present in the trigeminal system, where half of the neurons synthesize it [9]. βCGRP is transcribed from a different gene and is expressed primarily in the enteric nervous system [9]. Based on several lines of evidence which suggest CGRP as an important molecule in the pathogenesis of migraine [10,11,12,13,14,15,16,17,18,19,11]. All studies conducted so far in vitro and in vivo did not show any harmful vasoconstriction [9, 64]. However, the effects of anti-CGRP antibodies in patients suffering ischemic events remain largely unknown [11].

One final issue to discuss relates to the site of action of anti-CGRP antibodies. Antibodies are large molecules, with a molecular weight of ~150,000 Da. Therefore, they have only a minimal possibility (0.1–0.5%) to cross the blood brain barrier under physiological condition [9]. Even if a sporadic dysfunction exists, the amount of antibodies trespassing it would be too low to block CGRP effectively [9]. Consequently, antibodies are supposed to have a primary peripheral site of action, binding to the CGRP released at trigeminal nerve endings or its receptor in ganglion or dura mater. The efficacy of anti-CGRP antibodies supports the hypothesis that a peripheral component plays a pivotal role in migraine pathophysiology and migraine can be aborted by blocking peripheral mechanisms.

Conclusion

Phases I and II trials show us that mAbs, which block the CGRP pathway, are safe, tolerable, and effective treatment options. Each phase II study has produced positive efficacy results, and no safety issues have emerged. The positive results of large phase III trials in EM and CM for erenumab and fremanezumab confirm phase II data, and further long-term studies are under way to confirm their safety and efficacy profile. However, registries for use in the real world, e.g., for pregnancy, are needed. Anti-CGRP and anti-CGRP-receptor antibodies are the first effective treatment specifically developed for the prevention of migraine based on molecular pattern involved in disease pathogenesis. The efficacy of monoclonal antibodies provides further evidence for the importance of CGRP in migraine pathophysiology and the therapeutic value to antagonize its effect within the trigeminovascular system.