Chronic Migraine Pathophysiology and Treatment: A Review of Current Perspectives

Abstract

Chronic migraine is a disabling neurological disorder that imposes a considerable burden on individual and socioeconomic outcomes. Chronic migraine is defined as headaches occurring on at least 15 days per month with at least eight of these fulfilling the criteria for migraine. Chronic migraine typically evolves from episodic migraine as a result of increasing attack frequency and/or several other risk factors that have been implicated with migraine chronification. Despite this evolution, chronic migraine likely develops into its own distinct clinical entity, with unique features and pathophysiology separating it from episodic migraine. Furthermore, chronic migraine is characterized with higher disability and incidence of comorbidities in comparison to episodic migraine. While existing migraine studies primarily focus on episodic migraine, less is known about chronic migraine pathophysiology. Mounting evidence on aberrant alterations suggest that pronounced functional and structural brain changes, central sensitization and neuroinflammation may underlie chronic migraine mechanisms. Current treatment options for chronic migraine include risk factor modification, acute and prophylactic therapies, evidence-based treatments such as onabotulinumtoxinA, topiramate and newly approved calcitonin gene-related peptide or receptor targeted monoclonal antibodies. Unfortunately, treatments are still predominantly ineffective in aborting migraine attacks and decreasing intensity and frequency, and poor adherence and compliance with preventative medications remains a significant challenge. Novel emerging chronic migraine treatments such as neuromodulation offer promising therapeutic approaches that warrant further investigation. The aim of this narrative review is to provide an update of current knowledge and perspectives regarding chronic migraine background, pathophysiology, current and emerging treatment options with the intention of facilitating future research into this debilitating and largely indeterminant disorder.

Central Sensitization in Migraine: A Narrative Review

“…The hypothalamus is a possible origin of migraine attacks as the trigeminovascular system, innervating the dura mater and of the major brain blood vessels, is activated during the headache phase. 34 , 47 Some studies have suggested that patients with migraine exhibit subtle differences in brain structures related to pain processing or in the trigeminovascular system during the interictal phase. 41 Calcitonin gene‐related peptide (CGRP), abundant in trigeminal ganglion neurons, has an important role in generating migraine headaches.…”

“…The hypothalamus is a possible origin of migraine attacks as the trigeminovascular system, innervating the dura mater and of the major brain blood vessels, is activated during the headache phase. 34,47 Some studies have suggested that patients with migraine exhibit subtle differences in brain structures related to pain processing or in the trigeminovascular https://doi.org/10.2147/JPR.S329280…”

Treatment of resistant chronic migraine with anti-CGRP monoclonal antibodies: a systematic review

“…Although the pathophysiology of migraine is still, at this date, not completely understood, several recent exhaustive reviews have gathered and explained the multifactorial causes of this neurologic condition [ 78 – 80 ]. Such causes include genetic, anatomical and physiological (neurovascular) alterations, being the bases for the numerous theories that try to explain the various phases of migraine [ 78 – 80 ].…”

“…Although the pathophysiology of migraine is still, at this date, not completely understood, several recent exhaustive reviews have gathered and explained the multifactorial causes of this neurologic condition [ 78 – 80 ]. Such causes include genetic, anatomical and physiological (neurovascular) alterations, being the bases for the numerous theories that try to explain the various phases of migraine [ 78 – 80 ]. In particular, the neurovascular theory correlates the dura mater vessels innervation by fibres from the trigeminal ganglion and the release of inflammatory neuropeptides, such as the calcitonin gene-related peptide (CGRP) with consequent vasodilation, inflammation and initiation of headache [ 10 ].…”

“…CGRP is peripherally released after activation of the trigeminovascular system by migraine triggers and acts also on afferent nerve fibres to exacerbate peripheral sensory inputs and sensitised central trigeminal pathways [ 22 ]. For more details on the role of CGRP and the trigeminovascular system and other aspects of migraine pathophysiology please see [ 78 , 80 , 86 ]. Small molecule CGRP receptor antagonists, denominated gepants (namely, ubrogepant, atogepant and rimegepant) had demonstrated clinical efficacy for the treatment of migraine [ 51 – 53 ], but its use has been discontinued after reports of serious liver toxicity associated with their frequent use [ 54 – 56 ].…”