The Middle Meningeal Artery (MMA) occupies a pivotal role in the pathophysiology of migraine, functioning as a vascular and neuroimmune interface that precipitates the characteristic pulsatile pain. The inhibition of this pathophysiological cascade has been investigated as a therapeutic strategy. However, fewer than a dozen centers globally have disseminated procedural or mechanistic data. Given the nascency of this field and the imperative for standardization, the present review synthesizes mechanistic and clinical evidence underpinning intra-arterial pharmacological modulation of the MMA for migraine management. Methods: A focused narrative review was undertaken, drawing upon select but influential studies from pioneering research groups investigating intra-arterial interventions targeting the MMA. The extant literature was thematically categorized and organized according to the loci of cascade interruption and their corresponding clinical outcomes. Results: Since 2009, intra-arterial therapies for severe headache syndromes have evolved, initially utilizing nimodipine for vasospasm-related headaches, progressing to verapamil for reversible cerebral vasoconstriction, and more recently, lidocaine for refractory or status migrainosus, occasionally in conjunction with MMA embolization. Contemporary research uses language that conceptualizes migraine as an immunologically mediated neurovascular disorder, as opposed to a purely vascular or neuronal entity. Recent investigations have identified interleukins such as Interleukin-1β, Tumor Necrosis Factor-α, and Interleukin-6 as critical amplifiers of trigeminovascular activation. Purinergic signaling through the P2X3 receptor and the P2Y13 receptor, in conjunction with pituitary adenylate cyclase-activating polypeptide and vasoactive intestinal peptide pathways, has been implicated in the modulation of MMA excitability and neuropeptide release. The development of novel calcitonin gene-related peptide receptor antagonists, such as zavegepant, further substantiates the artery’s significance as a pharmacological target. Conclusions: These findings support a shift toward immune-modulating intra-arterial therapeutic strategies, with migraine interventions targeting cytokine and neuroimmune signaling within the MMA, rather than relying exclusively on vasodilatory mechanisms.

Background: The middle meningeal artery (MMA) plays a central role in migraine pathophysiology as a vascular and neuroimmune interface driving the throbbing pain. Inhibition of this cascade has been explored as a therapeutic approach, yet fewer than a dozen centers worldwide have published procedural or mechanistic data. Given the nascency of this field and the need for standardization, this review synthesizes the mechanistic and clinical evidence supporting intra-arterial pharmacologic modulation of the MMA for migraine treatment. Methods: A focused narrative review was conducted using limited but high-impact studies from pioneering groups exploring intra-arterial approaches to the MMA. Literature was arranged thematically and organized by the sites of cascade interruption and associated outcomes. Results: Since 2009, the use of intra-arterial therapies for severe headache syndromes has evolved from nimodipine for vasospasm-related headaches to verapamil for reversible cerebral vasoconstriction and, more recently, lidocaine for refractory or status migrainosus cases, sometimes with MMA embolization. Current research reframes migraines as an immunologically mediated neurovascular process, rather than purely a vascular or neuronal phenomenon. Recent studies have identified interleukins such as IL-1β, TNF-α, and IL-6 as key amplifiers of trigeminovascular activation, while emerging evidence implicates purinergic (P2X3, P2Y13) and PACAP/VIP pathways in modulating MMA excitability and neuropeptide release. Novel CGRP receptor antagonists, including zavegepant further reinforce the artery’s role as a therapeutic target. Conclusion: Our findings highlight a transition toward immune-modulating intra-arterial strategies, suggesting that future migraine therapies may increasingly focus on cytokine and neuroimmune signaling within the MMA rather than traditional vasodilatory control.