Migraine/Headache

Calcitonin gene-related peptide (CGRP) is probably the most potent vasodilator in cerebral circulation. Forty years after its discovery, the new CGRP-targeted therapy monoclonal antibodies, and the small molecule gepants, are now available for clinical practice. While randomized controlled trials and real-world experience consistently demonstrated the high efficacy and tolerability of monoclonal antibodies, limited evidence is available to characterize gepants fully. Depending on pharmacokinetics, these CGRP receptor antagonists can be used for acute (ubrogepant, rimegepant, and the not yet approved zavegepant) or preventive (atogepant and rimegepant) migraine treatment. Randomized placebo-controlled trials demonstrated gepants efficacy in treating acute attacks to obtain 2 h pain freedom in about 20% of patients and pain relief in about 60%, while up to 60% of treated patients with episodic migraine may experience a 50% reduction in monthly migraine days. The most common treatment-related emergent adverse events were gastrointestinal (nausea, constipation) for the acute or preventive use. No vascular or hepatic concerns have emerged so far. More studies are ongoing to investigate gepant tolerability and safety also if associated with monoclonal antibodies targeting CGRP and other therapeutic classes. Gepants are also under investigation to treat other painful and non-painful conditions. Real-life studies are necessary to confirm the trials' findings and investigate more practical clinical aspects.

Several preclinical and clinical lines of evidence suggest a role of neuroinflammation in migraine. Neuroimaging offers the possibility to investigate and localize neuroinflammation in vivo in patients with migraine, and to characterize specific inflammatory constituents, such as vascular permeability, and macrophage or microglia activity. Despite all imaging data accumulated on neuroinflammation across the past three decades, an overview of the imaging evidence of neuroinflammation in migraine is still missing.We conducted a systematic review in the Pubmed and Embase databases to evaluate existing imaging data on inflammation in migraine, and to identify gaps in the literature. We included 20 studies investigating migraine without aura (N = 4), migraine with aura (N = 8), both migraine with and without aura (N = 3), or hemiplegic migraine (N = 5).In migraine without aura, macrophage activation was not evident. In migraine with aura, imaging evidence suggested microglial and parameningeal inflammatory activity. Increased vascular permeability was mostly found in hemiplegic migraine, and was atypical in migraine with and without aura. Based on the weight of existing and emerging data, we show that most studies have concentrated on demonstrating increased vascular permeability as a marker of neuroinflammation, with tools that may not have been optimal. In the future, novel, more sensitive techniques, as well as imaging tracers delineating specific inflammatory pathways may further bridge the gap between preclinical and clinical findings.

In this review, we illustrate and discuss the recent findings regarding the epidemiology and pathophysiology of migraine triggers and their implications in clinical practice.

The pathophysiological understanding of cluster headache has evolved significantly over the past years. Although it is now well known that the trigeminovascular system, the parasympathetic system and the hypothalamus play important roles in its pathomechanism, we increasingly understand the functional role several neurotransmitters and hormones play in the communication between these structures.

The calcitonin gene-related peptide (CGRP) is implicated in the pathogenesis of several pain-related syndromes, including migraine. Targeting CGRP and its receptor by their antagonists and antibodies was a breakthrough in migraine therapy, but the need to improve efficacy and limit the side effects of these drugs justify further studies on the regulation of CGRP in migraine. The expression of the CGRP encoding gene, , is modulated by epigenetic modifications, including the DNA methylation, histone modification, and effects of micro RNAs (miRNAs), circular RNAs, and long-coding RNAs (lncRNAs). On the other hand, CGRP can change the epigenetic profile of neuronal and glial cells. The promoter of the gene has two CpG islands that may be specifically methylated in migraine patients. DNA methylation and lncRNAs were shown to play a role in the cell-specific alternative splicing of the primary transcript. CGRP may be involved in changes in neural cytoarchitecture that are controlled by histone deacetylase 6 (HDAC6) and can be related to migraine. Inhibition of HDAC6 results in reduced cortical-spreading depression and a blockade of the CGRP receptor. CGRP levels are associated with the expression of several miRNAs in plasma, making them useful peripheral markers of migraine. The fundamental role of CGRP in inflammatory pain transmission may be epigenetically regulated. In conclusion, epigenetic connections of CGRP should be further explored for efficient and safe antimigraine therapy.