Migraine is currently ranked the sixth most disabling disorder in the world in terms of disability adjusted life years [
1], with ~ 1.04 billion migraine sufferers globally. Given the severe disabling nature of the condition [
2], the need for effective acute treatments is clear. Unfortunately, currently available therapies are often nonspecific, poorly tolerated, ineffective, or have cardiovascular contraindications that limit their utility. In fact, 50% of patients report dissatisfaction with current therapies in relation to pain recurrence and almost the same proportion is dissatisfied with the need for supplementary dosing leading to the majority (~80%) of patients considering alternate acute therapies [
3]. When we consider the growing concern of medication overuse headache [
2] which now ranks in the top 20 disabling disorders [
4] globally, the development of novel effective acute therapies is critical. This program of development is borne from an ever increasing understanding of migraine pathophysiology. Migraine is now considered a disorder of the nervous system which is extensively reviewed elsewhere [
5‐
7]. In brief, activation and sensitization of the trigeminovascular system in humans are known to be painful [
8,
9] and its stimulation was shown to result in increased levels of calcitonin gene-related peptide (CGRP), pituitary adenylate cyclase-activating peptide (PACAP), and substance P in the cranial circulation of cats and humans [
10‐
13]. A response was later partially confirmed during spontaneous migraines [
14]. The trigeminal afferents that arise in the trigeminal ganglion synapse peripherally on the pain sensing intra- and extracranial structures including the dura mater [
9,
15,
16] and centrally on the trigeminal nucleus caudalis (TNC) and its cervical counterparts (C1–2). From here, second-order ascending projections terminate in several medullary, brainstem [
17‐
24], hypothalamic [
25‐
30], and thalamic nuclei [
23,
29,
31‐
34]. The trigeminothalamic projections in turn converge on thalamocortical projections that distribute the craniovascular nociceptive signals to multiple cortical regions including the somatosensory, motor, auditory, and visual cortices [
35,
36]. Recent studies have highlighted that several of these CNS areas are abnormally active/functionally connected during the earliest attack phases, suggesting that this trigeminovascular activation occurs on a background of dysfunctional sensory integration [
7,
37,
38]. Initially, this approach of targeting neuropeptides that were upregulated following experimental trigeminovascular activation and further based on a developing theory of migraine as a disorder of neurogenic inflammation [
39] focussed on substance P. Despite initial demonstrations of the ability of substance P antagonists to block this neurogenic inflammation [
40], ultimately they failed to translate to the clinic [
41], as predicted by a lack of substance P increase in spontaneous attacks [
14].