CGRP-induced migraine-like headache in persistent post-traumatic headache attributed to mild traumatic brain injury

In this open-label study of patients with persistent post-traumatic headache, 43 (72%) of 60 participants developed migraine-like headache during the 12-hour observational period after intravenous infusion of CGRP. This finding accords well with a recent randomized, double-blind, placebo-controlled trial in which the 21 (70%) of 30 participants with persistent post-traumatic headache developed migraine-like headache after CGRP infusion [11]. The similar induction rates of migraine-like headache also suggest that there are limited to no nocebo effects in provocation experiments with CGRP in patients with persistent post-traumatic headache. However, the median time to peak headache intensity was 40 min after the start of CGRP infusion in the present study, compared with 120 min in the aforementioned randomized, double-blind, placebo-controlled trial [11]. It remains unclear whether the more rapid time to peak headache intensity is, in part, attributable to nocebo effects, which could also the higher peak headache intensity in the present study, compared with placebo-controlled trials.

The site and mechanism of action by which CGRP induces migraine-like headache is incompletely delineated [17‐20], albeit multiple animal studies have established that CGRP can modulate nociceptive transmission in concussed rodents [21‐24]. A compelling theory has recently been posited to explain migraine pathogenesis and might also extend, in part, to the genesis of migraine-like headache in people with post-traumatic headache [17]. This theory suggests that CGRP binds to its G protein-coupled receptor on the vascular smooth muscle cell within the walls of intracranial arteries and then initiates downstream intracellular signaling resulting in the opening of specific potassium channels. The latter causes efflux of potassium and accompanying vasodilation [17, 25‐27]. This, in turn, is thought to provide chemical and mechanical stimuli sufficient to activate and sensitize perivascular nociceptors that project to first-order neurons in the trigeminal ganglion and upper cervical dorsal root ganglia [17]. From here, ascending trigeminal pain pathways relay the nociceptive information to cortical and subcortical regions that are responsible for the perception of migraine-like pain. In support of this theory, ample experimental data have shown that dilators of intracranial arteries (including specific potassium channel openers) can induce migraine attacks in people with migraine [26‐34]. However, further studies are needed to draw firm conclusions on the link between dilation of intracranial arteries and subsequent activation of perivascular nociceptors in the genesis of migraine-like headache.

Another possible explanation is that CGRP elicits migraine-like headache through direct binding to its receptors on primary afferents that originate from the trigeminal ganglion [35]. Increased attention is being paid to this line of reasoning because animal data have shown that fremanezumab – a monoclonal antibody (mAb) against CGRP – inhibits nociceptive transmission from meningeal nociceptors by decreasing their responsiveness [36]. The same lab also reported that injection of fluorescently-labeled fremanezumab in rodents can be detected in the meninges and its blood vessels as well as in the sensory and autonomic ganglia [37]. However, no fluorescently-labeled fremanezumab was observed within CNS structures, including the brain stem, thalamus, hypothalamus, and cortex. Although these findings do not exclude involvement of the intracranial vasculature in the genesis of migraine-like headache, it seems reasonable to further explore whether CGRP mediates its pro-nociceptive effects via direct receptor-binding on primary afferents of the trigeminal ganglion and (upper cervical dorsal root ganglia). It should also be noted that some intriguing evidence suggest that CGRP-mediated nociceptive signals might be mediated via Schwann cells [38].

The involvement of CGRP in the mechanisms underlying post-traumatic headache is a rapidly expanding field. Recent open-label trial data also suggest that erenumab – a mAb against the CGRP receptor – holds promise for the preventive treatment of persistent post-traumatic headache [39]. However, it is unlikely that CGRP is the only pathogenic driver of migraine-like headache in people afflicted by persistent post-traumatic headache. There is a clear need to study responses to other signaling molecules that are well-established modulators of nociceptive transmission in migraine, e.g. adrenomedullin, amylin, and pituitary adenylate cyclase-activating polypeptide [31, 32, 40]. Establishing the contribution of possible pathogenic drivers should facilitate the identification of novel drug targets which, in turn, can be applied for patient benefit. Concerted efforts are also needed to clarify the pathogenic drivers involved in disease persistence and chronification of post-traumatic headache [9, 41, 42]. The most obvious unanswered scientific question remains why post-traumatic headache remits in some people and persists in others. In addition, the phenotypic and pathophysiologic similarities between post-traumatic headache and migraine should capture more interest, as it remains unclear whether head trauma can evoke migraine in susceptible individuals and perhaps even chronic migraine in those who previously had episodic migraine. If the latter is proven to be true, head trauma would constitute a risk factor for migraine chronification.