Author: Nazia Karsan

The premonitory phase and its treatment – what have we learned?

The recognition that a migraine starts neurobiologically, 1-10 electrophysiologically, 11-14 and symptomatically, 15-22 hours to days before the headache, has provided insights into the mechanisms of attack initiation and migraine pathogenesis.23 Neurologist, Dr Nazia Karsan, who works as a postdoctoral researcher in the Headache Group at King’s College London, UK, discusses recent progress in mechanism research and opportunities for early attack treatment with the aim of preventing headache and reducing attack-related disability. 24

During the premonitory or prodrome phase of migraine, symptoms such as mood change, cognitive difficulty, neck stiffness, yawning, thirst, food cravings and sensory sensitivities (to light, sound, smell and movement), can present before headache, and in some patients reliably predict headache onset. 15,16  In such patients, intervening in the premonitory phase is a more attractive strategy for migraine therapy compared to waiting for the headache to start. Although headache escalation can be rapid, 25,26 and headache may arise from sleep, 27 making treatment during mild pain challenging in some patients, an early and targeted approach based on premonitory symptoms would at least provide an option for daytime attacks for a select group of patients, with hopefully favourable outcomes.

Historically, the cranial vasculature was thought to be the target of migraine abortive therapy, via agonism of the 5HT1 receptor, as triptans 28 and ergot alkaloids 29 were found to be specific and efficacious treatments for acute migraine, with mechanisms likely related to this receptor and its subtypes. However, vasoconstrictive side effects of these treatments can make their use in certain populations challenging. It has since become clear that vasodilatation may not play a significant part in migraine pathophysiology, 30 and certainly not in migraine pathogenesis, 31 and that vasoconstriction is not needed for an acute migraine effect. 32,33 Indeed, vasodilatation alone cannot plausibly account for the entire migraine clinical phenotype. 34

These findings, along with supportive functional imaging results during the premonitory or pre-ictal phase of the migraine attack, contribute to a theory of central neuronal attack initiation causing early dysfunction of sensory, limbic and homeostatic processing. 31 The hypothalamus has consistently emerged from functional imaging studies using different techniques, as one of the key brain areas of interest in the premonitory phase. 31

The hypothalamus is the brain’s physiological homeostasis centre, controlling arousal, feeding and autonomic activity, amongst other neuroendocrine functions. 35 Our imaging work in the Headache Group at King’s College Hospital in London has supported the involvement of the hypothalamus, thalamus, midbrain and basal ganglia regions, as well as sensory and limbic cortices, in the premonitory phase of migraine.1-3  The thalamus is the brain’s sensory relay centre, responsible for processing light, sound and touch amongst other senses, as well as controlling sleep, arousal and cognition, 36 and sending information to the appropriate cortical areas for interpretation.

Our research supports the theory of migraine attacks being initiated centrally, as we have shown that there are feasible neural substrates for premonitory symptoms within diencephalic, brainstem and cortical regions. These brain regions are engaged and lead to dysfunctional sensory, homeostatic and limbic processing prior to headache onset, using multiple neurotransmitters to exert their function. Some of these neurotransmitters are potential targets for migraine treatment. For example, the hypothalamus, substantia nigra and ventral tegmentum produce dopamine which is involved in mood and emotional regulation via striatal, thalamic and cortical projections from these regions. 37,38

Historical studies suggest a potential preventive effect of domperidone, a D2/D3 receptor antagonist, when administered in the premonitory phase of migraine. 39,40 Serotonin is also expressed in hypothalamus, thalamus and sensory cortices, amongst other brain areas, and 5HT1 receptor agonism with the triptans, 5HT1B/1D agonists ,41 and dihydroergotamine (DHE), the most currently used ergot alkaloid, 42-46 has demonstrated efficacy in the acute treatment of migraine. Naratriptan, a triptan with a half-life of around five to six hours, 47 has open label evidence of efficacy when administered during the premonitory phase of migraine. 48 Frovatriptan, the longest acting triptan with a half-life of 25 hours, 47 has not been studied as a treatment specifically administered during the premonitory phase, but has shown short-term preventive efficacy in menstrual and fasting-induced migraine. 49-51 A French study and follow up Swiss study 52 have suggested potential efficacy of nasal DHE when administered during the premonitory phase or aura, although nasal DHE is not widely available and its use is frequently complicated by variable efficacy, drug loss and adverse effects. 53

CGRP is widely expressed in brain areas implicated in migraine neurobiology and in the trigeminovascular system, including the brainstem and the hypothalamus, 54 and is released on activation of perivascular nerve fibres mediating vasodilatation amongst other functions. 55 Importantly, CGRP-targeting drugs seem to lack the adverse vasoconstrictive profile of the 5HT1 agonist migraine-specific drugs, at least with short term use. 56 There is evidence of increased blood pressure with longer-term use of the CGRP-targeted monoclonal antibodies in migraine prevention, but with readings still mostly within normal parameters, and with only 3.7% of those treated with erenumab requiring antihypertensive treatment at three months. 57 Recent evidence suggests that the small molecule CGRP receptor antagonist (gepant), ubrogepant, which is approved for acute treatment of migraine in the USA, can safely and effectively prevent migraine headache when administered during the premonitory phase in patients who are able to reliably predict headache. 58 For the first time in decades, this trial provides randomised controlled evidence for early and targeted therapy in the prevention of migraine using premonitory symptoms to predict the attack.

Exploiting this strategy for early intervention during the migraine attack will hopefully continue to yield more promising results, as further novel therapies enter our practice. In particular, rimegepant, another small molecule CGRP receptor antagonist which is approved for both acute and preventive treatment of migraine in some countries, may demonstrate interesting results as it exploits the bridge between acute and preventive therapy for migraine. Its impact on headache frequency and premonitory symptoms with preventive use is eagerly awaited. Similarly, the positive Phase 3 findings for intranasal zavegepant, 59 a nasally administered gepant with a 6.5 hour half-life and peak plasma concentration within around 30 minutes60, may also provide insights on possible prodromal effects. Lasmiditan, a specific 5HT1F receptor agonist without significant vascular effects, may hold promise for early attack intervention, given its likely central mechanism of action. 61,62 Treatments targeting the PACAP pathway are likely to be studied in phase 3 trials in the near future and may bring another targeted strategy to the table. 63

The neuroimaging research on the premonitory phase by our Headache Group continues to focus on better understanding of the mechanisms of migraine attack initiation, with the hope of identifying novel therapeutic substrates. We aim to develop understanding about the level of blood brain barrier penetration that is needed for central effects of migraine therapies, as well as about where such agents work within the brain and the trigeminovascular system. Whilst this is a large mission, it is imperative in our opinion to advancing targeted therapeutics in migraine, and to further exploring the opportunities for early attack intervention.

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