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REVIEW ARTICLE
Year : 2021  |  Volume : 69  |  Issue : 7  |  Page : 98--104

Emerging Targets for Migraine Treatment

David Moreno-Ajona1, María Dolores Villar-Martínez1, Peter James Goadsby2,  
1 Basic and Clinical Neurosciences, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom
2 NIHR-Wellcome Trust King's Clinical Research Facility/SLaM Biomedical Research Centre, King's College Hospital, London, United Kingdom; Department of Neurology, University of California, Los Angeles, Los Angeles CA USA

Correspondence Address:
Dr. Peter James Goadsby
Wellcome Foundation Building, King's College Hospital, London SE5 9PJ

Abstract

Background: While understanding the pathophysiology of migraine has led to CGRP-based treatments, other potential targets have also been implicated in migraine. Objectives: To catalog new promising targets for the treatment of migraine. Methods: We completed a literature review focusing on 5HT1F, PACAP, melatonin, and orexins. Results: The 5HT1F receptor agonist lasmiditan, following two positive randomized placebo-controlled trials, was FDA-approved for the acute treatment of migraine. PACAP-38 has shown analogous evidence to what was obtained for CGRP with its localization in key structures, provocation tests, and positive studies when antagonizing its receptor in animal models, although a PAC-1 receptor monoclonal antibody study was negative. Melatonin has undergone several randomized controlled trials showing a positive trend. Filorexant is the only dual orexin receptor antagonist, which was tested in humans with negative results. Conclusions: Further and ongoing studies will determine the utility of these new therapies with lasmiditan and melatonin having demonstrated efficacy for the treatment of migraine.



How to cite this article:
Moreno-Ajona D, Villar-Martínez MD, Goadsby PJ. Emerging Targets for Migraine Treatment.Neurol India 2021;69:98-104


How to cite this URL:
Moreno-Ajona D, Villar-Martínez MD, Goadsby PJ. Emerging Targets for Migraine Treatment. Neurol India [serial online] 2021 [cited 2021 Aug 2 ];69:98-104
Available from: https://www.neurologyindia.com/text.asp?2021/69/7/98/315989


Full Text



The clinical and economic burden of migraine is without a doubt.[1] Insufficient efficacy, tolerability issues and potential interactions or contraindications of the therapeutic arsenal available to date for both the acute and preventive treatment of migraine have driven the development of new medicines.[2] For this purpose, the understanding of migraine pathophysiology is essential.[3] Indeed, the paradigm of bench-to-bedside medicine, calcitonin gene-related peptide (CGRP), showed its importance in migraine pathophysiology[4] and, in a matter of years, its utility as a target for the treatment of migraine, both acutely[5] and as a preventive[6] therapy. The first preventive treatments specifically developed to treat migraine are currently available.[7],[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24] However, we are far from curing migraine. Different potential pathways implicated in migraine have already been targeted, or are potential, or promising targets that will be covered in this article.

 Methods



We performed several literature searches of the Pubmed and Cochrane databases in October 2020, utilizing the keywords: “5-HT1F receptor agonists”, “ditans”; “PACAP”, “PACAP antagonists”; “Hypothalamus AND migraine”, “Orexins AND migraine”, “Melatonin AND migraine”. Articles addressing the pathophysiology and translational research related to 5-HT1F receptors, the potential role of amylin, PACAP, NMDA, and glutamate, the hypothalamus and its neuropeptides in migraine as well as phase II to phase IIIb randomized-controlled trials of acute or preventive migraine treatments targeting the aforementioned were included. Case reports were not included. Our search only included publications in English. In total, 21 published studies were included. The reference lists of relevant and recent articles focusing on the latest acute and preventive migraine medications were also reviewed, and added if deemed appropriate.

 Results



Novel targets

Neuropeptides are small proteins produced by hormones that exert their action on receptors coupled to G-protein. These are responsible for the slow modulation of synaptic transmission.[4],[25],[26] Several of these neuropeptides have been implicated in migraine pathophysiology over time opening the doors to migraine acute and preventive medications.[3]

Serotonin 5-HT1F receptor agonists: Ditans

One of the first molecules implicated in migraine pathophysiology was serotonin, 5-hydroxytryptamine (5HT). Currently available acute medications, namely 5-HT1B and 5-HT1D receptor agonists or triptans, are a consequence of this discovery.[27],[28],[29],[30],[31] The action of triptans is believed to include inhibition of trigeminocervical complex (TCC) activation. Not only 5-HT1B but also 5-HT1F agonism can produce this effect.[32],[33],[34] In contrast with 5-HT1B, 5-HT1F receptor agonism leads to no vasoactive effects.[35] Interestingly, all triptans have a different degree of action on the 5-HT1F receptor.[36],[37]

Lasmiditan, is the only ditan approved by the FDA for the acute treatment of migraine.[38],[39] In line with the importance of CGRP, the release of this molecule has been shown to be reduced at different levels in the CNS including the TCC.[40] As a marker of efficacy, previously demonstrated with triptans,[41] lasmiditan leads to inhibition of the TCC nociceptive.[33]

Two phase III randomized placebo-controlled trials, the SAMURAI and SPARTAN studies, have been published with positive results.[42],[43] Interestingly, a sub-group analysis showed the efficacy of the drug regardless of previous response to triptans.[44] The GLADIATOR study, a phase III open-label study including patients from the previous studies, showed that both the 100-mg and 200-mg doses led to pain-freedom in 26.9% and 32.4% of the attacks, respectively.[45] Including all published studies, the most commonly reported side effect is dizziness, relative risk of which has been established at 5.81 (P < 0.00001). Fatigue, paresthesia, and somnolence have been reported to a lesser degree.[46] These associated side effects may be due to the fact that lasmiditan, as a lipophilic compound, crosses the blood-brain barrier.[38] Patients who suffer from dizziness or vertigo along with their headache attacks may be better candidates for other acute medications such as the currently available or the new CGRP receptor antagonists, gepants.[5]

PACAP

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide, which has similarities with the vasoactive intestinal peptide (VIP), both being part of the VIP/secretin/growth hormone-releasing hormone/glucagon neuropeptide superfamily.[26],[47],[48],[49] Two isoforms of the peptide have been described: PACAP-27 and PACAP-38,[50] with the latter having been more studied in the headache field.[51],[52] A G-protein coupled receptor, PAC1, has a higher affinity for both isoforms of PACAP, whereas the VPAC1 and VPAC2 receptors have similar affinities for PACAP and VIP.[53] Alike CGRP, PACAP may act as a vasodilator of almost all vasculatures.[26] PACAP has been localized in key structures for migraine such as the cerebral and dural vessels, the trigeminal nucleus caudalis, the thalamus, the hypothalamus, the TCC,[54],[55] and the trigeminal ganglion, where it has been co-localized with CGRP.[56] PACAP, like VIP, is believed to play an important role as a vasodilatory peptide in the parasympathetic reflex.[57] Indeed, PACAP has also been localized in the pterygopalatine ganglion.[58] Analogously to the experience with CGRP, injected PACAP-38 was shown capable of inducing migraine attacks in patients with migraine without aura,[59],[60] its levels were higher during the occurrence of a migraine attack as compared to an interictal phase[61] and levels of PACAP-38 dropped following the administration of sumatriptan for the treatment of an attack.[57] Recently, PACAP-27 has also been shown capable of provoking migraine-like attacks in migraineurs.[62] PACAP-27 has been shown to act as a modulator of nociceptive C-fibers, more potently than PACAP-38 and VIP.[63] A recent publication reported the efficacy of the Ab181, an anti-PAC1 antibody, in a rat model. The blockade of the PAC1 receptor was shown to inhibit the nociceptive activity in the TCC evoked by electrical stimulation of perivascular meningeal afferents.[64] This result contrasts with a phase II randomized placebo-controlled trial which tested a monoclonal antibody targeting PAC1 receptor (AMG 301).[65] Although these results have only been abstracted to date, they showed no difference between the drug and placebo. The lack of efficacy as compared to the rodent model could be explained by the lesser affinity to the PAC1 of the human antibody[64] and the fact that in humans VPAC1 and VPAC2 may play a more important role than in rodents. An ongoing trial with a neutralizing antibody that targets both peptides: PACAP-38 and PACAP-27, ALD1910,[66] will help us understand the potential role of PACAP as a migraine therapeutic target.

The hypothalamus

Migraine headaches are frequently accompanied by preceding or concomitant associated symptoms, including lethargy, cognitive impairment, or neck stiffness.[67] Canonical symptoms possibly denoting hypersensitization, established as necessary diagnostic criteria for migraine,[68] such as nausea,[69] photophobia or phonophobia, as well as other homeostatic alterations frequently displayed systemically, including yawning, food cravings, thirst, polyuria or sleep disturbances, have suggested a potential involvement of hypothalamic areas.[70],[71] Unsurprisingly, the distribution of axonal projections from the hypothalamus that descend uncrossed, encompass segments of the entire spinal cord.[72] The activation of hypothalamic areas was shown in neuroimaging studies during a spontaneous attack of migraine without aura, and furthermore, this activation was persistent after pain resolution following acute treatment with sumatriptan.[73] Further evidence implicating the hypothalamus in the pathophysiology of migraine,[3],[74] and satellite symptoms that orbit around the headache attack, particularly during the premonitory phase,[75] suggests several neuropeptides related to the hypothalamic axes that have been targeted for migraine treatment.

Melatonin

Among hypothalamic neuropeptides, melatonin, and its role in circadian rhythms deserves mention. Oral melatonin was approved by the National Institute of Health and Care Excellence (NICE) in the United Kingdom for the treatment of chronic insomnia.[76] Insomnia is a frequent migraine comorbidity, a debatable migraine trigger,[77] and migraine attacks are preceded by alterations in the sleep structure.[78] The secretion of melatonin is physiologically increased in dark hours, and inhibited by light.[79]

In the last decade, several randomized-controlled trials have explored the benefits of melatonin in patients with migraine, most of them episodic, and a recent meta-analysis supported its use in episodic migraine.[80],[81] Four randomized-controlled trials had positive results using the immediate-release formulation and only one used sustained-release melatonin, which was negative. In the latter, melatonin 2 mg was tested against placebo in a crossover trial that included 46 patients during eight weeks. Overall, the reduction in the number of attacks was around 2 per month.[82] Two studies in adults using 3 mg of melatonin immediate-release against well-established first-line migraine preventives had positive results. The first study compared the number of headache days in 196 patients randomized to amitriptyline 25 mg and placebo over a 12-weeks period. The mean (± standard deviation -SD-) baseline headache days were 7.3 ± 2.8 per month, which were reduced to 4.6 ± 2.3 and 5.0 ± 2.5 for melatonin and amitriptyline, respectively as compared to placebo, 6.2 ± 2.5 (P < 0.05). Additionally, the active groups experienced a reduction in the intake of acute medications, headache severity, and headache duration. The efficacy of amitriptyline was similar to that of melatonin, but the latter was better tolerated.[83] The second study compared the adjuvant efficacy of melatonin against valproate 200 mg in reducing the frequency of attacks in 105 patients for 8 weeks. All the participants had a baseline preventive treatment with nortriptyline (10-25 mg) and propranolol (20-40 mg). Starting from a mean baseline of 4.2 ± 1.2 migraine attacks per month, there was a comparable and statistically significant reduction in the melatonin and valproate arms (2.5 ± 1.3 and 2.3 ± 1.5, respectively), in contrast with the placebo group, 3.8 ± 1.1.[84]

In the pediatric population, a single-blinded study compared amitriptyline 1mg/Kg against immediate release melatonin 0.3 mg/Kg in 80 patients. The maximum dose was 6 mg. Mean age (±SD) was 10.44 ± 2.26 years, and they had a mean monthly headache frequency of 16.7 ± 6.68 in the melatonin group and 15.8 ± 8.49 in the amitriptyline group. They were followed up for 12 weeks. The study found superiority of amitriptyline in primary outcomes (attack frequency decreased to 9.03 ± 4.47 with amitriptyline vs 4.28 ± 2.68 with melatonin).[85] Currently, this is the only study supporting the benefit of melatonin in chronic migraineurs. After a pilot study,[86] a recent study compared high and low doses of melatonin as an acute medication in 84 pediatric migraine patients with a mean age of 12 ± 3.5 years.[87] Although the study had a more than 40% of drop-out rate in both treatment arms, higher doses of melatonin and a subsequent nap were independently associated with greater headache benefit. Mean headache days per month was 5.6 ± 3.8, and, using a visual analog scale for pain intensity at 2 hours, there was a change of -2.7 ± 2.1 cm in the high-dose group (<40 kg: 4 mg; ≥40 kg: 8 mg) vs. -2.3 ± 2.1 cm in the low-dose group (P = 0.581) (1 mg or 2 mg, respectively). After 2 hours, pain-freedom was achieved in 41% (7/17) vs. 27% (4/15) in the high-dose vs. low-dose groups (P = 0.415), and pain-relief rate in 94% (16/17) vs. 80% (12/15), (P = 0.482). Interestingly, the doses used in the pediatric population were higher than those of the adult studies.

Orexins

When discussing orexins (hypocretins) it is unavoidable to think about narcolepsy. Patients with narcolepsy exhibit a two to four-fold higher rate of migraine (according to the Kiel Headache questionnaire), in comparison with the general population,[88] and children with migraine showed a greater risk of developing narcolepsy in a prospective Taiwanese study.[89] Narcolepsy patients have a characteristic deficit in orexinergic neurons.[90],[91] These are a small group of neurons, whose soma is localized in the perifornical nucleus and the dorsolateral hypothalamic areas. Their axons were initially mapped in the late nineties, showing a wide distribution of their projections to other extra-hypothalamic brain territories[92] that were subsequently confirmed in the human anatomy. These areas included the medullary reticular formation, the raphe nuclei, and especially the locus coeruleus, and also long descending axonal projections containing orexin were detected to extracranial areas of the spinal cord, to sacral segments.[93] They have potential activity in physiological functions such as the sleep-waking cycle, neuroendocrine system, or the regulation of body temperature.[94],[95],[96]

There are two types of orexins: orexin-A (hypocretin 1) and orexin-B (hypocretin 2).[92],[97] They were initially postulated as neurons responsible for the regulation of feeding behavior.[97] The role of orexins in nociception was initially investigated in in-vivo studies of pain processing. Orexin-A was capable of increasing the latency response to nociceptive inputs,[98],[99] and this efficacy was similar to that of morphine,[99] also in animal models of neuropathic pain.[100] When infusing orexin receptor antagonists, the latency decreased, showing a nociceptive activity,[99] and animals lacking endogenous precursors had higher levels of hyperalgesia and similar basal nociceptive thresholds.[101] In migraine models, injections of Orexin-A in the posterior hypothalamus[102] or periaqueductal gray (PAG)[103] decreased the firing of nociceptive neurons in the trigeminal nucleus caudalis after electrical dural stimulation, and this inhibition was reverted by an orexin A antagonist.[104] Orexin-B, however, increased this pro-nociceptive activity.[102] Therefore, the orexinergic system was confirmed to have a key role in the modulation of nociceptive pathways and possibly in the maintenance of the nociceptive threshold.

In migraine models, the intravenous administration of a precursor of suvorexant, a dual orexin receptor antagonist (DORA), was able to reduce the neurogenically-induced vasodilation of the middle meningeal artery, inhibit the neuronal activity of second-order neurons arising from the TCC and increase the threshold to cortical spreading depression generated by the administration of KCl.[105] Additionally, it inhibited responses related to sensitization and allodynia, which is the experience of an otherwise not noxious stimulus as painful.[106] In patients with chronic migraine, CSF levels of orexin-A and corticotrophin releasing factor were found higher as compared to controls, and this difference was significant in patients with medication overuse headache,[107] suggesting a possible implication in the maintenance of chronic pain or in the rewarding system.

Unfortunately, there has been, hitherto, only one randomized, placebo-controlled trial that assessed the efficacy of the DORA, filorexant 3 mg dosed nightly, in 235 patients with episodic migraine. After 12 weeks, the filorexant group had a reduction of 1.7 mean monthly migraine days (MMD), in contrast with placebo, with a reduction of 1.3 mean monthly migraine days, although the difference was not statistically significant. The most commonly reported side effect was somnolence, higher in the active group.[108] Given the possible relationship with chronic modulation of pain, it seems reasonable to complete clinical trials with patients suffering from chronic migraine. The utilization of selective orexin receptor antagonists (SORA) in future clinical trials appears to be the next reasonable step.

 Discussion and Conclusions



Except for melatonin which, although scarce, has a larger body of evidence for migraine prevention,[82],[83],[84],[85],[86] and lasmiditan, which was recently FDA approved for acute migraine treatment,[39] the other targets discussed herein have not been followed by positive studies regarding migraine treatment.[65],[108] Nevertheless, there is ongoing clinical[66] and preclinical research[105] that may lead to effective therapies for patients. Despite our increasing knowledge of migraine pathophysiology, there are still several gaps to fill. Our understanding of the disease should still rely on a careful clinical history where all the migraine phases are apparent. Namely, premonitory symptoms that may precede or accompany the headache phase, migraine aura, and symptoms that follow the migraine attack, the so-called postdrome, tell us about the potential role of different brain structures as it has been shown by functional neuroimaging studies.[3]

Alike the non-motor manifestations of Parkinson's disease,[109] the role of these non-headache symptoms in migraine has a growing importance, as it may help us understand better the migraine pathophysiology, and this may lead to the development of new therapeutic targets.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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