Migraine is the third most prevalent illness in the world, with almost one billion people around the world affected. The severely disabling attacks can last from several hours to days and exert a massive toll on the well-being of the patient, as well as an enormous economic toll.
Symptoms of migraine span a spectrum from throbbing and recurring headaches to nausea, dizziness, extreme sensitivity to light, sound, smell and/or touch during and after an attack, and sometimes, visual disturbances known as aura. Premonitory symptoms have been documented up to 72 hours before the attack.
Migraines are neurovascular in origin:
It was long believed that migraines were vascular in origin due to meningeal vasodilation. However, it is now established that migraines are neurological in origin, with complex inputs from both the central and peripheral nervous systems. Early studies on sumatriptan, the serotonin (5HT)IB/D–like receptor agonist, which showed its action against the nociceptive duravascular neurons in the trigeminal neurons suggested the purely neuronal action of sumatriptan.
The cause of migraines is the activation of diencephalic and brain stem nuclei, which drive the activation of the trigeminovascular system. Evidence supports that migraine results from activation of the peripheral trigeminovascular neurons, the neurons that innervate the meningeal blood vessels. There is peripheral nociceptor (first-order trigeminovascular neurons) sensitization and activation of central second-order trigeminovascular neurons.
The posterior thalamus, which receives the spinal trigeminal nucleus projections, showed activation in patients experiencing touch sensitivity during a migraine attack. Hypothalamus activity is also increased during a migraine attack, and increased functional coupling to trigeminal nucleus caudalis (TNC) is also observed.
Many migraines are also genetically transmitted, with the gene for familial hemiplagic migraine and others showing a genetic element in familial studies.
CGRP and the trigeminal system:
Calcitonin gene–related peptide (CGRP) is found abundantly in the trigeminovascular neurons. The expression of CGRP is limited to the nociceptive unmyelinated C fibers of the trigeminal nerve. These, ophthalmic, and to some extent, maxillary and mandibular fibers innervate the cerebral and meningeal arteries and project into the poorly vascularized dura. The neighboring thinly myelinated Aδ fibers richly express calcitonin receptor–like receptors (CLR) and RAMP1, which are functional receptors for CGRP. About half of trigeminal neurons express CGRP and a third express CLR and RAMP1 of the CGRP receptor. CGRP and CGRP receptors are never expressed in the same neurons.
The release of CGRP triggers a cascade of events that includes secretion of nitric oxide (NO) and sensitization of trigeminal nerves and satellite glia. The interaction of CGRP with glia and satellite cells drives the activation of second-order neurons. Elevation in CGRP levels leads to the increased sensitization of several neuronal circuits. It is believed that the shift in central sensitization from activity-dependent to activity-independent is the mechanism behind progression from episodic to chronic migraine.
Novel migraine therapeutics:
These migraine therapeutics are prescription drugs due to the requirement of personalization of treatment as well as close monitoring of adverse events. Pain management has seen many developments, but most of these therapeutics are NSAIDs and/or inhibit the nociceptive receptors but do not address the CGPR system.
The first line of treatment is often nonprescription pain management drugs like NSAIDs, which are analgesics containing acetaminophen, aspirin, and caffeine. For moderate to severe cases of migraine, the identification of triggers, pathophysiology, and first-line medications is critical. First-line therapy typically includes drugs like divalproex and topiramate, followed by treatment with amitriptyline, venlafaxine, etc.
Growing understanding of the mechanisms underlying migraine has led to the development of novel treatments that primarily target the trigeminovascular nervous system. Migraine therapy can be divided broadly into acute and preventive or prophylactic treatments based on their mode of action.
Acute or episodic migraine therapeutics:
Acute treatments reduce the attack duration and the severity of symptoms.
5-HT1F receptor agonists (ditans):
Triptans are 5-HT1B/1D receptor agonists with affinity for the 5-HT1F receptor subtype that exert a vasoconstricting effect. 5-HT1B/1D receptors express and colocalize with CGRP in the trigeminal neurons. The 5-HT1F receptor subtype is also expressed in the trigeminal ganglion but does not cause vasoconstriction when activated.
Ditans are a class of agonists developed against 5-HT1F receptors. This receptor binds to sumatriptan and naratriptan with high affinity. Tests in humans are underway for LY-334370 and lasmiditan, and lasmiditan is undergoing Phase III clinical trials. In one of the trials, nearly 41% of patients (compared to 29.5% for placebo) achieved relief from the most severe symptoms 2 hours after treatment.
In October 2019, the FDA approved lasmiditan (Eli Lilly’s Reyvow) for oral use for treatment of acute migraine, with or without aura.
CGRP receptor antagonists (gepants):
Small molecule CGRP antagonists that inhibit downstream signaling have shown encouraging results in relieving migraine attacks. Small-molecule CGRP antagonists such as olcegepant, telcagepant, MK‐3207, and BI 44370 TA have shown efficacy in treatment of migraine. Atogepant is still in unpublished clinical trials. Due to the inability of oral administration or adverse events such as hepatotoxicity, some trials were terminated.
Allergan’s Ubrelvy (ubrogepant), an oral therapy, received FDA approval in December 2019, and Biohaven’s Nurtec ODT (rimegepant) received FDA approval in February 2020. It is an oral disintegrating tablet with sustained efficacy and durability for 48 hours after treatment with a single dose.
Prophylactic migraine therapeutics:
These therapies are suggested to patients with recurrent episodic or chronic migraines as a means of prevention.
Anti-CGRP mAbs:
Four monoclonal antibodies (mAbs) targeting the CGRP pathway have been developed. This is a great advancement in migraine therapy, as the responder rate is highly favorable compared to the adverse event profile.
Erenumab, a humanized IgG that targets the CGRP receptor, has been launched by Novartis and Amgen as Aimovig and received FDA approval as a preventive treatment in adults in May 2018. It is administered as a monthly subcutaneous injection.
Fremanezumab, a humanized monoclonal anti‐CGRP antibody, inhibits firing of Aδ, not of C fibers. Fremanezumab (available from Teva Pharmaceuticals as Ajovy as an autoinjector) was approved by the FDA in September 2018 for prevention of migraine in adults.
Galcanezumab is effective in the treatment of chronic migraine and is well tolerated in adults. The Emgality (galcanezumab-gnlm) injection from Eli Lilly for the prevention of recurrence of episodic migraine in adults received approval by the FDA in September 2018.
Eptinezumab, a humanized monoclonal IgG that binds both the ɑ and β forms of the CGRP ligands, has completed clinical trials and was approved by the FDA in February 2020. It is available as an intravenous injection from Lundbeck as Vyepti given quarterly.
Anti-pituitary adenylate cyclase-activating polypeptide (PACAP) mAbs:
PACAP, a glucagon/secretin peptide, exists in two bioactive forms: PACAP38 and PACAP27. PACAP38 is found in the trigeminovascular neuronal and deep brain structures and mediates its vasodilatory effects through three receptors: PAC1, VPAC1, and VPAC2. These receptors act like CGRP and increase the cGMP production.
Two mAbs against PACAP38 have entered clinical trials. ALD1910 from Alder Biopharmaceuticals, which targets the PACAP38 ligand, is in Phase I clinical trials as a preventative for migraine. AMD 301, a humanized monoclonal antibody against the PAC1 receptor, has completed Phase II clinical trials.
The clinical outcomes of mAbs against PACAP38 are the same as the mAbs against CGRPs. Because the mechanistic outcome and mode of action is different from therapeutics directly targeting CGRPs, it is hoped that these treatments will provide relief to a wider set of patients who may not respond to current anti-CGRP drugs.
Prophylactic therapies under development:
Curcumin and ⍵-3 fatty acids work as a combination therapy in a new approach to migraine prevention. Another treatment strategy that has found some success in the clinic utilizes the underestimated metabolic facets of migraine physiology. Riboflavin and Q10 are effective as a complementary therapy for treatment and management of migraine.
Transcranial direct current stimulation is a new therapy that has shown efficacy in clinical trials as a technological intervention for the prophylactic and therapeutic treatment of episodic and chronic migraine. Alternative therapies like acupuncture, hypnotherapy, and osteopathic manipulation treatment have also had some success in management of migraine pain, although further investigation is required.
Beyond migraines and the vast field of discoveries:
A highly prevalent and disabling illness of neurological origin, migraine takes a vast toll on patients as well as healthcare providers. Growing understanding of the neuroscience behind migraine and the development of novel therapies will ease the burden. There are a vast number of neuropeptides that are encoded by the human genome and are abundantly present in the trigeminovascular nervous system. Their crosstalk with the CGRP and the PACAP system involves intracellular mechanisms, gene expression, and modulation of sensory information. It will be interesting to understand the ontogeny and functioning of these molecules in the central and peripheral trigeminal system, as well as responses to established and hitherto undiscovered migraine drugs.
Despite early successes in approving drugs targeting CGRP, it is recognized that these migraine therapeutics do not work for every individual, and other molecules must be involved. Ongoing research is expected to reveal multiple neuropeptides that can be targeted in migraines, thus leading to a number of novel drugs that could benefit individuals who do not respond to products currently on the market.
