Migraine is a chronic neurologic disease that has different frequency, intensity, and influence on patient’s quality of life. In addition to the patient's diagnosis, symptoms, and comorbid conditions, a treatment plan should also take into account the patient's expectations, requirements, and objectives. An ideal migraine management should start with an accurate diagnosis, excluding other potential causes, conducting appropriate tests, and considering the headache's effect on the patient. This process involves educating the patient about available treatment options, potential side effects, the expected duration of therapy, and anticipated outcomes. Furthermore, a comprehensive treatment plan should be developed that addresses any coexisting and comorbid conditions. Comorbidity is the occurrence of two or more conditions, the association of which is more frequent than would occur by chance. Stroke, comorbid pain disorders, angina, patent foramen ovale (aura), epilepsy, and certain psychiatric disorders, such as depression, psychosis, anxiety, and panic disorder, are conditions that occur in patients with migraine with a higher prevalence than coincidence. Patients who experience recurrent headaches which are severe require both acute (abortive) and preventive (prophylactic) pharmacologic treatments for migraine. Preventive therapy is implemented to mitigate the severity, duration or frequency of attacks. Additional advantages may encompass the enhancement of acute treatment responses, the enhancement of a patient's functional capacity, and the reduction of disability. Preventive treatment may also lead to a decrease in health care expenses.[1] Currently, migraine is the sixth most prevalent disease worldwide and is a significant cause of disability, resulting in a significant personal and socio-economic burden.[2] The economic burden of migraine is the second highest of all neurological diseases, with an estimated annual cost of €111 billion in the European Union alone.[3]

CLASSIFICATION OF MIGRAINE:

Migraines can be classified into several subtypes according to the Headache Classification Committee of the International Headache Society.

1. Migraine without aura

• Recurrent headache attacks lasting 4 to 72 hours
• Typically unilateral, pulsating, moderate to severe in intensity
• Aggravated by physical activity
• Associated with nausea, photophobia, and phonophobia

2. Migraine with aura

• Recurrent, completely reversible episodes lasting minutes
• Usually includes unilateral symptoms such as speech, visual, language, sensory, motor, retinal and brainstem; headache and other migraine symptoms follow.

3. Chronic migraine

• Headache occurring on 15 or more days per month for more than three months
• Migraine symptoms present on at least 8 days per month.

Complications of migraine

Status Migrainosus:

A severe migraine episode lasting more than 72 hours.

Persistent Aura without Infarction:

Aura lasting longer than a week without neuroimaging evidence of infarction.

Migraineous Infarction:

Brain ischemia associated aura symptoms visible on neuroimaging.

Migraine Aura-Triggered Seizure:

Seizure occurring during a migraine attack with aura.

Probable Migraine:

A symptomatic headache episode that does not fully meet the criteria for the above categories and does not fit another headache classification. [4]

ETIOLOGY

Genetics and Inheritance

The hereditary component of migraine is really high. Though no hereditary pattern was found, unwell relatives are at 3 times higher risk of developing migraine than in relatives of non-ill patients. The genetic foundation of migraine is complicated and it is unknown which genes and loci are involved in the pathogenesis. Knowing which genes a migraine sufferer carries could help determine the specific preventive medication.

Familial Hemiplegic Migraine

Hemiplegic migraine can manifest either within families or sporadically, with one person being the first member of a family to experience this type of migraine. These migraines are primarily attributed to channelopathies, which are abnormalities affecting ion channels in the brain. These channelopathies give rise to 3 primary types of hemiplegic migraine caused by:

1. Chromosomal 19p13 CACNA1A gene mutation (calcium voltage-gated channel alpha 1A subunit).
2. Chromosomal 1q23 ATP1A2 gene mutations (ATPase, Na+/K+ transporting alpha two subunit).
3. SCN1A gene mutations (sodium voltage-gated channel Type 1 alpha subunit).

• PRRT2 (Proline-Rich transmembrane 2) gene mutations can also be considered as one of the possible causes. A protein encoded by the PRRT2 gene interacts with the synaptosomal nerve-associated protein 25, or SNAP25, which may be involved in the control of voltage-gated calcium channels.
• SLC4A4 (solute carrier family four member 4) gene mutations can also be a part of this forms of migraine

Triggers

Migraine headaches can result from withdrawals or from exposure to a number of circumstances. A retrospective research study revealed that around 76% patients mentioned triggers. While some are only hypothetical or untested, others are most likely contributing elements.

• Probable factors include stress (80%), Hormonal changes (65%), Skipped meals (57%), Weather changes (53%), Exposure to lights (38%)
• Possible factors include Hypersomnia or insomnia (50%), Odors like perfumes, colognes, petroleum distillates (40%), Neck pain (38%), Alcohol ingestion (38%)
• Unproven factors include smoking (36%), tyramine and chocolate (27%). [4]

EPIDEMIOLOGY

• Migraine and headache are worldwide debilitating illnesses causing great individual suffering and reduced QOL in adults, children and adolescents. Therefore, epidemiological studies are needed to estimate the breadth of the issue. This review contains epidemiological research on migraine and headache in children and adolescents published in the previous 25 years. A total of 64 cross-sectional studies have been discovered, published in 32 different countries and containing a total of 227,249 people. Mean prevalence of headache was 54.4 % (95 % CI 43.1–65.8) and mean prevalence of migraine was 9.1 % (95 % CI 7.1–11.1). There is a scarcity of population-based research from poor and low-middle income nations. Furthermore, there is a notable lack of data concerning the prevalence of chronic migraine and probable migraine, with a particular gap in understanding menstrual migraine among young individuals.
• Migraine represents a widespread health concern, impacting approximately 12% population annually, with a higher prevalence observed in women, affecting up to 17% of females and 6% of males. Notably, among children, migraine also appears to occur more frequently in females. The adjusted prevalence of migraine demonstrates regional variations, with North America exhibiting the highest prevalence, followed by Central America, South America, Asia, Europe, and Africa.
• Migraine typically ranks as the fourth most common reason for emergency department visits (approximately 3% visits annually). Its prevalence tends to increase during puberty and continues to rise until individuals reach the age range of 35 to 39 years, after which it tends to decrease, particularly following menopause.[5]

PATHOPHYSIOLOGY

• Pathogenesis entails several peripheral and central nervous system components, yet being poorly understood. This part outlines some of the most well-known concepts.
• The previous vascular theory of migraine states that aura is caused by vasoconstriction and headache by vasodilation; but, this idea is no longer valid. These days, theories contend that a number of fundamental neuronal abnormalities result in a cascade of intracranial and extracranial modifications that trigger headaches.
• Trigeminal afferents are activated when neuronal pannexin-1 mega channel opens, caspase-1 is then activated, proinflammatory mediators are released, NF-kB (nuclear factor kappa-B) is activated, and this inflammatory signal spreads to trigeminal nerve fibers surrounding vessels of the pia mater. By a sequence of meningeal, cortical and brainstem events, this inflames the pain-sensitive meninges and, via both central and peripheral pathways, results in headaches. This circuit can thus account for the aura-establishing cerebral depression and the headache-causing extended stimulation of trigeminal nociception.
• The aura phenomenon in migraine is theorized to stem from of Leão’s cortical spreading depression, characterized by a wave-like propagation of glial and neuronal depolarization across the cortex. This cascade of events triggers the activation of trigeminal afferents and alters the permeability of the blood-brain barrier by inducing the activation of brain matrix metalloproteinases.
• The trigeminal nerve ophthalmic division primarily innervates the anterior structures, providing a possible explanation for the frontal head pain often experienced during migraines.
• Neurogenic inflammation occurs as a consequence of the activation of nociceptors, particularly within the trigeminal system. This activation leads to edema, vasodilation and plasma protein extravasation. The conjunction of fibers from upper cervical roots, originating from neurons within the trigeminal nerve and ganglion, along with the trigeminal nucleus caudalis, explains the anterior-to-posterior distribution of pain. These fibers rise up to the sensory cortex and thalamus, contributing to the perception of pain. This may lead to release of vasoactive neuropeptides such as calcitonin gene-related peptide, substance P and neurokinin from the trigeminal ganglion. These neuropeptides are elevated in spinal fluid of individuals with migraines. Sensitization, whereby neurons become more responsive to stimuli, may result from neurogenic inflammation. This phenomenon helps explain certain clinical manifestations of pain and the progression from episodic to chronic migraines. [4]

Several neuropeptides may have significant roles in the pathogenesis of migraines:

Serotonin:

It is hypothesized that low serotonin levels between migraine attacks might lead to a weakened serotonin pain inhibition system, possibly enabling the activation of the trigeminal system. Serotonin may influence migraines through cortical projections of brainstem serotonergic nuclei, central pain control pathways, or direct effects on cranial arteries.

Calcitonin Gene-Related Peptide (CGRP):

 Neurons within the trigeminal ganglion express high levels of CGRP. It increases the synthesis of nitric oxide and sensitizes trigeminal nerves upon release from peripheral terminals. CGRP acts as a potent vasodilator of the dura mater and cerebral vessels, contributing to neurogenic inflammation and facilitating the transmission of trigeminal pain from vessels to CNS.

Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP):

PACAP levels are elevated during migraine episodes, suggesting its potential role in mediating migraine attacks. Its infusion has been observed to induce migraine in susceptible individuals, further implicating its involvement in migraine pathophysiology.[3]

TREATMENT / MANAGEMENT

A. DRUGS APPROVED AND TESTED FOR TREATMENT OF ACUTE MIGRAINE— COMPARISON OF EARLIER AND CURRENT DEVELOPMENT STRATEGIES

Seventeen medications received FDA approval for acute migraine treatment between 1970 and 2020. These drugs predominantly fall into two categories: those specifically designed to target acute migraine, such as drugs acting on anti-CGRP pathways and 5-HT (serotonin) receptor agonists. Additionally, among the latter are general analgesics like COX inhibitors, commonly used for various pain-related conditions. Notably, the period between 2018 and 2020 saw the approval of four drugs that target CGRP and 5-HT1F receptors, marking a shift in drug development strategies towards novel targets. This shift reflects advancements in understanding the roles of CGRP and 5-HT1F receptors in migraine pathogenesis. The emergence of novel 5-HT1F receptor agonists (ditans) and CGRP receptor antagonists (gepants) represents promising alternatives due to their improved efficacy and milder side effect profiles compared to older migraine treatments. However, the full spectrum of pharmacological effects induced by these agents is not yet fully elucidated. Since 2018, there has been a notable expansion in the range of drug targets compared to those approved between 1970 and 2018, particularly focusing on the 5-HT system and its 5-HT1D/1B receptors. This diversification in drug targets underscores ongoing efforts to develop more effective and better-tolerated treatments for acute migraine episodes.[8] [9]

a. Drugs used in clinical trials between 2018 and 2020 for acute migraine—Spectrum of molecular targets

A total of 12 drugs underwent clinical trials between 2018 and 2020 for acute migraine. Among them, six drugs had already received FDA approval for other indications and were being repurposed for migraine treatment. These repurposed drugs, primarily acting as anaesthetics or analgesics, are currently being evaluated for their effectiveness in managing migraine symptoms. Notably, studies on five of these drugs are being conducted through medical centers (lidocaine, dexamethasone and bupivacaine) or driven by universities (ketorolac and indomethacin), while ketamine is being tested through an industry-driven study. These repurposed drugs employ new mechanisms of action (MOAs) for migraine treatment, such as targeting the greater occipital nerve (GON) and the NDMA receptor, while others act on established targets including COX enzymes, 5-HT receptors, and the CGRP receptor. Additionally, six drugs already approved by the FDA for acute migraine treatment are undergoing further company-initiated clinical trials to explore novel drug combinations, new formulations and long-term safety, or to expand their indications within the migraine field. These drugs primarily operate via the 5-HT or CGRP systems.[3]

b. Characterisation of drug classes approved and in clinical trials for the treatment of acute migraine

i. Drugs targeting the 5-HT system (triptans, ergot alkaloids  and ditans)

• Ergot alkaloids, like ergotamine, have been utilized since the 1970s to manage acute migraine symptoms. However, the advent of triptans, starting with sumatriptan's approval in 1992, marked a significant advancement in symptomatic treatment. Recently developed agents targeting the 5-HT system, known as ditans, demonstrate potent pharmacological effects with fewer adverse effects compared to triptans and ergot alkaloids.
• Dihydroergotamine (DHE), another ergot alkaloid, is indicated for treating acute migraine with or without aura and cluster headache episodes. It binds strongly to 5-HT1D? and 5-HT1D? receptors.
• Triptans, such as zolmitriptan and rizatriptan, target 5-HT1B/1D receptors and were first approved in 1997 and 1998, respectively. Zolmitriptan inhibits vasoactive neuropeptide release and inhibits pain signal transmission in the trigeminal dorsal horn. Rizatriptan is undergoing clinical studies for vestibular migraine and combination therapy with meloxicam or naproxen for acute migraine. Triptans can cause peripheral vasoconstriction, thereby restricting their use in patients with cardiovascular diseases or hemiplegic migraine. Novel acute migraine treatments, like ditans, targeting trigeminal pathways without affecting vasoactive 5-HT1B and 5-HT1D receptors, are being developed.[3]
• Ditans, exemplified by lasmiditan, selectively target the 5-HT1F receptor for acute migraine treatment. Lasmiditan was approved in 2019. Structurally distinct from triptans, ditans contains a pyridine-piperidine scaffold instead of an indole group. Triptans bind non-selectively to 5-HT1B and 5-HT1D receptors, causing vascular vasoconstriction, while ditans offer a promising alternative with fewer vasoactive effects. [7]

ii. Drugs targeting the CGRP system—Gepants

CGRP, or calcitonin gene-related peptide, is known to be a trigger for migraine attacks in patients. Hence by Blocking the canonical CGRP receptor, these agents may be effective in the acute management of migraine. Low molecular weight CGRP receptor antagonists, also known as gepants, have been investigated for their potential in both acute migraine therapy and migraine prevention. Two gepants, ubrogepant and rimegepant, have received approval from the FDA for acute migraine treatment. Ubrogepant (brand name: Ubrelvy™) is an orally administered compound developed by Allergan in collaboration with Merck & Co. It is highly selective and acts as a competitive CGRP receptor antagonist. Ubrogepant offers a potent option for the acute management of migraine, providing patients with an effective and convenient oral medication to manage their symptoms.[8]

iii. Anaesthetics

The notion of ketamine's potential as a treatment for migraine is not a recent one; it has been under investigation for over two decades. However, there has been a resurgence of interest in ketamine's role in migraine treatment in recent times. Ketamine has previously been explored as a means to reduce opioid usage in pain management and as a therapeutic option for mood disorders, with compelling evidence supporting its efficacy in these areas. In contrast, there is currently a lack of robust data demonstrating a significant effect of ketamine in migraine treatment. NMDA receptors, which ketamine targets, are widely distributed throughout the central nervous system. Under normal conditions, the channel pores of these receptors are blocked by magnesium ions (Mg2+), preventing the flow of ions through the receptor channel. However, during neuronal depolarization, Mg2+ is expelled from the pores, allowing calcium ions (Ca2+) to enter. [3]

iv. Non-steroidal antiinflammatory drug

†For acute migraine treatment, only 1 or 2 doses are usually recommended; doses are for adults. ‡Absorbed more quickly than naproxen.

Tmax = time to maximum plasma concentration; NNT = number needed to treat: the number of patients that must be treated to obtain a response on a given end point over and above the response rate obtained from placebo.[9]