Migraine: Pathogenesis, Treatment, and Prevention Updates

Migraine is a ubiquitous neurological disorder estimated to affect approximately one billion people worldwide, predominantly women.1 According to the 2016 Global Burden of Disease Study, migraine is the second leading cause of disability and accounts for the most disability than all other neurological disorders combined.2

The diagnosis is based on clinical criteria provided by the International Classification of Headache Disorders , 3rd edition , ICHD-3).3

General clinical features suggestive of migraine are recurrent headache attacks with moderate to severe pain intensity, lasting 4 to 72 hours.3 A diagnosis of migraine should be considered if a typical headache attack is unilateral, throbbing, and aggravated. by physical activity.3

Common accompanying symptoms are nausea, vomiting, photophobia, and phonophobia.3

Some people report that migraine is preceded by an aura , which is characterized by reversible focal neurological symptoms, usually comprising visual or hemisensory disturbances.3

Although the pathogenesis of migraine is not completely understood, it is considered to involve the trigeminal nerve and its axonal projections to the intracranial vasculature (termed the trigemino-vascular system).4 Nociceptive signals from the trigemino-vascular system are transmitted to areas in the brain that produce the perception of migraine pain.4

Further progress has been made in understanding the pathogenesis with the identification of signaling molecules that are involved in the genesis of the migraine attack. This advance has facilitated the development of mechanism-based therapies for migraine.5

This review describes the current understanding of migraine pathogenesis, which is predominantly based on clinical data published in the last 10 years, and describes recommended practices for the treatment of acute migraine and for the preventive treatment of migraine, highlighting the medications that have recently been approved.

Migraine is the second most prevalent neurological disorder (after tension-type headache), with a female to male ratio of 3:1 and an estimated annual prevalence of approximately 15% in the general population.1

Prevalence peaks between the ages of 35 and 39 years, with around 75% of affected people reporting the onset of migraine before the age of 35 years.1,6

Migraine also affects a considerable proportion of children , with one population-based study showing an annual prevalence of around 7% among school-aged children.7

Since the disorder tends to subside with increasing age, the appearance of migraine after the age of 50 should raise suspicion of a secondary headache disorder.1,8

The ICHD-3 provides diagnostic criteria for the three main categories of migraine: migraine without aura, migraine with aura, and chronic migraine (Table 1).3 Migraine with aura usually involves visual flickers and scotomas and, less frequently, symptom spread. hemisensory or speech dysfunction; These reversible focal neurological symptoms develop gradually over a period of 5 to 60 minutes.3

The aura phase of migraine is usually followed by headache within 60 minutes, although aura symptoms may occur during or in the absence of a subsequent headache.3

Diagnosis should include a physical examination, although there are usually no abnormal findings. The differential diagnosis of migraine includes other primary headache disorders, mainly tension-type headache, and some secondary headache disorders, such as post-traumatic headache.3

Features suggestive of a secondary headache disorder include recent head trauma, progressively worsening headache, and thunderclap headache (sudden onset of an extremely severe headache). Warning signs on physical examination that require consideration of diagnoses other than migraine include fever, neck stiffness, and weight loss.8

It is common to have a family history of migraine, with heritability estimated at approximately 42%.9 In a genome-wide association meta-analysis, 38 susceptibility loci for migraine were identified, and risk variants were enriched in genes related to migraine. vascular and visceral smooth muscle.10

These findings are intriguing because vascular involvement in migraine pathogenesis has been debated over the years.11 In another analysis, the findings also suggested neuronal enrichment of genetic markers.12

In summary, genetic studies have shown that migraine risk is polygenic, with rare exceptions of monogenic migraine-related syndromes such as familial hemiplegic migraine.

The trigemino-vascular system is considered the anatomical and physiological substrate from which nociceptive transmission originates and the perception of migraine pain occurs.4

In 1984, Moskowitz proposed that the onset of migraine depends on the activation and sensitization of first-order trigeminovascular neurons.

The afferent fibers of these neurons innervate the meninges and their vessels and also project to structures in the central nervous system.21 Activation of these neurons releases vasoactive peptides and induces local inflammatory reactions.21

This process, in turn, sensitizes and discharges second-order neurons in the brainstem and then third-order neurons in the thalamus,4 until finally the nociceptive impulses reach the somatosensory area and other cortical areas that are involved in the perception of the pain.4

The mechanisms that initiate a migraine attack are unclear. Some evidence favors a peripheral origin at the level of perivascular trigeminal afferent pathways,4,11 while other data suggest that genesis is more likely within the central nervous system, implicating dysfunction of neurons in the brainstem and diencephalon.4, eleven

An inherent feature of migraine is its recurring nature. Patients often describe factors they perceive as triggers for their migraine attacks (e.g., stress, sleep disorders, certain foods, fasting).22 However, retrospective evaluations are limited by recall bias and false attribution. .2. 3

The high frequency of misattribution to triggers is supported by a study aimed at inducing migraine attacks by exposing patients with a history of migraine with aura to self-perceived triggers.24

Only 3 of 27 patients had migraine attacks after exposure to their personal trigger, suggesting, contrary to popular belief, that the role of these triggers is limited.

Signaling molecules involved in the genesis of a migraine attack have been identified in clinical models.5 These molecules, which are potent vasodilators and are widely distributed in the trigeminovascular system, include the calcitonin gene-related peptide ( PRGC), pituitary adenylate cyclase-activating peptide 38 (PAACP-38), and nitric oxide.5 To determine whether these and other molecules play a role in the pathogenesis of migraine, the author and his colleagues administered them to patients with migraine and healthy volunteers.5

Three decades of studies using this model have established that migraine attacks develop in migraine patients when exposed to these molecules, while healthy people report mild or no headache. For example, intravenous infusion of nitric oxide donor glyceryl trinitrate (TNG) induced attacks in 80% of migraine patients, PRGC infusion in 57%, and PAACP-38 infusion in 58%.13 -fifteen

Furthermore, drugs that block the degradation of cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP) induced migraine attacks in more than 80% of migraine patients.16,17

The observation that TNG causes an increase in intracellular cGMP and that PRGC and PAACP-38 cause an increase in intracellular cAMP5 has led to speculation that these are unifying neurochemical mechanisms that drive migraine. There is preclinical evidence that activation of cAMP- and cGMP-mediated pathways results in the opening of ATP-sensitive potassium channels (KATP).18,19

These findings have led to the hypothesis that the modulation of nociceptive transmission by ion channels, mainly potassium channels, may be a final common pathway in the genesis of a migraine attack.20 This hypothesis has been supported by the observation that attacks developed in all migraine patients after an intravenous infusion of the KATP channel opener levcromakalim.20

Explaining findings from clinical models of migraine within the framework of the trigeminal-vascular system has been challenging.21 It is possible that during a migraine attack, KATP channels open in vascular smooth muscle cells of the walls of arteries. intracranial,25 causing vasodilation.26,27

This, in turn, activates primary perivascular trigeminal afferents, generating nociceptive impulses that are transmitted to cortical and subcortical brain regions via ascending trigeminal pain pathways and ultimately results in the perception of migraine pain.4

This line of reasoning emphasizes that elevations in extracellular levels of positively charged ions, perhaps not exclusively potassium, can activate and sensitize perivascular trigeminal primary afferents. The modulatory activity of ion channels has been described in other paroxysmal pain disorders, such as familial episodic pain syndrome.28,29

Insights from clinical models of migraine and supporting preclinical data have also provided a basis for the development of targeted therapies. Not all have been found to be effective in the treatment of migraine, and some provide only modest therapeutic benefits, findings that underscore the complex biological underpinnings of the disorder.

For example, initial evidence from a small randomized clinical trial showed that targeting nitric oxide signaling through nonselective inhibition of nitric oxide synthetase (ONS) showed promise as a treatment for migraine.30

However, selective inhibition of inducible ONS (one of the three isoforms) was not beneficial in larger trials.31,32 It is unknown whether other ONS isoforms (endothelial and neuronal ONS) could be effective for initial or preventive treatment. .

Clinical models of migraine have also led to the development of drugs targeting PRGC or its receptor.4 Three small receptor antagonists have been found to be beneficial for the initial treatment of migraine, and four monoclonal antibodies directed against PRGC or its receptor have been shown to be effective. for its prevention.

These drugs and their integration into the clinical management of migraine are described below. Drugs targeting PAACP-38 or the pituitary adenylate cyclase-activating polypeptide type I (PAC1) receptor have also been developed for the prevention of migraine.33,34

A PAC1 receptor monoclonal antibody failed in a proof-of-concept study,33 while another monoclonal antibody, designed to target PAACP, is in an early stage of development.34

The physiological basis of the aura phase of migraine is thought to be a cortical spreading depression, a wave of self-propagating depolarization through the cerebral cortex that disrupts ionic gradients and is followed by cerebral hypoperfusion.35

Hemodynamic changes accompanying cortical spreading depression have been documented in neuroimaging of patients with migraine with aura, while no changes have been found in patients with migraine without aura.36

A fundamental question regarding the pathogenesis of migraine concerns the underlying mechanisms of activation of the trigemino-vascular system through the spread of cortical depression, leading to the headache phase of migraine with aura.4,35 In a Possible cascade of events, the spread of depression transiently opens neuronal pannexin-1 channels,37 resulting in the release of inflammatory mediators (e.g., nitric oxide and prostanoids) that are dilators of intracranial arteries.5

These processes are assumed to activate and sensitize the trigeminal primary afferent pathways that terminate in the perivascular space of the intracranial arteries.38 In this way, the spread of depression activates and sensitizes the perivascular trigeminal primary afferent pathways that are responsible for the transmission of nociceptive impulses, which are subsequently processed in cortical areas, giving the perception of migraine pain.

Clinical treatment of migraine should ideally be initiated and maintained by primary care physicians, with referral to a specialist in cases that are difficult to diagnose or do not respond to treatment.8 Pharmacological therapy, the mainstay of treatment, includes initial and preventive medications, with non-pharmacological therapies used as complements to medication.8

Non-pharmacological therapies can be used as a stand-alone preventive treatment for patients who are better off avoiding medication, such as pregnant women.8,39

There is modest evidence of benefit from noninvasive neuromodulatory devices, biobehavioral therapies, and acupuncture,40-42 while there is little or no evidence to support physical therapy, chiropractic manipulation, or dietary approaches for the treatment of migraine in adults. .43-45

As a general principle, medications used in clinical practice to relieve or eliminate migraine pain should be administered early in the headache phase of an attack (i.e., when the headache is still mild).8 The most initial medications used for migraine are non-steroidal anti-inflammatory drugs (NSAIDs),45 which are low-cost, over-the-counter analgesics.

Efficacy has been best documented for aspirin, ibuprofen, and diclofenac.46-48 Triptans are considered second-line medications, and in patients for whom an oral triptan is ineffective, others in the same drug class may provide a adequate pain relief.55

To date, seven oral triptans (almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, and zolmitriptan) are available for clinical use. Patients are advised to switch from one triptan to another if they have had three unsuccessfully treated migraine attacks.8 If treatment with an oral triptan provides some but inadequate pain relief, doctors may recommend combining a triptan. oral with a fast-acting NSAID (for example, sumatriptan and naproxen sodium).49

Subcutaneous sumatriptan is the most effective dosing method based on the proportion of patients who report being pain-free 2 hours after treatment, but its use is limited because it costs more and is much less available than oral triptans. Therefore, subcutaneous sumatriptan is first offered when a patient has had inadequate pain relief with oral triptans.50

An exception may be made for patients who cannot take oral triptans due to vomiting or a rapidly exacerbating headache. Clinicians should be aware of the risk of medication overuse headache, which is the condition of headache or increased pain frequency resulting from regular overuse of migraine medications by patients who have headache at least 15 days per month. .3,56 Discontinuation of excessive medication use and initiation of preventive treatment are the necessary behaviors in such cases.56

There has been cautious enthusiasm for small molecule PRGC receptor antagonists, called gepants, and 5-hydroxytryptamine type 1F (5-HT1F) receptor agonists, called ditans, in the treatment of acute migraine.51-54 The Food and Drug Administration (FDA) has approved the following oral gepants and ditans for the treatment of acute migraine: ubrogepant, rimegepant, and lasmiditan.

At present, the high costs and restrictive availability of gepants and ditans likely limit their use to patients for whom NSAIDs and triptans are ineffective, have unacceptable side effect profiles, or are contraindicated. Lasmiditan is associated with driving difficulties and an inability to evaluate one’s own driving competence.57

Consequently, because patients are advised not to drive a motor vehicle or operate machinery for at least 8 hours after ingestion,57 the widespread use of lasmiditan may be limited. Consensus guidelines advise against the use of opioids and barbiturates in the treatment of migraine due to the risk of adverse effects and dependence.8,58

Migraine is a recurring disorder, and long-term management may require preventative treatment. The goal is to reduce the frequency, duration, or severity of attacks rather than to cure the migraine.8 Doctors can convey such information to patients to reach agreement on realistic treatment goals.

Advice on when preventive treatment should be initiated in the course of an individual patient’s migraine trajectory varies between countries, but such treatment is generally recommended for patients who have at least two migraine days per month and whose lives are affected. negatively despite therapy.8

Off-label use of certain therapies has become common due to the limited number of approved preventive medications.59

The most commonly used drug classes are antihypertensive agents (e.g., beta blockers and candesartan), antidepressants (e.g., amitriptyline), anticonvulsants (e.g., topiramate and sodium valproate), and calcium channel blockers (flunarizine).45 For chronic migraine, the evidence-based efficacy of topiramate and onabotulinumtoxin A (Botox) has been documented.60,61

New mechanism-based preventive treatments have been recently introduced. These include four injectable monoclonal antibodies directed against PRGC or its receptor (eptinezumab, erenumab, fremanezumab, and galcanezumab), which have demonstrated effectiveness in randomized trials for the preventive treatment of episodic and chronic migraine.62-71

These medications have a rapid onset of effect and result in few adverse events, the most common being injection site reactions and pain.62 Erenumab, fremanezumab, and galcanezumab have also been shown to be beneficial in patients who do not respond to other classes. of preventive medications.62

In a 5-year open-label extension study, erenumab continued to be safe in patients with episodic migraine,63 although more data are needed to confirm these findings and evaluate the long-term safety of all agents in this class. The agents have not been compared to the commonly used oral preventive medications listed above, which are less expensive and more accessible.

Clinical experience suggests that response to treatment can be assessed and substitution with another medication considered after approximately 2 to 3 months for oral preventive medications, after 3 to 6 months for monoclonal antibodies targeting CGRP or its receptor. , and after 6 to 9 months for onabotulinumtoxin A.

A proposed treatment algorithm for the clinical management of migraine that may support decision making is shown in Figure 1. Professional organizations have published guidelines for the clinical management of migraine, including the American Headache Society and the European Federation of Migraines. Headaches.36,54,57

Clinical management strategies for migraine in children and adolescents differ somewhat from management strategies in adults and may require the involvement of family members.

When a doctor determines that migraine medication is necessary in a child, ibuprofen is considered the initial drug of choice.74,75 If ibuprofen is ineffective, oral triptans and the combination of sumatriptan and naproxen sodium may be tried.74 .75

There is less evidence to support the use of preventive medications, such as topiramate, amitriptyline, and propranolol in children and adolescents. In a placebo-controlled trial, topiramate and amitriptyline were not superior to placebo for the prevention of migraine in patients 8 to 17 years of age.76

Children and adolescents may benefit from biobehavioral therapies, such as biofeedback, relaxation, and cognitive behavioral therapy.74 A review of treatment strategies for children and adolescents has been published.74

Understanding of the mechanisms underlying migraine has evolved over the past decade, with new insights into its pathogenesis and the development of mechanism-based therapies, but questions remain about these mechanisms and certain medications.

These uncertainties include the exact origin of migraine pain, the mechanism underlying the paroxysmal nature and characteristics of migraine, and the exact site and mode of action of migraine-specific medications. Effort is needed to find new drug targets and develop biomarkers that can predict which patients will have a response to each targeted therapy.

Table 1. Diagnostic criteria for migraine without aura, migraine with aura and chronic migraine*

*Diagnostic criteria of the International Classification of Headache Disorders, 3rd edition (ICHD-3).3

Figure 1 . Proposed treatment algorithm for the clinical management of migraine.

Nonsteroidal anti-inflammatory drugs (NSAIDs) should be considered first-line medications for the treatment of migraine attacks. For patients in whom NSAIDs provide no or insufficient pain relief, an oral triptan should be offered. If an oral triptan does not provide pain relief, other triptans should be offered.

Combination therapy with naproxen sodium should be offered to patients who have inadequate pain relief with a triptan. Ideally, physicians should first offer subcutaneous sumatriptan when a patient has not had adequate pain relief with all oral triptans.

However, subcutaneous sumatriptan can be tried at an earlier stage if oral triptans cannot be swallowed due to vomiting or if headache intensity peaks quickly. Ditans and geptans may be considered for patients in whom NSAIDs and all available triptans are ineffective, have unacceptable side effect profiles, or are contraindicated.

The decision on when to substitute a triptan for a gepant or ditan may differ between countries and should be made in accordance with local practice guidelines. Antiemetic agents may be offered as adjunctive therapy in patients with attacks accompanied by nausea or vomiting. Initiation of preventive treatment depends on local practice guidelines, but in general, it should be considered for patients who have at least 2 migraine days per month and are negatively affected despite treatment.