Epidemiology

The global prevalence of migraine is approximately 14.4% and it is three times more frequent in females than males.⁹ In children, abdominal migraine is a subtype of functional abdominal pain affecting about 13.5% of children worldwide. A high incidence of infant colic has been reported in migraineurs compared to controls.¹⁰ In females, there is a sudden increase in prevalence during puberty and a decline following menopause. Considering the high prevalence during the most productive years of a patient’s life, there is, consequently, a substantial cost to society due to decreased productivity and increased healthcare utilization. According to the 2016 Global Burden of Disease (GBD) study, migraine is the second most disabling condition in the world (second to low back pain).¹¹ The consequential impaired functioning and decreased quality of life make migraine a debilitating neurologic disease.¹² It is therefore no surprise that an increased risk of suicidal behavior has been reported in chronic migraineurs.¹³ About a third of migraineurs also experience auras, and female migraineurs who experience auras are more susceptible to ischemic stroke.¹⁴

Pathophysiology

Migraine is a complex neurovascular headache.¹⁵ Its etiopathophysiology is not completely understood. The phenomenon underlying the migraine pain and aura is cortical spreading depression (CSD), which is a self‐propagating neuronal and glial depolarization that spreads across the cerebral cortex. This process results in neuronal dysfunction, substantiated by recent evidence of microstructural abnormalities of the trigeminal nerve in migraineurs.¹⁶ The headache also involves recurrent activation of the trigeminocervical complex by neurotransmitters, such as neuropeptides, of which the calcitonin gene‐related peptide (CGRP) is known to be a key player, and other inflammatory mediators, which cause neurogenic inflammation and neuronal sensitization.¹⁷ Research on gut–brain interaction suggests that the gut microbiota profile also plays a role in migraine pathogenesis.¹⁸

There appears to be a genetic and familial risk, as more than half of all migraineurs report having other family members who suffer from migraine. In addition, specific mutations leading to rare causes of vascular headache have been identified.¹⁵ Hemiplegic migraine, for example, is caused by mutations in genes that encode ion channel and transport proteins. Genetic mutations cause impaired neurotransmission and cortical hyperexcitability, which result in increased susceptibility to CSD and impaired sensory processing. The gene and environment interaction has received much attention in the last decade. This epigenetic link in migraine suggests that DNA methylation of numerous genes is also involved in migraine pathogenesis.¹⁹

Migraine is a spectrum disorder. In some people, episodic migraine increases in frequency and evolves into chronic migraine, a process known as transformation. The pathophysiologic mechanisms responsible for chronification are not well understood, but likely involve genetic and epigenetic factors, neurogenic inflammation, and central sensitization. In recent years, TTH and migraine have been considered to be part of the same continuous spectrum rather than individual and distinct disease states.

Migraine, especially greater headache pain intensity and frequency, is significantly comorbid with insomnia, depression, anxiety, gastric ulcers, angina, and epilepsy.²⁰ The comorbidity of migraine and temporomandibular disorders (TMD) is also well established.²¹ Individuals suffering from both TMD and migraine also had higher prevalence of bodily pain and systemic diseases.²² A prospective cohort in the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) study identified migraine as a risk factor for the development of TMD.²³ Therefore, prompt management of migraine may reduce the risk of developing TMD.

Clinical Features

The migraine headache is a moderate to severe, pulsating, unilateral head pain that is aggravated by routine physical activity (such as walking or climbing stairs). In addition, nausea and/or vomiting, or photophobia and phonophobia, are present. Osmophobia has been reported to increase the diagnostic sensitivity of migraine.²⁴ The headache begins with gradual onset, reaching a peak in 2–4 hours. The pain typically lasts 4–72 hours untreated or unsuccessfully treated. Migraine may present as isolated facial pain, rendering it an important differential diagnosis for dental pain and TMD.²⁵ Orofacial migraine is an episodic or chronic pain that presents exclusively in the orofacial region, without head pain, with the characteristics and associated features of migraine as described in the ICHD‐3.⁶ The three‐item ID Migraine screener is a valid and reliable screening instrument for migraine, which is especially useful in primary care and epidemiologic settings.²⁶

In migraine with aura, the headache is preceded or accompanied by one or more fully reversible aura symptoms. An aura is a unilateral, stereotyped, sensory, motor, visual, speech, brainstem, or retinal focal neurologic symptom. The aura symptoms usually develop gradually and last minutes. Visual aura is the most common. Sensory aura such as paresthesia follow a cortical somatotopic pattern and may involve the face, lips, and tongue. Rarely, focal motor weakness may occur. Prodromal symptoms such as fatigue, poor concentration, and neck stiffness may begin hours to a few days before a migraine. These symptoms should not be confused with aura symptoms. What was previously misconstrued as migraine triggers, such as eating chocolate and bright light, is now known to be prodromal symptoms warning of the impending migraine. These symptoms announce the arrival of the migraine and precede the head pain. Patients should be taught to recognize these prodromal symptoms so that abortive medications can be administered early in the migraine attack for maximum efficacy. Similarly, postdromal symptoms, such as fatigue or mood change, may last hours or a few days following the migraine.

Migraines occurring at least 15 days per month for more than 3 months fulfill the criteria for chronic migraine, although patients with 8 or more migraine days per month are similarly disabled.²⁷ Data from the Chronic Migraine Epidemiology and Outcomes (CaMEO) study suggests that the presence of noncephalic pain (pain in the face, neck, back, arms, legs, chest, abdomen, and other locations) may identify episodic migraineurs who are at risk of chronicity.²⁸ The American Academy of Neurology recommends neuroimaging only for migraine with atypical headache patterns or neurologic signs.²⁹

Management

The management of migraine includes patient education, in addition to pharmacologic and nonpharmacologic strategies. The patient needs to be educated about the diagnosis, etiology, trigger avoidance (if applicable), and management strategies. Generally, pharmacotherapy is divided into prophylactic or preventative therapy, and acute or abortive therapy.

Patients experiencing four or more migraine headache days per month, patients whose migraines significantly interfere with daily routine despite acute treatment, and patients in whom acute treatment is contraindicated, has failed, or is overused (defined as use in 10 or more days per month) are candidates for prophylactic therapy.³⁰ First‐line migraine preventatives (Table 12‐3) include anticonvulsants (such as topiramate, which is the only US Food and Drug Administration (FDA)‐approved oral chronic migraine preventative), β‐adrenergic receptor blockers (metoprolol, propranolol, and timolol), frovatriptan, and onabotulinum toxin A. Second‐line therapy includes amitriptyline, venlafaxine, atenolol, and nadolol. The oral prophylactics must be taken daily and usually have a 2–6‐week period before an effect is observed. Onabotulinum toxin A is FDA approved for the management of chronic migraine and is injected every 3 months via the PREEMPT protocol using a total of 155 units into 31 injection sites.³¹ Onabotulinum toxin A acts via blocking the release of pro‐inflammatory and excitatory neurotransmitters and reducing the pronociceptive ion channels on the afferent neurons. Monoclonal antibodies (MABs) targeting the CGRP receptor (such as erenumab, fremanezumab, and galcanezumab) have been recently approved by the FDA for the prevention of migraine.³² CGRP pathway blockers are the first mechanism‐specific migraine treatment. The CGRP MABs are injected subcutaneously monthly and are devoid of drug interaction concerns. The most common adverse effects are injection site discomfort, constipation, and hypertension. They are indicated upon failure of at least two oral preventatives or inadequate response to at least two quarterly injections of onabotulinum toxin A.³⁰ A reasonable goal for preventative therapy is a 50% reduction in migraine headache days, a significant decrease in migraine duration or pain intensity, improved response to acute treatment, reduction in migraine‐related disability, or improvement in quality of life.

Episodic migraine can often be managed with abortive therapy alone. While most individual attacks are successfully managed with oral agents, parenteral drugs may be necessary when nausea and/or vomiting accompany the attacks. Abortive agents for migraine (Table 12‐4) include the nonsteroidal anti‐inflammatory drugs (NSAIDs), ergotamine derivatives, the triptans (5‐HT_1B/1D/1F agonists), opioids, and the gepants (CGRP receptor antagonists). Ergotamine and its derivatives are nonselective 5‐hydroxytryptamine (5‐HT₁) receptor agonists, whereas the triptans are selective 5‐HT₁ receptor agonists. Triptans are available in oral, nasal, and parenteral formulations, and in combination with NSAIDs. They are contraindicated in ischemic vascular conditions, uncontrolled hypertension, and other significant cardiovascular disease. A novel selective 5‐HT_1F receptor agonist, lasmiditan, is devoid of vasoconstrictor properties.³³ Lasmiditan acts presynaptically to block the release of pro‐nociceptive neurotransmitters, and therefore has a high positive response rate. It is also a more specific agonist, resulting in fewer side effects, most commonly dizziness. Novel CGRP receptor antagonists, the gepants (such as ubrogepant and rimegepant), have also been recently approved by the FDA for the acute treatment of migraine.³⁴ The gepants do not have a vasoconstrictor effect either. The blockage of the CGRP pathway in the form of both abortive agents and prophylaxis has blurred the line in the concept of acute versus preventative therapy. It is noteworthy that the presence of cutaneous allodynia increases the likelihood of poor response to treatment for all oral abortive agents, urging the need for prompt administration at migraine onset and the use of intranasal and injectable agents (due to faster onset compared with oral agents).³⁵ It is also noteworthy that frequent use of migraine‐abortive medications may cause medication‐overuse headaches (defined as the use of abortive medication for 10–15 days per month and that the abortive is causing the increase in headaches).

Nonpharmacologic management plays an important role in the management of migraine. This includes biobehavioral therapies such as relaxation training, biofeedback, cognitive behavioral therapy, mindfulness and meditation, and other forms of complementary and alternative therapies such as acupuncture treatment.³⁶ These modalities are important for patients in whom pharmacologic management is contraindicated and for those who prefer nonpharmacologic management. In addition, when combined with pharmacotherapy, they may enhance the clinical therapeutic outcome or permit a reduction in the amount of medications used. Pericranial nerve blocks, including occipital nerve blocks and sphenopalatine ganglion blocks, have been investigated for both migraine abortion and prevention.³⁷ They are associated with few contraindications, good safety, and are generally well tolerated. Percutaneous implantation of neurostimulators and surgical decompression procedures have also received much attention despite the lack of well‐designed clinical trials. Neuromodulation approaches such as single‐pulse transcranial magnetic stimulation, noninvasive vagus nerve stimulation, and external trigeminal nerve stimulation have been approved by the FDA for migraine treatment.³⁸ Last but not least, adequate management of migraine comorbidities is integral to the success of migraine management. Comorbid depression, anxiety, insomnia, and widespread pain (including TMD) should be identified and their management prioritized.

Epidemiology