Migraine is a condition characterized by moderate to severe headaches. They are often pulsatile, unilateral, last for 4-72 hours, and are associated with photophobia and phonophobia, nausea, and/or vomiting. While once thought to be due to dysfunction of cerebral blood vessel dilation, migraines are now understood to be related to a phenomenon known as cortical spreading depression. Cortical spreading depression is a self-disseminating wave of neuronal and glial cell depolarization that extends across the cerebral cortex. This event may lead to activation of the trigeminovascular system, leading to inflammatory changes in the pain-sensitive meninges. This is primarily mediated by the release of vasoactive polypeptides such as calcitonin gene-related peptide (CGRP), substance P, and possible alteration in serotonin metabolism contributes to further inflammation.[1][2][3][4][5]

Clinical Course

Migraine attacks evolve through a pattern of events that occur over hours to days. A typical migraine has four phases: prodrome, aura, headache, and postdrome. These phases may overlap and appear variable.

The prodrome may occur hours prior to the headache and is seen in about three-quarters of migraine sufferers.[6] Prodromal symptoms may include mood changes, yawning, food cravings, irritability, constipation, or neck stiffness.[7]

Aura occurs in 25% of patients, usually during, and sometimes prior to, the headache phase. Aura symptoms most commonly affect vision and sensation, followed by language and motor functions.[8] They are subdivided into positive symptoms, such as tingling or bright lights, and negative symptoms, such as aphasia, numbness, unilateral weakness, or vision loss. Auras typically develop over 5 minutes or more and resolve within an hour. They are completely reversible. Aura without headache (acephalgic migraine or migraine equivalent) may also occur.

Often, but not always, the headache is experienced unilaterally and tends to have a pulsating or throbbing quality. Pain escalation is usually gradual, progressing from dull to severe, and can be exacerbated by light, sound, and activity. Nausea is common and vomiting may result. Symptoms are often partially relieved by lying still in a dark, quiet room. The headache may last anywhere from a few hours to multiple days. The headache often resolves during sleep in patients who are able to sleep. Sudden onset, “thunderclap” headaches should be investigated for alternative causes, although this pattern, too, may represent migraine.

The postdrome is characterized by exhaustion or, less commonly, euphoria, as well as possible focal areas of pain in the distribution of the preceding headache.

Epidemiology

Migraines typically begin in the teenage years or early adulthood and are most common in those aged 30 to 39.[9] Migraine without aura (previously termed “common” migraine) accounts for 75% of cases. Migraine with aura (“classic” migraine) is the second most common type. There are various subtypes of migraine with aura including: migraine with brainstem aura (manifested by cranial nerve deficits, vertigo, tinnitus, or decreased level of consciousness), hemiplegic migraine, ocular/retinal migraine (manifested by visual loss), vestibular migraine (with vertigo), and estrogen-associated/menstrual migraine, which occurs at the onset of menses. Migraines are further categorized as chronic or episodic. Chronic migraine is diagnosed when patients experience at least 15 headache days per month for more than 3 months, with migraine features occurring at least 8 of those days. Episodic migraine occurs when there are ≤14 headache days per month.

Up to 50% of migraine cases are familial, with polygenic inheritance. Genetic migraine does not usually follow a typical Mendelian inheritance pattern.[10]

Triggers

Migraine triggers include menses, stress, weather changes, changes in eating or sleeping schedules, and certain foods and additives.[11] Chronically poor sleep and obesity are both associated with increased frequency and severity of migraines.[12][13]

Risk Factors

Women are affected about 3 times more often than men. Estrogen shifts may precipitate migraine. This may occur with normal menstrual cycles, menopause, or variation in oral exogenous doses (e.g., missed oral contraceptive pills or drug interactions that affect estrogen concentrations).[14]

Several studies have linked obesity to the frequency and severity of migraine attacks, although not all studies are in agreement.[13][15]

There is conflicting evidence on the association of patent foramen ovale or atrial septal defects and migraine with aura. It has been hypothesized that migraine may be triggered by hypoxemia or vasoactive chemicals, such as serotonin, which are typically metabolized during passage through the lungs.[16] This helps explain why people with right-to-left cardiac shunts (usually due to patent foramen ovale) have increased prevalence of migraine with aura.[17][18][19] So far, closure is not recommended based on migraine as an indication.[18]

Diagnosis

Migraine is a clinical diagnosis. Neuroimaging is only necessary if another etiology is suspected due to the presence of neurologic abnormalities, an atypical pattern of headache, or progression of symptoms despite appropriate treatment. Providers should consider a CT brain scan without contrast and lumbar puncture for patients with sudden onset of severe headache (to rule out subarachnoid hemorrhage). MRI brain scan may be indicated in patients with auras that have focal features including changes in vision, sensation, or motor strength.

The International Classification of Headache Disorders, 3rd edition (ICHD-3) lists the following criteria for migraine diagnosis:[20]

Migraine without aura

At least 5 attacks that have all of the following:

1. Headache attacks lasting 4-72 hours (untreated or unsuccessfully treated).
2. Headache has at least 2 of the following characteristics: unilateral, pulsating, moderate-to-severe pain, aggravation by routine physical activity.
3. Headache is accompanied by at least 1 of the following: nausea and/or vomiting or photophobia and phonophobia.
4. Not better accounted for by another ICHD-3 diagnosis.

Migraine with aura

1. At least 2 attacks fulfilling criteria for migraine without aura.
2. One or more of the following fully reversible aura symptoms: visual, sensory, speech and/or language, motor, brainstem, retinal.
3. At least 2 of the following:
   1. At least 1 aura symptom spreads gradually over ≥ 5 minutes.
   2. 2 or more symptoms occur in succession.
   3. Each individual aura symptom lasts 5-60 minutes.
   4. At least 1 aura symptom is unilateral.
   5. At least 1 aura symptom is positive.
   6. The aura is either accompanied or followed within 60 minutes by headache.
   7. Not better accounted for by another ICHD-3 diagnosis.

Treatment

Lifestyle modification can be highly effective for migraine prevention. The patient may benefit from avoiding situations that trigger or exacerbate migraines, for example, by maintaining appropriate sleep patterns, avoiding fasting and trigger foods, and participating in aerobic exercise and stress management. Conversely, there is also evidence that exposure to triggers may aid with desensitization and better migraine control.[21]

Abortive therapy. Abortive therapies are more effective when given early and in larger appropriate doses. Non-oral (suppository, intranasal, intramuscular, or intravenous) drugs may work better for patients who suffer from nausea and vomiting during episodes and cannot tolerate oral options. It is generally best to start with medications that are known to be effective and safe based on the patent’s history of migraine treatment. However frequent use of certain classes (more than 10 times per month) can lead to medication-overuse headaches. Common offenders include opioids and combination analgesics containing butalbital or acetaminophen-aspirin-caffeine. There is limited data on CGRP antagonists and ditans. When patients are using abortive treatments with this frequency, they should be evaluated for prophylactic treatment to reduce the number of headache days and the need for frequent abortive treatments.

The following agents are commonly used for abortive treatment:

Analgesics (aspirin, other NSAIDs, and acetaminophen). NSAIDs are a first-line treatment. Medication overuse headache can result from frequent use of many acute medications, but risk is lowest with NSAIDs, and this class of medications may even prevent the development of chronic migraine in individuals who have less than 10 headache days per month.[22]

Triptans (sumatriptan, rizatriptan, almotriptan, zolmitriptan). Triptans are used as second-line treatments. They inhibit vasoactive peptide release, cause vasoconstriction, and block pain pathways in the brainstem,[23] although sensitization may decrease the analgesic effect. These serotonin receptor agonists are for moderate-to-severe migraine. Choice and route of administration of triptan are determined by drug interactions and tolerability. There is a paucity of head-to-head trials comparing efficacy among triptans.

Triptans are more effective when combined with NSAIDs as part of an acute treatment plan. The combination of sumatriptan and naproxen has been best studied.[24] Triptans should be used with caution in patients with vascular disease or pregnancy given the theoretical risk of complications from vasoconstriction caused by these drugs and are typically not first-line treatments in these populations. Serotonin syndrome is uncommon, but the risk is increased when combined with selective serotonin reuptake inhibitors (SSRIs) or other serotonergic drugs.

Antiemetics (prochlorperazine, metoclopramide). These can be administered as monotherapy or as an adjunct to above therapies.

Dexamethasone. This is an effective adjunctive treatment when added to first-line therapies. Oral prednisone has not been found to be effective.

CGRPT antagonists (rimegepant and ubrogepant, zavegepant) These reduce headache severity and are typically well tolerated.[23] They may be considered if triptans are contraindicated (e.g., cardiovascular histories), ineffective, or poorly tolerated. Rimegepant may also be used as a prophylactic agent.[25] Care should be taken when using these medications with CYP3A4 substrates. CGRP antagonists’ safety has not been evaluated in those who have taken triptans within the last 24 hours. Head-to-head trials comparing them to other classes of acute migraine treatments are lacking.

Lasmiditan is a 5-HT1F receptor agonist. This drug does not cause vasoconstriction, so it can be use in those who have used a triptan within the last 24 hours. It causes drowsiness and dizziness and may cause impairment due to central nervous system depression. Driving should be avoided within 8 hours of use.[26]

Dihydroergotamine (intranasal or injectable) is effective for moderate-to-severe attacks. Given its contraindication for patients who have received a triptan in the last 24 hours, risk of vasoconstriction in those with vascular disease or are pregnant, and lack of availability and familiarity, it is rarely used outside of headache specialty clinics.

Benzodiazepines, narcotics, and barbiturates, including butalbital-containing medications, should be avoided if possible, due to their high potential for analgesic-overuse (analgesic-rebound) headache, risk of dependance, and questionable benefits for migraine relief.[27][28][29]

Prophylactic therapy. Prophylaxis is indicated if headaches occur at least 4 times per month or last longer than 12 hours or are associated with severe disability or complications. At least 4 weeks of prophylactic treatment is usually necessary before benefits are evident. It’s best to start at low doses and slowly titrate these medications to minimize risk of side effects. Many prophylactic agents are pharmaceuticals, although there is also good evidence for effectiveness of some botanicals, vitamins, and minerals.[30] Choice of agent largely depends on comorbidities, side effect profile, mediation interactions, and cost. A thorough review of the patient’s history is essential. The following agents are commonly used:

Beta-adrenergic blockers, such as propranolol, metoprolol, or timolol. Propranolol increases rizatriptan levels, so doses of rizatriptan being used to abort migraine should be adjusted.

Anticonvulsants, such as topiramate or valproic acid. Unless contraindications are present, topiramate is generally considered to be a first-line agent and may be preferred for patients who are overweight or obese given weight loss is a common side effect.[31] Valproic acid is generally avoided in women of reproductive age due to risk of birth defects.

Nonsteroidal anti-inflammatory drugs (NSAIDs), such as naproxen.[32] These agents are most useful when there is a short period of migraine susceptibility each month, such as may occur with menstrual migraine. Longer acting NSAIDs (e.g., naproxen) are preferred for this purpose.

Antidepressants. Tricyclic antidepressants, such as amitriptyline, and serotonin-norepinephrine reuptake inhibitors, such as venlafaxine, are effective.[33]

Riboflavin (see Nutritional Considerations below).

Cognitive behavioral therapy.

Botulinum toxin is effective for chronic migraine, and is generally considered if oral medications are ineffective or poorly tolerated at therapeutic doses.

Injectable CGRP antagonists including erenumab, fremanezumab, and galcanezumab have been shown to be highly efficacious and well-tolerated options.[34] These medications are typically dosed by a once monthly or every 3 months injection or infusion depending on the formulation.

Oral CGRP antagonists. Currently, atogepant and rimegepant are approved for migraine prevention. Both appear well tolerated.

Butterbur (Petasites hybridus root). While historical evidence suggests some efficacy for butterbur in reducing migraine frequency, preparations of this compound are not well regulated, and it carries risk of hepatotoxicity. Therefore, it is no longer recommended.[35]

Feverfew (tanacetum parthenium) is an herb with anti-inflammatory properties. Joint practice guidelines from the American Academy of Neurology and American Headache Society classify feverfew as “probably effective” with level B evidence. However, a recent review concluded that the evidence for feverfew is inconclusive, given heterogeneity in trial design and mixed results for effectiveness.[36] It increases the risk for bleeding when combined with antithrombtoics such as aspirin and is contraindicated in pregnancy, so it is not recommended for routine use.[37]

MIG-99 is a relatively newer extract of feverfew. A Class I study demonstrated that a baseline migraine frequency of 4.76 decreased to 1.9 attacks/month in the treatment group and by 1.3 attacks in the placebo group. A Class II dose-finding study looked at 6.25mg TID, which was effective in reducing migraine frequency by 1.8 attacks/month from 4.5 at baseline, whereas the placebo group had 0.3 fewer attacks each month.[38]

Behavioral interventions. Relaxation training, thermal biofeedback, EMG biofeedback, and cognitive behavioral therapy have relatively strong evidence for episodic migraine prevention.[39][40] Behavioral care may improve coping strategies and reduce migraine-related disability.[41] Aerobic exercise, combined with behavioral interventions, may further improve migraine management.[42]

Neuromodulatory devices. Several nonpharmacologic devices have been FDA cleared for both the prevention and acute treatment of migraine, including the Cefaly (an external trigeminal nerve stimulator), Nerivio (a remote electrical neuromodulation device), gammaCore (a noninvasive vagal nerve stimulator), and a transcranial magnetic stimulator device. While these options are not typically first-line treatments, they may be helpful for patients who wish to avoid oral treatments or who are unable to tolerate prescription medications. Access may be limited by out-of-pocket cost as they are often considered experimental treatments by many insurance companies given the lack of large, randomized controlled trials compared to standard treatments.

Nutritional Considerations

Nutritional approaches to migraine are often effective and are appealing to patients. Avoiding dietary triggers and following a healthful diet to reduce the risk of comorbidities, such as overweight and metabolic syndrome, are recommended.

Foods containing tyramine, such as aged cheese, cured meats, smoked fish, beer, and fermented foods, and other biogenic amines have long been suspected of triggering migraine, although dietary triggers will vary among patients. A review of randomized, double-blind, placebo-controlled studies failed to establish these as a cause of either headache or migraine.[43] Other studies (see below) indicate that dietary treatment may nonetheless be helpful for preventing migraine in some individuals.[44] Additional controlled clinical trials are required to firmly establish the role for diet in the causation or prevention of migraine. Nevertheless, dietary treatment may be considered first as a low-cost, low-risk treatment before medication is used, or in patients who either do not respond to or tolerate medication well.

A healthy weight. Being either underweight or overweight can increase migraine risk. Underweight is associated with an approximately 20% increased risk for migraine. Obese individuals had a 75% greater risk for chronic migraine, while overweight individuals had a roughly 40% higher risk when compared with normal weight persons.[45] Weight loss has been found to reduce migraine frequency, intensity, and duration.[46][47]

Diets that are low in fat, higher in omega-3 fatty acids, or plant-based. Several types of dietary interventions have been shown to be effective for reducing migraine pain. One central feature of these diets is that they would be expected to reduce oxidative stress, which is known to impact migraine through the TRPA1 ion channel that triggers nociception.[48] These studies are described below.

Some evidence suggests that reducing total and omega-6 fat and increasing the ratio of omega-3 to omega-6 fatty acids in the diet may reduce migraine occurrence in some patients.[49][50][51] One suggested mechanism for this effect relates to arachidonic acid metabolism. This omega-6 fatty acid, found in animal products, is a precursor for both prostaglandin E2 (PGE2) and leukotriene B4 (LTB4), levels of which are elevated during migraine attacks.[52][53] Although inhibition of the production of these eicosanoids by NSAIDs (see above Treatment section) and by antileukotriene drugs has been found effective for migraine prevention, changes in diet that limit the intake of omega-6 fats may have a similar benefit.[54][55]

Elimination diets. Randomized, controlled clinical trials found significant reductions in migraine in individuals who removed foods from their diets for which they had IgG antibodies. One of these found a 29% reduction in migraine days, while the other revealed a 19% reduction.[56][57] In addition, a crossover trial using a low-fat, vegan diet, followed by an elimination diet, was found to be helpful in reducing migraine pain.[58]

Previous research studies have established that avoidance of foods found to trigger migraine can reduce or eliminate headache in approximately 20-50% of patients.[44][59]

Elimination of suspected trigger foods may be done with the help of an allergist, although patients can also pursue an elimination diet on their own. The procedure is as follows:

Start with a baseline diet including only those foods not implicated in migraine:

• Brown rice.
• Cooked or dried fruits, such as cherries, cranberries, pears, or prunes (avoid citrus fruits).
• Cooked green, yellow, and orange vegetables (artichokes, asparagus, broccoli, chard, collards, lettuce, spinach, string beans, squash, sweet potatoes, tapioca, and taro).
• Plain or carbonated water.
• Condiments flavorings (modest amounts of salt, maple syrup, and vanilla extract).

Eliminate foods, beverages, and additives suspected of triggering migraines, including the following:

• Dairy products (including nonfat dairy products)
• Chocolate
• Alcohol
• Caffeine
• Aspartame
• Eggs
• Citrus fruits
• Meat
• Wheat
• Nuts
• Tomatoes
• Onions
• Corn
• Apples
• Bananas

Wean from caffeine-containing beverages gradually or avoid caffeine if not habitually consumed.

When migraines have stopped or diminished (usually within a week or so), the patient should keep a food diary and return the eliminated foods to the diet one at a time, every other day, starting at the bottom of the elimination list. Each newly added food should be added in generous amounts to observe which cause migraine recurrence. Needless to say, foods that raise other health concerns (e.g., meat and dairy products) do not need to be added back at all. If a newly added food is associated with a migraine attack, it should be removed from the diet for 1-2 weeks and then reintroduced to see if the same reaction occurs. If no symptoms are experienced, that food can remain in the diet.

Caffeine. A study that analyzed data from more than 50,000 individuals over 2 decades found a 10% higher risk for migraine in persons consuming more than 540 mg of caffeine per day compared to those consuming between 0 and 240 mg/day (about 2 cups of coffee).[60] Conversely, caffeine has been found useful for the treatment of headaches caused by post-dural puncture and hypnic (“alarm clock”) headaches, possibly because plasma adenosine increases during migraines and caffeine is a well-known adenosine antagonist.[44][61] Despite the conflicting evidence on caffeine’s role in the prevention or treatment of migraine, caffeine withdrawal is an established migraine precipitant.

Heart-health-promoting diets. Metabolic syndrome, obesity, stroke, subclinical vascular brain lesions, coronary artery disease, and hypertension often coexist with migraines.[62] In the Women’s Health Study, those with a history of migraine had a significantly higher risk for myocardial infarction compared with women who had no migraine history.[63] Similarly, the Physicians Health Study of more than 20,000 individuals found that those with a history of migraine had a more than 40% greater risk for myocardial infarction compared with other people.[64] (See also Coronary Heart Disease chapter.)

Supplements. Several supplements have shown promise for migraine prevention or treatment. Their utility is based on evidence indicating that a defect in mitochondrial energy production and increase in oxidative stress exists in migraine sufferers.

In a multicenter trial with 130 patients, a combination of 150 mg CoQ10, 400 mg B2, and 600 mg magnesium, combined with a multivitamin-mineral formula containing 200 mg vitamin C, 134 mg vitamin E, and amounts close to Recommended Daily Intakes (RDI) of other micronutrients was taken daily for 3 months. The number of monthly days with migraine fell from 6.2 at baseline to 4.4 during active treatment (-1.8 days), compared with a reduction of 1 day in the control group. While these results were modest, the treatment group experienced a greater reduction in pain severity and improved scores on a headache impact survey.[48]

A meta-analysis of trials involving the use of intravenous or oral forms of magnesium in migraine patients concluded that intravenous magnesium provided significant relief in acute migraine within 15-45 minutes and lasting up to 24 hours after infusion, while oral magnesium significantly reduced both the frequency and intensity of migraines.[65] Individuals with lower ionized magnesium levels (0.54 mmol/L or less) may be more likely to respond. Overall, evidence is limited for oral magnesium supplementation as a preventive option, when considering a typical dose of 600 mg elemental magnesium daily. The American Academy of Neurology has rated intravenous magnesium as level B for acute migraine treatment,[66] while a 2014 meta-analysis suggests it is probably ineffective, or of uncertain effect.[67] Preventive evidence is considered level B.

One small class II study demonstrated that CoQ10 100 mg TID was significantly more effective than placebo in reducing the frequency of migraines. Nearly 50% of those treated had at least a 50% reduction in migraine.[68]

Riboflavin, a cofactor in mitochondrial energy production, has been shown to reduce migraine. A review of studies on both adults and children concluded riboflavin may be beneficial in reducing frequency and duration of migraine in adults.[69] The American Academy of Neurology and the American Headache Society have therefore classified the evidence of riboflavin’s efficacy for migraine as Level B (probably effective and should be considered for migraine prevention).[66]

Ginger. In a double-blind randomized placebo-controlled trial, an eighth teaspoon of powdered ginger was found to work as well as the drug sumatriptan (Imitrex) without side effects.[70]

Orders

Nutrition consultation to identify food triggers, prescribe elimination diet as described above, formulate meal plans, and help with the attainment of a healthy body weight. (See also Coronary Heart Disease chapter.)

Consider allergist referral on an outpatient basis.

What to Tell the Family

Migraine is a relatively common condition that can affect patients starting in childhood. The patient’s family should be taught about the possible role of dietary and environmental triggers. A headache diary that keeps track of sleep, exercise, dietary choices, and stressors may help patients identify migraine triggers that can be avoided or minimized.

References