US Pharm. 2007;33(1):32-37.

Individuals with chronic pain that lasts for more than three to six months may experience multiple types of pain in the head and neck region, including headache and facial pain.1 Approximately 18% of women and 6% of men suffer from some form of frequent headaches, and many cases go undiagnosed and undertreated.2 Headaches have a major socioeconomic impact on society.

This article will review the classifications and pathogenesis of migraine, various pharmacologic and nonpharmacologic treatments, and the pharmacist's role in patient education.

The International Headache Society has developed a classification system for headache disorders ( TABLE 1).3 Headaches are broadly classified into primary and secondary headaches. Primary headache disorders, which are due to a primary neurologic process without an underlying cause, include migraine, tension-type headache, cluster headache, and other trigeminal autonomic cephalalgias. Primary headache disorders are subdivided one, two, or three times into headache types, subtypes, and subforms based on the presence or absence of symptoms or on the frequency of attacks.3,4

Secondary headache disorders have a specific underlying cause. These headaches can be attributed to such causes as head and/or neck trauma; infection; a substance or its withdrawal; cranial or cervical vascular disorders; nonvascular intracranial disorders; psychiatric disorders; and disorders of the cranium, neck, eyes, ears, nose, sinuses, teeth, mouth, or other facial or cranial structures.

In the United States, migraine affects approximately 28 million people.5 The prevalence of migraine is similar for boys and girls in the prepubescent years, but is higher in adolescent girls than boys. In adulthood, migraine is three times more frequent in women than in men; about 75% of all individuals who experience migraines are women.6

The word migraine comes from the Greek word hemicrania, meaning "pain on one side of the head." The World Health Organization ranks migraine 19th of all diseases worldwide causing disability.7 Migraine, predominately an inherited disorder, is divided into two major subtypes: migraine without aura and migraine with aura. Although it is considered a type of primary headache, migraine can be a secondary headache if it occurs for the first time in close temporal relation to another disorder that is a known cause of headache. Migraine attacks are commonly unilateral and throbbing, and the pain is aggravated by routine activities such as walking, climbing stairs, or bending over.

Diagnosis of migraine is difficult because of the periodic nature of the condition and the absence of radiographic and laboratory markers of disease. Reliance on the patient's ability to describe past attacks is important for diagnosis.

Phases and Pathogenesis
Migraine is a neurochemical reaction involving the trigeminovascular system rather than a vascular event, as was once believed. Although vascular changes do occur, they are not related to the clinical features of the migraine.8 Stimulation of the trigeminal nerve causes the release of vasoactive peptides; this is responsible for the head pain, as well as the facial and neck pain, experienced during migraine. The facial and neck pain often lead to misdiagnosis of the migraine as a sinus or tension headache.8

A migraine has four phases: prodrome, aura, headache (pain), and postdrome.9 Not all migraineurs experience all four phases.

Prodrome: The prodrome, which occurs hours or days before (or sometimes during) the headache, is characterized by altered mood, irritability, depression or euphoria, stiff neck, light sensitivity, yawning, excessive sleepiness, tiredness, fluid retention, and food cravings. These symptoms occur in 40% to 60% of migraineurs.10

The exact etiology of prodrome is not fully understood, but it is hypothesized that prodrome is caused by a dysfunction in the hypothalamus.11

Migraine with Aura: Migraine with aura is characterized by episodes of neurologic symptoms including visual, sensory, or motor dysfunction, or a combination of these. Most aura symptoms, which usually precede (hours or days before) or sometimes occur with the migraine, develop gradually over five to 20 minutes and last less than 60 minutes. Aura represents a transient episode of focal neurologic dysfunction caused by an imbalance between excitatory and inhibitory neuronal activity at different levels in the central nervous system.11

Visual aura, which is present in up to 99% of migraineurs, may manifest as bright flashing lights, specks of light, geometric shapes, shimmering, or scotoma (partial obliteration or loss of vision in a portion or the whole of the visual field).12 It has been postulated that some of the surreal adventures depicted in Alice in Wonderland were based on visual auras experienced by the author, Lewis Carroll.13 It is believed that visual aura is caused by a wave of cortical spreading depression (CSD) moving across the cerebral cortex and resulting in depressed neuronal activity and then intense neuronal activity. In migraineurs who experience visual aura, CSD may occur in areas of the brain that are "clinically silent" in those who do not experience visual aura.8,14,15

Sensory aura, which occurs in up to 40% of migraineurs, may take the form of a paresthesia that involves the arms, face, hands, or other parts of the body. It also may present as cheiroaural numbness, which is a tingling followed by numbness starting in the hand, moving superiorly up the arm, and then jumping to the face, where it is felt around the mouth.16

Migraine Without Aura: To establish a diagnosis of chronic migraine without aura, five attacks lasting for four to 72 hours must have occurred on 15 or more days a month for more than six months. Migraine without aura is usually associated with photophobia (sensitivity or intolerance to light), phonophobia (fear of sounds, including one's own voice), nausea, and vomiting; some patients experience cutaneous allodynia (pain evoked by normally nonpainful stimulus of the skin) during an attack.11

Individuals who experience migraine with aura also may experience attacks of migraine without aura. Conversely, however, those who experience migraine without aura will not experience migraine with aura.11

Headache/Pain: Headache begins during or within 60 minutes of the aura and is usually unilateral and throbbing. Although vascular changes are evident during a migraine, the cause of the headache is neurologic, not vascular. Migraine headache pain is induced primarily by vasodilation and inflammation leading to nociception (perception of pain) and central and peripheral sensitization. Stimulation of the trigeminal nerve (fifth cranial nerve), which carries sensory information from the face, can cause referral of pain to any of the nerve's three branches, resulting in facial pain. It can also cause referred pain to the sensory nerves of the posterior head and neck, resulting in neck pain.8,11,17

Perivascular nerve activity also results in the release of substances such as substance P, neurokinin A, calcitonin gene-related peptide, and nitric oxide, which interact with the blood-vessel wall to produce dilation, protein extravasation, and sterile inflammation, stimulating the trigeminocervical complex.9 Substance P, a short-chain polypeptide, is a chemical messenger that, when released, signals the brain to feel pain.18

Additionally, activation of vascular 5-HT2B and/or 5-HT7 (serotonin receptors), possibly as a consequence of the sudden rise in 5-HT levels at the onset of a migraine, hypothetically would result in the dilation of cerebral blood vessels and the concomitant activation of sensory trigeminovascular nerves, initiating the manifestation of head pain. At this stage in the migraine process, the activation of specific subtypes of 5-HT 1 receptors has proven clinically effective for relieving migraine pain. The recent availability of subtype-selective 5-HT1D and 5-HT1F receptor agonists could possibly lead to antimigraine drugs with a safer cardiovascular profile.19

Postdrome: About 25% of migraineurs experience a postdrome, which involves changes in mood and behavior after the migraine attack. Precipitating factors include caffeine (and caffeine withdrawal), menstruation, stress, smoking, lack of sleep, certain foods, and strenuous exercise.11

Migraine Triggers
Various factors can trigger migraines, including stress, emotions (e.g., depression, anxiety), hormonal changes (e.g., menstruation, pregnancy, birth control pills), weather changes, fumes and vapors (e.g., smoke, perfume), lack of sleep, bright light, noises, and foods. Some foods and additives that can trigger migraines are monosodium glutamate (also known as MSG), alcohol, tyramine-containing foods (e.g., pickled herring, aged cheese, cured meats, yeast), chocolate, excessive caffeine, and nitrites. Migraine triggers are different for each person.

Drug Therapy
Only one-half of patients seek medical attention for migraine, and only about half of these are properly diagnosed.20 Drug therapy aims to abort a migraine at the time it occurs, provide symptomatic pain relief, and prevent a migraine from recurring.21 Any symptomatic drug therapy, whether prescription or OTC, should not be used more than twice a week; beyond that, the patient should be taking preventive medications. The patient should start by eliminating all products containing caffeine, which causes vasoconstriction. The following are classifications of drugs used in the treatment of acute migraine attacks and for prophylaxis (TABLE 2).

Abortive Treatment of Acute Migraine
Triptans: Introduced in the United States in the late 1990s, triptans (hydroxytryptamine receptor agonists) are effective and well tolerated for the initial treatment of acute moderate or severe migraine to abort the attack or in patients with mild to moderate migraine who respond poorly to NSAIDs.22,23 A recent study found sumatriptanñnaproxen to be more effective than monotherapy.24

Triptans bind with high affinity to 5-HT1B/1D receptors and are referred to as selective serotonin agonists. Activation of these receptors results in cranial-vessel constriction, inhibition of neuropeptide release, and reduction of transmission in trigeminal pain pathways. Formulations available include oral, suppository, injection, and nasal spray. Orally administered triptans provide pain relief within 30 minutes, and injected sumatriptan has an onset of action of less than 15 minutes.

Triptans are metabolized primarily by monoamine oxidase enzymes, similar to monoamine oxidase (MAO) inhibitors. Thus, taking triptans and MAO-A inhibitors together generally leads to an increase of blood triptan levels. It is necessary to wait more than two weeks after the MAO inhibitor is discontinued before initiating triptan therapy.

Triptans should not be administered to patients with ischemic heart disease (e.g., angina pectoris, history of myocardial infarction, silent ischemia), symptoms of ischemic heart disease, or coronary-artery vasospasm. Triptans may increase blood pressure and should not be given to patients with uncontrolled hypertension. Velentgas et al, however, found no association between triptans and increased risk of any ischemic events.25

The combined use of triptans and antidepressants, including selective serotonin reuptake inhibitors (SSRIs) and selective serotonin/norepinephrine reuptake inhibitors (SNRIs), may cause serotonin syndrome resulting from excessive blood levels of serotonin; however, the risk is low.26,27 Signs and symptoms include restlessness, hallucinations, rapid heartbeat, diarrhea, nausea, vomiting, and rapid changes in blood pressure. Serotonin syndrome is more likely to occur when starting or increasing the dose of a triptan, SSRI, or SNRI. This combination is not contraindicated, but care should be taken when the two drugs are given concurrently.

Common adverse reactions with triptans are head and jaw discomfort, flushing, dizziness, sleepiness, and tiredness.

Ergot Derivatives: Drugs such as ergotamine and dihydroergotamine nasal spray are alpha-adrenergic blockers and vasoconstrictors of cranial smooth muscle and are used in the treatment of moderate or severe migraine in selected patients. 23 Caffeine, a vasoconstrictor, is added to enhance absorption and potentiate analgesia.28 Elevated blood levels of ergot derivative occur when the drug is taken with erythromycin and clarithromycin. Many adverse effects, including nausea, localized edema and itching, and numbness and tingling in the fingers and toes preclude ergot derivatives for long-term use or for prevention. Prolonged use may cause medication-overuse headache (MOH; formerly known as rebound headache). Er!= gotamine derivatives are contraindicated during pregnancy or in patients with peripheral vascular disease, hepatic or renal disease, coronary artery disease, hypertension, or sepsis.

Analgesics: For mild migraine attacks, analgesics alone or in combination with caffeine are the drug of choice.29 Overuse of analgesics and caffeine can aggravate the migraine (i.e., cause MOH). Most of the pain-relievers patients use are OTC. Caffeine is added to enhance the drug's absorption and to potentiate the drug's activity. Excedrin Migraine (which is identical to Excedrin Extra Strength) contains acetaminophen, aspirin, and caffeine. Two tablets contain roughly the amount of caffeine found in a cup of coffee. Long-term use of analgesics is discouraged, as this may lead to MOH upon withdrawal. Adverse effects include nausea and gastrointestinal upset and bleeding. NSAIDs (e.g., ibuprofen, naproxen) reduce the release of serotonin and can be used in combination with triptans.21

Narcotic analgesics, which are used for more severe pain, are not FDA-approved. They may carry a greater risk of MOH, and they have the potential for abuse and dependency. Refractory patients may require narcotic injections for acute attacks.30

Migraine Prophylaxis

Choosing a drug for prevention is based upon the adverse-effect profile of the drug and on the patient's medical status. Prophylaxis should reduce or eliminate the need for abortive drugs.

Anticonvulsants: Topiramate is approved for migraine prevention in adults.31 It is a sulfamate-substituted monosaccharide with a broad spectrum of anticonvulsant activity. Common adverse effects include lowered bicarbonate levels in the blood causing an increase in blood acidity (metabolic acidosis), hyperventilation, and fatigue. Adequate fluid intake is important to minimize the risk of renal-stone formation. Other side effects are tingling in the arms and legs, loss of appetite, nausea, diarrhea, taste change, and weight loss. 32

Valproic acid is approved for migraine prophylaxis and can take up to two to three weeks to be effective. Common adverse effects, including weight gain, sedation, and xerostomia, may preclude its use in some patients.

Beta Blockers: The use of beta blockers for the treatment of migraine started in the 1960s, when patients being treated for heart problems found that their migraine frequency decreased. The reason for the drugs' effectiveness may be that they limit the tendency for cranial blood vessels to overdilate. It may take up to four to six weeks to see a reduction in migraine frequency. Timolol and propranolol are FDA-approved for prophylaxis, but propranolol has more research evidence of efficacy than timolol.

Calcium Channel Blockers: Similar to beta blockers, calcium channel blockers were originally used to treat cardiovascular conditions. These drugs also may work by stabilizing blood-vessel membranes by preventing them from overdilating. It can take up to two months to see effects.

Tricyclic Antidepressants: Antidepressants are used for migraine prevention for their analgesic effect. A lower dose is prescribed than would be used for the treatment of depression. It can take up to three to four weeks before the drug is effective.33

Botulinum Toxin Type A: In addition to being used cosmetically and for dystonia (sustained contraction of muscles), botulinum toxin type A--which is derived from the exotoxin produced by the bacterium Clostridium botulinum--is used for the prevention of migraines for up to six months and for refractory chronic migraine in patients who previously failed to respond to at least three prophylactic medications. Although the exact mechanism is unclear, it has been hypothesized that the drug works by inhibiting the release of transmitters from pain-sensitive nerve endings.34

Alternative Treatments: Some alternative remedies used in the prophylaxis of migraine are feverfew, riboflavin, coenzyme Q10, magnesium, butterbur, and melatonin. There are no randomized, controlled studies of melatonin.35,36 There is concern about the lack of standardization of the contents and the purity of herbal supplements.

A number of alternative modalities have been recommended for the treatment and prevention of migraine, including hypnosis, biofeedback, meditation, acupuncture, massage, and transcutaneous electrical nerve stimulation.

MOH is a syndrome or cycle that occurs when a patient overuses medications of different classes (but not of a single class), which contributes to the headache rather than easing it.37 MOHs can occur in headache-prone individuals when acute headache medications are taken for other indications. OTC pain relievers containing caffeine (e.g., Excedrin Migraine, Excedrin Tension Headache) are a possible cause; caffeine in coffee, sodas, and various other foods and beverages also may contribute to MOH. To prevent MOH, the amount of pain medication being used should be reduced (limited to two days per week) or stopped. MOH is difficult to diagnose. The signs and symptoms of MOH include nausea, anxiety, insomnia, and restlessness.

Migraine places a significant burden not only on patients, but on their families and employers as well. Many types of headache are associated with temporary disability (e.g., missed work, school, and household responsibilities) and with high personal and socioeconomic costs. Since many people suffer from migraines, the pharmacist plays a pivotal role in patient education.

Pharmacists should take a proactive approach in managing patients with migraines and other types of headache. To do this more effectively, the pharmacist must have a good understanding of the physiologic and neurologic processes involved in headache disorders and a broad knowledge of the available pharmacologic treatments.

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