A fresh look at migraine therapy

New treatments promise improved management

Seymour Diamond, MD

VOL 109 / NO 1 / JANUARY 2001 / POSTGRADUATE MEDICINE

CME learning objectives

• To become familiar with the pathophysiology and clinical features of migraine
• To learn the common signs of various types of migraine
• To understand the various options available for acute and prophylactic therapy of migraine

Dr Diamond discloses financial interests in or connection with the following pharmaceutical companies: Glaxo Wellcome, Wyeth-Ayerst, Bayer, Merck, AstraZeneca, Carnrick, Bristol-Myers Squibb, and Abbott.

This is the second of four articles on headache

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Preview: About 26 million Americans, nearly 70% of them women, are challenged by persistent, sometimes incapacitating migraine headaches. Although treatment has improved dramatically during the last decade, migraine headaches continue to raise diagnostic dilemmas and management questions among primary care physicians. In this article, Dr Diamond discusses diagnosis, current management, and prophylactic measures that can offer hope to many patients.
Diamond S. A fresh look at migraine therapy: new treatments promise improved management. Postgrad Med 2001;109(1):49-60

The malady known as migraine was identified thousands of years ago and is known throughout all civilizations on earth. The earliest recorded description of headache dates to Mesopotamia in 4000 BC. Aretaeus of Cappadocia (130 to 200 AD) devised the first true description of migraine as a distinct entity because of its unilateral occurrence, association with nausea, regular recurrence, and paroxysms of pain separated by pain-free intervals. Because the pain was unilateral, Aretaeus called this type of headache "heterocrania." We now use the word "hemicrania," which literally means "half a head." Aretaeus also recognized the differences between acute headache attacks that lasted for days (cephalalgia) and chronic headaches (cephalea).

Classification of headache

Many elaborate classifications of headache have been formulated, including the 1962 recommendations of the Ad Hoc Committee on Classification of Headache of the National Institutes of Health (1). The most recent effort was published in 1988 by the International Headache Society (2). These classifications are complex and lengthy and are used primarily for research purposes. Therefore, they are difficult to translate into clinical practice.

My colleague Donald J. Dalessio, MD, and I devised a practical classification of headache for clinical use (3). We classified headaches into three primary categories (table 1): vascular (migraine, cluster) headache, tension-type (muscle contraction) headache, and organic (traction, inflammatory) headache. We also subdivided migraine into three types: migraine with aura (classic), migraine without aura (common), and complicated migraine (hemiplegic, ophthalmoplegic, and basilar artery migraine).

Table 1. Classification of headache

Vascular Migraine    With aura    Without aura    Complicated       •Hemiplegic       •Ophthalmoplegic       •Basilar artery Cluster (histamine) Toxic vascular Hypertensive Tension-type (muscle contraction) Depressive equivalents and conversion reactions Chronic anxiety states Cervical osteoarthritis Chronic myositis Organic Mass lesions (tumors, edema, hematomas, cerebral hemorrhage) Diseases of eye, ear, nose, throat, and teeth Arteritis, phlebitis Occlusive vascular disease Atypical facial pain Temporomandibular joint dysfunction Cranial neuralgias (facial, glossopharyngeal)

A large number of patients have coexisting migraine and tension-type headache, which we consider an overlapping category. This combination headache is sometimes called mixed headache syndrome, transformed migraine, or chronic daily headache. Patients who have these headaches usually can differentiate the severe headache that has migraine characteristics and occurs two to five times a month from the chronic daily headache that is less severe (4).

Pathophysiology

Although the pathophysiology of migraine has not been firmly established, we owe a great deal of our knowledge about migraine pathophysiology to Harold G. Wolff, MD. During the 1930s, Dr Wolff did extensive research on migraine, including performing a craniotomy on a patient who was having an acute migraine attack. He observed initial cerebral vasoconstriction, followed by extracranial and intracranial vasodilation (5). He also noted that sterile inflammation surrounded the affected vessel and secondary muscle contraction was present.

On the basis of this information, Dr Wolff formulated the vascular theory of migraine. He also noted that certain vasoactive substances found in the inflamed tissue around the blood vessels contained catecholamines, histamine, serotonin, peptides, prostaglandins, and the slow-reacting substance of anaphylaxis, which is an acidic lipid. Dr Wolff speculated that prolonged migraine attacks (lasting 24 to 48 hours) seemed to be related to sterile inflammation. As a result of Dr Wolff's findings, corticosteroids were used for treating prolonged migraine headaches.

The work of Sicuteri and associates (6) and Curran and colleagues (7) confirmed the role of serotonin and its metabolites during all phases of a migraine attack. These investigations demonstrated that serotonin-releasing agents can induce migrainelike attacks. The fact that many of the newer drugs used for management of acute migraine are serotonin receptor agonists further implicates serotonin as a key player in migraine pathogenesis.

Neurologic theories of migraine have also been proposed. Studies by Olesen and associates (8) suggested that migraine results from an abnormal firing of a brain neuron. Spreading depression, a part of the neurologic theory, could explain the prodrome or aura of migraine. Moskowitz (9) identified the trigeminal ganglion as a factor in inducing neurogenic dural inflammation and the subsequent vascular pattern of the migraine attack. Other, more recent investigations suggested that substance P (10), calcitonin (11), and nitric oxide (12) are all active in the dural inflammatory cascade that occurs with or causes the vascular changes.

Definition of migraine

Although several definitions of migraine have been formulated, we rely on the definition developed by the World Federation of Neurology (13). It defines migraine as "a familial disorder characterized by recurrent attacks of headache widely variable in intensity, frequency, and duration. Attacks are commonly unilateral and are usually associated with anorexia, nausea, and vomiting. In some cases, they are preceded by, or associated with, neurological and mood disturbances."

The definitive characteristic of migraine with aura is the occurrence of a neurologic symptom complex 5 to 30 minutes before the onset of an acute migraine attack. Complicated migraine is described as a migraine attack associated with focal neurologic symptoms that may persist after the headache disappears. Ophthalmoplegic, hemiplegic, and basilar artery migraine are considered forms of complicated migraine.

Among adults who have migraine, about 70% are women and, of those, about 70% report a relationship between acute migraine attacks and menstruation. Menstrual migraine attacks can occur immediately before, during, or after menses. However, some women may also have attacks at other times of the month. Many women report a decrease in or complete remission of migraine attacks after the first trimester of pregnancy.

Clinical features

Migraine is not a daily headache. Frequency varies from a few headaches each week to one or two episodes each year. Most often, attacks occur two to eight times a month. Average duration is 4 to 24 hours, although some patients complain of headache lasting several days (status migrainosus). The degree of severity varies from moderate to incapacitating.

Patients who have migraine headaches often describe them as throbbing or pulsating. Although migraine pain is usually unilateral, it can occur on both sides of the head. Pain often affects the frontal and temporal regions but may be localized behind the eye. Also, pain can radiate across the head and to other regions of the face and neck.

Because of its association with nausea, vomiting, photophobia, phonophobia, dizziness, tinnitus, and blurred vision, migraine is often depicted as a "sick" headache. Symptoms can influence the selection of abortive and pain-relieving medication, as well as the route of administration. Migraine headaches are often exacerbated by physical activity.

Although migraine can first occur in childhood or as late as age 50, it usually starts during adolescence or young adulthood. In childhood migraine, boys and girls are affected equally until puberty, when the predominance shifts to girls (60% to 70%). Up to 70% of migraineurs report a family history of similar headaches.

The warning phase
As stated earlier, the two major types of migraine are differentiated by the presence of an aura (prodromata). The aura consists of focal neurologic symptoms localized to the cerebral cortex or brainstem that may initiate or accompany the headache phase. Symptoms develop gradually over 5 to 20 minutes and are attributed to initial vasoconstriction. The aura typically lasts less than an hour.

The symptoms of the aura usually include such visual phenomena as flashing lights, zigzag or jagged lines, blind spots, difficulty in focusing, and distorted perception. Sometimes visual images are out of focus or appear to be unusually large or small.

Another occasional warning symptom is difficulty in speech, such as inability to find the right word or use of wrong words. A complete inability to speak occurs on rare occasions. Some patients are not able to understand what has been said. Also, headache may be preceded by motor aphasia.

Some patients who have migraine attacks, with or without aura, also have vague premonitory symptoms that start from 12 to 36 hours before the actual headache occurs. The symptoms usually begin imperceptibly and develop slowly. Premonitory symptoms vary and may range from one extreme to the other (eg, from euphoria to withdrawal, hyperactivity to sluggishness, extreme hunger to anorexia, diarrhea to constipation, frequent urination to fluid retention).

Other premonitory symptoms include yawning and fatigue, difficulty focusing, changes in personality, slurred speech, impaired concentration, irritability, agitation, sensitivity to light or sound, stiff neck, general muscle weakness, sensitive skin, and thirst. Some people have a feeling of well-being, become unusually talkative, and notice a surge of energy. The person's face may be pale, and the eyes may appear dark, heavy, or sunken. Although the migraine victim is not aware of these warning signs, friends or relatives may notice them.

Variations in hormone levels trigger headaches in many women, and fatigue, oversleeping, or skipping a meal can bring on migraine in some people. Medications have also been implicated in migraine attacks, including such agents as nitroglycerin, reserpine, indomethacin (Indocin), oral contraceptives, and cyclic estrogen replacement drugs. Psychological factors, such as anxiety, depression, repressed hostility, anger, and fear, can play a role as well.

Treatment

Migraine treatment can be divided into four types: general measures, abortive therapy, pain relief measures, and prophylactic therapy. Status migrainosus may require that additional strategies be tried.

General measures
An important step in migraine management is identifying and avoiding headache triggers. Because migraine patients are particularly sensitive to changes in routine, regular sleep and meal schedules should be maintained. Although stress cannot be avoided, training in coping strategies or stress management may be beneficial. Similarly, a significant number of migraine sufferers appear to be obsessive, compulsive, and rigid, although this hypothesis has been debated. They may create environments that present enormous challenges. For example, a working mother returns to school and also participates in a number of volunteer activities. In many cases, a migraine sufferer endures a stressful period but then has a severe headache once the stress is alleviated.

Certain activities often trigger acute migraine attacks, such as looking at bright lights or the sun or watching a flickering or out-of-focus television program or film. I recommend use of tinted glasses during times of exposure to bright light for my migraine patients. In addition, flying or being at high altitudes, where the oxygen tension and concentration are usually lower than normal, can precipitate migraine attacks. Acetazolamide (Dazamide, Diamox), a diuretic and carbonic anhydrase inhibitor, taken the day before and the day of flying, may help patients who have migraine related to altitude changes. Changes in barometric pressure have also been identified as a migraine trigger, and migraine patients may be especially sensitive to weather conditions.

Abortive therapy
Until the early 1990s, only a few drugs were available for the acute treatment of migraine. Many physicians started with over-the-counter analgesics or prescription nonnarcotic nonsteroidal anti-inflammatory drugs (NSAIDs), progressed through the ergotamine drugs, and used narcotics as a last resort in patients who had acute migraine attacks. Many times, management involved a litany of trial and error before a suitable drug was found. With the introduction of the triptans, early intervention with these migraine-specific drugs may act to reverse the migraine cascade.

Since then, advances have been made in pharmacologic therapy for migraine. Nevertheless, management of the migraine patient still requires frequent office visits, open communication between physician and patient, and an understanding by both physician and patient of the intricacies of drug treatment and interactions. For example, the route of administration is important in obtaining relief because it impacts the speed of action. Although oral administration is the simplest, it may not be appropriate for many of the 70% of migraineurs who have associated nausea and vomiting. Parenteral administration offers the quickest action, but self-injection may not be the optimal choice for many patients. A trip to the physician's office or emergency department delays the relief so badly needed.

Triptans: Discovery of the 5-hydroxytryptamine₁ (5-HT₁) receptor agonists ("triptans") has brought about remarkable advances in the treatment of migraine (14). These drugs have demonstrated efficacy in aborting migraine attacks and have variable affinity for the 5-HT_1A, 5-HT_1B, 5-HT_1D, and 5-HT_1F receptors. Their antimigraine effect is exerted by way of a receptor-mediated neural pathway in both the central nervous system and the trigeminal nerve, at which point neurogenic inflammation is blocked.

Sumatriptan succinate (Imitrex), the first triptan to be approved for migraine abortive therapy in the early 1990s, originally was available only for subcutaneous injections. Now sumatriptan can be given by oral or intranasal routes, as well as by injection. It is usually well tolerated and causes only minor side effects (eg, flushing, tingling, neck or chest tightness or pain, nausea, throat discomfort). If the first dose of sumatriptan offers at least partial headache relief, a second dose can be given an hour later or anytime within the next 24 hours if the headache recurs. However, a 5-day hiatus should be maintained between days of use. Sumatriptan should not be used in patients with basilar or hemiplegic migraine, ischemic heart disease, or Prinzmetal's angina and cannot be used concomitantly with ergotamine preparations or monoamine oxidase inhibitors (MAOIs).

Several oral second-generation 5-HT_1B/1D agonists have been developed in the past few years. In 1998, the US Food and Drug Administration (FDA) approved naratriptan (Amerge), rizatriptan benzoate (Maxalt, Maxalt-MLT), and zolmitriptan (Zomig) for migraine therapy. It should be noted that none of the triptans can be used concomitantly with ergotamine derivatives nor should they be used in patients with basilar or hemiplegic migraine, ischemic heart disease, or Prinzmetal's angina.

Naratriptan has a longer half-life than the other triptans and remains active in the blood vessels for up to 6 hours. It has a low incidence of side effects, the most common of which are nausea and vomiting. Naratriptan holds promise for management of menstrual migraine because it has a long half-life. In addition, it can be used with MAOIs.

Rizatriptan is absorbed rapidly, and its effects can be noted within 30 minutes of ingestion. It is well tolerated but can cause a few mild side effects (eg, bitter taste, dizziness, fatigue, sleepiness, nausea). Rizatriptan is the only triptan currently available in an orally disintegrating tablet, which offers patients a convenient alternative if they prefer not to take water with their migraine medication. The formulation quickly dissolves on the tongue and is absorbed through the gastrointestinal tract. It does not exacerbate the nausea often associated with an acute migraine attack.

Zolmitriptan is also absorbed quickly and alleviates migraine attacks faster than some of the other triptans. It appears to be effective in alleviating associated symptoms, including nausea and sensitivity to light and sound. Its side effects are similar to those with sumatriptan and include nausea, dizziness, prickling or tingling of the skin, drowsiness, warm or cold sensations, jaw pain, and tightness of the neck or throat.

Three new triptans (eletriptan [Relpax], almotriptan, frovatriptan) may be available in the near future.

Ergotamine derivatives: Ergotamine tartrate preparations are vasoconstrictors that have been used in migraine abortive therapy for more than 50 years. These agents are available for oral administration in combination with caffeine. Ergotamine is also available for sublingual administration, but in the United States, it is no longer available in the parenteral form. An adequate dose should be taken as early as possible in a migraine attack to achieve a maximum response.

To prevent ergotamine rebound headaches or ergotism, care should be taken to remain within the limits of the recommended dosage. Ergotamine derivatives should not be used in patients with cerebrovascular, cardiovascular, peripheral vascular, ischemic heart, renal, or hepatic diseases; sepsis; or severe hypertension. In addition, ergotamine preparations should be used cautiously in patients with peptic ulcer and recent infection and should not be used in pregnancy.

Dihydroergotamine mesylate (D.H.E. 45, Migranal) has also been used safely and effectively in the abortive therapy of migraine, and it has recently been "rediscovered" because of its action as a 5-HT_1D receptor agonist. It also has a potent effect at a number of other biogenic amine receptor sites. Unlike ergotamine tartrate, dihydroergotamine is associated with a lower incidence of nausea and is more of a venoconstrictor than an arterial vasoconstrictor. It can also be used to help patients who are ergotamine-dependent withdraw from ergotamine use.

Dihydroergotamine is available for intramuscular, subcutaneous, and intravenous injection and as a nasal spray. It also has been successfully used in repeated intravenous doses in patients with intractable migraine; a dose of 0.5 mg given as an intravenous push over 2 to 3 minutes, in combination with 10 mg of the antiemetic/antivertigo drug metoclopramide, may be repeated every 8 hours for 3 days in these cases.

Because of its vasoconstrictive properties, dihydroergotamine is contraindicated in patients who have peripheral vascular disease, ischemic heart disease, Prinzmetal's angina, uncontrolled hypertension, hemiplegic or basilar migraine, impaired hepatic or renal function, or sepsis, as well as in pregnant women. It should not be used concomitantly with other 5-HT₁ agonists or ergotamine preparations. Also, dihydroergotamine should not be given to patients who have risk factors for coronary heart disease (CAD) unless a cardiovascular evaluation provides satisfactory clinical evidence that a patient is reasonably free of CAD, ischemic myocardial disease, and other significant cardiovascular disorders.

For patients with risk factors predictive of CAD who have a satisfactory cardiovascular evaluation, the first dose of dihydroergotamine should be given in a physician's office. Because cardiac ischemia can occur in the absence of clinical symptoms, consideration should be given to obtaining an electrocardiogram after the first dose is given to a patient with known risk for CAD.

Isometheptene mucate: In patients who cannot tolerate ergotamine or in whom ergotamine derivatives are contraindicated, isometheptene may be an effective alternative. Like ergotamine, isometheptene has cerebral vasoconstrictive actions. It is available in a preparation that also contains acetaminophen and dichloralphenazone, a mild sedative.

Aspirin and NSAIDs: Aspirin and other of the NSAIDs (eg, ibuprofen, naproxen sodium) have been used successfully in migraine abortive therapy. NSAIDs stabilize proteins and inhibit formation of active prostaglandins. They also inhibit inflammation through their effects on chemotaxis, phagocytosis, lysosomal enzyme release, and kinin generation.

Phenothiazines: The phenothiazines chlorpromazine hydrochloride (Thorazine) and prochlorperazine (Compazine) have been used effectively in the emergency department setting for the abortive treatment of acute migraine. Efficacy of these drugs is attributed to their antinauseant and sedative effects. In addition, their dopaminergic and adrenergic actions may trigger specific mechanisms involved in aborting migraine.

Lidocaine: A recent report (15) has suggested that use of intranasal lidocaine is helpful for abortive treatment of acute migraine. A 50% reduction in headache was noted by 55% of patients who used lidocaine. However, relapse was common and occurred early after treatment. In selected patients, this treatment has demonstrated significant benefit.

Pain relief measures
Abortive therapy may not completely resolve a migraine attack, and analgesics may be needed to alleviate pain. Over-the-counter analgesics (eg, aspirin, acetaminophen, ibuprofen, naproxen sodium, ketoprofen) may be effective. However, overconsumption of these analgesics, particularly those containing caffeine, can produce serious side effects. Withdrawal from caffeine-containing drugs may trigger caffeine withdrawal headache. Therefore, these drugs should be avoided in patients who have frequent migraine attacks.

The first over-the-counter agent approved by the FDA for relief of migraine pain was the combination of aspirin, acetaminophen, and caffeine (Excedrin Migraine). This combination agent is suggested for the acute treatment of mild to moderate headache without associated vomiting and disability. Recently, two other nonprescription preparations of ibuprofen (Advil Migraine, Motrin Migraine) have also received approval for the relief of migraine pain. In addition, a parenteral NSAID, ketorolac tromethamine (Toradol), offers analgesia that is nonnarcotic and nonhabituating, and it has a low side-effect profile. The drug is given intramuscularly in a 60-mg dose.

Among the other options for pain relief are use of narcotic analgesics, antiemetics, phenothiazines, and cold packs. Narcotic analgesics (eg, codeine, meperidine hydrochloride [Demerol HCl], methadone hydrochloride [Dolophine HCl, Methadose]), preferably administered parenterally, are effective for pain relief but are potentially habituating. As with other pain syndromes, these drugs should not be used in patients with frequent migraine attacks and should never be used for daily headaches.

Antiemetics and phenothiazines, given parenterally or rectally, may be indicated in some migraine patients. The phenothiazines (including promethazine hydrochloride [Anergan, Phenergan], chlorpromazine, and prochlorperazine) are also useful because of their sedative and antinauseant action. Some antiemetics, such as trimethobenzamide hydrochloride and metoclopramide, have little sedative effect. However, metoclopramide, a 5-HT₃ receptor agonist, enhances absorption of oral medications and has been used effectively in combination with intravenous dihydroergotamine. This use of metoclopramide occasionally causes nervousness and tremor.

Transnasal butorphanol tartrate (Stadol NS) is a totally synthetic mixed agonist-antagonist opioid analgesic that originally was available for parenteral administration. Its quick absorption through the nose is enhanced by its lipophilic nature. The highly vascular character of the nasal mucosa speeds uptake and absorption. Caution must be exercised because of the possibility of habituation to butorphanol, and it should not be prescribed for patients who have daily headaches.

Cold packs have been used by migraine patients for many years. Application of ice bags or commercially manufactured ice packs to the site of the pain, along with gentle pressure, may reduce the pulsating pain associated with acute migraine attacks.

Prophylactic therapy
Prophylactic drug therapy should be considered in patients who have more than two acute migraine attacks per month. It may also be considered in patients who have attacks that seriously compromise daily activities or that last several days.

Beta blockers: For the past two decades, the beta blockers have been recognized for their efficacy in migraine prevention. Researchers have suggested that beta blockers without intrinsic sympathomimetic activity are more beneficial than those possessing such activity. Propranolol hydrochloride (Betachron E-R, Inderal), timolol maleate (Blocadren), and nadolol (Corgard), all of which lack intrinsic sympathomimetic activity, are recognized as effective migraine prophylactic agents. Each of these drugs is considered nonselective and should not be used in patients with pulmonary disorders.

For patients with asthma and other respiratory disorders, treatment with a cardioselective beta blocker, such as metoprolol (Lopressor, Toprol XL), is indicated. Beta blockers are also contraindicated in patients with congestive heart failure and atrioventricular conduction disturbances. In addition, beta blockers should be used cautiously in patients who use insulin, oral hypoglycemics, or MAOIs.

Anticonvulsant drugs: Divalproex sodium (Depakote) has shown efficacy in migraine prophylaxis. It may be of particular use in migraineurs with concomitant convulsive disorders, because it has the potential for preventing seizures. Divalproex should be avoided in patients who have a history of hepatitis or abnormal liver function. Recently, an extended-release formulation that can be used once a day received FDA approval.

NSAIDs: The use of NSAIDs has become increasingly common for prophylactic management of migraine. Acceptance of NSAID therapy was accelerated by the results of a randomized study of more than 22,000 male physicians who used low-dose aspirin or placebo every other day (16). About 6% of those on active medication had migraine attacks, compared with 7.4% of the placebo group. Although this decrease in headache frequency (20%) was modest, the results suggest that NSAID therapy may be effective in migraine prevention. Several NSAIDs have demonstrated prophylactic efficacy in decreasing the frequency and severity of migraine.

Calcium channel blockers: Calcium channel blockers may be considered in migraine prophylaxis, particularly in patients refractory to beta blocker therapy. The rationale for using these agents stems from their effect on intracranial vasoconstriction. Nimodipine (Nimotop) appears to have marked selectivity for the cerebral vasculature, and verapamil hydrochloride (Calan, Isoptin, Verelan) has also demonstrated antiplatelet effects.

Alpha-adrenergic blockers: For patients who experience food-related migraine, clonidine hydrochloride (Catapres) has demonstrated efficacy. Clonidine, an alpha agonist, has also been observed as beneficial for patients undergoing opiate withdrawal.

Antidepressants: Antidepressants have shown continued efficacy in migraine prophylaxis for several decades. The tricyclic drugs, particularly amitriptyline hydrochloride (Elavil), are believed effective in headache prevention because of analgesic actions independent of their antidepressant effects. Use of antidepressants is preferred for the treatment of coexisting migraine and tension-type headaches. Antidepressant therapy also may prove helpful in patients refractory to other standard forms of treatment. In these patients, a trial of the MAOIs should be considered.

Antihistamine and serotonin blockers: Cyproheptadine hydrochloride (Periactin) is the agent of choice in childhood migraine because it blocks both histamine and serotonin receptors. Side effects include drowsiness and weight gain. Efficacy in adults is minimal.

Methysergide: A lysergic acid derivative, methysergide maleate (Sansert) is closely linked to ergotamine. In addition to its vasoconstrictor actions, methysergide also appears to block the inflammatory mechanisms of serotonin. Although it has shown efficacy in migraine prevention, it is not widely used because of its serious side effects with prolonged therapy. When it is used, patients should be evaluated at monthly intervals to rule out pulmonary, coronary, or retroperitoneal fibrosis, as well as peripheral vascular disease. If a patient has been maintained on methysergide for 6 consecutive months, a 4- to 6-week drug hiatus must be ordered and an intravenous urographic study should be performed to rule out retroperitoneal fibrosis.

Status migrainosus
In patients who have this disorder, migraine attacks are unrelenting and refractory to conventional therapy. For some migraine attacks that persist for more than 24 hours, the treatment of choice is adrenocorticosteroid therapy, such as dexamethasone or methylprednisolone in dose packs. Sterile inflammation is considered the cause of these prolonged migraine attacks.

When migraine persists, the associated symptoms (eg, nausea, vomiting) may pose a threat to the patient's well-being. Dehydration can become a problem, and hospitalization may be needed for intravenous fluid replacement and to monitor serum electrolytes. Intravenous dihydroergotamine (0.5 mg) given with metoclopramide (10 mg) every 8 hours for 2 days has demonstrated efficacy in treating status migrainosus. This therapy avoids use of habituating narcotic analgesics.

Summary

Successful management of migraine headaches involves identifying and avoiding headache triggers and using appropriate abortive therapy once a headache is recognized. Pain relief measures include over-the-counter analgesics, parenteral NSAID therapy when needed, and use of antiemetics and cold packs. Narcotic analgesics are best used only as a "last resort" measure.

Prophylactic therapy should be considered for patients who have more than two acute migraine attacks each month or whose daily activities are seriously compromised by headaches. For the patient in whom status migrainosus threatens well-being, hospitalization and more intensive therapy may be needed.

References

1. Classification of headache. Ad Hoc Committee on Classification of Headache. JAMA 1962;179(6):717-8
2. Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Headache Classification Committee of the International Headache Society. Cephalalgia 1988;8(Suppl 7):1-96
3. Diamond S, Dalessio DJ. The practicing physician's approach to headache. New York: Medcom, 1973:2
4. Diamond S. Migraine headache. In: Diamond ML, Solomon GD, eds. Diamond and Dalessio's the practicing physician's approach to headache. 6th ed. Philadelphia: WB Saunders, 1999:46-70
5. Wolff HG. Headache and other head pain. 2d ed. New York: Oxford University Press, 1963
6. Sicuteri F, Testi A, Anselmi B. Biochemical investigations in headache: increase in hydroxyindoleacetic acid excretion during migraine attacks. Int Arch Allergy 1961;19:55-8
7. Curran DA, Hinterberger H, Lance JW. Total plasma serotonin, 5-hydroxyindoleacetic acid and p-hydroxy-m-methoxymandelic acid excretion in normal and migrainous subjects. Brain 1965;88(5):997-1010
8. Olesen J, Larsen B, Lauritzen M. Focal hyperemia followed by spreading oligemia and impaired activation of rCBF in classic migraine. Ann Neurol 1981;9(4):344-52
9. Moskowitz MA. The neurobiology of vascular head pain. Ann Neurol 1984;16(2):157-68
10. Goadsby PJ, Edvinsson L, Ekman R. Release of vasoactive peptides in the extracerebral circulation of humans and the cat during activation of the trigeminovascular system. Ann Neurol 1988;23(2):193-6
11. Goadsby PJ, Edvinsson L, Ekman R. Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann Neurol 1990;28(2):183-7
12. Buzzi MG, Moskowitz MA. The antimigraine drug, sumatriptan (GR43175), selectively blocks neurogenic plasma extravasation from blood vessels in dura mater. Br J Pharmacol 1990;99(1):202-6
13. Critchley M. Definition of migraine. In: Cochrane A, ed. Background to migraine: third migraine symposium. New York: Springer Verlag, 1970:181-2
14. Peroutka SJ. Developments in 5-hydroxytryptamine receptor pharmacology in migraine. Neurol Clin 1990;8(4):829-39
15. Maizels M, Scott B, Cohen W, et al. Intranasal lidocaine for treatment of migraine: a randomized, double-blind, controlled trial. JAMA 1996;276(4):319-21
16. Buring JE, Peto R, Hannekens CH. Low-dose aspirin for migraine prophylaxis. JAMA 1990;264(13):1711-3

For a helpful guide to electronic and print resources on headache for physicians and patients, see the Resource Guide in this issue.

Dr Diamond is director, Diamond Headache Clinic and Diamond Inpatient Headache Unit, Columbus Hospital, Chicago; adjunct professor, department of cellular and molecular pharmacology, and clinical professor, department of family medicine, Finch University of Health Sciences/Chicago Medical School, North Chicago. Correspondence: Seymour Diamond, MD, Diamond Headache Clinic, 467 West Deming Place, Suite 500, Chicago, IL 60614-1726. E-mail: macf48@aol.com.

Symposium Index

• HEADACHE: Introduction to a four-article symposium by Seymour Diamond, MD
• MIGRAINE'S IMPACT TODAY: Burden of illness, patterns of care by Richard B. Lipton, MD, Walter F. Stewart, MPH, PhD, Michael Reed, PhD, Seymour Diamond, MD
• A FRESH LOOK AT MIGRAINE THERAPY: New treatments promise improved management by Seymour Diamond, MD
• RELIEF OF CLUSTER HEADACHE AND CRANIAL NEURALGIAS: Promising prophylactic and symptomatic treatments by Donald J. Dalessio, MD
• SEXUAL ASPECTS OF HEADACHE: How sexual function relates to headaches and their causes and treatment by Jerome Goldstein, MD

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