Abstract
Migraines are among the most common headache disorders. They are now considered to be of neuronal, rather than vascular, origin. Because they can vary widely in their presentation, intensity, and associated symptoms, they tend to be underdiagnosed and thus untreated or undertreated. With some frequency, migraines are confused with symptoms of infectious or allergic sinusitis and treated as such. The number of drugs available for treatment and prevention, including routes of administration, continues to expand at a rapid pace and provides ever increasing options for treatment. Nonetheless, effectiveness of these drugs still proves unsatisfactory for many patients and prompts them to try unproven treatments. Increasingly, patients opt for treatment that may be limited to, or include, complementary and alternative modalities; several over-the-counter supplements with possible activity, and one with a warning, are listed. The trigeminal autonomic cephalagias (TAC) are a group of headaches that are related to each other and to migraines. Trigeminal neuralgia is differentiated from the TAC by the absence of autonomic symptoms in the neuralgia. Although TAC frequently respond to the same drugs as migraines, each also responds to specific treatments.
Keywords
cluster, migraine, paroxysmal hemicrania, SUNCT
Migraine Headache
Epidemiology
Migraine headache represents a very common benign headache syndrome; it is sometimes referred to as a vascular headache. Approximately two-thirds of migraines occur in women. The prevalence in North America, ascertained through epidemiologic studies, is 12%–17.6% in females and 4%–6% in males. Prior to puberty, the prevalence of migraine in boys and girls is similar; during and after adolescence, the incidence increases more rapidly in girls. In females, prevalence increases up to the age of about 40, after which it decreases; the decrease becomes steeper as women approach menopause. Among those with severe migraine, about 25% have four or more migraines per month. More than 80% of patients with severe migraines experience headache-related disability that ranges from decreased productivity to time off work during an attack. The cost in productivity may exceed $20 billion per year in the United States. Although the cause of migraines is unknown, the risk of suffering from migraines is about 50% higher among those who have a first-degree relative with migraines; however, genetic factors appear to account for fewer than 50% of all migraines.
Pathophysiology
The pain-generating structures of the head include the venous sinuses, meningeal and large cerebral arteries, basal meninges, muscles, skin, and cranial nerves V, IX, and X. A plexus of largely unmyelinated fibers arises from the trigeminal ganglion (cranial nerve V) and innervates the cerebral and pial arteries, the venous sinuses, and the dura mater; this plexus is referred to as the trigeminovascular system. A similar plexus arises from the dorsal roots of the upper three cervical nerves and innervates comparable structures in the posterior fossa. The neurons in the trigeminovascular system contain substance P, one of the major nociceptive neurotransmitters of primary sensory neurons; calcitonin gene-related peptide (CGRP), which causes vasodilatation and when infused intravenously into susceptible individuals triggers headache; and neurokinin A, which is similar in structure and function to substance P. When the trigeminal ganglion is stimulated and causes antidromic activation of the trigeminovascular system, these peptide neurotransmitters are released near the blood vessels they innervate; this results in vasodilatation with consequent extravasation of plasma, or so-called sterile neurogenic inflammation. Leakage of plasma proteins from the dilated blood vessels in turn stimulates the trigeminal nerve endings and causes nociceptive orthodromic signals to the trigeminal ganglion; the end result of this sterile neurogenic inflammation is the perception of pain in and around the head. Neurogenic inflammation is blocked by substances that act as agonists on a subset of serotonin (5-hydroxytryptamine [5-HT]) receptors: the 5-HT 1D and 5-HT 1B receptors. The major drugs used to abort acute migraine attacks are agonists at the 5-HT 1D/1B receptors. Drugs that act as agonists at these sites are thought to reduce neurogenic inflammation by inhibiting the trigeminal nerve endings and by their actions on blood vessels; their vasoconstricting action may or may not be necessary for analgesia. Agonists at the 5-HT 1D/1B receptors include ergot alkaloids (ergotamine, dihydroergotamine [DHE]) and triptans (sumatriptan and others). Similarly, stimulation of pain-generating structures in the head activates neurons in the trigeminal nucleus caudalis and in the dorsal horn at the upper cervical levels.
Thus stimulation of the trigeminal ganglion, through antidromic release of neurotransmitters, results in increased cerebral and extracerebral blood flow. Stimulation of the dorsal raphe nucleus, a serotonergic nucleus in the midbrain, also increases cerebral blood flow. In contrast, stimulation of the nucleus coeruleus, the major source of central noradrenergic input, causes a decrease in cerebral blood flow.
Interneurons in the spinal cord and brainstem that are part of the descending pain modulation system use enkephalins and gamma-aminobutyric acid (GABA) as neurotransmitters. An ascending serotonergic pathway in the midbrain raphe region relays painful stimuli to the ventroposteromedial (VPM) thalamus via the quintothalamic tract. A descending endogenous pain modulating system originates in the periaqueductal gray region of the midbrain, one of whose major relay structures is the nucleus raphe magnus in the medulla. After this relay, the descending pain modulating system connects with the spinal tract of the trigeminal nerve and the dorsal horns of the first through third cervical nerves. Stimulation of the periaqueductal gray region causes headache. The major neurotransmitters of this pain modulating system are norepinephrine, serotonin, and enkephalins.
In patients who have migraines with aura, it is thought that the cortex, particularly the occipital cortex, is hyperexcitable. The cause of this hyperexcitability is unknown, but may relate to decreased intracellular magnesium levels, to a dysfunction of brain mitochondria, or to abnormal calcium channels. The aura phase of migraine begins as a wave of cortical neural excitation, accompanied by hyperemia, and is followed by an electrical wave of spreading neural depression and oligemia that advances at a rate of 2–6 mm/min (a rate similar to that of the developing aura). During the oligemic phase, blood flow remains above the ischemic threshold. Neither the spreading neural excitation/hyperemia nor the ensuing spreading depression and oligemia respect vascular territories; they are thus thought to represent neural, not vascular, phenomena. The trigeminovascular system might be activated through polysynaptic pathways from the activated cortex, or directly by the same mechanism that causes the aura. Aura usually precedes but sometimes accompanies the headache phase of migraine. Spreading neural depression and oligemia in the cortex might also occur in migraine without aura.
A growing body of evidence points to the importance of dopamine in the pathophysiology of migraine and its associated symptoms. Dopamine receptor hypersensitivity may be responsible for the nausea, vomiting, hypotension, and dizziness that frequently accompany and sometimes characterize attacks of migraine. These symptoms can be elicited by low doses of dopamine or by dopamine agonists—especially in migraneurs. Antiemetics, most of which are dopamine receptor antagonists (especially at the D2 receptor), are frequently useful, and sometimes effective in and of themselves in treating migraine attacks.
Diagnosis
The diagnosis of migraine is made by a suggestive clinical history and a normal neurologic examination ( Table 19.1 ). The classic description of migraine is that of a recurrent headache lasting 2–72 hours, of moderate to severe intensity, pulsating, aggravated by routine physical activity, and associated with nausea, emesis, photophobia, phonophobia, and/or osmophobia (aversion to odors). The major subtypes of migraine are migraine with aura and migraine without aura. The most frequent migrainous aura consists of visual symptoms such as bright spots, dark spots, tunnel vision, or zigzag lines (fortification spectra). Other common auras include numbness or paresthesias in one arm or on the side of the body. The aura is followed (or sometimes accompanied) by an intense, crescendo head pain, frequently unilateral or retro-ocular; it may be described as pounding, throbbing, pressurelike, exploding, stabbing, or viselike. Migrainous auras, particularly visual ones, occasionally occur independently of pain; these are called migraine equivalents. Typically, the headache phase lasts from 30 minutes to 1 day. Occasionally the headache becomes intractable and lasts a week or longer: this is status migrainosus. There seems to be a slightly increased risk for stroke among migraneurs, particularly in women who have migraine with aura. The absolute number of strokes in this population remains low, and epidemiologically, the increase in risk is most easily defined for women older than age 40 or 50.
| Migraine Without Aura |
| At least five headache attacks |
| Headaches last 4–72 h if untreated |
Has at least two of the following, but not weakness:
|
Has at least one of the following:
|
| Migraine With Aura |
| At least two headache attacks that also fulfill the characteristics of migraine without aura |
| Headaches usually follow the aura but may begin with it and last 4–72 h if untreated. |
| Has at least one of several reversible symptoms (lasting 4 min–60 min), but no weakness |
| Positive or negative visual symptoms such as scintillating scotomas, blind spot (scotoma), blurred vision, zigzag lines, homonymous hemianopsia |
| Postive or negative sensory symptoms such as tingling or numbness |
| Basilar Migraine |
| At least two attacks of migraine with an aura whose symptoms are reversible and localize to the brainstem or are bihemispheric, but without weakness |
Symptoms can include:
|
| Aura Without Headache |
| At least two attacks of symptoms typical of auras, but not weakness, such as visual, sensory, or speech disturbances that resolve within 1 h and are not followed by a headache |
| Hemiplegic Migraine |
| At least two attacks of migraine with a reversible aura of motor weakness that can last 1 h to days |
Also includes one of the following:
|
| Frequently accompanied by symptoms typical of basilar migraine |
| If at least one first- or second-degree relative has a migrainous aura that includes motor weakness, it is familial hemiplegic migraine and is associated with a mutation in the neuronal calcium channel. |
| If no first- or second-degree relative has a migrainous aura that includes motor weakness, it is sporadic hemiplegic migraine. |
A migraine whose aura seems to originate in the brainstem or involve both hemispheres is called basilar migraine. A typical aura in basilar migraine might present with bilateral visual loss or blindness. Following, or independent of, the visual phenomena, patients may complain of vertigo, dysarthria, diplopia, tinnitus, ataxia, a decreased level of consciousness, or bilateral sensory (paresthesias) or subjective motor symptoms (there should be no objective weakness); sometimes nausea and emesis are prominent. Some patients present with other types of auras such as a dysphasia, and as such may resemble a transient ischemic attack (TIA), a stroke, or an evolving neurologic catastrophe.
Some patients develop severe headache, sometimes described as exploding, related to exertion: These are exertional migraines. Exertional migraines can develop while engaged in heavy work or sports, lifting weights, or during sexual climax (the latter are more frequent in males). On the other hand, a severe ocular headache that presents with ophthalmoplegia (usually of the oculomotor nerve, including a dilated pupil) is no longer considered an “ophthalmoplegic migraine.” The ophthalmoplegia can last hours to months and is now believed to represent an inflammatory neuritis or the Tolosa–Hunt syndrome. Painful ophthalmoplegia usually has a dramatic presentation and always warrants a careful evaluation.
Given a typical history and reasonable clinical judgment, a migraine can be recognized and treated as such. Occasionally the clinical circumstance requires that the physician be more circumspect and make an effort to exclude other causes for headache that, if left undiagnosed and untreated, will result in an adverse patient outcome. Some other causes for headache include a cerebral aneurysm with or without subarachnoid hemorrhage, vascular malformations with or without hemorrhage, venous thrombosis, central nervous system infections, space-occupying lesions, increased intracranial pressure, vascular dissection, and arteritis.
Treatment
Migraines can be treated abortively (after they start) or prophylactically (with daily medication aimed at reducing the frequency or intensity of the headaches).
Acute Migraine Headaches (Abortive Treatment)
The following are drugs that are useful for the treatment of acute migraine headaches (abortive treatment).
- A.
Triptans (Imitrex, Maxalt, Zomig, Frova, Relpax, Amerge, and others) are 5-HT 1D/1B receptor agonists. These drugs are available in a variety of forms. For example, Imitrex is available in an autoinjector, as a tablet, as a nasal spray, and as of this year, as a nasal powder; Maxalt and Zomig are available as tablets and as orally disintegrating tablets; and Zomig is also available as a nasal spray. In general, injectable preparations have a quicker onset of action, followed by nasal sprays and orally disintegrating tablets and tablets that must be swallowed. These different formulations allow treatment to be tailored to the patient’s needs. Patients whose headaches are accompanied by significant nausea and vomiting, or whose productivity depends on a timely return to work, might prefer an injectable preparation or a nasal spray. Orally disintegrating tablets also are useful in patients with significant nausea and vomiting. Approximately 60%–80% of patients achieve significant relief from a triptan; however, the headache will recur in up to one-third of patients. A second dose of the same preparation, taken 2–24 hours after the first, may again provide significant relief. A triptan should not be used again for at least 24 hours after the second dose. Triptans should not be administered within 24 hours of another substance with vasoconstricting properties (e.g., another triptan, ergotamine, DHE, or isometheptane). Triptans should not be administered within 2 weeks of discontinuation of a monoamine oxidase inhibitor. Triptans should not be prescribed to patients with ischemic or other heart disease or uncontrolled hypertension; they should be avoided in patients with complicated auras such as dysphasias and confusional states and in basilar migraine. The major side effects of triptans include a sensation of chest pressure, flushing, tingling, dizziness, and dysphoria. These usually resolve in less than 1 hour. Vasoconstrictor drugs should be avoided during pregnancy, although several large population-based studies have failed to identify an increase in birth defects or in pregnancy-related complications among women who used triptans (mainly sumatriptan or naraptriptan) during pregnancy. Although each of the triptans has unique pharmacokinetic properties, clinically there is little practical difference between them. That said, the different formulations allow treatment to be individualized, and if a patient does not respond well to or suffers unacceptable side effects from one triptan, they may tolerate or respond better to another. For example, in patients whose pain returns within a few hours of taking a triptan, one with a longer half-life (Frova, Amerge) can be tried instead.
- B.
Ergotamine tartrate is an older drug with 5-HT agonist activity that also is very effective for migraines. One to two tablets are taken at the onset of the headache or aura, followed by 1 tablet every 30 minutes until the headache is gone or until a maximum of 5 tablets per headache or 10 tablets per week have been consumed. If consumed in excess, ergotamine-containing preparations can cause vasospastic complications and are emetogenic.
- C.
Isometheptane (Midrin) is another older but effective drug with 5-HT agonist and sympathomimetic (vasoconstrictive) activity. Midrin also contains dicholralphenazone, a mild sedative-hypnotic drug similar to chloral hydrate. One to two capsules are taken at the onset of the headache or aura, followed by 1 capsule every hour until the headache is gone or until a maximum of 5 capsules per headache or 10 capsules per week have been consumed. Isometheptane has fewer vasospastic complications than ergotamine. Ergots and isometheptane should be avoided during pregnancy and are relatively contraindicated in basilar migraine.
- D.
Preparations containing butalbital (such as Fioricet, which also contains acetaminophen and caffeine, or Fiorinal, which contains aspirin and caffeine) are effective and can be used alone or together with one of the vasoconstricting abortive drugs (a triptan, ergotamine, or isometheptane). One to two tablets can be taken every 4 hours as needed. Barbiturate-containing preparations cause drowsiness and can be habit forming if used excessively.
- E.
Narcotic-containing preparations, such as those with codeine, hydromorphone, or hydrocodone (in combination with aspirin or acetaminophen), are used too frequently, particularly in the emergency room, and should be used only as drugs of last resort. Narcotics bind opiate receptors and mask pain, but they do not bind serotonin receptors and therefore do not interrupt the putative pathophysiologic mechanism of migraine. The short- and long-term complications associated with the frequent use of narcotics argues that they should be used sparingly at best.
- F.
Antinauseants, such as prochlorperazine, chlorpromazine, or metoclopramide, by virtue of their effect on serotonin receptors, are effective against migraine pain. Their action as antagonists of the D2 dopamine receptor helps control the associated gastrointestinal symptoms, and this makes them excellent adjuvant drugs.
- G.
DHE, is generally administered parenterally, but also is available as a 4 mg/mL nasal spray. Administered by the intravenous or intramuscular route, the dose should not exceed 2–3 mg in 24 hours. Administered over 1 day or several days, intravenous DHE remains the drug of choice for treatment of status migrainosus. As a vasoconstrictor, this drug should be avoided during pregnancy and is relatively contraindicated in basilar migraine.
- H.
Nonsteroidal antiinflammatory drugs (NSAIDs) work for some patients with mild to moderate migraine pain. Ketorolac, which can be administered intramuscularly, and indomethacin, which also is available as a suppository, may be particularly useful. Some patients with mild headache or headaches that do not last long respond well to over-the-counter analgesic preparations. Aspirin, particularly combined with acetaminophen and caffeine (Excedrin), remains an effective and inexpensive over-the-counter treatment. Cambia (diclofenac combined with potassium bicarbonate) is US Food and Drug Administration (FDA) approved for the treatment of migraine; it likely owes its effectiveness to its rapid gastrointestinal absorption. Cambia is as effective as a triptan in onset of action and control of symptoms, and is worth considering in patients in whom vasoconstricting drugs are contraindicated or who experience intolerable side effects.
- I.
Corticosteroids are sometimes useful when used for a limited time and under strict medical supervision; in fact, short courses of steroid have been shown to decrease the recurrence and frequency of migraine. They can be used alone or with other abortive medication for the relief of an intractable migraine (status migrainosus). Both short- and long-term use of steroids entails significant potential for morbidity.
Chronic Use of Drugs
The chronic use (averaging at least 10 times per month over a prolonged period of time) of any of the triptans, NSAIDs, acetaminophen, butalbital, narcotics, ergotamine, DHE, and isometheptane can lead to development of a medication overuse, or rebound, headache syndrome. Chronic use of these compounds more than twice per week should be discouraged. Prophylactic regimens generally are not effective in the setting of rebound. The treatment of medication overuse headache is discontinuation of all analgesics (including triptans, ergots, etc.). In patients who take frequent narcotics or barbiturates, these should be discontinued slowly. Painkiller withdrawal frequently results in a temporary but dramatic exacerbation of the pain, which can last several days. The physiologic washout period, during which patients may continue to experience frequent headaches, lasts at least 2 weeks; patients should continue to refrain from analgesic medications for a total of 10–12 weeks, although the physician should use judgment with respect to treatment of an occasional breakthrough migraine during that period. If patients require analgesics at least twice per week, they should be offered a prophylactic regimen.
Prophylactic Treatment
The following are drugs that are useful for prophylactic treatment.
- A.
Beta-blockers, such as propranolol, metoprolol, atenolol, timolol, and nadolol, are frequently effective first-line prophylactic drugs; propranolol and timolol are FDA approved for migraine prophylaxis. In most healthy people, 60–80 mg once per day of a long-acting propranolol preparation can be started, and the dosage can be adjusted as necessary. Side effects include dizziness from bradycardia or hypotension, fatigue, depression, worsening of symptoms in patients with asthma, or chronic obstructive pulmonary disease, gastrointestinal distress, blunting of hypoglycemic symptoms in patients with diabetes, and vivid dreams.
- B.
Anticonvulsants such as valproic acid (Depakote and Depakote ER) and carbamazepine have been used as prophylaxis against migraine for a long time. Depakote and Topamax are FDA approved for migraine prophylaxis; carbamazepine is classified as only “possibly effective” based on the evidence available. The usual starting dose for Depakote ER is 500 mg per day; the dose should be adjusted as necessary at 2–4-week intervals. Valproic acid can cause weight gain, hair loss, tremor, abdominal distress, and easy bruisability. Frequent side effects of Topamax are mental confusion and paresthesiae; another is weight loss, which has made this drug increasingly popular. In addition, Topamax is an inhibitor of carbonic anhydrase, and it has been reported to be useful in treating the syndrome of idiopathic increased intracranial pressure (previously called pseudotumor cerebri).
- C.
Antidepressants, particularly amitriptyline (at a starting dose of 10–25 mg at bedtime) and venlafaxine (at a starting dose of 37.5 mg in the morning), are active prophylactic drugs. Most patients who respond to amitriptyline usually do so at doses of 25–200 mg at bedtime; the effectiveness of other tricyclic antidepressants such as nortriptyline, imipramine, or desipramine has not been established. Tricyclics help induce sleep, which may constitute one of the mechanisms by which they help migraneurs. The major side effects from tricyclics relate to their anticholinergic action and include a dry mouth, excessive daytime sleepiness, dizziness, urinary retention, glaucoma, cardiac arrhythmias, and photosensitization. There is inadequate evidence to recommend the specific serotonin reuptake inhibitors (SSRIs) and other serotonin norepinephrine reuptake inhibitors (SNRIs). Antidepressants are relatively contraindicated in patients who use triptans, as they may suffer from excessive serotonin stimulation (serotonin syndrome), although the incidence of this complication is virtually negligible unless the patient is on very high doses of the antidepressant. The association between migraine and depression (depressed patients have more migraines and migraines are a risk factor for depression) make antidepressants a good choice for prophylaxis.
- D.
Candasertan (an angiotensin receptor blocker) or lisinopril (an angiotensin converting enzyme [ACE] inhibitor) are occasionally useful as prophylactic agents. There is inadequate evidence to support the use of calcium channel blockers such as verapamil for migraine (although they are of proven use in cluster). Evidence does not support the use of gabapentin, lamotrigine, or oxcarbazepine as migraine preventives.
- E.
Individualized injections of botulinum toxin A injection (Botox) into the pericranial muscles (31 injections into 7 specific sites) increases the number of headache-free days in some patients with chronic migraine. The drug is approved for treatment in patients who have 15 or more headache days per month, each lasting 4 hours or more. Improvement may be delayed for up to 2 weeks following treatment, and the beneficial effect may last up to 90 days postinjection.
Complementary and Alternative Modalities
Many patients with chronic headaches use some form of complementary and alternative modalities (CAM). There are several reasons they might, including among others, patient dissatisfaction with the efficacy or side effects of more conventional drugs, cost, and availability without a prescription. It should be noted that, as supplements, these compounds have not been through rigorous clinical trials, and their manufacture, quality control, and labeling is not supervised by the FDA. In that regard, some equally uncontrolled studies have found that many preparations may, or may not, contain what is stated on the label. One particular supplement to be aware of is butterbur (Petasites). Butterbur has been through two small Class A trials that demonstrated effectiveness in migraine prevention ; however, the studies were conducted with a specifically purified preparation that was certified to be free of pirrolizidine alkaloids (PA), highly toxic compounds that are hepatotoxic and may cause cancer. Following the trials, the purification method was changed and the subsequent preparations have not been subject to rigorous analysis for PA. After multiple reports of mild to severe liver toxicity, several European countries have had butterbur removed from their markets. Supplements that might be tried in the right setting include magnesium citrate or oxide, 400 mg/day; riboflavin (vitamin B2), 400 mg/day; co-Q10 150 mg/day to 300 mg/day; and the transcutaneous nerve stimulator (TENS) device.
Self-Help Strategies
The following are self-help strategies that can minimize the incidence of migraines.
- A.
If the patient consumes caffeinated beverages (coffee, tea, soda, cocoa), total caffeine should be limited to less than 400 mg/day (to avoid caffeinism), and the decrease in intake should include weekends, vacations, and holidays (to avoid a caffeine withdrawal headache).
- B.
If they trigger headaches, foods high in tyramine (a metabolite of tyrosine often a product of fermentation or decay), which are thought to play a role as a migraine trigger, can be avoided. Some foods high in tyramine are chocolate, aged cheeses, yogurt, sour cream, soy sauce, chicken liver, banana, avocado, nuts, and yeast extracts (including beer).
- C.
Foods high in nitrates can be avoided, as these might precipitate a migraine by virtue of their vasodilating properties. Some foods high in nitrates include processed meats (hot dogs, salami, bacon, sausage, corned beef) and other canned, smoked, or aged meats.
- D.
Some patients are sensitive to certain food additives. Two examples include monosodium glutamate, frequently used in restaurants and added to cooked, packaged, and canned foods as a flavor enhancer, and aspartame (Nutrasweet). These substances contain glutamate, an excitatory neurotransmitter.
- E.
Many migraneurs are sensitive to alcoholic beverages, particularly those that are aged, such as beer, wines, and some spirits. Alcohol also tends to dilate blood vessels.
- F.
Miscellaneous, but not unusual, causes of migraine include new medications, stressful situations, poststress situations, lack of adequate rest or changes in sleep habit, allergies, and noncompliance with a prophylactic regimen. Patients should not allow themselves to become dehydrated, either during a headache or between headaches. If bright light is an irritant during or between headaches, patients should wear optical-quality sunglasses that block at least 85% of incident sunlight (and 100% of ultraviolet light) when outdoors.
- G.
The trigeminal autonomic cephalalgias (TAC): Cluster headache, paroxysmal hemicrania and short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT).
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