Headache is one of the most common pain syndromes for which patients consult physicians. Surveys indicate that in any given year, more than 90% of American adults will have some kind of headache or head pain.¹ A wide variety of conditions can present with headache. The first step in treating a patient with a primary complaint of headache is to determine whether there is a primary or a secondary headache disorder. Then it is important to make a specific, accurate diagnosis. Secondary headache disorders have an underlying cause, which can usually be determined, such as infection, eye or jaw dysfunction, tumor, aneurysm, dissection or other vascular problems, meningitis, and trauma. Fortunately, very few headaches are caused by serious organic conditions, and most of them are actually primary headache disorders, idiopathic conditions that are benign and tend to recur. The great majority of patients that present to a physician with bad headaches are diagnosed with migraine. The pathophysiology of primary headache disorders is complex and probably involves, among other things, the activation of the trigeminovascular system, meningeal inflammation, and involvement of the cortex, brainstem, and thalamus (see Chapter 29 for a discussion on the pathophysiology of headaches). Chapter 28 presents the historical features in primary headache syndromes and describes the diagnostic criteria for the three most common primary headache disorders, which are migraine, tension-type headache (TTH), and cluster headache. This chapter discusses the differential diagnosis, diagnostic testing, and management of patients with these common primary headache disorders.

Migraine is a chronic neurologic disorder with episodic manifestations. The two most common patterns of migraine are migraine without aura and migraine with aura, formerly called common migraine and classic migraine, respectively. Migraine prevalence in the United States has remained stable, reported to be 12% in the general population. There is a female predominance; migraine affects approximately 18% of women compared with 6% of men.² Migraine can be extremely disabling, with more than 50% of individuals with migraine reporting severe impairment or the need for bed rest during a migraine attack compared with only 7.2% reporting no attack-related disability.³

CLINICAL FEATURES

A migraine attack is best looked at as being divided into four phases: the prodrome, the aura, the headache phase, and the postdrome. All four phases are not always present, and no single phase is necessary in order to diagnose migraine in a specific patient.^4,5

The first phase, or prodrome, consists of various combinations of psychological, neurologic, autonomic, and constitutional symptoms that precede the headache phase of the migraine attack by several hours or even days. The reported prevalence of this phase has been variable, but more than 80% of patients have reported at least one prodromal symptom.⁶ Symptoms may include altered mood, irritability, depression or euphoria, fatigue, yawning, excessive sleepiness, food cravings, dizziness, pale face, stiff neck, photophobia, phonophobia, blurry vision, sensitive skin, frequent urination, nausea, excessive thirst, concentration difficulties, speech difficulties, reading or writing difficulties, or other vegetative symptoms. The prodromal phase of a migraine attack indicates that changes in the central nervous system (CNS), possibly involving the hypothalamus and altered dopamine regulation, begin well before the onset of the headache phase. Prodromal symptoms are variable among individuals but are often consistent within the same individual, and astute individuals with migraine can predict with relative accuracy that a migraine attack has begun when these symptoms are present.^6–8 Many physicians are unaware of these symptoms if they do not ask about them, and the patient often does not mention them.

The second phase of migraine is the aura, which consists of either visual or sensory phenomena (the two most common aura symptoms), or motor weakness, incoordination, or dysphasic symptoms (e.g., word-finding difficulties). As many as 38% of patients with migraine may experience aura with at least some of their attacks, but migraine with aura remains infrequent compared with migraine without aura. Approximately 60% to 80% of patients who experience migraine with aura also experience migraine without aura, but more than one-third of patients report migraine headache attacks exclusively with aura. In patients reporting aura, however, aura occurs with an average of only 20% of migraine headache attacks. The aura symptoms usually precede the headache phase of the migraine attack, but they occasionally occur simultaneously and rarely after the headache. Up to one-third of patients have experienced aura without headache at some point.^9,10 The occurrence of aura without headache becomes more common as individuals with migraine grow older than 50 years of age.

The aura symptoms appear gradually over 5 to 20 minutes and usually last less than 60 minutes, subsiding just before the onset of the headache phase, which usually occurs within 30 minutes. A typical aura lasts about 20 minutes and is followed fairly quickly by headache. Visual aura is by far the most common, occurring in more than 90% of patients with aura. It is often the only aura symptom, and nonvisual aura symptoms are rarely present without the presence of a visual aura, suggesting that the occipital cortex is especially susceptible to cortical-spreading depression. The visual aura is often described as a series of both positive and negative phenomena. One commonly described aura begins as a flickering, zig-zag line beginning in the center of the visual field and enlarging as it migrates toward the periphery in a hemianopic distribution, often leaving a scotoma in its wake. Many other positive and negative symptoms occur, including seeing small dots that move, flashes of light, blind spots, homonymous hemianopsias, and various types of distortion of vision. Sensory auras in the form of paresthesias are the second most common type of aura symptom, occurring in approximately one-third of patients with aura. The typical sensory aura is unilateral, beginning in the hand and moving up the arm to affect the face and tongue in a cheiro-oral or digitolingual distribution. The leg is rarely but sometimes involved in sensory auras. As with visual aura, positive phenomena (paresthesias) are often followed by negative phenomena (numbness). Motor symptoms have been reported in up to 18% of patients and almost always occur in association with both visual and sensory auras. True weakness, however, is rare, and it is essential not to confuse sensory ataxia with weakness, an error that has both diagnostic and therapeutic implications. The most common motor aura is strictly unilateral weakness of the hand and arm. Unlike other aura symptoms, which usually last less than 60 minutes, motor auras are often prolonged, lasting a mean of 13 hours. Aphasic auras can take the form of paraphasia, impaired production of language, or impaired comprehension of language. Aphasic aura has been reported to occur in approximately 20% of patients^4,5,9–13

When examining a patient who has recently experienced only one or two such attacks for the first time, the clinician must determine whether these focal neurologic symptoms represent migrainous aura or are manifestations of a transient ischemic attack (TIA) or even a focal sensory seizure. Passage of time, repeated identical attacks, and diagnostic testing may be required to obtain certainty, but certain features are more typical of migraine aura. First, whereas visual and sensory symptoms of TIA and seizures usually develop abruptly, a migrainous aura gradually progresses over 5 to 20 minutes. Second, migraine aura is characterized by a combination of both negative and positive symptoms; the individual with migraine experiences a visual scotoma or hole in the vision (negative symptoms) and dazzling, glimmering, scintillating lights (positive symptoms). The sensory aura of migraine usually consists of numbness (negative symptoms) and tingling or paresthesias (positive symptoms). TIA, such as amaurosis fugax or hemianopic scotoma, usually manifests as a black or blank negative visual loss.

Sometimes, especially in those older than 50 years of age, the visual aura occurs repeatedly without any headache. C.M. Fisher described these features as “late life migraine accompaniments.”¹⁴ Sometimes these patients experienced more typical migraine in youth, with the migraine subsiding for many years only to recur as migraine aura without headache in later life. In this setting, the clinician may be more secure in the diagnosis. However, these late-life migraine accompaniments often develop with no previous history of migraine. Patients with new late-life migraine symptoms must be carefully evaluated to rule out cerebrovascular disease, structural hemispheric disease, or even retinal detachments.

The aura phase is usually, although not always, followed by the headache phase, which is the third phase of the migraine attack and usually the most dramatic. It is the headache phase of migraine for which most patients consult a physician. The International Classification of Headache Disorders, Third Edition (beta version) (ICHD-3 beta) defines a migraine attack as lasting from 4 to 72 hours and characterized by at least two of the following four pain characteristics: unilateral location, throbbing quality, moderate or severe in intensity, and aggravated by or causing avoidance of routine physical activity. Additionally, either nausea or vomiting or both photophobia and phonophobia must be present.¹⁵ It is important to remember that these strict criteria were designed chiefly for purposes of finding a uniform population of migraine patients to be entered into investigational drug trials and epidemiologic studies. The experienced clinician uses the ICHD-3 beta as a guide but is not rigidly bound by them. Often a patient may be missing one or more component of the ICHD-3 beta criteria (Table 30-1), at which time a diagnosis of probable or possible migraine can be made. Furthermore, both migraine and TTH are very common, and when patients report symptoms of both, there may be overlapping features that may make it difficult to differentiate between probable migraine and episodic or chronic TTH.

The headache of migraine is unilateral in 60% of cases and usually alternates sides from one attack to the next.⁵ Often, patients state that the headache is always on one side but when pressed recall that rarely, perhaps 10% of the time, the headache occurs on the opposite side. This alternating hemicrania, however infrequent, makes the clinician more secure in the diagnosis of migraine. Some individuals with migraine report that the headache is bilateral but worse on one side. Others report that an attack may start on one side and subsequently spread to other areas of the head or neck to become more generalized. The headache usually builds over a period of 30 minutes to several hours but may occur with sudden intensity, sometimes resembling a thunderclap headache. Although possibly attributed to migraine, a thunderclap headache must always be thoroughly investigated because an underlying secondary cause is often found. Although the pain of migraine is usually moderate to severe, many patients report milder headaches, which they refer to as “sinus headaches” or “regular headaches” and that, in reality, are probably milder migraine attacks. A migraine attack may occur at any time of day but happens most often in the morning hours between 5 AM and noon.^5,16

Contributing to the disability of a migraine attack are the associated features that accompany the pain of the headache phase. The ICHD-3 beta mandates that either nausea or vomiting or both light and sound sensitivity be present, but other features are also frequently present. The individual with migraine frequently reports a decreased appetite or just a queasy feeling but sometimes may report cravings for specific foods. Other gastrointestinal (GI) disturbances, such as diarrhea, constipation, and gastroparesis, may occur. Gastroparesis is common amongst individuals with migraine and leads to lack of absorption of oral medications from the small bowel, which may prevent optimal treatment by tablet. In addition to light and sound sensitivity, the individual with migraine is often especially sensitive to smells. Many patients report that they feel lightheaded or even vertiginous during an attack or even between attacks. Autonomic symptoms may occur, even unilaterally, such as red eyes and tearing. These autonomic symptoms are more common in cluster headache, invariably unilateral and often diagnostic. Systemic symptoms such as blurred vision, nasal congestion, facial pallor or redness, sweating, sensations of heat or cold, fluid retention, and increased urination have also been reported. There may be neck or sinus pain and discomfort. The individual with migraine is often unable to brush or comb his or her hair and must remove any hats, scarves, earrings, and necklaces and change into loose clothing because of tenderness of the scalp, neck, or limbs due to the allodynia caused by central sensitization. Prodromal symptoms can continue and may even become more prominent in the headache phase of the attack.^4,5,7,17,18

The duration of a headache attack is approximately 4 to 72 hours in adults when untreated or ineffectively treated. It typically lasts 12 to 36 hours. Sleep, even a brief nap of 1 or 2 hours, is the most common natural method of headache resolution, but biofeedback training and relaxation exercises may train the patient in other beneficial techniques that may help terminate an attack. Pharmacologic treatment, briefly discussed later in this chapter and in more detail in Chapter 33, is the most common medical treatment to terminate an acute migraine attack.

The fourth and final phase of a migraine attack is the postdrome. This phase has been reported in up to 94% of patients, but the symptoms have not been widely studied.¹⁹ Postdromal symptoms may last from several hours to approximately 24 hours or even longer in some patients and range from feeling drained or exhausted to an unusual sense of elation or euphoria. Patients may have trouble functioning, reading, speaking, and thinking. The headache is usually milder but may still be present. Symptoms that occur during the prodromal phase and headache phase of the attack often continue into the postdrome.⁷

DIFFERENTIAL DIAGNOSIS

Clinicians must always be aware of so-called migraine mimics, which are paroxysmal headaches caused by arteriovenous malformations, pheochromocytoma, repeated exposure to carbon monoxide, transient increased spinal fluid pressure resulting from a colloid cyst of the third ventricle, adult-onset of headaches caused by type I or II Arnold-Chiari malformations, or other structural brain disease. In the elderly, especially women older than 55 years with unilateral headaches and tender temples, temporal arteritis (giant cell arteritis) must always be considered. Primary CNS angiitis may manifest as frequent headaches before other symptoms, such as encephalopathy, seizures, or infarctions, occur as a result of the vasculitis.

When evaluating a patient with headaches, it is essential to look for so-called red flags, or danger signals that warn the clinician that a headache may be more serious than migraine (Table 30-2).^1,20 The problem is that some of these red flags are prominent symptoms of migraine and can be difficult to differentiate:

1. 
   

   Headache that is changing or different from previous headaches may herald a brain tumor superimposed on a long-standing primary headache disorder, such as migraine or TTH.

   
   
2. 
   

   Headache with progressive worsening over 24 hours or several days suggests a mass lesion or infectious disease such as meningitis, abscess, subdural or intracerebral hematoma, or vasculitis.

   
   
3. 
   

   Headache precipitated by exertion, bending over, coughing, or sneezing, may result from transient blockage of cerebrospinal fluid (CSF) flow or increased intracranial pressure.

   
   
4. 
   

   Sudden explosive onset of severe headache spontaneously or during exercise or sexual activity can occur with subarachnoid hemorrhage (SAH) or with primary exercise headache, primary headache associated with sexual activity, or primary thunderclap headache. A thunderclap headache reaches maximum intensity within seconds and can be attributable to SAH, arterial dissection, cerebral venous occlusion, and reversible cerebral vasoconstriction syndrome (RCVS).

   
   
5. 
   

   Vomiting may result from a brain tumor or other mass lesion with increased ICP.

   
   
6. 
   

   Early morning headache can occur with obstructive sleep apnea, medication overuse, and hypertension.

   
   
7. 
   

   Any abnormal physical or neurologic finding must be considered suspect: fever, stiff neck, rash, lymphadenopathy, proximal leg weakness suggestive of polymyalgia rheumatica, scalp tenderness, altered sensorium, or focal neurologic signs other than typical visual or sensory aura.

   
   
8. 
   

   Headache in a patient with papilledema may suggest increased intracranial pressure (ICP) related to idiopathic intracranial hypertension, cerebral venous sinus thrombosis, or intracranial mass lesion.

   
   
9. 
   

   New onset of a headache during pregnancy or postpartum may suggest headache secondary to cerebrovascular disease or cerebral venous sinus thrombosis.

   
   
10. 
    

    Headache in a patient with cancer, HIV, or other systemic illness may indicate metastatic disease, a structural lesion, or CNS infection such as meningitis or encephalitis.

    
    
11. 
    

    Headache with an onset after the age of 55 years may suggest temporal arteritis, other cerebrovascular disease, glaucoma, or structural brain disease.

A young, healthy patient with a textbook history of migraine and a normal physical and neurologic examination seldom requires diagnostic investigation. It is often done to rule out secondary disorders. If, however, the patient fails to respond as expected to treatment efforts, diagnostic testing may be wise.

Unsuspected granulomatous inflammations, such as sarcoidosis; meningeal malignancy; and cryptococcal, tuberculous, or Lyme meningitis, can be diagnosed only by CSF examination. Elevated or reduced spinal fluid pressure may confirm the diagnosis of pseudotumor cerebri or spontaneous intracranial hypotension, respectively. Low CSF pressure can usually be noticed on MRI scans with and without gadolinium as the meninges light up with contrast and other structural changes can be seen.

For structural brain lesions, magnetic resonance imaging (MRI) is much more sensitive than computed tomography (CT) scanning and is always preferable unless there is a contraindication to MRI or if bone windows are desired. Whereas CT scanning is more sensitive for demonstrating SAH in the first 24 hours, MRI becomes more sensitive after 48 hours. Unenhanced CT scans made within 24 hours of SAH have a sensitivity of 98%, falling to only 50% within 1 week, stressing the importance of immediate neuroimaging in cases of suspected SAH.²¹ If a small SAH, a so-called sentinel bleed, is being considered, CSF examination is essential even when results of the CT are normal. The presence of fresh blood or xanthochromia should prompt angiography. Cerebral angiography is also required if primary CNS granulomatous angiitis is suspected. Magnetic resonance angiography is sensitive for identifying unruptured aneurysms as small as 3 to 4 mm, and conventional angiography would be definitive.²² CT angiography is another noninvasive technique for detecting intracranial aneurysms.

There is a high familial incidence of aneurysms; unsuspected asymptomatic intracranial aneurysms were found in 9% of 396 persons having a first-degree relative with an aneurysm.²² A careful family history is, therefore, important if a warning leak is suspected. If two first-degree relatives of a patient have aneurysms, then the patient should be investigated.

As discussed earlier, sinus pressure and pain can be symptoms associated with the headache phase of a migraine attack. Often patients may believe that this represents “sinus headaches” rather than migraine. A thorough history in this case is important, and recurrent benign headaches, even if they involve pain and discomfort over the sinuses or nasal congestion, most likely represent migraine or TTH rather than acute sinusitis or sinus disease. Sometimes radiography is needed to settle the issue and CT scanning of the sinuses is more sensitive than sinus radiography or MRI in diagnosing acute sinusitis.

Clinicians must not omit dental disease or jaw dysfunction as a cause of head or facial pain or localized eye disease, such as glaucoma, which can cause unilateral orbital pain that mimics migraine. Cervical spine disease or lesions at the foramen magnum may cause suboccipital pain, and plain radiography or other imaging modalities (CT or MRI) may be considered.

Certain medications, such as the nonsteroidal anti-inflammatory drug (NSAID) indomethacin, estrogen and estrogen withdrawal, progestins, selective serotonin reuptake inhibitors (SSRIs), certain calcium channel blockers, or certain anticonvulsants, may cause headaches (Table 30-3). Because these drugs are often used to treat headaches, sorting out the diagnosis may be difficult, and the temporal pattern of headache development or progression in relation to when the drug in question was initiated is essential in diagnosing a headache secondary to a medication.

MANAGEMENT

The first step in treating a patient with migraine or any other medical condition is to establish an accurate diagnosis. The diagnosis must be conveyed to the patient who, very often, is fearful of a tumor or aneurysm or may erroneously believe he or she has a chronic sinus or psychiatric condition. Many of these patients have been discouraged in the past by physicians who have ignored their complaints of headache. Headache is a common complaint, and many busy physicians are reluctant to take the time or may not have the time required to obtain an adequate headache history, or they may view headache as being a result of nervousness or stress. Busy physicians may choose to direct the brief office visit at management of hypertension, diabetes, or arthritis even if the patient is more troubled by headache.

Headache treatment begins with educating patients about the nature of migraine and setting realistic expectations. Patients should be reassured that migraine is a biological disorder, usually with a hereditary predisposition, that is caused by altered brain biochemistry with secondary vascular, peripheral nervous system, and CNS changes. Patients need to be told that although migraine cannot be cured, treatments are available that can control and reduce the pain and associated symptoms that lead to the severe disability of a migraine attack. Patients often are relieved that at last they have found a physician who is knowledgeable about headaches and who expresses an interest in helping them. Sometimes it is helpful to have the spouse or another family member present and explain that headaches in general, and migraine in particular, are often provoked by hormonal changes, stress, certain food triggers, missing meals, irregular sleep patterns, travel, or specific environmental changes. Visual and sensory stimuli, such as bright lights, excessive noise, cigarette smoke, certain perfumes or smells, or other stimuli, may also act as migraine triggers.^23–27 Some medications, both over-the-counter (OTC) and prescription drugs, can precipitate headache (Table 30-3).^4,28,29 There is also an underlying predisposition for people with migraine to have a biochemical comorbidity of depression, anxiety, or other psychiatric problem.²

It is vital to consider behavioral medicine therapies for most patients, whether they think they need it or not (Table 30-4). For many patients, this can be more helpful than medication and there are no adverse effects.

In a specialty headache practice, there is usually a nurse, nurse practitioner, or physician’s assistant who instructs the patient to keep a headache calendar, watch for repeated food or environmental triggers, and record the amount of medication taken and response to treatment. Having this accurate record enables the physician to alter pharmacologic treatment depending on response. The power of the written word cannot be overemphasized, and publications are available that describe and explain many of these issues for individuals with migraine. Information is available free of charge from the American Headache Society (www.americanheadachesociety.org), American Council for Headache Education (www.achenet.org), National Headache Foundation (www.headaches.org), American Migraine Foundation (www.americanmigrainefoundation.org), Headache Cooperative of New England (www.hacoop.org), ProMyHealth (www.promyhealth.org), Canadian Headache Society (headachenetwork.ca), and the Headache Cooperative of the Pacific (www.hcop.com).

Some headache patients express a desire to be treated without “drugs,” and others prefer to take natural substances, such as herbal or vitamin supplements. Biofeedback training can be beneficial in conjunction with or without medication.^30,31 Biofeedback training teaches relaxation skills as part of overall headache management. Patients learn to be aware of skeletal muscle status and hand temperature and learn how to relax general and specific muscle contraction and tension, breathing techniques, and how to enhance blood flow to the peripheral vessels producing hand warming. With practice, patients can alter autonomic nervous function to produce measurable temperature changes in the hands. These exercises may reduce afferent sensory volleys from peripheral muscular pain and modulate sensory impulses ascending through cervical segments into the trigeminal nerve complex in the brainstem.

Cognitive behavioral therapy and relaxation techniques can help patients deal with the headache condition in a positive way.³¹ If the patient spontaneously asks about stress or if he or she recognizes anxiety or depression as significant problems, consultation with a behavioral psychologist may be very helpful.

Physical therapy with heat or cold applications, ultrasonography, myofascial release, a structured exercise program, and massage therapy are beneficial for many patients. Attention to nutrition and observing for food triggers, especially alcohol, are important. The patient’s headache diary can be especially useful in this aspect because the patient can identify food triggers and as a result can avoid the specific foods that may trigger a migraine attack. Correcting irregular eating and sleeping habits may be beneficial.

Some of these measures, such as keeping an accurate headache calendar, practicing biofeedback exercises, daily exercise, and paying attention to diet and lifestyle, have the added benefit of insisting that the patient play an active role in the treatment program. Many patients express a sense of empowerment and satisfaction that they are contributing to the management of their headache disorder and gaining more control over their lives and the condition.

PHARMACOTHERAPY

The U.S. Headache Consortium Guidelines, published in 2000, recognize that migraine is a heterogeneous disorder and that treatment must be tailored to the individual patient.³² A treatment plan must take into consideration the frequency, severity, and duration of attacks; the associated symptoms; and the degree of disability that the patient experiences. Pharmacotherapy may be divided into three types: (1) acute treatment with nonspecific analgesics; (2) acute treatment with migraine-specific agents that have pharmacologic affinity to bind to certain serotonin and other receptors and alter the neurochemical, inflammatory, and vascular processes of migraine; and (3) the daily use of preventive medications.

Nonspecific analgesics that may be useful for patients with mild to moderate migraine headaches include simple analgesics, such as aspirin and acetaminophen, NSAIDs in low doses (e.g., naproxen sodium), and combination analgesics (e.g., acetaminophen, aspirin, and caffeine). The butalbital-containing combination analgesics, including Fioricet and Fiorinal, are prescription medications that may be beneficial in those with migraine if taken early, but these compounds have a strong potential to cause dependency and analgesic overuse (rebound) headache if taken too frequently (see later discussion). They are not approved for migraine, only for TTH, but they can work and are probably safe to take for migraine attacks that occur three or four times a month or less. Analgesic overuse headache is more likely related to the frequency of dosing of these drugs rather than to the total number of doses that may be taken safely in a day or week. One of the reasons that patients like the butalbital-containing medications is that they treat anxiety as well as pain and make patients feel better in addition to relieving pain. This results in patients taking them more frequently than the number of headache days per month. This leads to dependency and overuse syndromes, and they start losing their effectiveness.

Treatment of acute migraine attacks was revolutionized in the United States in 1993 with the introduction of sumatriptan. There are currently seven triptans approved by the U.S. Food and Drug Administration (FDA). Each of them—sumatriptan, zolmitriptan, naratriptan, rizatriptan, almotriptan, eletriptan, and frovatriptan—can be good therapeutic options. All seven are available in tablet formulation, and rizatriptan and zolmitriptan are also available as orally dissolving tablets (ODT), zolmitriptan and sumatriptan are also available in nasal spray formulation, and sumatriptan is available as a subcutaneous injection (both with a needle and in a needle-free formulation). An iontophoretic transdermal delivery system of symatriptan has been FDA approved, but is not yet available. Sumatriptan also comes in a fixed-dose combination with naproxen sodium under the name Treximet. Dihydroergotamine (DHE) has been available since 1945 as an injection; a nasal spray formulation, Migranal NS, was introduced in 1997. An inhaled formulation of DHE has had a successful phase 3 trial, but issues with the manufacturing of the inhaler has delayed FDA approval.³³

The 2000 U.S. Headache Consortium Guidelines (Table 30-5) consider NSAIDs and combination analgesics that contain caffeine reasonable choices for mild to moderate migraine attacks or for severe migraine attacks that have responded to such agents in the past. Migraine-specific medications such as triptans and ergots such as ergotamine tartrate and DHE are considered appropriate first-line therapy for patients with moderate to severe intensity migraine attacks and for patients who do not respond to nonspecific analgesics.^34,35 One other medication that is migraine specific and approved by the FDA only for acute treatment of migraine with and without aura is Cambia (diclofenac potassium for solution, 50 mg). It probably works both peripherally and centrally as an anti-inflammatory, with a more rapid onset of action than the same medication in a tablet formulation.³⁶

All of these migraine specific drugs, except Cambia, are effective because of their specific pharmacologic affinity to bind to serotonin (5-HT) and other receptors and interrupt the neurochemical, inflammatory, and vascular changes that occur in migraine. It is thought that triptans work on both peripheral and central mechanisms by binding to 5-HT_1B receptors on vascular smooth muscle cells causing cranial vasoconstriction and binding to 5-HT_1D receptors on the presynaptic trigeminovascular nerve terminals in the meninges and within the trigeminal nucleus caudalis in the pons or dorsal horn in the spinal cord. This prevents the release of vasoactive peptides from the perivascular trigeminal neurons peripherally and the presynaptic nerve terminal at the synapse of the first- and second-order neurons in the trigeminal nucleus caudalis in the pons. Peripherally, this prevents mast cell degranulation, neurogenic inflammation, and vasodilation and centrally prevents increased transmission of pain signals heading toward the third-order neurons in the thalamus. This latter action may prevent central sensitization that begins in the brainstem. Through unknown mechanisms, it is theorized that triptans may also facilitate descending pain inhibitory systems, especially in the periaqueductal gray area and rostral ventromedial medulla.³⁷

Although the triptans are more similar than different, there are differences in lipophilicity, metabolism, route of administration, and differential therapeutic response of patients. Differences in lipophilicity leads to differential ability to cross the blood–brain barrier. The slight molecular differences of each triptan confer different pharmacologic properties, such as bioavailability, time to peak concentration, onset of action, metabolic half-life, and excretion, among others (Table 30-6).^37,38 Sumitriptan, zolmitriptan, and rizatriptan are metabolized by the enzyme monoamine oxidase-A (MAO-A); therefore, these drugs are contraindicated in patients taking MAO inhibitors or within 2 weeks of their discontinuation. The other four triptans and DHE are not contraindicated with MAO inhibitors. Almotriptan and eletriptan are metabolized by the hepatic enzyme CYP3A4, and thus a reduction in dose of almotriptan to 6.25 mg when used concurrently with drugs that are potent CYP3A4 enzyme inhibitors is appropriate. Eletriptan should not be used concurrently with such drugs because metabolism may be inhibited, resulting in higher blood levels and an increased risk of adverse effects. Propranolol inhibits the metabolism of rizatriptan, and a dose reduction to 5 mg is recommended for patients taking propranolol. Other beta-blockers are not problematic. Of note, sumatriptan contains a sulfonamide group and should not be used in patients with definite sulfa allergies. Almotriptan contains a sulfonyl group, and although structurally different from a sulfonamide, caution should be exercised when prescribing almotriptan to patients with sulfa allergies. Other triptan formulations do not contain a sulfa group.^37,38