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Migraine diagnosis and treatment
Prim Care Clin Office Pract 31 (2004) 277–292
Migraine diagnosis and treatment Elizabeth Loder, MD, FACP Harvard Medical School, 25 Shattuck Street, Boston, MA 02114, USA Pain and Headache Management Programs, Spaulding Rehabilitation Hospital, 125 Nashua Street, Boston, MA 02114, USA
Recognizing migraine Migraine is a highly prevalent condition, affecting as many as 28 million people in the United States. It is responsible for significant disability in otherwise healthy, generally young people [1]. In its pure form, migraine is recognized easily. Its presentation varies enough from patient to patient and even from attack to attack, however, that more subtle forms and variations on the theme of migraine may be recognized less quickly. Making a specific diagnosis of migraine is important because the diagnosis increasingly has treatment implications. When only nonspecific or sedative medications were available, it was enough to simply make a diagnosis of benign, recurrent headaches. Now, however, with the advent of targeted abortive and preventive medications that have efficacy in one benign headache disorder and none in another, clinicians must go beyond simply a diagnosis of benign headache and must attempt to characterize what kind of benign headache the patient has. In most patients, migraine is an intermittent headache syndrome with episodes of headaches interspersed with periods of complete well being. (For reasons that are poorly understood, a subset of patients experience gradual evolution of this intermittent pattern into chronic migraine, in which headache-free time is limited or nonexistent.) No one of the many signs and symptoms that can occur in migraine, other than headache, is absolutely required for diagnosis. There is great variability in the timing of attacks between patients and even within the same patient. Attacks can occur almost daily or rarely, suggesting that changes in the brain’s threshold of susceptibility to attacks may be important in determining when and whether they occur. Standardized diagnostic criteria for migraine and other headache syndromes (Box 1) have been developed by the International Headache
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Box 1. Diagnostic criteria for migraine with and without aura Migraine without aura At least five attacks fulfilling criteria B–D Headache lasting 4–72 hours (untreated or unsuccessfully treated) Headache has at least two of the following characteristics: Unilateral location Pulsating quality Moderate or severe intensity (inhibits or prohibits daily activities) Aggravation by walking stairs or similar routine physical activity During headache, at least one of the following occurs: Nausea or vomiting Photophobia and phonophobia At least one of the following is present: History and physical and neurologic examinations do not suggest an organic disorder History and physical and neurologic examinations do suggest such disorder, but it is ruled out by appropriate investigations Such disorder is present, but migraine attacks do not occur for the first time in close temporal relation to the disorder Migraine with aura At least two attacks fulfilling criterion B At least three of the following four characteristics are present: One or more fully reversible aura symptoms occur, indicating brain dysfunction At least one aura symptom develops gradually over more than 4 minutes or two or more symptoms occur in succession No single aura symptom lasts more than 60 minutes. Headache follows aura with a free interval of less than 60 minutes (may also begin before or simultaneously with the aura) History, physical examination, and, where appropriate, diagnostic tests, exclude a secondary cause (Adapted from The International Classifications of Headache Disorders. Cephalalgia 2004;(Suppl 1):1–160.
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Society (IHS). These have been enormously useful for research purposes, but perform poorly in the clinical setting because of low sensitivity for the diagnosis. Familiarity with these criteria is helpful, but in office practice less stringent requirements for making the diagnosis allow identification of more patients with the disorder, who presumably will benefit from treatment. An untreated or unsuccessfully treated attack of migraine generally lasts 4–72hours. A common misconception is that migraine must be unilateral. This mistake is understandable, because the term migraine derives from the Greek word hemicrania, meaning one side of the head. In fact, however, the location of pain in migraine can be generalized, on top of the head, in the occipital area, and in the classic location over one temple or the other. Additionally, the pain, if unilateral, can switch sides from attack to attack or even within a single attack. This variability in the location of the pain often is said to be a reassuring sign that the underlying headache mechanism is benign, because a fixed structural abnormality leading to headache would be more likely to produce a headache of unvarying location. With the exception of occipital discomfort, which may have a different origin than pain in other parts of the head, the pain of migraine is produced and felt in areas that are innervated by the first division of the trigeminal nerve and connect with the trigeminocervical complex and then to the dorsal horns of C1 and C2, finally transmitting signals to the brainstem, thalamus, and cortex. Certain brainstem areas (the periaqueductal gray matter [PAG] and locus ceruleus [LC]) probably modulate incoming pain signals and blood flow [2]. Placement of electrodes into the PAG region produces a migraine-like headache, and stimulation of the LC in animals reduced blood flow [3]. Most patients describe the pain of migraine as pounding or throbbing and report that at its peak the pain is at least moderate to severe in intensity. In clinical trials of migraine treatments, pain intensity is usually rated on a 0–3 scale, with 0 being no pain, 1 mild pain, 2 moderate pain, and 3 severe pain. Because pain ratings can vary significantly depending on how stoic or histrionic an individual patient is, it may be more helpful to judge pain intensity based on the amount of disability it induces. Patients can describe the impact of pain on their ability to carry out such daily activities as attending work and school, performing housework, or participating in leisure activities, with disability rated as absent (0), mild (1), moderate (2), or severe (3). In most patients, the pain of a full-blown migraine attack is sufficiently intense to interfere with daily activities or prohibit them altogether. In addition, everyday activities that do not cause pain ordinarily, such as walking or climbing stairs, aggravates the pain of a migraine headache. It is important to remember, however, that even patients who have severe attacks of migraine generally have other attacks of headache that are less severe. Although these milder headaches sometimes are classified as tension headaches, a variety of evidence suggests that, in a patient who is known to have migraine, these attacks are milder versions
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of migraine that are aborted through natural mechanisms or fail to develop fully. It can be useful to think of migraine as a ‘‘headache plus’’ syndrome, in which headache is rarely the only feature but is instead accompanied by other symptoms. Nausea is probably the most typical accompanying symptom. It usually builds up in parallel with the headache pain, but in some patients it may precede the attack, making the use of oral treatment difficult. Vomiting does not occur with all attacks or with all patients; when it does, it usually develops later in the attack. Vomiting seems to be more characteristic of childhood migraine, and many patients with migraine report that vomiting improves and may even disappear as they age. Cyclic vomiting is a childhood variant of migraine in which repeated bouts of abdominal pain and vomiting occur. Headache may be absent or only a minor feature. It responds well to treatment with typical migraine medications such as propranolol. Photophobia (sensitivity to light) and phonophobia (sensitivity to sound) are also extremely common accompaniments of headache in migraine sufferers. In fact, strong sensory stimuli of many kinds in addition to bright light and noise can precipitate or aggravate headache in many migraine sufferers. Abnormal sensitivity to sensory stimuli seems to be present even interictally, although it is most pronounced during an attack. These accompanying symptoms account for the clinical picture many clinicians and lay people have of a patient experiencing a migraine: a person who has a strong desire to lie motionless in a dark, quiet room. One way of helping patients understand their heightened sensitivity to the world around them is to point out that such highly developed sensory reactions probably improved the odds of survival at some point in human evolution. They may simply have inherited ‘‘too much of a good thing’’ [4]. The visual distortions and abnormalities of aura are widely recognized as a feature of migraine by physicians and patients alike. Only 15%–20% of patients with migraine experience aura, however. Many patients experience aura with some but not all of their headaches, and aura can occur in the absence of headache; this seems to become more common as patients age. In the usual presentation of migraine with aura, headache is preceded by focal neurologic signs or symptoms. Especially common are transient visual disturbances that can include a scintillating scotoma or even complete visual loss. Other neurologic symptoms and signs, such as numbness, weakness, paresthesias, or confusion can occur as part of an aura but are much less common than visual changes. In the typical aura, the neurologic event builds up gradually and lasts no longer than 0.5–1.0 hour. As the aura symptoms gradually diminish, the headache begins. As mentioned, patients may not experience aura with every headache, but auras within an individual patient are consistent from one attack to another; it is not common for a patient to have cognitive disturbance before one headache and visual loss with another. Patients who have sudden, unpredictable onset of significant visual aura may occasionally report that it is the aura and not
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the headache that is of most concern to them and for which they most desire treatment. Although not common, aura can in some circumstances be prolonged, lasting into or even beyond the headache. Studies of families with a rare autosomal dominant form of migraine with aura known as familial hemiplegic migraine (FHN) have identified an amino acid substitution in the pore-forming and voltage sensor regions of neuronal calcium channels. This has been traced to a missense mutation in a neuronal specific P/Q calcium channel gene, and is present in roughly half of affected families [5]. In total, four different missense mutations in the alpha1 subunit have been identified. Abnormalities of chromosome 19 also may be involved in more common forms of migraine [6]. Many patients experience recurrent, predictable changes before migraine attacks that do not technically meet the criteria for aura. These premonitory symptoms occur in roughly 25% of patients and consist of such things as mood or appetite changes, altered gastrointestinal function, and yawning [7]. Administration of a dopamine agonist, apomorphine, reproduces many of these prodromal symptoms, leading to speculation that changes in dopaminergic transmission in the CNS may be involved in migraine. Several theories have been suggested to explain the cause of migraine. The first originated with Harold Wolff and often is referred to as the vascular or vasogenic theory of migraine. This holds that vasoconstriction and ischemia account for the symptoms of the migraine aura, whereas rebound vasodilation activates primary sensory neurons [8]. Belief in this hypothesis was reinforced by the fact that ergotamine, an effective antimigraine agent, was also a potent vasoconstrictor. The blood vessels of the meninges are known to be richly innervated and to produce pain when dilated; in contrast, brain tissue itself is insensate. Vasodilation of blood vessels in the meninges thus is theorized to activate perivascular sensory nerves and produce the pain of headache [9]. The neurogenic theory of migraine, in contrast, holds that the vascular changes that occur in migraine are a result of primary disturbances in the function of neurons, and that neurogenic inflammation and plasma protein extravasation in the meninges generate headache pain through activation of primary sensory neurons [10]. This theory was bolstered by early blood flow studies that seemed to contradict the vascular theory of migraine by demonstrating that although reduced blood flow did occur during the aura, it persisted well into the headache phase of a migraine [11]. Attempts to reconcile these two theories have led to the concept of migraine as a neurovascular phenomenon in which the neural abnormalities that occur are fundamental but lead to reactive changes in vascular, sensory, and painsensing pathways. A recent summary of many of the data from neuroimaging and blood flow studies concluded that there is no evidence that migraine without aura is associated with significant blood flow changes. Evidence does suggest important differences between the physiology of cortical neurons and
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neuronal energy metabolism in patients who have migraine with aura compared with those who have migraine without aura, and between both of these groups and normal control subjects. Trigeminovascular activation has been theorized to lead to release of various neuroinflammatory peptides, such as calcitonin gene-related peptide (CGRP) and Substance P (SP), which promote leakage of plasma proteins from vessels into surrounding tissues, often referred to as plasma protein extravasation (PPE). Release of these substances is blocked by many compounds that are also effective antimigraine agents, such as ergots, triptans, and indomethacin [12]. Levels of CGRP are elevated in the cranial circulation during attacks of migraine and normalize with successful treatment of migraine. Further evidence of the role of CGRP in migraine comes from the fact that CGRP infusions can precipitate migraine in some situations [13].
The treatment of migraine Abortive treatment General principles Evidence-based guidelines for abortive, preventive, and nonpharmacologic therapy of migraine have been released by the United States Headache Consortium [14], and guidelines for acute and preventive therapy also have been put forth by the American College of Physicians [15]. These guidelines summarize the quality of existing evidence for many therapies. No evidence is available, however, for many of the everyday treatment decisions that must be made in real-life clinical practice, and the guidelines are thus only partially useful. Evidence-based recommendations and guidelines inevitably seem to favor the use of newer medicines that have been studied more rigorously; the exclusion of many older medications reflects the generally lower scientific quality of the trials done at the time they were introduced, not their intrinsic value. In addition, because of the amount of time required for their preparation and approval, guidelines do not incorporate up-to-the-minute treatment advances and information. Guidelines are thus often a look back at what was state-of-the-art treatment a few years before their publication. Some general principles of abortive therapy should be borne in mind. In general, early treatment at a mild stage of the attack is more successful than treatment used late in an attack. Such early intervention has been shown to increase the number of patients who are pain-free as opposed to simply improved at 2 and 4 hours after treatment. It also has been shown to lead to reduced requirements for a second dose of medication, decreased functional disability, and other desirable outcomes [16]. Intervention at a mild stage of headache thus proves cost effective for the bulk of migraine patients and should be encouraged. Adequate doses of medication should be used, and associated symptoms such as nausea treated separately when necessary. In
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general, acute medication for migraine should not be used more than 2 or 3 days per week to avoid the possibility of rebound or analgesic-induced headache. Which abortive headache medications can cause rebound headache, however, and how much of each is required to induce this syndrome is a matter of dispute [17]. A limit of two or three times per week errs on the side of caution, and patients using abortive medications less frequently than this are unlikely to experience headache worsening as a result of medication overuse. Because migraine is characterized by recurrent episodes of headache over a lifetime in people who are otherwise generally healthy, the aims of treatment go beyond simply providing pain relief and include avoiding treatment-related disability. Selection of appropriate agent Abortive therapy for migraine can be divided broadly into nonspecific and specific therapies. Box 3 lists some commonly used abortive agents (Box 3). Sedative and general analgesic medications that cover up the symptoms of an attack fall into the first category, whereas ergot preparations and the new category of triptan medications fall into the latter. Because their use is associated all too frequently with addiction, dependence, or sedation, it is preferable to avoid medications that contain short-acting barbiturates, benzodiazepines, or narcotics for the acute treatment of migraine. It is generally not possible to predict accurately those patients at risk for the development of these serious overuse syndromes; once established, these behavior patterns are notoriously difficult to change. Because of the dangers associated with these nonspecific treatments and the availability of newer, more specific treatments that do not confer such risks, the use of migrainespecific agents such as the triptans is increasingly the standard of care for acute migraine. Ergotamine compounds have been available since the early decades of the 1900s for the treatment of migraine but have complex receptor pharmacology, with prolonged vasoconstriction and nausea being especially undesirable effects of treatment. The triptan class of medications has proved an advance over the ergots, with response rates of approximately 70%–80%, depending on the agent used, dose, and route of administration. Although they are the current standard of care for abortive treatment of migraine, triptans are not perfect. Headache recurrence, lack of response in up to 30% of patients, and chest symptoms are among their limitations. The ergot medications and the triptans are theorized to work by way of agonist activity at serotonin 1 B and D receptors. Activation of these receptors is postulated to constrict cerebral blood vessels, decrease the activation of trigeminal neurons, and prevent central sensitization. The small degree of coronary constriction caused by the triptans at pharmacologically relevant doses has no clinical consequences in healthy patients, but accounts for the fact these medications are contraindicated in patients with known coronary artery disease or risk factors for coronary artery disease. More than 10 years
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of clinical experience with this class of medications, however, has proved reassuring regarding their safety and tolerability. The largest study to date of triptan safety approximated real world conditions and provided reassuring evidence for the safety of these drugs [18]. The choice of acute treatment depends on many factors, including the severity of the headache attack and any associated features. Nausea or vomiting may make use of oral medications difficult, or the presence of coexisting disorders may preclude use of various categories of medication. Simple analgesics available over the counter, with or without caffeine, may be appropriate treatment for mild to moderate attacks of migraine, but more severe attacks usually require prescription medications. Opioid medications generally should be reserved for patients who are not candidates for more specific medications or who have failed the use of other medications. Short-acting opioids are used most appropriately for most migraine sufferers as rescue therapy for individual attacks that do not respond to treatment. In general, the use of meperidine (Demerol) should be avoided, as it is a neuroexcitant and may predispose to seizures. If opioids are used, an adequate dose should be used and adjunctive treatment of nausea considered. Stage-specific treatment To conceptualize acute treatment strategies, it can be useful to arbitrarily divide a migraine attack into the stages of prodrome, aura, headache phase, and postdrome. The prodrome consists of subtle signs or symptoms that, if recognized, can alert the patient and physician to an impending attack. Many patients report such things as changes in appetite, mood, bowel habits, or mild muscle pain. Early intervention during prodrome may hold promise as a means of aborting a full-blown attack. Clinical experience indicates that prodrome often may be treated successfully with the use of modest doses of milder medications than are necessary once an attack is fully underway. Anti-inflammatory drugs seem to be particularly useful in this setting. Few interventions have been shown to be successful in aborting or preventing aura; one recent report suggested that ketamine was successful in aborting aura in approximately half of treated attacks [19]. Such an intervention is interesting for what it might mean about the origins of aura but is not a practical treatment. In contrast to smaller doses of milder medications that may be successful in treating prodrome, attack-based therapy for established headaches may require larger doses of migrainespecific medications. Treatment of postdrome often is ignored, yet anecdote suggests that anti-inflammatory agents may play a role here also. Nonpharmacologic therapy For many patients, lifestyle modification and nonpharmacologic treatment strategies can be a helpful starting point, although rarely adequate
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treatment by themselves. Identification and elimination of typical headache triggers can be helpful in minimizing attacks that occur, although it should be recognized that not all triggers are avoidable. Many triggers are probably weak provocative agents and need to occur in concert to cause an attack. In addition, scientific evidence is lacking for many commonly mentioned headache triggers. Over attention to headache triggers with resultant somatic preoccupation should not be encouraged. Box 2 lists commonly mentioned migraine triggers. When the patient averages one or fewer headaches per week, abortive treatment alone often proves successful. For patients whose headaches do not respond optimally to abortive treatment or who have more than two headache episodes per week, preventive therapy aimed at decreasing attack frequency may be necessary. Most patients have a preference for abortive therapy alone, and when possible this should be the first strategy attempted. The introduction of highly effective, disease-specific abortive therapies underscores the importance of this statement. Currently available preventive therapies for migraine have side effect profiles that can be difficult for young, otherwise healthy people to tolerate, and many patients have a philosophic preference to avoid taking medication when they are not experiencing an attack. Finally, many migraine sufferers are women of childbearing age; the high rate of unintended pregnancies (approximately 50% in the United States) makes avoidance of daily medication important in this group whenever possible. Preventive therapy of migraine Patients whose headaches do not respond well to abortive treatment or who have frequent headaches may be candidates for preventive therapy of migraine. Opinion differs on the number of headaches beyond which
Box 2. Frequently mentioned migraine triggers Emotional stress Prolonged physical exertion Relaxation after stress (‘‘let-down headache’’) Lack of sleep; oversleeping Skipping meals Alcohol, especially red wine and beer Preserved meats Aged cheeses Orgasm Vasodilating medications such as nitrates, sildenafil
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prophylactic therapy should be considered. In the past, some authorities have advocated prophylaxis for any patient with more than two headaches per month, whereas more recently other investigators have suggested that prophylaxis need not be considered necessary until the patient averages two headaches a week. This change in the threshold for institution of prophylaxis likely reflects recognition of the improved efficacy and reliability of newer abortive agents that can obviate in some cases the need for prophylaxis. Certainly given the limited effectiveness and side effect profiles of many of the preventive medications, patient preference is usually to avoid their use unless necessary. Prophylactic therapy is given daily with the intention of reducing the frequency and intensity of migraine episodes and improving response to abortive agents. Several classes of medications have proved useful for this purpose, but it should be remembered that the bar for demonstration of effect is set low. In general, an agent is considered an effective migraine preventive drug if it decreases headache frequency by at least 50% in 50% of patients. The choice of preventive agents often is based on side effect profile and patient comorbidity. For example, migraine patients with hypertension or essential tremor may find benefit for both disorders with the use of beta blockers. In contrast, in patients with pre-existing asthma or depression, this class of medications should be avoided. Patients with comorbid bipolar disorder or epilepsy might be well managed with divalproex (Depakote) or topiramate (Topamax). The use of long-acting, scheduled opioids for chronic treatment of headache is controversial. Clinical experience suggests that only a minority of headache patients benefit long term from this form of treatment and that the need for concomitant treatment of headache does not decrease. This treatment, although increasingly accepted for other kinds of chronic, nonmalignant pain syndromes, thus seems to have only a limited role in the treatment of chronic headache disorders. Table 1 lists commonly used preventive agents and doses for migraine.
Table 1 Preventive agents for migraine Agent
Typical dose
Low-dose tricyclic antidepressants (eg, amitriptyline) Beta blockers (eg, inderal)a Sodium valproatea Topiramate
25–150 mg/day
Calcium blockers (eg, verapamil) Cyproheptadine NSAIDs (eg, naproxen sodium) a
80–160 mg/day 250 mg bid–500 mg bid 15–25 mg po q hs to initiate; increase as tolerated to 50 mg po bid or higher 80–240 mg/day 4–8 mg bid 550 mg bid
Approved by the Food and Drug Administration for prevention of migraine.
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Special treatment situations Special considerations may apply in the treatment of certain subpopulations of migraine patients. These include women who are attempting pregnancy or who are pregnant, women whose headaches are associated predictably with the menstrual cycle, patients whose headaches occur during the climacteric, and children and elderly patients. Pregnancy For most women with migraine, some improvement in headache frequency and intensity can be expected during the second and third trimesters of pregnancy. Because organogenesis is occurring during the first trimester, most women and their physicians are highly motivated to avoid drug therapy of migraine during this time. If headaches have not improved by the beginning of the second trimester, however, they are unlikely to do so, and treatment may be necessary. Acetaminophen and narcotics are safe choices when abortive treatment cannot be avoided, and most experts would recommend the use of beta blockers or low-dose tricyclic antidepressants if prophylactic therapy is needed [20]. The triptans currently are not recommended for use in pregnancy, but evidence to date from an ongoing prospective pregnancy registry maintained by the manufacturer and evidence from other sources is reassuring that the drug ultimately may prove safe for use in pregnant patients [21]. The importance of trigger avoidance and nonpharmacologic treatment during pregnancy cannot be overemphasized [22]. Menstrual-associated migraine A substantial minority of women with migraine note a link between menstrual periods and headache. Currently, acute therapy of menstrual migraine for most patients with the disorder is similar to that of nonmenstrual attacks. Nonsteroidal anti-inflammatory drugs (NSAIDs) may be more useful, however, in view of the role of prostaglandins in other menstrual-related symptoms. Ergot derivatives and triptans and nonspecific medications, such as butalbital compounds and narcotics, are used successfully in menstrual migraine. Contrary to widely held belief, there is substantial evidence that most of these treatments work equally well in migraine associated with menstruation as they do in nonmenstrual migraine. In post-hoc analyses, rizatriptan (Maxalt) [23], zolmitriptan (Zomig) [24], sumatriptan (Imitrex) [25], and eletriptan (Relpax) [26] have been shown to be equally effective in menstrual and nonmenstrual migraine, and similar evidence exists for the nonspecific combination analgesic aspirin-caffeineacetaminophen (Excedrin) [27]. Prospective evidence that these drugs are effective in treating menstrual-associated migraine exists for sumatriptan [28] and zolmitriptan [29]. Short- or long-term prophylactic therapy with NSAIDs, ergot derivatives, SSRIs, calcium channel blockers, and magnesium supplements have
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been advocated for menstrual migraine also. Naproxen sodium (Anaprox DS) in a dose of 550 mg twice daily has been best studied [30,31]. Some investigators advocate perimenstrual increases in the dose of a preventive agent being used throughout the month, whereas others advocate the use of short-term perimenstrual prophylaxis only around the menstrual period. The latter often is recommended for women whose menstrual-related headaches alone are resistant to therapy. Because estrogen withdrawal has been implicated as the cause of menstrual associated migraine, there has long been enthusiasm for the use of estrogen supplementation to prevent or blunt the premenstrual decrease in estrogen levels. Results of clinical trials have been variable, however. There may be a critical level of estrogen necessary for efficacy. That this is the case is suggested by a study done by Pradalier in which 25-mcg patches were not effective in preventing menstrual migraine, whereas 100-mcg patches were effective [32]. Still other studies found that the 50-mcg patch was not effective [33]. Many prophylactic hormonal treatments for refractory menstrual migraine are based on expert experience or small, open-label trials. Some that have been suggested are the use of bromocriptine [34], tamoxifen [35], danazol [36], and GnRH analogs with add-back estrogen therapy [37]. It is important to remember that the risk-to-benefit ratio of most of these treatments has not been studied carefully. Menopause Some women whose headaches previously followed a stable pattern find that the hormonal changes of the climacteric make headaches less predictable or more severe. They may require prophylaxis for a period of time until the pattern stabilizes. Questions regarding the advisability of hormone replacement therapy in women with a history of migraine cannot be answered on the basis of rigorous studies. Clinical experience, however, suggests that most women with migraine do not have aggravation of headaches with the use of daily low-dose estrogen/progesterone hormonal replacement. The older, interrupted estrogen regimens in which treatment was discontinued for 5–7 days at the end of the month were more likely to produce estrogen-withdrawal headache and may account for the commonly held view that patients with migraine should not use hormone replacement. Some women may find the stable hormonal levels of estrogen replacement beneficial for migraine. Elderly patients Most patients with migraine note an improvement in headache frequency and intensity over time, so that headache is often less troublesome when they are older. There are exceptions to this rule, however, and treatment can be complicated. Older patients have cardiac risk factors that may make the
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Box 3. Abortive agents for migraine Over-the-counter drugs for mild–moderate attacks Aspirin Acetaminophen Ketoprofen Naproxen sodium Aspirin-acetaminophen-caffeine Prescription drugs for mild–moderate attacks Midrin Tramadol Aspirin (or acetaminophen)-butalbital-caffeine combinations Prescription drugs for moderate–severe attacks Sumatriptan Rizatriptan Zolmitriptan Naratriptan Ergotamine preparations Opioids Drugs to treat associated nausea/vomiting Metoclopramide Chlorpromazine Hydroxyzine Prochlorperazine
use of triptans or other highly effective therapy problematic. They are also at higher risk for structural or other medical causes of headache, such as temporal arteritis, and care must be taken not to overlook these diagnostic possibilities in someone with a prior history of migraine. Children Migraine is a condition that frequently begins in childhood or adolescence. In children, headache attacks may be shorter than in adults and the period of disability and illness significantly compressed. This makes early treatment all the more important. Studies are ongoing to show effectiveness of new treatments such as triptans in children, but these drugs currently are not FDA-approved for use in children and adolescents; still, their off-label use in this population is common. Many physicians prefer specific agents such as the triptans to nonspecific drugs such as barbiturates with their high potential for abuse and sedation. Children often respond well to trigger avoidance and interventions such as biofeedback. Whenever possible, treatment should be incorporated into the child’s routine and absences from school or extracurricular activities minimized.
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Summary Migraine is a prevalent condition in young, otherwise healthy people. Its diagnosis is clinical, based on criteria developed by the International Headache Society. Migraine currently is understood as a neurovascular disorder in which involvement of vascular structures is secondary to inciting central nervous system events. Treatment must be individualized. Avoidance of known triggers and alterations in daily routines can be helpful. Abortive treatment of individual attacks with medication is necessary for most migraineurs who consult a physician. Simple analgesics may be appropriate for mild, nondisabling attacks, but triptans or other specific treatments are preferred for attacks that are moderate or severe. Preventive treatment with daily medication is necessary for patients who have more than one attack per week or whose attacks respond poorly to abortive medication. Subpopulations of migraineurs, such as children, elderly patients, and women, have special treatment needs.
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[14] Headache Consortium US. American Academy of Neurology Headache Guidelines. Available at: http://www.aan.com/professionals/practiceguidelines/index.cfm. (Accessed April 14, 2004). [15] Snow V, Weiss K, Wall EM, Mottur-Pilson C, for the American Academy of Family Physicians and the American College of Physicians–American Society of Internal Medicine. Pharmacologic management of acute attacks of migraine and prevention of migraine headache. Ann Intern Med 2002;137:840–9. [16] Cady RK, Sheftell F, Lipton RB, O’Quinn S, Jones M, Putnam DG, Crisp A, Metaz A, McNeal S. Effect of early intervention with sumatriptan on migraine pain: retrospective analyses of data from three clinical trials. Clin Therapeutics 2000;22(9):1035–48. [17] Silberstein S, Welch KMA. Painkiller headache. Neurology 2002;59:756. [18] Gobel H, Heinze A, Stotze H, Heinze-Kuhn K, Lindner V. Open-labeled long-term study of the efficacy, safety, and tolerability of subcutaneous sumatriptan in acute migraine treatment. Cephalalgia 1999;19(7):676–83. [19] Kaube H. Ketamine is effective in aborting aura [abstract]. Headache World 2000; September 3–7, 2000, London, England. [20] Wood A. Drugs in pregnancy. N Engl J Med 2000;338(16):1130–7. [21] Shuhaiber S, et al. Pregnancy outcome following first trimester exposure to sumatriptan. Neurology 1998;51:581–3. [22] Scharff L, et al. Maintenance of effects in the nonmedical treatment of headaches during pregnancy. Headache 1996;36:285–90. [23] Silberstein SD, Massiou H, LeJeunne C, Johnson-Pratt L, McCarroll KA, Lines CR. Rizatriptan in the treatment of menstrual migraine. Obstet Gynecol 2000;96:237–42. [24] Loder E, Silberstein S. Clinical efficacy of 2.5- and 5-mg zolmitriptan in migraine associated with menses or in patients using non-progestogen oral contraceptives [abstract]. Neurology 1998;50(Suppl 4):A341–6. [25] Salonen R, Saiers J. Sumatriptan is effective in the treatment of menstrual migraine: a review of prospective studies and retrospective analyses. Cephalalgia 1999;19(1):16–9. [26] Massiou H, Pitei D, Poole PH, Sikes C. Efficacy of eletriptan for the treatment of migraine in women with menstrually associated migraine, and in women on contraceptives or hormone replacement therapy: meta-analyses of randomized clinical trials. Poster presentation. Headache World 2000; September 3–7, 2000, London, England. [27] Silberstein SD, Stewart WF, Lipton RB. Treatment of menstruation-associated migraine with the nonprescription combination of acetaminophen, aspirin and caffeine: results from three randomized, placebo-controlled studies. Clin Therapeutics 1999;21(3): 475–91. [28] Facchinetti F, Bonellie G, Kanasniemi P, Pascual J, Shuaib A. The efficacy and safety of subcutaneous sumatriptan in the acute treatment of menstrual migraine. The Sumatriptan Menstrual Migraine Study Group. Obstet Gynecol 1995;86(6):911–6. [29] Loder E. Zolmitriptan is effective in the treatment of menstrual-associated migraine [abstract]. Presented at the American Academy of Neurology Annual Scientific Meeting. April 19, 2002, Denver, CO. [30] Szekely B, Merryman S, Croft H, et al. Prophylactic effects of naproxen sodium on perimenstrual headache: a double blind placebo controlled study. Cephalalgia 1989; 9(Suppl 10):S452–3. [31] Sances G, Martignoni E, Fioroni L, Blandini F, Facchinetti F, Nappi G. Naproxen sodium in menstrual migraine prophylaxis: a double-blind, placebo-controlled study. Headache 1990;30(11):705–9. [32] Pradalier A, Vincent D, Beaulieu PH, Baudesson G, Launay JM. Correlation between oestradiol plasma level and therapeutic effect on menstrual migraine. In: Rose FD, editor. New advances in headache research. 4th edition. London: Smith-Gordon; 1994. p. 129–32. [33] Pfaffenrath V. Efficacy and safety of percutaneous estradiol vs. placebo in menstrual migraine [abstract]. Cephalalgia 1993;13:168.
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[34] Herzog AG. Continuous bromocriptine therapy in menstrual migraine. Neurology 1997; 48:101–2. [35] O’Dea PK, Davis EH. Tamoxifen in the treatment of menstrual migraine. Neurology 1990; 40:1470–1. [36] Powles TJ. Prevention of migrainous headaches by tamoxifen. Lancet 1986;2:1344. [37] Silberstein SD, Merriam GR. Sex hormones and headache. J Pain Symptom Manage 1993; 8(2):98–114.
Migraine diagnosis and treatment Elizabeth Loder, MD, FACP Harvard Medical School, 25 Shattuck Street, Boston, MA 02114, USA Pain and Headache Management Programs, Spaulding Rehabilitation Hospital, 125 Nashua Street, Boston, MA 02114, USA
Recognizing migraine Migraine is a highly prevalent condition, affecting as many as 28 million people in the United States. It is responsible for significant disability in otherwise healthy, generally young people [1]. In its pure form, migraine is recognized easily. Its presentation varies enough from patient to patient and even from attack to attack, however, that more subtle forms and variations on the theme of migraine may be recognized less quickly. Making a specific diagnosis of migraine is important because the diagnosis increasingly has treatment implications. When only nonspecific or sedative medications were available, it was enough to simply make a diagnosis of benign, recurrent headaches. Now, however, with the advent of targeted abortive and preventive medications that have efficacy in one benign headache disorder and none in another, clinicians must go beyond simply a diagnosis of benign headache and must attempt to characterize what kind of benign headache the patient has. In most patients, migraine is an intermittent headache syndrome with episodes of headaches interspersed with periods of complete well being. (For reasons that are poorly understood, a subset of patients experience gradual evolution of this intermittent pattern into chronic migraine, in which headache-free time is limited or nonexistent.) No one of the many signs and symptoms that can occur in migraine, other than headache, is absolutely required for diagnosis. There is great variability in the timing of attacks between patients and even within the same patient. Attacks can occur almost daily or rarely, suggesting that changes in the brain’s threshold of susceptibility to attacks may be important in determining when and whether they occur. Standardized diagnostic criteria for migraine and other headache syndromes (Box 1) have been developed by the International Headache
E-mail address: [email protected] 0095-4543/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.pop.2004.02.003
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Box 1. Diagnostic criteria for migraine with and without aura Migraine without aura At least five attacks fulfilling criteria B–D Headache lasting 4–72 hours (untreated or unsuccessfully treated) Headache has at least two of the following characteristics: Unilateral location Pulsating quality Moderate or severe intensity (inhibits or prohibits daily activities) Aggravation by walking stairs or similar routine physical activity During headache, at least one of the following occurs: Nausea or vomiting Photophobia and phonophobia At least one of the following is present: History and physical and neurologic examinations do not suggest an organic disorder History and physical and neurologic examinations do suggest such disorder, but it is ruled out by appropriate investigations Such disorder is present, but migraine attacks do not occur for the first time in close temporal relation to the disorder Migraine with aura At least two attacks fulfilling criterion B At least three of the following four characteristics are present: One or more fully reversible aura symptoms occur, indicating brain dysfunction At least one aura symptom develops gradually over more than 4 minutes or two or more symptoms occur in succession No single aura symptom lasts more than 60 minutes. Headache follows aura with a free interval of less than 60 minutes (may also begin before or simultaneously with the aura) History, physical examination, and, where appropriate, diagnostic tests, exclude a secondary cause (Adapted from The International Classifications of Headache Disorders. Cephalalgia 2004;(Suppl 1):1–160.
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Society (IHS). These have been enormously useful for research purposes, but perform poorly in the clinical setting because of low sensitivity for the diagnosis. Familiarity with these criteria is helpful, but in office practice less stringent requirements for making the diagnosis allow identification of more patients with the disorder, who presumably will benefit from treatment. An untreated or unsuccessfully treated attack of migraine generally lasts 4–72hours. A common misconception is that migraine must be unilateral. This mistake is understandable, because the term migraine derives from the Greek word hemicrania, meaning one side of the head. In fact, however, the location of pain in migraine can be generalized, on top of the head, in the occipital area, and in the classic location over one temple or the other. Additionally, the pain, if unilateral, can switch sides from attack to attack or even within a single attack. This variability in the location of the pain often is said to be a reassuring sign that the underlying headache mechanism is benign, because a fixed structural abnormality leading to headache would be more likely to produce a headache of unvarying location. With the exception of occipital discomfort, which may have a different origin than pain in other parts of the head, the pain of migraine is produced and felt in areas that are innervated by the first division of the trigeminal nerve and connect with the trigeminocervical complex and then to the dorsal horns of C1 and C2, finally transmitting signals to the brainstem, thalamus, and cortex. Certain brainstem areas (the periaqueductal gray matter [PAG] and locus ceruleus [LC]) probably modulate incoming pain signals and blood flow [2]. Placement of electrodes into the PAG region produces a migraine-like headache, and stimulation of the LC in animals reduced blood flow [3]. Most patients describe the pain of migraine as pounding or throbbing and report that at its peak the pain is at least moderate to severe in intensity. In clinical trials of migraine treatments, pain intensity is usually rated on a 0–3 scale, with 0 being no pain, 1 mild pain, 2 moderate pain, and 3 severe pain. Because pain ratings can vary significantly depending on how stoic or histrionic an individual patient is, it may be more helpful to judge pain intensity based on the amount of disability it induces. Patients can describe the impact of pain on their ability to carry out such daily activities as attending work and school, performing housework, or participating in leisure activities, with disability rated as absent (0), mild (1), moderate (2), or severe (3). In most patients, the pain of a full-blown migraine attack is sufficiently intense to interfere with daily activities or prohibit them altogether. In addition, everyday activities that do not cause pain ordinarily, such as walking or climbing stairs, aggravates the pain of a migraine headache. It is important to remember, however, that even patients who have severe attacks of migraine generally have other attacks of headache that are less severe. Although these milder headaches sometimes are classified as tension headaches, a variety of evidence suggests that, in a patient who is known to have migraine, these attacks are milder versions
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of migraine that are aborted through natural mechanisms or fail to develop fully. It can be useful to think of migraine as a ‘‘headache plus’’ syndrome, in which headache is rarely the only feature but is instead accompanied by other symptoms. Nausea is probably the most typical accompanying symptom. It usually builds up in parallel with the headache pain, but in some patients it may precede the attack, making the use of oral treatment difficult. Vomiting does not occur with all attacks or with all patients; when it does, it usually develops later in the attack. Vomiting seems to be more characteristic of childhood migraine, and many patients with migraine report that vomiting improves and may even disappear as they age. Cyclic vomiting is a childhood variant of migraine in which repeated bouts of abdominal pain and vomiting occur. Headache may be absent or only a minor feature. It responds well to treatment with typical migraine medications such as propranolol. Photophobia (sensitivity to light) and phonophobia (sensitivity to sound) are also extremely common accompaniments of headache in migraine sufferers. In fact, strong sensory stimuli of many kinds in addition to bright light and noise can precipitate or aggravate headache in many migraine sufferers. Abnormal sensitivity to sensory stimuli seems to be present even interictally, although it is most pronounced during an attack. These accompanying symptoms account for the clinical picture many clinicians and lay people have of a patient experiencing a migraine: a person who has a strong desire to lie motionless in a dark, quiet room. One way of helping patients understand their heightened sensitivity to the world around them is to point out that such highly developed sensory reactions probably improved the odds of survival at some point in human evolution. They may simply have inherited ‘‘too much of a good thing’’ [4]. The visual distortions and abnormalities of aura are widely recognized as a feature of migraine by physicians and patients alike. Only 15%–20% of patients with migraine experience aura, however. Many patients experience aura with some but not all of their headaches, and aura can occur in the absence of headache; this seems to become more common as patients age. In the usual presentation of migraine with aura, headache is preceded by focal neurologic signs or symptoms. Especially common are transient visual disturbances that can include a scintillating scotoma or even complete visual loss. Other neurologic symptoms and signs, such as numbness, weakness, paresthesias, or confusion can occur as part of an aura but are much less common than visual changes. In the typical aura, the neurologic event builds up gradually and lasts no longer than 0.5–1.0 hour. As the aura symptoms gradually diminish, the headache begins. As mentioned, patients may not experience aura with every headache, but auras within an individual patient are consistent from one attack to another; it is not common for a patient to have cognitive disturbance before one headache and visual loss with another. Patients who have sudden, unpredictable onset of significant visual aura may occasionally report that it is the aura and not
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the headache that is of most concern to them and for which they most desire treatment. Although not common, aura can in some circumstances be prolonged, lasting into or even beyond the headache. Studies of families with a rare autosomal dominant form of migraine with aura known as familial hemiplegic migraine (FHN) have identified an amino acid substitution in the pore-forming and voltage sensor regions of neuronal calcium channels. This has been traced to a missense mutation in a neuronal specific P/Q calcium channel gene, and is present in roughly half of affected families [5]. In total, four different missense mutations in the alpha1 subunit have been identified. Abnormalities of chromosome 19 also may be involved in more common forms of migraine [6]. Many patients experience recurrent, predictable changes before migraine attacks that do not technically meet the criteria for aura. These premonitory symptoms occur in roughly 25% of patients and consist of such things as mood or appetite changes, altered gastrointestinal function, and yawning [7]. Administration of a dopamine agonist, apomorphine, reproduces many of these prodromal symptoms, leading to speculation that changes in dopaminergic transmission in the CNS may be involved in migraine. Several theories have been suggested to explain the cause of migraine. The first originated with Harold Wolff and often is referred to as the vascular or vasogenic theory of migraine. This holds that vasoconstriction and ischemia account for the symptoms of the migraine aura, whereas rebound vasodilation activates primary sensory neurons [8]. Belief in this hypothesis was reinforced by the fact that ergotamine, an effective antimigraine agent, was also a potent vasoconstrictor. The blood vessels of the meninges are known to be richly innervated and to produce pain when dilated; in contrast, brain tissue itself is insensate. Vasodilation of blood vessels in the meninges thus is theorized to activate perivascular sensory nerves and produce the pain of headache [9]. The neurogenic theory of migraine, in contrast, holds that the vascular changes that occur in migraine are a result of primary disturbances in the function of neurons, and that neurogenic inflammation and plasma protein extravasation in the meninges generate headache pain through activation of primary sensory neurons [10]. This theory was bolstered by early blood flow studies that seemed to contradict the vascular theory of migraine by demonstrating that although reduced blood flow did occur during the aura, it persisted well into the headache phase of a migraine [11]. Attempts to reconcile these two theories have led to the concept of migraine as a neurovascular phenomenon in which the neural abnormalities that occur are fundamental but lead to reactive changes in vascular, sensory, and painsensing pathways. A recent summary of many of the data from neuroimaging and blood flow studies concluded that there is no evidence that migraine without aura is associated with significant blood flow changes. Evidence does suggest important differences between the physiology of cortical neurons and
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neuronal energy metabolism in patients who have migraine with aura compared with those who have migraine without aura, and between both of these groups and normal control subjects. Trigeminovascular activation has been theorized to lead to release of various neuroinflammatory peptides, such as calcitonin gene-related peptide (CGRP) and Substance P (SP), which promote leakage of plasma proteins from vessels into surrounding tissues, often referred to as plasma protein extravasation (PPE). Release of these substances is blocked by many compounds that are also effective antimigraine agents, such as ergots, triptans, and indomethacin [12]. Levels of CGRP are elevated in the cranial circulation during attacks of migraine and normalize with successful treatment of migraine. Further evidence of the role of CGRP in migraine comes from the fact that CGRP infusions can precipitate migraine in some situations [13].
The treatment of migraine Abortive treatment General principles Evidence-based guidelines for abortive, preventive, and nonpharmacologic therapy of migraine have been released by the United States Headache Consortium [14], and guidelines for acute and preventive therapy also have been put forth by the American College of Physicians [15]. These guidelines summarize the quality of existing evidence for many therapies. No evidence is available, however, for many of the everyday treatment decisions that must be made in real-life clinical practice, and the guidelines are thus only partially useful. Evidence-based recommendations and guidelines inevitably seem to favor the use of newer medicines that have been studied more rigorously; the exclusion of many older medications reflects the generally lower scientific quality of the trials done at the time they were introduced, not their intrinsic value. In addition, because of the amount of time required for their preparation and approval, guidelines do not incorporate up-to-the-minute treatment advances and information. Guidelines are thus often a look back at what was state-of-the-art treatment a few years before their publication. Some general principles of abortive therapy should be borne in mind. In general, early treatment at a mild stage of the attack is more successful than treatment used late in an attack. Such early intervention has been shown to increase the number of patients who are pain-free as opposed to simply improved at 2 and 4 hours after treatment. It also has been shown to lead to reduced requirements for a second dose of medication, decreased functional disability, and other desirable outcomes [16]. Intervention at a mild stage of headache thus proves cost effective for the bulk of migraine patients and should be encouraged. Adequate doses of medication should be used, and associated symptoms such as nausea treated separately when necessary. In
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general, acute medication for migraine should not be used more than 2 or 3 days per week to avoid the possibility of rebound or analgesic-induced headache. Which abortive headache medications can cause rebound headache, however, and how much of each is required to induce this syndrome is a matter of dispute [17]. A limit of two or three times per week errs on the side of caution, and patients using abortive medications less frequently than this are unlikely to experience headache worsening as a result of medication overuse. Because migraine is characterized by recurrent episodes of headache over a lifetime in people who are otherwise generally healthy, the aims of treatment go beyond simply providing pain relief and include avoiding treatment-related disability. Selection of appropriate agent Abortive therapy for migraine can be divided broadly into nonspecific and specific therapies. Box 3 lists some commonly used abortive agents (Box 3). Sedative and general analgesic medications that cover up the symptoms of an attack fall into the first category, whereas ergot preparations and the new category of triptan medications fall into the latter. Because their use is associated all too frequently with addiction, dependence, or sedation, it is preferable to avoid medications that contain short-acting barbiturates, benzodiazepines, or narcotics for the acute treatment of migraine. It is generally not possible to predict accurately those patients at risk for the development of these serious overuse syndromes; once established, these behavior patterns are notoriously difficult to change. Because of the dangers associated with these nonspecific treatments and the availability of newer, more specific treatments that do not confer such risks, the use of migrainespecific agents such as the triptans is increasingly the standard of care for acute migraine. Ergotamine compounds have been available since the early decades of the 1900s for the treatment of migraine but have complex receptor pharmacology, with prolonged vasoconstriction and nausea being especially undesirable effects of treatment. The triptan class of medications has proved an advance over the ergots, with response rates of approximately 70%–80%, depending on the agent used, dose, and route of administration. Although they are the current standard of care for abortive treatment of migraine, triptans are not perfect. Headache recurrence, lack of response in up to 30% of patients, and chest symptoms are among their limitations. The ergot medications and the triptans are theorized to work by way of agonist activity at serotonin 1 B and D receptors. Activation of these receptors is postulated to constrict cerebral blood vessels, decrease the activation of trigeminal neurons, and prevent central sensitization. The small degree of coronary constriction caused by the triptans at pharmacologically relevant doses has no clinical consequences in healthy patients, but accounts for the fact these medications are contraindicated in patients with known coronary artery disease or risk factors for coronary artery disease. More than 10 years
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of clinical experience with this class of medications, however, has proved reassuring regarding their safety and tolerability. The largest study to date of triptan safety approximated real world conditions and provided reassuring evidence for the safety of these drugs [18]. The choice of acute treatment depends on many factors, including the severity of the headache attack and any associated features. Nausea or vomiting may make use of oral medications difficult, or the presence of coexisting disorders may preclude use of various categories of medication. Simple analgesics available over the counter, with or without caffeine, may be appropriate treatment for mild to moderate attacks of migraine, but more severe attacks usually require prescription medications. Opioid medications generally should be reserved for patients who are not candidates for more specific medications or who have failed the use of other medications. Short-acting opioids are used most appropriately for most migraine sufferers as rescue therapy for individual attacks that do not respond to treatment. In general, the use of meperidine (Demerol) should be avoided, as it is a neuroexcitant and may predispose to seizures. If opioids are used, an adequate dose should be used and adjunctive treatment of nausea considered. Stage-specific treatment To conceptualize acute treatment strategies, it can be useful to arbitrarily divide a migraine attack into the stages of prodrome, aura, headache phase, and postdrome. The prodrome consists of subtle signs or symptoms that, if recognized, can alert the patient and physician to an impending attack. Many patients report such things as changes in appetite, mood, bowel habits, or mild muscle pain. Early intervention during prodrome may hold promise as a means of aborting a full-blown attack. Clinical experience indicates that prodrome often may be treated successfully with the use of modest doses of milder medications than are necessary once an attack is fully underway. Anti-inflammatory drugs seem to be particularly useful in this setting. Few interventions have been shown to be successful in aborting or preventing aura; one recent report suggested that ketamine was successful in aborting aura in approximately half of treated attacks [19]. Such an intervention is interesting for what it might mean about the origins of aura but is not a practical treatment. In contrast to smaller doses of milder medications that may be successful in treating prodrome, attack-based therapy for established headaches may require larger doses of migrainespecific medications. Treatment of postdrome often is ignored, yet anecdote suggests that anti-inflammatory agents may play a role here also. Nonpharmacologic therapy For many patients, lifestyle modification and nonpharmacologic treatment strategies can be a helpful starting point, although rarely adequate
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treatment by themselves. Identification and elimination of typical headache triggers can be helpful in minimizing attacks that occur, although it should be recognized that not all triggers are avoidable. Many triggers are probably weak provocative agents and need to occur in concert to cause an attack. In addition, scientific evidence is lacking for many commonly mentioned headache triggers. Over attention to headache triggers with resultant somatic preoccupation should not be encouraged. Box 2 lists commonly mentioned migraine triggers. When the patient averages one or fewer headaches per week, abortive treatment alone often proves successful. For patients whose headaches do not respond optimally to abortive treatment or who have more than two headache episodes per week, preventive therapy aimed at decreasing attack frequency may be necessary. Most patients have a preference for abortive therapy alone, and when possible this should be the first strategy attempted. The introduction of highly effective, disease-specific abortive therapies underscores the importance of this statement. Currently available preventive therapies for migraine have side effect profiles that can be difficult for young, otherwise healthy people to tolerate, and many patients have a philosophic preference to avoid taking medication when they are not experiencing an attack. Finally, many migraine sufferers are women of childbearing age; the high rate of unintended pregnancies (approximately 50% in the United States) makes avoidance of daily medication important in this group whenever possible. Preventive therapy of migraine Patients whose headaches do not respond well to abortive treatment or who have frequent headaches may be candidates for preventive therapy of migraine. Opinion differs on the number of headaches beyond which
Box 2. Frequently mentioned migraine triggers Emotional stress Prolonged physical exertion Relaxation after stress (‘‘let-down headache’’) Lack of sleep; oversleeping Skipping meals Alcohol, especially red wine and beer Preserved meats Aged cheeses Orgasm Vasodilating medications such as nitrates, sildenafil
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prophylactic therapy should be considered. In the past, some authorities have advocated prophylaxis for any patient with more than two headaches per month, whereas more recently other investigators have suggested that prophylaxis need not be considered necessary until the patient averages two headaches a week. This change in the threshold for institution of prophylaxis likely reflects recognition of the improved efficacy and reliability of newer abortive agents that can obviate in some cases the need for prophylaxis. Certainly given the limited effectiveness and side effect profiles of many of the preventive medications, patient preference is usually to avoid their use unless necessary. Prophylactic therapy is given daily with the intention of reducing the frequency and intensity of migraine episodes and improving response to abortive agents. Several classes of medications have proved useful for this purpose, but it should be remembered that the bar for demonstration of effect is set low. In general, an agent is considered an effective migraine preventive drug if it decreases headache frequency by at least 50% in 50% of patients. The choice of preventive agents often is based on side effect profile and patient comorbidity. For example, migraine patients with hypertension or essential tremor may find benefit for both disorders with the use of beta blockers. In contrast, in patients with pre-existing asthma or depression, this class of medications should be avoided. Patients with comorbid bipolar disorder or epilepsy might be well managed with divalproex (Depakote) or topiramate (Topamax). The use of long-acting, scheduled opioids for chronic treatment of headache is controversial. Clinical experience suggests that only a minority of headache patients benefit long term from this form of treatment and that the need for concomitant treatment of headache does not decrease. This treatment, although increasingly accepted for other kinds of chronic, nonmalignant pain syndromes, thus seems to have only a limited role in the treatment of chronic headache disorders. Table 1 lists commonly used preventive agents and doses for migraine.
Table 1 Preventive agents for migraine Agent
Typical dose
Low-dose tricyclic antidepressants (eg, amitriptyline) Beta blockers (eg, inderal)a Sodium valproatea Topiramate
25–150 mg/day
Calcium blockers (eg, verapamil) Cyproheptadine NSAIDs (eg, naproxen sodium) a
80–160 mg/day 250 mg bid–500 mg bid 15–25 mg po q hs to initiate; increase as tolerated to 50 mg po bid or higher 80–240 mg/day 4–8 mg bid 550 mg bid
Approved by the Food and Drug Administration for prevention of migraine.
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Special treatment situations Special considerations may apply in the treatment of certain subpopulations of migraine patients. These include women who are attempting pregnancy or who are pregnant, women whose headaches are associated predictably with the menstrual cycle, patients whose headaches occur during the climacteric, and children and elderly patients. Pregnancy For most women with migraine, some improvement in headache frequency and intensity can be expected during the second and third trimesters of pregnancy. Because organogenesis is occurring during the first trimester, most women and their physicians are highly motivated to avoid drug therapy of migraine during this time. If headaches have not improved by the beginning of the second trimester, however, they are unlikely to do so, and treatment may be necessary. Acetaminophen and narcotics are safe choices when abortive treatment cannot be avoided, and most experts would recommend the use of beta blockers or low-dose tricyclic antidepressants if prophylactic therapy is needed [20]. The triptans currently are not recommended for use in pregnancy, but evidence to date from an ongoing prospective pregnancy registry maintained by the manufacturer and evidence from other sources is reassuring that the drug ultimately may prove safe for use in pregnant patients [21]. The importance of trigger avoidance and nonpharmacologic treatment during pregnancy cannot be overemphasized [22]. Menstrual-associated migraine A substantial minority of women with migraine note a link between menstrual periods and headache. Currently, acute therapy of menstrual migraine for most patients with the disorder is similar to that of nonmenstrual attacks. Nonsteroidal anti-inflammatory drugs (NSAIDs) may be more useful, however, in view of the role of prostaglandins in other menstrual-related symptoms. Ergot derivatives and triptans and nonspecific medications, such as butalbital compounds and narcotics, are used successfully in menstrual migraine. Contrary to widely held belief, there is substantial evidence that most of these treatments work equally well in migraine associated with menstruation as they do in nonmenstrual migraine. In post-hoc analyses, rizatriptan (Maxalt) [23], zolmitriptan (Zomig) [24], sumatriptan (Imitrex) [25], and eletriptan (Relpax) [26] have been shown to be equally effective in menstrual and nonmenstrual migraine, and similar evidence exists for the nonspecific combination analgesic aspirin-caffeineacetaminophen (Excedrin) [27]. Prospective evidence that these drugs are effective in treating menstrual-associated migraine exists for sumatriptan [28] and zolmitriptan [29]. Short- or long-term prophylactic therapy with NSAIDs, ergot derivatives, SSRIs, calcium channel blockers, and magnesium supplements have
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been advocated for menstrual migraine also. Naproxen sodium (Anaprox DS) in a dose of 550 mg twice daily has been best studied [30,31]. Some investigators advocate perimenstrual increases in the dose of a preventive agent being used throughout the month, whereas others advocate the use of short-term perimenstrual prophylaxis only around the menstrual period. The latter often is recommended for women whose menstrual-related headaches alone are resistant to therapy. Because estrogen withdrawal has been implicated as the cause of menstrual associated migraine, there has long been enthusiasm for the use of estrogen supplementation to prevent or blunt the premenstrual decrease in estrogen levels. Results of clinical trials have been variable, however. There may be a critical level of estrogen necessary for efficacy. That this is the case is suggested by a study done by Pradalier in which 25-mcg patches were not effective in preventing menstrual migraine, whereas 100-mcg patches were effective [32]. Still other studies found that the 50-mcg patch was not effective [33]. Many prophylactic hormonal treatments for refractory menstrual migraine are based on expert experience or small, open-label trials. Some that have been suggested are the use of bromocriptine [34], tamoxifen [35], danazol [36], and GnRH analogs with add-back estrogen therapy [37]. It is important to remember that the risk-to-benefit ratio of most of these treatments has not been studied carefully. Menopause Some women whose headaches previously followed a stable pattern find that the hormonal changes of the climacteric make headaches less predictable or more severe. They may require prophylaxis for a period of time until the pattern stabilizes. Questions regarding the advisability of hormone replacement therapy in women with a history of migraine cannot be answered on the basis of rigorous studies. Clinical experience, however, suggests that most women with migraine do not have aggravation of headaches with the use of daily low-dose estrogen/progesterone hormonal replacement. The older, interrupted estrogen regimens in which treatment was discontinued for 5–7 days at the end of the month were more likely to produce estrogen-withdrawal headache and may account for the commonly held view that patients with migraine should not use hormone replacement. Some women may find the stable hormonal levels of estrogen replacement beneficial for migraine. Elderly patients Most patients with migraine note an improvement in headache frequency and intensity over time, so that headache is often less troublesome when they are older. There are exceptions to this rule, however, and treatment can be complicated. Older patients have cardiac risk factors that may make the
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Box 3. Abortive agents for migraine Over-the-counter drugs for mild–moderate attacks Aspirin Acetaminophen Ketoprofen Naproxen sodium Aspirin-acetaminophen-caffeine Prescription drugs for mild–moderate attacks Midrin Tramadol Aspirin (or acetaminophen)-butalbital-caffeine combinations Prescription drugs for moderate–severe attacks Sumatriptan Rizatriptan Zolmitriptan Naratriptan Ergotamine preparations Opioids Drugs to treat associated nausea/vomiting Metoclopramide Chlorpromazine Hydroxyzine Prochlorperazine
use of triptans or other highly effective therapy problematic. They are also at higher risk for structural or other medical causes of headache, such as temporal arteritis, and care must be taken not to overlook these diagnostic possibilities in someone with a prior history of migraine. Children Migraine is a condition that frequently begins in childhood or adolescence. In children, headache attacks may be shorter than in adults and the period of disability and illness significantly compressed. This makes early treatment all the more important. Studies are ongoing to show effectiveness of new treatments such as triptans in children, but these drugs currently are not FDA-approved for use in children and adolescents; still, their off-label use in this population is common. Many physicians prefer specific agents such as the triptans to nonspecific drugs such as barbiturates with their high potential for abuse and sedation. Children often respond well to trigger avoidance and interventions such as biofeedback. Whenever possible, treatment should be incorporated into the child’s routine and absences from school or extracurricular activities minimized.
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Summary Migraine is a prevalent condition in young, otherwise healthy people. Its diagnosis is clinical, based on criteria developed by the International Headache Society. Migraine currently is understood as a neurovascular disorder in which involvement of vascular structures is secondary to inciting central nervous system events. Treatment must be individualized. Avoidance of known triggers and alterations in daily routines can be helpful. Abortive treatment of individual attacks with medication is necessary for most migraineurs who consult a physician. Simple analgesics may be appropriate for mild, nondisabling attacks, but triptans or other specific treatments are preferred for attacks that are moderate or severe. Preventive treatment with daily medication is necessary for patients who have more than one attack per week or whose attacks respond poorly to abortive medication. Subpopulations of migraineurs, such as children, elderly patients, and women, have special treatment needs.
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