Migraines and Migraine Management

Introduction

Frequency & Impact

In a recent US study on race-related differences, it was found that in women, migraine prevalence was significantly higher in Caucasians (20.4%) than in African- (16.2%) or Asian- (9.2%) Americans.⁹ A similar pattern was observed among men (8.6%, 7.2%, and 4.2% respectively).

Impact of Migraine on the Patient and Society

It is widely accepted that family factors may play a significant role in the etiology, perpetuation and treatment of chronic pain. Furthermore, it requires little imagination to appreciate that a debilitating headache with frequent episodes lasting between 4 and 72 hours has a significant impact on the relationship between the patient, their partner, children, other family members and close social contacts. Many individuals with migraine are apprehensive about their next attack, knowing that such an attack could disrupt their ability to work, care for their families, or meet social obligations.⁷ The need for and cost of, alternative arrangements for family, work and social obligations varies markedly, but can significantly contribute to the overall cost of migraine management.

Migraines cause a substantial economic and societal burden. Physician office visits, emergency department visits, costs of treatment and of treating complications of migraine—whether appropriate or inappropriate—constitute the direct costs of migraine. Migraine sufferers are high utilizers of health care. In an 18-month study in a managed care setting, migraine sufferers were found to have 1.7 times the number of medical claims compared to age and gender-matched controls, and migraine sufferers sought help for psychiatric disorders twice as often as those without a migraine diagnosis.⁴  In addition, migraine patients generated almost four times the number of emergency department claims compared to the control patients.⁴   However, these patients in the managed care study appear to represent a relatively small number of sufferers. It is generally accepted that emergency department use indicates failed migraine treatment, which may be the result of inappropriate diagnosis and/or drug treatment.⁸   Adequate pharmacotherapy, frequently with the newer serotonin receptor agonists, may reduce or eliminate emergency department use.¹⁰

Ineffective treatment of migraine obviously contributes to its cost (i.e., emergency department visits by patients with poor migraine control; treatment for complications of analgesic abuse, such as NSAID-induced gastropathy). In addition, unnecessary use of neuroradiology, such as head computed tomography or magnetic resonance imaging to rule out an organic cause of the headaches, also contribute to the cost of care. Days lost from work represent a societal and indirect economic loss from migraines. One survey of Maryland residents reported that 8% of men and 14% of women missed all or part of a day of work in the month prior to the survey because of migraine.¹¹   In another study, the 50% of migraineurs with the most severe headaches were responsible for 90% of work lost due to migraine. Translated into dollars, estimations of the cost of lost productivity range from $1.2 billion to $17.2 billion.⁷

Comorbidity of Migraine

The Epilepsy Family Study of Columbia University reported that the prevalence of migraine was more than twice as high in persons with epilepsy compared to those without a history of epilepsy. These results are consistent with those of other epidemiologic studies. Epilepsy and migraine can include overlapping symptoms. Both are chronic diseases with episodic attacks characterized by changes in mood or behavior, focal sensory or motor symptoms, and alterations in consciousness—which can make differential diagnosis difficult. One important clue is the length of the aura. An aura of greater than 5 minutes in duration suggests migraine, while an aura of less than 5 minutes suggests epilepsy. The comorbidity of migraine and epilepsy has implications for the pharmacologic management of patients, which will be discussed more thoroughly in the second module in this series.¹²

Epidemiologic studies have also shown a relationship between migraine and the major affective disorders, in particular, depression. The odds ratio for co-existing migraine and depression ranges from 2.2 to 3.4 in epidemiologic studies. Similar to epilepsy, there are overlapping symptoms, i.e. the mood disturbances in migraineurs. In addition, some patients with migraine and depression may have atypical depressive symptoms, such as increased appetite and sleep, and brief duration of depressive episodes. Migraineurs must be closely evaluated for co-existing depression not only for planning appropriate pharmacologic therapy, but also to assess the risk of suicide; migraine with aura is associated with suicidal ideation and attempts, regardless of associated diagnoses.¹³

Panic disorders have also been reported to be comorbid with migraine. In one population-based study of 10,000 respondents, migraines occurred more often among those with a history of panic attacks. However, any causal relationship between the two diseases is uncertain.¹⁴

Barriers to Effective Treatment of Migraine

Diagnosis and Treatment Issues

Despite the high prevalence of migraine, and the direct and indirect costs associated with patient suffering, a  significant number of individuals with migraine are not diagnosed and therefore, do not receive effective therapy. For practical reasons, physicians may focus more on ruling out serious and potentially fatal causes for headache pain, such as cerebral aneurysms or tumors; they are often less concerned about making a specific headache diagnosis. An analysis of survey data from over 20,000 individuals from 12 to 80 years of age, indicated that of those who met the diagnostic criteria for migraine, only 41% of women and 29% of men reported having received a medical diagnosis of migraine. Among those migraineurs who had not received a physician diagnosis, about 25% experienced severe disability (ie, required bedrest or some impairment in working) and approximately 80% had mild to moderate disability (ie, some impairment in working).⁸

In many instances, physicians may initially recommend analgesic treatment (eg, acetaminophen, NSAIDs, or combinations with sedative), that is effective for both migraine and tension-type headache. This strategy has several limitations—

• Patients consult a physician, not just to get pain relief, but to gain an understanding of the cause of their pain.¹⁵
• Treatments differ for migraine and tension-type headache; ergots and 5HT-1 agonists are effective only for migraine.
• Behavioral therapies may also differ, ie, migraine patients may benefit from dietary modification, while tension-type headache patients will not.
• Patients may be anxious to understand the cause of their headache, and the lack of a specific diagnosis can lead to frustration and dissatisfaction.

In a survey study of 20,000 individuals, about two-thirds of those individuals who met the criteria for migraine, self-treated with over-the-counter (OTC) drugs to the exclusion of prescription medications.⁸  Some of those individuals had little disability and were able to adequately self-manage with OTCs. Inadequately treated patients may be divided into four subsets—

• Those who have never sought care.
• Those refractory to all treatment.
• Those previously treated, but lapsed from further treatment.
• Those whose headaches are unsuccessfully managed with OTC drugs.

   

Patients with severe migraines, the focus of the survey, were unlikely to be either refractory to all therapy or adequately treated with OTC drugs.⁸ Therefore, the authors concluded that the majority of unsuccessfully treated patients either did not seek medical care, did not have access to medical care, or were inappropriately treated.

Additionally, based on data from the American Migraine Study, most patients with severe migraines self-medicate with OTC drugs.¹⁶ A total of 43% of women and 61% of men with three or more headaches per month do not take prescription medications. As discussed below, some of these patients with frequent headaches and associated disability may benefit from preventive therapy.

Physician Issues

Historically, physicians have received little education in medical school and residency training that applies to the diagnosis and treatment of primary headache disorders.¹⁷  While a physician diagnosis of migraine has a high positive predictive value, physicians may recognize only 45% to 51% of migraineurs.  In addition, there may be disagreement in diagnosis among neurologists, internists and other clinicians.  However, the prevalence of migraine, combined with the underdiagnosis and treatment of the condition, may create opportunities for improved care through appropriate physician and patient education.

The absence of physical measurements to establish the diagnosis and confirm response to treatment, the absence of a suitable animal model for headache or migraine, and its episodic nature make the study of migraine much more difficult compared to many other chronic conditions. The headache history is a key component of the migraine diagnosis, but unfortunately many patients are poor historians, or there may be inadequate time to take a thorough patient history.

Patient Attitudes

Several patient-driven barriers to appropriate and prompt migraine treatment have been identified.  Some patients may defer seeking medical treatment until the headache has persisted for many years, or until many OTC preparations have failed to provide relief.  Additionally, patients may not regard their headaches as severe enough to see a physician.  Patients may also attribute their headaches to stress, tension, allergies or sinus problems.  Thus, patients with frequent, disabling headache may consult a physician for other health problems without even mentioning headaches.  Given the high prevalence of headaches, it may seem logical to question all patients about their occurrence, frequency and severity of symptoms.   However, the problem with this approach is that 95% of the population has headaches, most of which do not require medical care.

It may be more effective to educate patients regarding "headache alarms" and to screen with the following questions—

"Do you have headaches which substantially interfere with your ability to work (study or play—for children/adolescents) or enjoy life?"

Even among patients who seek medical care, chronic headache has been found to be the condition with the lowest satisfaction rating among patients.  In one survey of patients treated for chronic headache, 23% were dissatisfied with the care they received.   This compares with a dissatisfaction rating of between 5% and 10% for conditions such as high cholesterol, high blood pressure and diabetes.⁵

Role of the Primary Care Physician

Recognition of headache symptoms and the diagnosis and treatment of migraines are well within the scope of practice of primary care physicians. One of the unique aspects of migraine is that the dynamics of this disorder change over time—the primary care physician is faced with the challenge of providing longitudinal headache care over the course of the patient’s life. For example, the initial diagnosis of migraine may occur during a routine pre-college physical and a straightforward treatment plan directed at controlling the acute episodes may prove effective. Years later, the same patient may return for advice on migraine management during her planned pregnancy. As time passes, she may notice her migraine pattern change into one with more frequent headaches, thus, requiring prophylactic management. Finally, she may, in later adult life, develop cardiovascular disease that could again affect her migraine management. Thus, the primary care physician must often modify a migraine care plan during the life of the migraine patient. Providing longitudinal care through the many nuances of migraine occurrence is a critical responsibility of the primary care physician. In the environment of managed care, the primary care physician will be expected to—and can manage most—uncomplicated cases of migraine.

Pathophysiology

Within the past decade or so, the understanding of migraine pathophysiology has rapidly evolved from the simplistic vascular theory to an understanding that migraine represents a complex brain disorder, probably originating in the brain stem. A landmark study demonstrated that brain stem activation occurs both during a migraine attack, and during pain relief achieved with sumatriptan, a serotonin receptor agonist. Activation of other cortical sites occurs during pain, but not after pain relief; this represents the neural response to pain. Activation of brain stem structures in the absence of pain may suggest a "migraine generator" or pacemaker in the brain stem,¹⁸ and that the pathogenesis of migraine may be related to an imbalance in activity between brain stem nuclei. These and other observations have given rise to the now prevailing opinion that blood vessels play only a secondary role in migraine pathophysiology. The ultimate mechanism of head pain may be trigeminal activation via the brainstem migraine generator, with release of vasoactive peptides from nerve endings, causing vasodilation and inflammation. However, whether this plays a role in migraine pathogenesis or whether it is an epiphenomenon, is uncertain.

Although the exact pathophysiology of the various components of migraine (ie, prodrome, aura, the actual migraine and postdrome) are still elusive, emerging evidence suggests that serotonergic transmission plays a key role in the pathogenesis of migraine based on the following observations—¹⁹

• Urinary excretion of 5-hydroxyindoleacetic acid, the main metabolite of serotonin, is increased in association with migraine attacks.

• Platelet serotonin or 5-HT drops rapidly during the onset of migraine attack.

• Intravenous injection of serotonin can abort pharmacologically-induced or spontaneous migraine.

These observations awakened interest in the study of serotonin receptors in the brain that could be etiologic in migraine, with a focus on developing a cranially-selective serotonin agonist. Seven general classes of serotonin receptors have been identified, and the Class 1 receptors have been further subdivided into five subclasses.²⁰  Much research has been devoted to the identification and classification of both serotonin (5-HT) receptors and drugs which have activity at 5-HT receptor sites. At present, five drugs used for migraines—dihydroergotamine (DHE-45), naratriptan (Amerge), sumatriptan (Imitrex), rizatriptan (Maxalt), and zolmitriptan (Zomig)—all activate a variety of 5-HT receptors (located on trigeminal nerve endings), which block the release of neuropeptides, thus preventing neurogenic inflammation. NSAIDs may also block neurogenic inflammation, although the mechanism is still unclear.

The Migraine Itself: Signs and Symptoms

Migraine episodes are typically divided into four separate components—

• Prodrome
• Aura
• Headache
• Postdrome

Not every component is experienced by all patients in every migraine attack. Within a given patient, the various components may vary from attack to attack.

Prodrome

The prodrome is experienced by 30% to 40% of patients from hours to days before the attack. Typical prodromal symptoms are listed in Table 1.

Aura

The aura is one or more of a variety of focal neurologic symptoms which typically lasts for less than one hour and is followed by the headache, and is the most familiar phenomenon which distinguishes migraine from other types of headache. It is thought to be related to a spreading transient decrease in neuronal activity, with a secondary decrease in blood flow (oligemia) in the cerebral hemisphere, contralateral to the aural symptoms. A wave of oligemia has been shown to spread or "march" across the cortex, and has been associated with a corresponding march of symptoms. The aura can consist of visual, sensory or motor phenomenon, or a combination of these phenomena. Visual auras are the most common type, consisting of scotomata (ie, blind spots) or teichopsia (also referred to as fortification spectra, a zigzag pattern reminiscent of the outline of a top of a fort). Teichopsia is almost pathognomic of migraine. Visual distortions and hallucinations (thought to be the basis of Lewis Carroll’s writing in Alice in Wonderland) are more common in children. Some of these hallucinations can be truly bizarre, such as disorders of visual perception, including metamorphosia, micropsia, zoom or mosaic vision. Sensory phenomena include paresthesias that often begin in the hand, migrate proximally, and occasionally involve the tongue or the lips. Motor disturbance or aphasia (difficulty in speaking or understanding language) is a particularly disturbing type of aura. Common features of aura are summarized in Table 2.

While aura is a pathognomic sign of migraine, only about 20% of migraineurs experience auras. Some physicians are hesitant to make a diagnosis of migraine without a history of an aura, but this approach will lead to a significant underdiagnosis of migraine. Additionally, in a minority of cases, an aura can exist without an accompanying headache, sometimes referred to as migraine sans-migraine. In these situations, the differential diagnosis might include transient ischemic attacks.

Headache

The headache itself is usually unilateral and throbbing, but can be bilateral or become generalized. Although the pain may appear at any time of the day, most frequently it begins on arising in the morning, develops gradually, reaches a plateau and then subsides after 4 to 72 hours. The pain is commonly exacerbated by physical activity; frequently, the patient retires to a darkened, quiet room. Nausea and vomiting are common accompanying symptoms and complicate the oral administration of anti-migraine drugs. Sensitivity to light (photophobia), sound (phonophobia), and odors (osmophobia) are common.

Postdrome

After the headache has resolved, most patients feel different for hours. In over half of patients, signs and symptoms include lowered mood and intellect levels, impaired concentration, feelings of irritability, lifelessness, muddled thinking and inattentiveness. Physical tiredness and muscular weakness are common. These clinical observations are supported by experimental findings of abnormalities in cerebral blood flow and EEG recordings up to 24 hours after the headache ends.²²

International Headache Classification

In 1988, the International Headache Society (IHS) published a seminal work, the Classification and Diagnostic Criteria for Headache Disorders, Cranial Neuralgia and Facial Pain, which established an explicit, accepted method for categorizing and diagnosing different types of headache, including migraine (see Table 3).²³

Table 3. – IHS Classification of Primary Headaches   1. Migraine 1.1 Migraine without aura 1.2 Migraine with aura 1.2.1 Migraine with typical aura 1.2.2 Migraine with prolonged aura 1.2.3 Familial hemiplegic migraine headache 1.2.4 Basilar migraine 1.2.5 Migraine aura without headache 1.2.6 Migraine with acute onset aura 1.3 Ophthalmoplegic migraine 1.4 Retinal migraine 1.5 Childhood periodic syndromes that may be precursors to or associated with migraine 1.5.1 Benign paroxysmal vertigo of childhood 1.5.2 Alternating hemiplegia of childhood 1.6 Complications of migraine 1.6.1 Status migrainosus 1.6.2 Migrainous infarction 1.7 Migrainous disorder not fulfilling above criteria 2. Tension-type headache 2.1 Episodic tension-type headache 2.1.1 Episodic tension-type headache associated with disorder of pericranial muscles 2.1.2 Episodic tension-type headache unassociated with disorder of pericranial muscles 2.2 Chronic tension-type headache 2.2.1 Chronic tension-type headache associated with disorder of pericranial  muscles 2.2.2 Chronic tension-type headache unassociated with disorder of pericranial  muscles 2.3 Headache of the tension-type not fulfilling above Criteria   3. Cluster headache and chronic paroxysmal hemicrania 3.1 Cluster Headache 3.1.1 Cluster headache,  periodicity undetermined 3.1.2 Episodic cluster headache 3.1.3. Chronic Cluster Headache 3.1.3.1 Unremitting from onset 3.1.3.2 Evolved from episodic 3.2 Chronic paroxysmal hemicrania 3.3 Cluster headache-like disorder not fulfilling above Criteria Headache Classification Committee of the International Headache Society, 198823

Migraine

This classification scheme was seen as a valuable research tool and created a standard diagnostic approach to patients. Prior to this classification, migraine was described as either "classical" or "common" migraine, referring to migraine with and without aura, respectively. These two terms have been replaced with descriptive terms. In addition, the IHS classification provides diagnostic criteria for migraine without and with aura.

Table 4. –IHS Diagnostic Criteria for Migraine Without and With Aura Migraine Without Aura A. At least five attacks fulfilling B-D. B. Headache attacks lasting 4-72 h (untreated or unsuccessfully treated). C. 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. D. During headache at least one of the following: Nausea and/or vomiting. Photophobia and phonophobia. E. At least one of the following: History and physical do not suggest headaches secondary to organic or systemic metabolic disease. History and/or physical and/or neurologic examinations do suggest such disorder, but 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 A. At least two attacks fulfilling B. B. At least three of the following four characteristics: One or more fully reversible aura symptoms indicating focal cerebral cortical and/or brain stem dysfunction. At least one aura symptom develops gradually over more than four minutes or two or more symptoms occur in succession. No aura symptom lasts more than 60 minutes. If more than one aura symptom is present, accepted duration is proportionally increased. Headache follows aura with a free interval of less than 60 minutes. (It may also begin before or simultaneously with the aura). C. At least one of the following: History and physical and neurologic examinations do not suggest headaches secondary to organic or systemic metabolic disease. History and/or physical and/or 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. Headache Classification Committee of the International Headache Society, 1988.23

The IHS classification includes several different types of migraine variants. Basilar migraine is defined as a migraine with an aura involving the brainstem (symptoms include ataxia, dysarthria, vertigo, tinnitus and/or changes in consciousness and cognition). Ophthalmoplegic migraine is associated with acute attacks of third nerve palsy with accompanying dilation of the pupil. In this setting, the differential diagnosis includes an intracranial aneurysm or chronic sinusitis complicated by a mucocele. The ophthalmoplegia can last from hours to months. Hemiplegic migraine is distinguished by the accompanying hemiplegia, which can be part of the aura, or the headache may precede the onset of hemiplegia. Hemiplegic migraine can be familial and may last for days or weeks, clinically simulating a stroke. An additional differential diagnosis includes focal seizures.

Status migrainosus describes a migraine lasting longer than 72 hours with intractable debilitating pain, and typically occurs in a setting of inappropriate and prolonged use of abortive anti-migraine drugs. These patients may require hospitalization, both for pain control, detoxification from the abused drugs, and treatment of dehydration resulting from prolonged nausea and vomiting.

Tension-Type Headache

The diagnostic criteria for tension-type headaches are summarized in Table 5. However, migraine symptomatology may overlap considerably with that of tension-type headaches. Tension-type headaches are believed by some experts to be a mild variant of migraine headache.²⁴ Patients with tension-type headaches, who also have migraines, may experience nausea and vomiting with a tension headache, though when they do, it typically is mild and for a shorter duration compared to that with a migraine. Tension-type headache may be a disorder unto itself in individuals who do not have migraines, and may manifest as attacks of mild migraine in individuals with migraines.

Chronic tension-type headache is a subtype of tension headaches, with patients experiencing headaches daily or almost every day. In practice, the term "chronic daily headache" is commonly used to describe headaches lasting for greater than 4 hours per day and for at least 15 days per month. The classification of chronic daily headaches is summarized in Table 6.

Chronic Daily Headache

Chronic daily headaches are best conceptualized as an umbrella category term, referring to a group of headache disorders characterized by headaches which occur greater than 15 days per month, with an average untreated duration of greater than 4 hours per day. There are many secondary causes of chronic daily headache, including post-traumatic headache, arteritis, intracranial mass lesions, etc. There are also short-lived primary headache disorders that occur greater than 15 days per month, such as chronic cluster headache or the paroxysmal hemicranias.²⁶ These secondary and short-lived disorders are outside the scope of this discussion. The most common primary, chronic daily headache disorders include transformed migraine, chronic tension-type headaches, new daily persistent headache or hemicrania continua. Each of these diagnoses can be complicated by medication overuse (eg, acetaminophen, aspirin, caffeine, barbiturates, ergotamine tartrate and opioids). When used daily, all of these medications can lead to a vicious cycle of rebound headaches.

Taking a Headache History

Alarm Signals

The first step in diagnosing headaches is to determine whether the signs and symptoms are suggestive of an organic cause, such as brain tumors or leaking arteriovenous malformations or aneurysms. The following signs and symptoms are considered alarm signals, which must be promptly evaluated:²⁷

• The "first or worst" headache of the patient’s life, particularly if it is of acute onset or is accompanied by other neurologic symptoms.
• A headache that is subacute in onset and gets progressively worse over days or weeks.
• A headache associated with fever, nausea, and vomiting that cannot be explained by a systemic illness.
• A headache associated with focal neurologic findings, papilledema, changes in consciousness or cognition, or a stiff neck.

The following questions will help to identify the patient with an organic cause of headache:

• Do you now have a headache that is new or different from your usual headache?
• Did your headaches start after an accident or illness?
• Do you suffer from headaches that begin during or after physical activity, coughing or sexual activity?
• Do you have neck stiffness or inability to put your chin on your chest, or pain radiating to one or both of your legs when bending your neck?

If any of the above signs or symptoms are noted, or the patient answers YES to any of the above questions, organic causes of the headache should be considered first.

The more common situation is the patient who has a stable pattern of headaches over a period of time. If questioned closely, most patients will report headaches, and the art of history-taking involves quickly identifying those patients with severe, disabling headaches for more focused questioning. Migraine should be conceptualized as the total migraine experience—which includes the severity of pain, its duration and frequency—as well as co-existing nausea and vomiting, which can be extremely disabling in and of themselves. The physician must thoroughly explore the headache history, a frequently time-consuming task. Since most patients with headaches will have a normal physical exam, the history is crucial in establishing the diagnosis. Filling out a self-report questionnaire during an initial patient visit may help, but may not be adequate to elicit a headache history. A headache history from a patient with an established diagnosis of headache should not simply be lifted from the referring physician’s records, but should be obtained directly from the patient. It is also important to understand the impact migraines might have on the patients’ and their families’ psychosocial functioning. Finally, as with any chronic disease, migraine management to a certain extent depends on patient self-management, the success of which is enhanced by patient education and a trusting patient physician relationship. These seeds are best planted during the initial interview.²⁸

Number of Headaches and Types

In taking a headache history, the physician should investigate the number of different types of headaches occurring recently or in past years. It is important to make sure that the patient describes all headaches and not just the most severe headache. For example, the patient might relate a history of 2 headaches per month. However, closer questioning may reveal that the patient has near-daily, lower-grade headaches, and initially reported only the most severe headaches. In addition, patients may only report a recent onset of headaches, and neglect to mention that low-grade headaches have persisted for years. It is important to determine if the patient has daily headaches in order to avoid medication (eg, analgesics, ergots, etc.) habituation. Questions that may be helpful include:

• How long have you had this type of headache?
• How old were you when this type of headache began?
• Did you have headaches in grade school, high school or college?

Most migraines present in the first three decades of life; therefore, onset of migraines in the elderly is somewhat unusual and should raise the suspicion of temporal arteritis, intracranial hemorrhage or brain tumor. Headaches that have gotten progressively worse are worrisome and may suggest an organic cause. A long, unchanged history of headaches is consistent with a benign etiology.

Frequency, Regularity and Periodicity

The frequency, regularity and periodicity of headaches provide information on possible trigger factors and give insight into the impact of headaches on the patient’s psychosocial functioning. Headache frequency and severity is an important determinant of whether the patient is an appropriate candidate for prophylactic treatment. Prophylactic therapy may be considered in patients with 3 or more attacks per month that produce disability; when there are infrequent, but incapacitating attacks that do not respond to acute treatment; or when migraine is associated with hemiparesis or aphasia. Questions that may be asked include:

• When do you get the headaches?
• How often are the headaches?
• Do your headaches increase at certain times of the month or year?
• When or at what time of day do the headaches occur?

Migraines occur most commonly in the early morning hours, while cluster headaches commonly arise after sleep onset. Migraines are also typically associated with stressful events, or a post-stress let down, such as around holiday time, or with work-related stress. Cluster headaches and trigeminal neuralgia appear to be more common in the spring or fall.

Approximately 85% of patients will be able to identify trigger factors. The use of a headache diary may also facilitate their recognition. Potential provoking factors of migraine are summarized in Table 7.

Migraine Triggers

Hormonal trigger factors are very common among women. Migraines are associated with the onset of menses in 60% of women and may be associated with dysmenorrhea. Migraines may occur exclusively at menses in 14% of women. Menopause, oral contraceptives and pregnancy all have a variable effect on migraine, with migraines remaining unchanged, worsening, or improving. Among pregnant migraineurs, approximately 60% to 70% will report improvement, while others will report their first migraine during pregnancy.²⁹  The pathophysiology of hormonal effects is uncertain, but may be related to the variable estrogen receptor sensitivity of the hypothalamic neurons.

Other Triggers of Migraine

Approximately 45% of patients will identify various foods as trigger factors.³⁰ Common dietary triggers include nitrites (found in cured foods such as bacon), monosodium glutamate (commonly found in Chinese food), red wine and chocolate. Foods with large amounts of vasoactive amines, such as tyramine, have also been implicated as trigger factors. Tyramine-rich foods include aged cheeses, pickled herring, chicken livers, canned figs and bean pods. On rare occasions, an elimination diet may be appropriate in patients with dietary triggers. However, both patients and physicians must be cautious—patients may self-treat with extremely restrictive and bizarre elimination diets. A headache diary may be particularly helpful in definitively identifying dietary triggers. In other instances, a trial of various foods in a controlled setting may help verify triggers.^27,30  Care must be taken to distinguish the food craving of prodromes (ie, chocolate cravings), from true triggers. In addition, food aversion, a psychological response to the food itself, may be a migraine trigger.

Other common trigger factors include irregular sleeping or eating patterns; light or glare; odors; weather or temperature change; physical exertion (including sex); stress and anxiety; or post-stress letdown.²⁷

Characteristics & Symptoms

Characteristics of the pain include its location, and description of pain and intensity. Questions that may be asked include:

• Where is the pain located?
• Where does the pain begin and how does it spread?
• Does the pain move around?
• What is the pain like? Aching, burning, throbbing?
• How bad is the pain?
• How long does it take for the pain to reach its maximum?
• How long does the pain last?

The location of the head pain gives important clues about headache type. For example, unilateral head pain that alternates from side to side is suggestive of migraine. The most common locations of migraine pain are in the temple, but migraines can be located anywhere. The headache associated with periodontal, eye or sinus disease is usually frontal, but may be referred to the back of the neck. Posterior fossa tumors are associated with occipital headaches, while supratentorial tumors are associated with frontal or vertex pain. Unilateral orbital pain of brief duration (about 30 to 90 minutes) is more typical of a cluster headache. The quality of the pain may suggest alternative diagnoses. For example, a short, stabbing pain (lasting less than 1 minute) that occurs in waves, may be suggestive of trigeminal neuralgia.

The quality of the pain offers diagnostic clues. Cluster headaches are typically described as deep and boring "like a hot poker in the eye," while headaches associated with migraine are described as throbbing or pulsating. A steady, aching headache may be more suggestive of a brain tumor or meningitis. Assessing the severity of the pain may be enhanced by using some type of a rating scale. Asking the patient how the headaches affect their activities provides an important subjective assessment of pain intensity and quality.

Migraine headaches can last a variable length of time, ranging from brief headaches of 20 to 30 minutes to days in length. The typical migraine will last less than 24 hours, and patients are typically pain-free between headaches. In contrast, headaches associated with brain tumors typically occur every day. Tension headaches may last for days, weeks or even years.²⁷ Migraine and tension-type headaches usually build in intensity over time. The acute onset "thunderclap" headache is an alarming symptom suggestive of a subarachnoid hemorrhage.

Associated Symptoms

It is important to assess symptoms of the prodrome or aura, and those symptoms associated with the migraine itself. Nausea and vomiting are extremely common in migraine and are important factors in terms of treatment planning; however, nausea and vomiting may be seen with any type of severe headache. Other symptoms associated with migraine include photophobia, phonophobia, osmophobia, mucous membrane injection, polyuria, abdominal distention, constipation, diarrhea and flatulence. Associated symptoms such as redness or tearing of the eyes and nasal congestion suggest cluster headache, while teeth grinding and neck tenderness may be seen in tension headaches. Depression is comorbid with migraine and is commonly associated with chronic daily headaches; symptoms of depression may include insomnia, early morning awakening, fatigue, anorexia or change in libido. Migraineurs often report changes in mood such as irritability and a desire to be alone. While patients with tension headaches may be extremely irritable, they do not typically withdraw from other people. Patients with cluster headaches typically pace, walk or rock during the headache, and this behavior is almost pathognomic of cluster headaches.²⁷

Questions that may be asked include:

• What happens before the onset of headache pain?
• Do coughing, exercise or other activities increase the headache pain?
• What other symptoms do you experience during the headache?

Managing Migraine Today: Medication History

• What medications have you taken and when?
• What medications seemed to provide the most relief?
• When do you take your medications?
• Do you take medication in anticipation of headaches?
• How much coffee or caffeine do you consume?

Many patients assume that the physician is only inquiring about the use of prescription drugs, and do not report the use of OTC drugs or "health food" supplements. Patients who specifically seek medical care for migraines have typically not responded to OTC medications. Importantly, the use of these drugs can be considerable, and can contribute to the development of a chronic daily headache. The most prevalent problem associated with frequent or daily use of nonprescription analgesics is the development of rebound headaches, a self-sustained headache phenomenon where frequent use of drugs creates a reliable headache cycle.^17,27 Patients may also develop the inappropriate habit of taking medication in anticipation of a headache—another contributor to medication misuse.

The role of caffeine consumption in headache is underappreciated. Although caffeine is an effective analgesic adjuvant and thus, is a common component of OTC and prescription analgesics, excessive consumption can be associated with withdrawal headache. The dietary consumption of caffeine in this country is prodigious, with an average daily consumption of 200 mg by more than 85% of Americans. Asking patients how many cups of coffee they consume in a day may be misleading. Although a typical 5-oz brewed cup of coffee contains 80-120 mg of caffeine, patients may actually be consuming mugs of coffee which contain 2 to 3 times as much caffeine.¹⁷  Patients with migraine should limit their caffeine consumption between migraine attacks to no more than 1 cup of coffee per day.

The treatment of chronic daily headache related to drug overuse is generally reserved for headache specialists, but primary care physicians need to recognize and understand these forms of headache. Many patients who abuse prescription headache medication have gotten their prescriptions from primary care physicians, and may not reveal that the same medication was prescribed by another clinician. This allows them to obtain excessive quantities of prescription products without raising concerns or objections from individual physicians. Most of these patients will fill the prescriptions in different pharmacies to avoid questions from the pharmacist. By misinforming their physicians, these patients make them an unwitting accomplice in maintaining their prescription drug abuse. Additionally, this tactic allows the medication abuse and headache problem to further increase. The following are possible signs of medication abuse and "prescription shopping"—

• New patient with in-depth knowledge of a particular product, its strengths and limitations.
• New patient who is evasive when asked about headache history.
• New patient providing anecdotes as to why they need this medication now and cannot go back to their regular physician.

Table 8 suggests strategies to reduce the risk of medication abuse.

Table 8. – Strategies to Reduce Medication Abuse Principles Limit caffeine consumption Limit use of analgesics, opiates, and opiate-like substances Restrict use of butalbital and analgesic containing mixtures to less than 3 days per week Avoid ergotamine compounds in more than twice-a-week administration Consider instituting prophylactic agents Comments No more than 1 cup of coffee/day Carefully instruct patient on when and how to use Frequently abused prescription Carefully instruct when and how to use; warn of rebound headache When migraine frequency exceeds once a week Modified from Elkind 1991.31

A final category for investigation in the history is the use of alternative therapies, including acupuncture, Chinese herb therapy, Ayurvedic medicine, naturopathy or homeopathy. Additional information on pharmacologic and nonpharmacologic treatments can be found in the companion CME module on this topic.

Understanding Patient's Expectations

Eliciting the patient’s thoughts about the cause of their headache and the associated pain is important to understand any related psychosocial aspects of the headache, and provides an opportunity for the physician to address the patient’s concerns and anxieties. Some patients may be especially concerned about a possible organic cause, such as malignancy. Questions that may be asked include:

• Why have you come for treatment now?
• What do you think is the cause of your pain?

Physical Exam & Imaging Studies

The physical exam should include a general medical examination, and a complete neurological exam to identify focal signs or symptoms suggestive of an underlying organic or local cause of the headaches. The head should be examined for tenderness. Migraineurs may experience tenderness not only over the scalp, but also over the nasal and paranasal sinuses and teeth; this tenderness may persist after the headache pain has subsided. Focal tenderness may be seen in patients with periostitis secondary to mastoiditis or sinusitis. Ptosis may occur in patients with ophthalmoplegic migraine or cluster headache, but can also be seen in patients with brain tumors or aneurysms of the Circle of Willis. Papilledema is an ominous sign suggestive of an expanding intracranial mass. Photophobia is a nonspecific symptom that is seen with a variety of headaches, including those associated with meningitis, brain tumor, or nasal and paranasal disease.

Imaging Studies

Controversy surrounds the appropriateness of neuroimaging studies in patients with a history and physical examination consistent with migraine. Many physicians and patients appreciate the assurance of magnetic resonance imaging (MRI), magnetic resonance angiography (MRA) or computed tomography (CT) studies that rule out a space-occupying lesion or a vascular abnormality. However, in many instances, such imaging is unnecessary. In 1994, the American Academy of Neurology published practice guidelines regarding neuroimaging in patients with headache, but with normal neurological exams.³² The following statement appears in the guideline summary:

"In adult patients with recurrent headaches that have been defined as migraine—including those with visual aura, with no recent change in pattern, no history of seizures and no other focal neurologic signs or symptoms, the routine use of neuroimaging is not warranted. In patients with atypical headache patterns, and/or a history of seizures, or physical examination findings of focal neurologic signs or symptoms, CT or MRI may be indicated."

These guidelines were based on a review of 17 studies that revealed the diagnostic yield of such routine imaging was very low. For patients diagnosed with migraine, the proportion with a treatable lesion identified with these imaging studies was only 0.4%.³³

Case Studies

Case Study: Woman with menstrual migraines and tension-headaches

A 32-year-old woman comes to the office complaining of headaches that occur monthly, with her period. The headaches last two days, may be right- or left-sided, with moderate pain, that is aggravated by moving. The patient has nausea without vomiting and no visual symptoms. The day before her headache she is euphoric, has cravings for chocolate, and notes increased urinary frequency. In addition to her primary headache, she experiences 1-2 mild, bilateral, dull headaches that last 4-6 hours and are associated with tightness in her neck each month. These headaches are not associated with nausea, vomiting or blurry vision. Her general medical and neurologic examinations are normal.

Case in Context

This patient has migraine without aura that is triggered by menstruation and associated with a prodrome. In addition, she has tension-type headaches, a common finding in migraineurs, most of whom experience tension-type headaches as well.

Case Study: Man with chronic daily headache/transformed headache

A 40-year-old male had a past history of episodic migraine of increasing frequency. Over the past year, he developed a daily, bilateral, mild-to-moderate headache, which twice a week became more severe, throbbing, and was associated with nausea. He had been taking ergotamine on a daily basis to control the pain. When he attempted to stop the drug, the headaches increased in intensity and he became bedridden. He is now depressed and despondent. His mother and maternal grandmother also experienced migraine. The patient’s general and neurologic examinations were normal. He appeared much older than forty.

Case in Context

This patient has chronic daily headache or transformed migraine associated with overuse of ergotamine. Patients with medication overuse often look older than their years. Transformed migraine is associated with a personal and family history of migraine and is frequently complicated by depression.

Conclusion

Migraine is a prevalent and under-diagnosed illness. As a consequence of less than optimal treatment, significant resources are expended on emergency department visits, referrals to specialists, radioimaging and analgesic and anti-migraine medications by a small proportion of migraine sufferers. Families and employers are additionally burdened by disruptions in family life and lost days at work, respectively. Therefore, physicians have an important opportunity to relieve symptoms and pain and restore good quality of life to their patients with migraine. Physicians should educate their migraine patients about headache triggers, optimal pharmacologic therapy, and changes in headache character that may indicate more serious conditions. Physicians should also understand the psychosocial impact of headaches, and work to develop an effective patient-physician partnership for headache management

Introduction To Treatment and Management

Goals of Migraine Management

Preventive therapy may be indicated when the patient experiences more than two migraine attacks per month or has very severe migraines, unresponsive to, or inadequately controlled by, acute treatment. Preventive therapy also makes use of a variety of agents including the use of antidepressant drugs, ß-blockers, and calcium channel blockers.

Principles of Migraine Management

Assess headache-related disability and the overall impact of headache on the patient’s life
Since migraine is a heterogenous disorder, treatment must be individualized; a diagnosis alone does not provide sufficient information to develop an effective treatment plan. Patients whose migraine is mild and occurs only occasionally require a treatment plan different from the patient whose migraine headaches are frequent and disabling. Patients need to be asked how their headaches affect their work performance, family interactions and leisure activities. Impairment of work and "sick days" are particularly important because of their impact on the cost of illness. Interference with social and family activities contributes to the burden of this disease on the migraine sufferer and society. Treatment should therefore both relieve symptoms and rapidly restore the ability to function normally.⁶

Provide patient education
Patient education is an important element of effective treatment. Patients need to be educated on the risk factors for migraine attacks, the underlying mechanism of migraine, and the steps that they can take to manage their disorder. Patients with a chronic illness like migraine should be encouraged to participate in the management of their condition. They need to be involved in reducing their risk for a migraine attack by identifying and avoiding triggers, and in initiating lifestyle changes. Migraine diaries, restrictive diets, and behavioral interventions provide the patient with a sense of control over their headaches and improve outcome. Ultimately, it is the patient who must decide whether or not to comply with the physician’s directions for when and how to take preventive and acute treatments for migraine.

Use information on migraine severity and impact on daily life to guide the treatment strategy
Migraine severity and impact on daily life are key factors in guiding the initial choice between nonspecific (analgesic) and specific therapies, and whether to follow a step-care or stratified care approach to treatment.⁶   With step-care, therapy is usually begun with an appropriate trial of simple analgesics. If this treatment is unsuccessful, therapy is escalated using stronger analgesics, such as prescription-strength, nonsteroidal anti-inflammatory drugs (NSAIDs) or combination products, such as isometheptene, acetaminophen and dichloralphenazone (eg, Midrin), until migraine control is achieved and the patient gets adequate relief from symptoms. The patient can also begin at a level of treatment that takes into consideration the prior history of response to particular treatments. For example, prior history of a poor response to simple analgesics might suggest stepped-up treatment with combination analgesics or stronger agents. Step-care can also be initiated in the treatment of a given migraine attack where a serotonin agonist is employed after nonspecific analgesics have failed.

Assess the need for "rescue" medications in patients with moderate to severe headaches if the initial therapy is ineffective
If the initial choice of therapy for an acute attack is a serotonin receptor agonist, an alternative rescue drug may be needed if the initial therapy is ineffective or the headache recurs and does not respond to a second dose of serotonin agonist. For example, headaches recur in up to 40% of patients taking serotonin receptor agonists. If the migraine recurrence is mild to moderate, simple analgesic preparations may be adequate, but stronger preparations may be required for more severe headaches. If the patient is taking a strong analgesic preparation as initial therapy, a serotonin receptor agonist may be used as the rescue medication.

Recognize that the choice of migraine-specific agents, ie, DHE, sumatriptan, naratriptan, rizatriptan or zolmitriptan may be made empirically and is based in part on patient preference
Sumatriptan and newer serotonin agonists, ie, naratriptan, rizatriptan and zolmitriptan, have broadened the treatment options for specific therapy. There is not yet extensive clinical experience comparing these agents head to head, and therefore, it is not possible to provide guidance as to which drug should be used for specific therapy in individual patients. However, preliminary data suggest that rizatriptan and zolmitriptan have an advantage of an earlier onset of action as compared to oral sumatriptan. This may allow some patients receiving sumatriptan injections to be switched to oral rizatriptan or zolmitriptan. This provides greater patient choice and, potentially, reduced costs. Naratriptan may have an advantage of longer duration of action, which may make it a suitable alternative for those patients who routinely need rescue medications with other serotoin agonists. Intranasal DHE may also provide a long duration of action with lower recurrence rates, but its speed of onset is slower compared to the selective serotonin agonists.

Use narcotics sparingly for migraine
Due to their potential for habituation and the development of chronic daily headaches, potent narcotics, such as propoxyphene, butorphanol, meperidine and morphine should be reserved for patients with very severe, but infrequent migraines.

Route of drug administration, (oral, intranasal, rectal or subcutaneous), based on patient preference, experience and desired immediacy of action
The route of administration is an important component of migraine therapy. Oral therapy is usually the first choice for most patients, and can be effective even if nausea and vomiting are associated with the migraine attack, provided that the oral route is initiated early in the migraine attack. Patients with severe vomiting may require non-oral treatment. Some patients may accept parenteral administration, while others will reject such routes of administration (eg, rectal suppositories). The recent availability of an intranasal preparation of sumatriptan and DHE has expanded parenteral treatment options.

Consider an anti-emetic agent only in patients whose nausea and vomiting are not relieved by specific migraine therapy
Nausea and vomiting are common accompaniments of migraine headache and can be as disabling as the headache itself. Serotonin receptor agonists (ie, oral and parenteral) are effective agents for preventing nausea and vomiting. In the instances where the patient continues to experience nausea and vomiting, an antiemetic agent can be prescribed.

Consider daily prophylactic (chronic) therapy in the following circumstances

• Two or more attacks a month that produce disability that lasts three or more days
• Contraindications to, or ineffectiveness of, symptomatic medications
• The use of abortive medication more than twice a week
• Special circumstances, such as hemiplegic migraine or rare headache attacks producing profound disruption or risk of permanent neurological injury.⁷

Recognize that a trial of preventive therapy may require 2 to 6 months to fully evaluate its effectiveness
It may take 4 weeks before the initial effects of prophylactic therapy are observed in the patient and this effect continues to increase for three months. Premature discontinuation of preventive therapy after one or two weeks is a common problem.

Explain to patients on prophylactic therapy that they will also frequently require acute therapy
Prophylactic therapy reduces the frequency of migraines, but may not eliminate them completely. In fact, preventive therapy is considered a success if it reduces attacks by 50%. Therefore, patients must have access to acute therapies when migraines occur. Selection of acute therapy, including rescue therapy, should follow the same principles as described above, although potential drug interactions between preventive and acute therapies should be recognized. Preventive therapy may reduce the severity and duration of any migraine attack and thus, may make acute therapy more effective. Drug interactions between prophylactic and acute therapies are summarized in Table 1.

Recognize that patients requiring both acute and prophylactic therapy are at higher risk for the development of chronic daily headaches
The overuse of acute therapy will decrease the effectiveness of prophylactic therapy, and this is one of the most common reasons for the secondary failure of prophylactic therapy. Additionally, the misuse of the symptomatic therapy that produced the rebound headache must be discontinued before there is a chance of success with a prophylactic therapy. Prophylactic therapy cannot overcome the effect of a rebound headache related to symptomatic agents.

Consider a drug holiday from preventive therapy
Migraines may improve spontaneously; thus, in patients with well-controlled headaches, preventive therapy may be successfully tapered and discontinued.

Consider nonpharmacologic approaches
Nonpharmacologic approaches may be an important adjunct to migraine management.  In addition, various types of relaxation therapy, including biofeedback and behavioral interventions (eg, maintaining a regular schedule, getting adequate sleep and exercise) may be helpful in some patients. Biofeedback may be a useful approach in certain patients, such as children, pregnant women, and individuals in whom stress is a trigger. Finally, physicians should question their patients about alternative medicines the patient may be using simultaneously with traditional drug therapy. Alternative therapies may include various herbal remedies and dietary manipulation or supplements.

Implement steps in order to decrease the incidence of drug abuse
Patients must clearly understand the appropriate dosing and dose limits for individual drugs. In some cases, prescription limits may be appropriate. Prevention of drug misuse, abuse, and development of chronic daily headaches is discussed later in this monograph.

Provide education and re-evaluation of treatment after 4-8 weeks for patients who have been to the emergency department or have missed work due to migraine
Emergency department visits or severe disability from migraine represent either failed management or patient compliance problems. Either of these occurrences should be red flags to reevaluate migraine management.

Pharmacologic Treatment of Migraine

Nonspecific Therapy with Analgesics and Analgesic Combinations

Low-Range Analgesics

Mid-Range Analgesics

Table 2. Analgesic-Sedative Combination Drugs

Agent Brand Name Dosage aspirin 325 mg butalbital 50 mg caffeine 50 mg Fiorinal 1-2 tablets q 4 h (maximum 6 tablets/d) acetaminophen 325 mg butalbital 50 mg caffeine 40 mg Esgic, Fioricet 1-2 tablets q 4 h (maximum 6 tablets/d) acetaminophen 500 mg butalbital 50 mg caffeine 40 mg Esgic Plus 1 tablet q 4 h (maximum 6 tablets/d) acetaminophen 325 mg butalbital 50 mg Phrenilin 1-2 tablets q 4 h (maximum 6 tablets/d) acetaminophen 500 mg butalbital 50 mg Phrenilin Forte 1-2 tablets q 4 h (maximum 6 tablets/d)

From Davidoff RA. Reprinted with permission.9

High-range Analgesics

High-range analgesics include aspirin or acetaminophen in combination with an opioid/narcotic analgesic or an opioid medication alone. Opioid analgesics have a controversial role in the management of acute migraine, although surveys suggest that opioids, such as codeine, meperidine and oxycodone are commonly prescribed for treatment of migraine.¹⁰  In addition, opioids in combination with antiemetics and antihistamines are commonly used in emergency departments to treat migraine. Opioids carry the threat of physical dependence, tolerance and addiction and thus, should be limited to patients with severe, but infrequent headaches, or the occasional headache that is unresponsive to either ergotamine or serotonin agonists (discussed below). Codeine is the opioid most commonly used. Intranasal butorphanol is a mixed agonist-antagonist, which has a lower potential for drug abuse. When used as a rescue medication in patients with nocturnal headaches, the impact of side effects, such as orthostasis and sedation are not as problematic. Opioids may also be an alternative in patients with menstrual migraine that does not respond to standard abortive agents. More potent narcotic analgesics, such as oxycodone or meperidine are available in combination with simple analgesics. Their use should be limited to reliable patients with severe migraines that are unresponsive to other analgesics, ergots and serotonin agonists.

Pharmacologic Treatment of Migraine

Specific Therapy

Ergotamine and DHE

Ergotamine and DHE, a derivative of ergotamine, are vasoconstrictors that function by counteracting the episodic dilation of extracranial arteries and arterioles. Routine use of ergotamine has been limited due to its side effects, including nausea and vomiting, which contribute to its unpredictable oral absorption, abdominal cramps, diarrhea, dizziness, muscle cramps and peripheral vasoconstriction. Additionally, the more serious side effects of vasospasm and encephalopathy (ergotism), may occur when ergotamine is used in large and/or frequent doses. Vasospasm can occur in any vascular bed, leading to myocardial ischemia or claudication of the legs and arms. Due to these side effects, there are many contraindications to the use of ergotamine, as summarized in Table 3.

Pharmacologic Treatment of Migraine

Selective Serotonin Recepter Agonists

Naratriptan, Rizatriptan and Zolmitriptan

Antiemetics

Migraines are typically associated with delayed gastric emptying from gastric paresis. Absorption is further compromised if the patient has migraine-associated nausea and vomiting. Therefore, 10 mg of oral metoclopramide, which functions both as an antiemetic and gastric stimulant, is often recommended as an adjunct to headache therapy. However, metoclopramide can cause dystonia and thus, should be used sparingly. Other commonly used antiemetics are perphenazine, prochlorperazine and chlorpromazine.²⁸

Pharmacologic Treatment of Migraine

Prophylactic Therapy

• ß-adrenergic blocking agents

• Calcium channel blockers

• Antidepressants

• Methysergide

• NSAIDs

• Anticonvulsants (ie, divalproex sodium)

The mechanism of action of prophylactic drugs is uncertain, but is thought to be related to an interaction with serotonergic neural systems, either by binding to 5-HT receptor sites, down-regulating the 5-HT receptor or influencing the discharge of serotonergic neurons. Prophylactic agents may be subdivided into first- and second-line therapies based on their side effects and efficacy, as summarized in Table 5.

ß-adrenergic Blocking Agents

ß-blockers are one of the first-line choices for migraine prophylaxis. Although the relative efficacy of different ß-blockers has not been clearly established, propranolol is a common choice, and produces an approximate 44% reduction in the frequency of attacks.³¹  Due to the high degree of individual variability in the bioavailability of propranolol, dosages are typically initiated at 60-80 mg/day and are increased every third to fourth day or weekly; the optimal dose for migraine prophylaxis must be balanced against drug side effects, such as hypotension. Twice-daily dosing maximizes patient compliance. A pulse of less than 50 or a systolic blood pressure of less than 100 mg Hg suggests the maximal dose has been reached. The patient should understand that most patients do not have an immediate response to propranolol and that most frequently, response improves over time; a trial of 3 months duration is necessary to confirm drug ineffectiveness. Although propranolol can be used indefinitely, treatment should be reassessed at 6-month intervals; as a result of these reassessments, treatment may be discontinued. If propranolol is discontinued, it should be tapered slowly to avoid headache acceleration from drug withdrawal. For a summary of ß-blockers used for migraine prophylaxis, see Table 7.

Tricyclic Antidepressants

Amitriptyline, nortriptyline, doxepin, and protriptyline are all tricyclic antidepressants that have been used for migraine prophylaxis. Amitriptyline, in particular, has been shown to decrease the frequency, severity and duration of migraine attacks. The selection of an antidepressant may be dictated by the drugs’ pharmacological action and the patient’s co-existing symptoms. For example, a patient who is suffering simultaneously from insomnia and migraine might benefit most from a tricyclic agent with sedative effects, such as amitriptyline. Weight gain is a side effect associated with tricyclic antidepressants, so they may be preferable for patients who are not overweight. The wide variation in drug bioavailability necessitates individual dosing and monitoring of plasma levels. Tricyclic antidepressants and their various side effects are summarized in Table 8.

Divalproex

NSAIDs

Calcium Channel Blockers

Calcium channel blockers are another commonly used prophylactic medication, although studies of their effectiveness have shown mixed results. Calcium channel blockers typically have a slow onset of action, ranging from 2-8 weeks. Common calcium channel blockers and their dosages are listed in Table 9.

Contraindications to the use of calcium channel blockers include ventricular dysfunction and sinoatrial or atrioventricular nodal disturbances. However, calcium channel blockers may be particularly appropriate for patients with comorbid hypertension, and in patients with a contraindication to ß-blockers. Common side effects of calcium channel blockers include dizziness and hypotension from drug-induced vasodilation. Patients often report an initial increase in headaches, which may effect compliance. Studies have shown promising results with verapamil, while nifedipine and diltiazem have demonstrated less impressive results. Prophylactic dosages of verapamil are typically 240 to 320 mg in divided doses of 80 mg.³⁰

Methysergide

Monoamine Oxidase Inhibitors (MAOIs)

Drug combinations are frequently used for migraine prophylaxis. A summary of drug combinations is listed in Table 10.

Drug Misuse and Abuse

Patients with frequent headaches often overuse simple over-the-counter analgesics, prescription opioid analgesics, and specific anti-migraine agents, such as ergotamine. This medication overuse by headache-prone patients can frequently evolve into a pattern of chronic daily headache with dependence on symptomatic medications. These types of headaches are referred to as drug-induced rebound headaches and represent a major challenge in the management of acute migraine. Therefore, physicians should carefully question their headache patients about their use of prescription pain relievers, ergotamine, sumatriptan (and other serotonin receptor agonists), and OTC medications, with particular focus on whether the patient may be experiencing a rebound headache secondary to overuse of aspirin or acetaminophen compounds. Analgesic rebound contributes to the chronicity of headache and reduces the effectiveness of other pharmacological and nonpharmacological measures. The possibility of analgesic rebound headache should be considered if the patient reports analgesic use more than three times a week for headaches, and especially if daily use is reported. Many patients overmedicate with OTC drugs, because they hope to prevent a mild or moderate headache from evolving into an incapacitating one, or they routinely take analgesics at night to prevent disabling headaches during the day. As the use of medication increases or becomes routine, a vicious cycle of rebound headaches is created, followed by additional analgesic use, evolving to a chronic daily headache. The following are features of drug-related headaches—^34,11

• The headaches are refractory; daily or nearly daily.
• Headaches occur in a patient who uses immediate-relief medications very frequently.
• Headache itself varies in its severity, type and location.
• The slightest physical or intellectual effort may bring on headache (ie, the pain threshold is low).
• Headaches are accompanied by asthenia, and nausea, and other gastrointestinal symptoms.
• There is a drug-dependent rhythmicity of headaches. Early morning headaches are frequent.
• There is evidence of tolerance to analgesics over time.
• Increase in severity and frequency of headache attacks.
• Spontaneous improvement is associated with medication withdrawal.
• Prophylactic medications are ineffective.
• More than 20 headache days per month.
• Daily headache duration exceeding 10 hours.
• Intake of analgesic or migraine drugs more than 20 days/month.
• Regular intake of analgesics and/or ergotamine preparations in combination with barbiturates, codeine, caffeine, antihistamines, or tranquilizers.

Patterns of symptomatic drug use in patients with chronic daily headaches are summarized in Table 11.

• A new patient with in-depth knowledge of a particular medication and its strengths and weaknesses.

• Patient is evasive when asked about headache history, last episode, severity and frequency of attacks.

• Patient has specific medication requests and may be evasive about why regular physician was not contacted for advice or prescription renewal.

Recognition of this pattern of behavior allows the physician to counsel, refer or appropriately treat the patient, instead of becoming an unknowing accomplice to medication abuse.

Strategies to prevent medication abuse and rebound headaches are summarized in Table 12.

Chronic daily headaches related to drug misuse must be distinguished from transformed migraine, which may present similarly, but is not always associated with drug misuse. In transformed migraine, the patient typically describes an initial onset of migraines in their teens or 20s, and these eventually become more frequent. The patient develops intercurrent paroxysmal tension-type headaches and eventually, the different types of headaches merge into chronic daily headache.

Nonpharmacologic Approaches to Migraine Management

Relaxation and Cognitive Therapy
Biofeedback Techniques

The physician is faced with a paradox when considering whether to refer the patient for biofeedback therapy. The lack of scientific validation contrasts with the generally favorable treatment reports of uncontrolled trials, or of trials which combine biofeedback with other relaxation strategies. It seems likely that the effects of biofeedback may not be explained by physiological parameters alone, but may be related to psychological factors as well, particularly in those patients who are anxious to assume some personal control over their migraine management. Biofeedback may foster feelings of hope, self-mastery and control, enhance relaxation skills, assist in developing coping strategies, and may help a patient to gain insight into the emotional and stressful aspects of headaches.³⁸

Nonpharmacologic Approaches to Migraine Management
Operant Behavior Therapy

Nonpharmacologic Approaches to Migraine Management
Alternative/Complementary Techniques

Conclusion

References

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3. Lipton RB, Amatniek JC, Gross M. Migraine: Identifying and removing barriers to care. Neurology. 1994;44:S63-S68.

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9.  Stewart WF, Lipton RB, Liberman J. Variation in migraine prevalence by race. Neurology. 1996;47: 52-59.

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11.  Linet MS, Stewart WF, Celentano DD, et al. An epidemiologic study of headache among adolescents and young adults. JAMA. 1989;261:2211-2216.

12.  Ottman R, Lipton RB. Comorbidity of migraine and epilepsy. Neurology. 1994; 44:2105-2110.

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