Pharmacotherapy A Pathophysiologic Approach, 9th Ed.

45. Headache Disorders

Deborah S. Minor and Marion R. Wofford


KEY CONCEPTS

 Images Acute migraine therapies should provide consistent, rapid relief and enable the patient to resume normal activities at home, school, or work.

 Images A stratified care approach, in which the selection of initial treatment is based on headache-related disability and symptom severity, is the preferred treatment strategy for the migraineur.

 Images Strict adherence to maximum daily and weekly doses of antimigraine medications is essential.

 Images Preventive therapy should be considered in the setting of recurring migraines that produce significant disability; frequent attacks requiring symptomatic medication more than twice per week; symptomatic therapies that are ineffective or contraindicated, or produce serious side effects; and uncommon migraine variants that cause profound disruption and/or risk of neurologic injury.

 Images The selection of an agent for headache prophylaxis should be based on individual patient response, tolerability, convenience of the drug formulation, and coexisting conditions.

 Images Each prophylactic medication should be given an adequate therapeutic trial (usually 6 months) to judge its maximal efficacy.

 Images A general wellness program and avoidance of headache triggers should be included in the management plan.

 Images After an effective abortive agent and dose have been identified, subsequent treatments should begin with that same regimen.


Headache is one of the most common complaints encountered by healthcare practitioners and among the top three principal reasons given by adults 18 years of age and over for visiting U.S. emergency departments.1 It can be symptomatic of a distinct pathologic process or can occur without an underlying cause. In 2004, the International Headache Society (IHS) updated its classification system and diagnostic criteria for headache disorders, cranial neuralgias, and facial pain2 (Table 45-1). Designed to facilitate headache diagnosis in clinical practice and research, the IHS classification provides more precise definitions and standardized nomenclature for both the primary (tension-type, migraine, and cluster headache) and secondary (symptomatic of organic disease) headache disorders. This chapter focuses on the management of the primary headache disorders.

TABLE 45-1 International Headache Society Classification System: Focus on Migraine Headache

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Most recurrent headaches are the result of a benign chronic primary headache disorder.3 Less often, headaches are symptomatic of a serious underlying medical condition, such as infection, cerebral hemorrhage, or brain mass lesion. The peak prevalence of tension-type and migraine headache, the most common of the primary headache disorders, occurs during the most productive years of life (18 to 59 years of age).3,4 Despite the prevalence of these disorders and their associated disability, studies indicate that most headache sufferers do not seek appropriate medical care for their headaches.4,5 An improved understanding of the diagnosis and pathophysiologic mechanisms of the primary headache disorders, particularly migraine, has led to the development of medications capable of providing rapid relief from moderate to severe attacks. However, a thorough evaluation of the headache history is essential to establish an accurate headache diagnosis and identify patients who can benefit from these specific therapeutic options.

MIGRAINE HEADACHE

Epidemiology

Results of the American Migraine Prevalence and Prevention Study indicate that 17.1% of women and 5.6% of men in the United States experience one or more migraine headaches per year. The prevalence of migraine varies considerably by age and gender, but the epidemiologic profile has remained stable over the past 15 years. After age 12, females are two to three times more likely than males to suffer from migraine. Gender differences in migraine prevalence have been linked to menstruation, but these differences persist beyond menopause. Prevalence is highest in both men and women between the ages of 30 and 49 years.4 In the American Migraine Prevalence and Prevention Study, 93% of those with migraine reported some headache-related disability, and 54% were severely disabled or needed bedrest during an attack.4 A number of neurologic and psychiatric disorders as well as cardiovascular diseases, including stroke, epilepsy, major depression, sleep apnea, obesity, and anxiety disorder, show increased comorbidity with migraine.57 Whether this relationship is causal or representative of a common pathophysiologic mechanism is unknown. The economic burden of migraine is substantial; however, the indirect costs from work-related disability far exceed the direct costs associated with treatment.7,8

Etiology and Pathophysiology

The etiologic and pathophysiologic mechanisms of migraine are not completely understood. According to earlier theories, the migraine aura was caused by intracerebral arterial vasoconstriction followed by reactive extracranial vasodilation and associated headache. Studies of regional blood flow in the brain do not support this hypothesis, and previous vascular and neural theories of migraine development have merged into a combined theory of neurovascular mechanisms. Most clinicians now believe that the pathogenesis of migraine may be related to complex dysfunctions in neuronal and broad sensory processing.2,5,9

The pain and symptoms of migraine may be understood as a combination of altered perceptions resulting from neural suppression and activation of subcortical structures and trigeminal systems. Migraine pain is believed to result from activity within the trigeminovascular system, a network of visceral afferent fibers that arises from the trigeminal ganglia and projects peripherally to innervate the pain-sensitive intracranial extracerebral blood vessels, dura mater, and large venous sinuses10 (Fig. 45-1). These fibers also project centrally, terminating in the trigeminal nucleus caudalis in the brain stem and upper cervical spinal cord, and thus provide a pathway for nociceptive transmission from meningeal blood vessels into higher centers of the CNS. Activation of trigeminal sensory nerves triggers the release of vasoactive neuropeptides, including calcitonin gene–related peptide (CGRP), neurokinin A, and substance P, from perivascular axons. The released neuropeptides interact with dural blood vessels to promote vasodilation and dural plasma extravasation, resulting in neurogenic inflammation. Orthodromic conduction along trigeminovascular fibers transmits pain impulses to the trigeminal nucleus caudalis, where information is relayed further to higher cortical pain centers. Continued afferent input can result in sensitization of these central sensory neurons, producing a hyperalgesic state that responds to previously innocuous stimuli and maintains the headache.5,911

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FIGURE 45-1 The pathophysiology of migraine headache. Vasodilation of intracranial extracerebral blood vessels (possibly the result of an imbalance in the brain stem) results in the activation of the perivascular trigeminal nerves that release vasoactive neuropeptides to promote neurogenic inflammation. Central pain transmission may activate other brain stem nuclei, resulting in associated symptoms (nausea, vomiting, photophobia, phonophobia). The antimigraine effects of the 5-HT1B/ID receptor agonists are highlighted at areas 1, 2, and 3. (CGRP, calcitonin gene–related peptide.)(Reprinted from reference 10, Copyright © 1998, with permission from Elsevier.).

Aura occurs in a subgroup of migraineurs and also with the other primary headache disorders. The neurologic changes of the aura parallel those that occur during cortical spreading depression, a neuronal event characterized by a wave of depressed electrical activity that advances across the brain cortex at a rate consistent with the spread of aura symptoms.5,9 Cortical spreading depression can cause inflammation and activation of the trigeminal nucleus caudalis. It is not clear whether this cortical spreading depression and the aura are the substrate of pain or actually trigger the presentation of migraine.5,11

Genetic factors seem to play an important role in susceptibility to migraine attacks. Studies in monozygotic twins suggest approximately 50% heritability of migraine with a multifactorial polygenic basis.12Although it is possible for any individual to experience a migraine attack, it is recurrence in the migraineur that is abnormal. Attack occurrence and frequency are governed by CNS sensitivity to migraine-specific triggers or environmental factors. Migraineurs appear to have a lowered threshold of response to specific environmental circumstances as a result of genetic factors that govern the balance of CNS excitation and inhibition at various levels.12 Thus, trigger factors can be viewed as modulators of the genetic set point that predisposes to migraine headache. The hyperresponsiveness of the migrainous brain may be the result of an inherited abnormality in calcium and/or sodium channels and sodium/potassium pumps that regulate cortical excitability through the release of serotonin (5-hydroxytryptamine [5-HT]) and other neurotransmitters. Increased levels of excitatory amino acids such as glutamate and alterations in levels of extracellular potassium also can affect the migraine threshold and initiate and propagate the phenomenon of cortical spreading depression.5,12,13

5-HT has long been implicated as an important mediator of migraine headache. Specific populations of 5-HT receptor subfamilies appear to be involved in the pathophysiology and treatment of migraine headache. Acute antimigraine drugs such as the ergot alkaloids and triptan derivatives are agonists of vascular and neuronal 5-HT1 receptor subtypes, resulting in vasoconstriction of meningeal blood vessels and inhibition of vasoactive neuropeptide release and pain signal transmission.5,14 Drugs used for migraine prophylaxis also modulate neurotransmitter systems.9 These actions and benefits in migraine management are consistent with the current understanding of migraine pathophysiology and neurovascular disorders.

Clinical Presentation

The migraine attack has been divided into several phases. Premonitory symptoms are experienced by 12% to 79% of migraineurs in the hours or days before the onset of headache.2,5,15 The previously popular terms prodrome and warning symptoms should be avoided because these are often used mistakenly to include aura.2 Premonitory symptoms vary widely among migraineurs but usually are consistent within an individual. Neurologic symptoms (e.g., allodynia, phonophobia, photophobia, hyperosmia, and difficulty concentrating) are common, but psychological (e.g., anxiety, depression, euphoria, irritability, drowsiness, fatigue, hyperactivity, and restlessness), autonomic (e.g., polyuria, diarrhea, and constipation), and constitutional (e.g., stiff neck, yawning, thirst, food cravings, and anorexia) symptoms also are reported.2,5,15

The migraine aura, a complex of positive and negative focal neurologic symptoms that precedes or accompanies an attack, is experienced by approximately 25% of migraineurs on some occasions.2,15 The aura typically evolves over 5 to 20 minutes and lasts less than 60 minutes. Headache usually occurs within 60 minutes of the end of the aura. Occasionally, aura symptoms begin at the onset of headache or during the attack. The aura is most often visual and frequently affects half the visual field.2 Visual auras vary in their complexity and can include both positive (scintillations, photopsia, teichopsia, or fortification spectrum) and negative (scotoma, hemianopsia) features. Sensory and motor aura symptoms, such as paresthesias or numbness involving the arms and face, dysphasia or aphasia, weakness, and hemiparesis, also are reported.2,15


CLINICAL PRESENTATION Migraine Headache

General

    • Migraine is a common, recurrent, severe headache that interferes with normal functioning. It is a primary headache disorder divided into two major subtypes, migraine without aura and migraine with aura.

Symptoms

    • Migraine is characterized by recurring episodes of throbbing head pain, frequently unilateral, that when untreated can last from 4 to 72 hours. Migraine headaches can be severe and associated with nausea, vomiting, and sensitivity to light, sound, and/or movement. Not all symptoms are present at every attack.

    • In the headache evaluation, diagnostic alarms should be identified. These include: acute onset of the “first” or “worst” headache ever, accelerating pattern of headache following subacute onset, onset of headache after age 50 years, headache associated with systemic illness (e.g., fever, nausea, vomiting, stiff neck, and rash), headache with focal neurologic symptoms or papilledema, and new-onset headache in a patient with cancer or human immunodeficiency virus (HIV) infection.

Signs

    • A stable pattern, absence of daily headache, positive family history for migraine, normal neurologic examination, presence of food triggers, menstrual association, long-standing history, improvement with sleep, and subacute evolution are all signs of migraine headache. Aura can signal the migraine headache but is not required for diagnosis.

Laboratory Tests

    • In selected circumstances and secondary headache presentation, serum chemistries, urine toxicology profiles, thyroid function tests, Lyme’s disease studies, and other blood tests such as a complete blood count, antinuclear antibody titer, erythrocyte sedimentation rate, and antiphospholipid antibody titer can be considered.

Diagnostic Tests

    • Perform a general medical and neurologic physical examination. Check for abnormalities: vital signs (fever, hypertension), funduscopy (papilledema, hemorrhage, and exudates), palpation and auscultation of the head and neck (sinus tenderness, hardened or tender temporal arteries, trigger points, temporomandibular joint tenderness, bruits, nuchal rigidity, and cervical spine tenderness), and neurologic examination (identify abnormalities or deficits in mental status, cranial nerves, deep tendon reflexes, motor strength, coordination, gait, and cerebellar function). Consider neuroimaging studies in patients with abnormal neurologic examination findings of unknown etiology and in those with additional risk factors warranting imaging.

Of those with migraine in the United States, 14% experience more than four attacks per month, 63% experience one to four attacks per month, and 23% experience less than one attack per month.4 Migraine headache pain is usually gradual in onset, peaking in intensity over a period of minutes to hours and lasting between 4 and 72 hours. Pain can occur anywhere in the face or head but most often involves the frontotemporal region. The headache is typically unilateral and throbbing or pulsating in nature; however, pain can be bilateral at onset or become generalized during the course of an attack.2,15 GI symptoms almost invariably accompany the headache. During an attack, as many as 90% of migraineurs experience nausea, and emesis occurs in approximately one third of patients. Other systemic symptoms associated with the headache phase include anorexia, food cravings, constipation, diarrhea, abdominal cramps, nasal stuffiness, blurred vision, diaphoresis, facial pallor, and localized facial, scalp, or periorbital edema. Sensory hyperacuity, manifested as photophobia, phonophobia, or osmophobia, is reported frequently. Because headache pain usually is aggravated by physical activity, most migraineurs seek a dark, quiet room for rest and relief. Impaired concentration, depression, irritability, fatigue, or anxiety often accompanies the headache. Once headache pain wanes, patients may experience a resolution phasecharacterized by feeling tired, exhausted, irritable, or listless. Impaired concentration may continue, as well as scalp tenderness or mood changes. Some patients experience depression and malaise, whereas others can feel unusually refreshed or euphoric.2,15 The reader is referred to the IHS classification and recent reviews for descriptions of the classic migraine variants and other migraine subtypes2,15 (Table 45-1).

Although headaches have many potential causes, most are considered to be primary headache disorders. A comprehensive headache history is the most important element in establishing the clinical diagnosis of migraine.5,16 A thorough headache history always should be obtained, and information collected should include age at onset, attack frequency and timing, duration of attacks, precipitating or aggravating factors, ameliorating factors, description of neurologic symptoms, characteristics of the headache pain (quality, intensity, location, and radiation), associated signs and symptoms, treatment history, family and social history, and the impact of headaches on daily life.

Secondary headache can be identified or excluded based on the headache history, as well as the results of general medical and neurologic examinations. Diagnostic and laboratory testing also can be warranted in the setting of suspicious headache features or an abnormal examination. The routine use of neuroimaging (computed tomography or magnetic resonance imaging) generally is not indicated in patients with migraine and a normal neurologic examination, but should be considered in patients with an unexplained abnormal neurologic examination or an atypical headache history.2,3,15 Because migraine headaches usually begin by the second or third decade of life, headaches beginning after age 50 years suggest an organic etiology such as a mass lesion, cerebrovascular disease, or temporal arteritis. Table 45-2 lists the IHS diagnostic criteria for migraine with and without aura.2

TABLE 45-2 IHS Diagnostic Criteria for Migraine

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TREATMENT

Migraines

Desired Outcome

Clinicians who care for migraineurs must appreciate the impact of this painful and debilitating disorder on the life of the patient, the patient’s family, and the patient’s employer. Treatment strategies must address both immediate and long-term goals.Images Acute migraine therapies should provide consistent, rapid relief and enable the patient to resume normal activities at home, school, or work. Recurrence of symptoms and treatment-related adverse effects should be minimal. Ideally, patients should be able to manage their own headaches effectively without a medical visit. In addition, migraineurs should take an active role in the creation of a long-term formal management plan. An individualized approach to treatment can result in a reduction in attack frequency and severity, thus minimizing headache-related disability and emotional distress and improving the patient’s quality of life. Goals of long-term and acute treatment of migraine are listed in Table 45-3.14,16

TABLE 45-3 Goals of Therapy in Migraine Management

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General Approach to Treatment

Nonpharmacologic and pharmacologic interventions are available for the management of migraine headache; however, drug therapy remains the mainstay of treatment for most patients. Pharmacotherapeutic management of migraine can be acute (i.e., symptomatic or abortive) or preventive (i.e., prophylactic). When choosing acute or preventive therapies, the clinician should consider the patient’s response to specific medications and their tolerability, as well as coexisting illnesses that can limit treatment choices. Abortive or acute therapies can be migraine-specific (e.g., ergots and triptans) or nonspecific (e.g., analgesics, antiemetics, nonsteroidal antiinflammatory drugs [NSAIDs], and corticosteroids) and are most effective at relieving pain and associated symptoms when administered at the onset of migraine14,16,17(Table 45-4). Images A stratified care approach in which the selection of initial treatment is based on headache-related disability and symptom severity is the preferred treatment strategy for the migraineur.14,16Because attack severity varies in individuals, patients may be advised to use nonspecific agents for mild to moderate headache not causing disability while reserving migraine-specific medications for more severe attacks. The absorption and efficacy of orally administered drugs can be compromised by gastric stasis or nausea and vomiting that accompany migraine. Pretreatment with antiemetic agents or the use of nonoral treatment (e.g., suppositories, nasal sprays, or injections) is advisable when nausea and vomiting are severe.14,18

TABLE 45-4 Drug Dosing Table—Acute Migraine Therapiesa

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The frequent or excessive use of acute migraine medications can result in a pattern of increasing headache frequency and drug consumption known as medication-overuse headache (or rebound headache).2,5,19 The syndrome appears to evolve as a self-sustaining headache–medication cycle in which the headache returns as the medication wears off, leading to the consumption of more drug for relief. The headache history often reflects the gradual onset of an atypical daily or near-daily headache with superimposed episodic migraine attacks. Medication overuse is one of the most common causes of chronic daily headache.19 Agents most commonly implicated in this syndrome include simple and combination analgesics and opiates. Triptans are also implicated but only in men with a high frequency of headaches.2,5,19 Discontinuation of the offending agent leads to a gradual decrease in headache frequency and severity and a return of the original headache characteristics. Although detoxification usually can be accomplished on an outpatient basis, hospitalization can be necessary for the control of refractory rebound headache and other withdrawal symptoms (e.g., nausea, vomiting, asthenia, restlessness, and agitation). Images Regulation of nociceptive systems and renewed responsiveness to therapy usually occur within 2 months following medication withdrawal.2Most experts recommend limiting use of acute migraine therapies to fewer than 10 days per month to avoid the development of medication-misuse headache.20

Preventive migraine therapies are administered on a daily basis to reduce the frequency, severity, and duration of attacks and improve responsiveness to symptomatic migraine therapies8,21,22 (Table 45-5).ImagesPreventive therapy should be considered in the setting of recurring migraines that produce significant disability despite acute therapy; frequent attacks occurring more than twice per week with the risk of developing medication-overuse headache; symptomatic therapies that are ineffective or contraindicated, or produce serious side effects; uncommon migraine variants that cause profound disruption and/or risk of permanent neurologic injury (e.g., hemiplegic migraine, basilar migraine, and migraine with prolonged aura); and patient preference to limit the number of attacks.8,23 Preventive therapy also may be administered preemptively or intermittently when headaches recur in a predictable pattern (e.g., exercise-induced migraine or menstrual migraine).7 The evidence to support the various agents used for migraine prophylaxis has recently been reviewed. Only propranolol, timolol, divalproex sodium, and topiramate are currently approved by the FDA for the indication, although other agents have established or probable efficacy.Images Guidelines identify which agents might be effective, but there is insufficient evidence as to how to choose one therapy over another. Thus, the selection of an agent typically is based on its side effect profile and the patient’s coexisting/comorbid conditions.16,21 Images A therapeutic trial of 2 to 3 months is necessary to achieve clinical benefit, but some reduction in attack frequency can be evident by the first month of therapy. Maximal benefits are typically observed by 6 months of treatment.7,8,21 Drug therapy should be initiated with low doses and gradually increased until a therapeutic effect is achieved or side effects become intolerable. Drug doses for migraine prophylaxis are often lower than those necessary for other indications.7,8 Overuse of acute headache medications will interfere with the effects of preventive treatment.16,19 Prophylactic treatment usually is continued for at least 6 to 12 months after the frequency and severity of headaches have diminished. After that time, based on discussions with the patient, gradual tapering or discontinuation may be reasonable.8,21 Many migraineurs experience fewer and less severe attacks for lengthy periods following discontinuation of prophylactic medications or taper to a lower dose. Figures 45-2 and 45-3identify treatment and management algorithms for migraine headache.

TABLE 45-5 Drug Dosing Table—Prophylactic Migraine Therapies

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FIGURE 45-2 Treatment algorithm for migraine headaches.

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FIGURE 45-3 Treatment algorithm for prophylactic management of migraine headaches. (NSAID, nonsteroidal antiinflammatory drug.)

Nonpharmacologic Therapy

Nonpharmacologic therapy of acute migraine headache is limited but can include application of ice to the head and periods of rest or sleep, usually in a dark, quiet environment. Preventive management of migraine should begin with the identification and avoidance of factors that consistently provoke migraine attacks in susceptible individuals2,3,16,24 (Table 45-6). Changes in estrogen levels associated with menarche, menstruation, pregnancy, menopause, oral contraceptive use, and other hormone therapies can trigger, intensify, or alleviate migraine.7 A headache diary that records the frequency, severity, and duration of attacks can facilitate identification of migraine triggers. Images Patients also can benefit from adherence to a wellness program that includes regular sleep, exercise, and eating habits, smoking cessation, and limited caffeine intake. Behavioral interventions, such as relaxation therapy, biofeedback (often used in combination with relaxation therapy), and cognitive therapy, are preventive treatment options for patients who prefer nondrug therapy or when symptomatic therapies are poorly tolerated, contra-indicated, or ineffective.16

TABLE 45-6 Commonly Reported Triggers of Migraine

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Clinical Controversy…

Most migraineurs have triggers for the acute attack, at least occasionally, and are generally advised to avoid these as part of management to reduce the frequency of attacks. However, the complexity and usefulness of trigger avoidance is poorly understood by many patients and clinicians. Triggers may change over time in the life of the migraineur and be modified by preventive medication. Trigger avoidance can also impose severe lifestyle restrictions and more stress. Avoidance may ultimately not allow for desensitization from the trigger and the subsequent development of relative immunity.24

Pharmacologic Management of Acute Migraine


Clinical Controversy…

A stratified care approach, in which the selection of initial treatment is based on headache-related disability and symptom severity, is the most recommended treatment strategy for the migraineur. This approach assumes that greater severity is a risk factor for failure of symptomatic treatments and reflects the need for more specific treatment, such as a triptan. However, recent reviews support the efficacy of aspirin and other NSAIDs in acute migraine, regardless of pretreatment headache intensity, and with efficacy comparable to oral triptans.25,26

Analgesics and NSAIDs

Simple analgesics and NSAIDs are effective medications for the management of many migraine attacks (Table 45-4). They offer a reasonable first-line choice for treatment of mild to moderate migraine attacks or severe attacks that have been responsive in the past to similar NSAIDs or nonopiate analgesics. Of the NSAIDs, aspirin, diclofenac, ibuprofen, ketorolac, naproxen sodium, tolf-enamic acid, and the combination of acetaminophen plus aspirin and caffeine have demonstrated the most consistent evidence of efficacy.14,18 Evidence for other NSAIDs is either limited or inconsistent. Although some patients may observe benefits, acetaminophen alone is not generally recommended for migraine because the scientific support is not optimal.17 Comparisons with other pharmacotherapeutic classes are limited; however, studies support the comparable efficacy of NSAIDs and triptans in acute migraine. Baseline headache intensity does not predict the success or failure of aspirin or other NSAIDs.25,26 There are no studies comparing the relative efficacy of different NSAIDs.18

NSAIDs appear to prevent neurogenically mediated inflammation in the trigeminovascular system through the inhibition of prostaglandin synthesis. Metoclopramide can speed the absorption of analgesics and alleviate migraine-related nausea and vomiting.14 Suppository analgesic preparations are an option when nausea and vomiting are severe.18 Acute NSAID therapy is associated with GI (e.g., dyspepsia, nausea, vomiting, and diarrhea) and CNS (e.g., somnolence, dizziness) side effects. NSAIDs should be avoided or used cautiously in patients with previous ulcer disease, renal disease, or hypersensitivity to aspirin.17,18

The nonprescription combination of acetaminophen, aspirin, and caffeine was approved for the treatment of migraine in the United States because of its proven efficacy in relieving migraine pain and associated symptoms.14,17Aspirin and acetaminophen are also available in prescription combination products containing a short-acting barbiturate (butalbital) or narcotic (codeine). No randomized, placebo-controlled studies support the efficacy of butalbital-containing products in the treatment of migraine. The use of butalbital-containing analgesics or narcotics should be limited because of concerns about overuse, medication-overuse headache, and withdrawal.17,18,20 Although frequent consumption of aspirin or acetaminophen alone can result in medication-overuse headache, combination analgesics appear to pose a greater risk.18,20

Opiate Analgesics

The use of narcotic analgesic drugs (e.g., meperidine, butorphanol, oxycodone, and hydromorphone) in migraine treatment is controversial, and evidence for use is generally negative. Opiates have no vasopressor or antiinflammatory effects and can cause central sensitization, increasing the risk of medication-overuse headache and interfering with the efficacy of other treatments even with intermittent use.14,20 Use should generally be reserved for patients with moderate to severe infrequent headaches in whom conventional therapies are contraindicated or as “rescue medication” after patients have failed to respond to conventional therapies.17 Opioid therapy should be supervised closely because of the risk of sedation and the potential for abuse.14,20

Antiemetics

Adjunctive antiemetic therapy is useful for combating the nausea and vomiting that accompany migraine headaches and the medications used to treat attacks (e.g., ergotamine tartrate). A single dose of an antiemetic, such as metoclopramide, chlorpromazine, or prochlorperazine, administered 15 to 30 minutes before ingestion of oral abortive migraine medications is often sufficient. Suppository preparations are available when nausea and vomiting are particularly prominent. Metoclopramide is also useful to reverse gastroparesis and improve absorption from the GI tract during severe attacks.14,17

In addition to antiemetic effects, dopamine antagonist drugs also have been used successfully as monotherapy for the treatment of intractable headache (Table 45-4). Prochlorperazine administered by the IV and intramuscular routes and IV metoclopramide provided more effective pain relief than placebo. Chlorpromazine and droperidol also have provided relief of migraine headache when administered parenterally at doses of 12.5 to 37.5 and 2.5 to 5 mg, respectively. The precise mechanism of action for these agents is unknown. The dopamine antagonists offer an alternative to the narcotic analgesics for the treatment of refractory migraine. Drowsiness and dizziness were reported occasionally, and extrapyramidal side effects were reported infrequently in migraine trials. Droperidol has a risk for QT prolongation.17,18,20

Miscellaneous Nonspecific Medications

Corticosteroids can be considered as rescue therapy for status migrainous (a severe, continuous migraine that can last up to 1 week).17 IV or intramuscular dexamethasone at a dose of 10 to 25 mg has also been used as an adjunct to abortive therapy.27

Limited studies suggest a role for intranasal lidocaine in the treatment of acute migraine headache. Intranasal lidocaine, one to four drops of a 4% solution, provides rapid pain relief within 15 minutes of administration, but headache recurrence is common. Adverse effects generally are limited to local irritation, an unpleasant taste, and numbness of the throat.17

IV valproate 500 to 1,000 mg and magnesium sulfate 1,000 mg are nonsedating options for use in acute migraine treatment.20 Future studies might establish a more defined role for these agents in migraine management.

Ergot Alkaloids and Derivatives

Ergotamine tartrate and dihydroergotamine are useful and can be considered for the treatment of moderate to severe migraine attacks (Table 45-4). These drugs are nonselective 5-HT1 receptor agonists that constrict intracranial blood vessels and inhibit the development of neurogenic inflammation in the trigeminovascular system.14 Central inhibition of the trigeminovascular pathway is also reported as well as agonist activity at dopaminergic receptors. Venous and arterial constriction occur with therapeutic doses, but ergotamine tartrate exerts more potent arterial effects than dihydroergotamine.14,18,20

Ergotamine tartrate is available for oral, sublingual, and rectal administration. Oral and rectal preparations contain caffeine to enhance absorption and potentiate analgesia. Ergotamine use is limited because of issues of efficacy and side effects. Dosage requirements should be titrated strictly to establish an effective but subnauseating dose for future attacks. Despite clinical use since 1926, evidence supporting the efficacy of ergotamine in migraine is inconsistent.18

Dihydroergotamine is available for intranasal and parenteral administration by the intramuscular, subcutaneous, and IV routes.20 Parenteral dihydroergotamine was viewed previously as inpatient or emergency department treatment for moderate to severe migraine or intractable headache, but patients can be trained to self-administer dihydroergotamine intramuscularly or subcutaneously. Mixing with 1% or 2% lidocaine can reduce burning at the injection site. Clinical opinion suggests its use is relatively safe and effective when compared with other migraine therapies.14,17

Nausea and vomiting (resulting from stimulation of the chemoreceptor trigger zone) are among the most common adverse effects of the ergotamine derivatives. Pretreatment with an antiemetic agent should be considered with ergotamine and IV dihydroergotamine therapy. Other common side effects include abdominal pain, weakness, fatigue, paresthesias, muscle pain, diarrhea, and chest tightness. Rarely, symptoms of severe peripheral ischemia (ergotism), including cold, numb, painful extremities, continuous paresthesias, diminished peripheral pulses, and claudication, can result from the vasoconstrictor effects of the ergot alkaloids. Gangrenous extremities, myocardial infarction, hepatic necrosis, and bowel and brain ischemia have also been reported. Dihydroergotamine is rarely associated with such side effects. Triptans and ergot derivatives should not be used within 24 hours of each other.14,18Ergotamine derivatives are contraindicated in patients with renal or hepatic failure; coronary, cerebral, or peripheral vascular disease; uncontrolled hypertension; and sepsis; and in women who are pregnant or nursing. Dihydroergotamine does not appear to cause rebound headache, but dosage restrictions for ergotamine tartrate should be observed strictly to prevent this complication.18,20

Serotonin Receptor Agonists (Triptans)

Introduction of the 5-HT receptor agonists, or triptans, represented a significant advance in migraine pharmacotherapy. The first member of this class, sumatriptan, and the second-generation agents zolmitriptan, naratriptan, rizatriptan, almotriptan, frovatriptan, and eletriptan are selective agonists of the 5-HT1B and 5-HT1D receptors. Relief of migraine headache is the result of three key actions: normalization of dilated intracranial arteries through enhanced vasoconstriction, inhibition of vasoactive peptide release from perivascular trigeminal neurons, and inhibition of transmission through second-order neurons ascending to the thalamus.14,28 These agents also display varying affinity for 5-HT1A, 5-HT1E, and 5-HT1F receptors. The triptans are appropriate first-line therapy for patients with mild to severe migraine and are used for rescue therapy when nonspecific medications are ineffective.28

Sumatriptan, the most extensively studied acute therapy, is available for subcutaneous, oral, and intranasal administration. Subcutaneous sumatriptan is consistently superior to placebo in alleviating migraine headache and associated symptoms, with relief reported in 70% of patients at 2 hours in a meta-analysis of placebo-controlled studies.28 In addition to enhanced efficacy, subcutaneous sumatriptan has a more rapid onset of action when compared with the oral formulation. The subcutaneous injection is packaged as an autoinjector device for self-administration by patients. Intranasal sumatriptan provides a faster onset of effect than the oral formulation and produces similar rates of response in placebo-controlled studies.18,28

Selection of a triptan is based on characteristics of the headache, convenience of dosing, and the patient’s preference. At all marketed doses, the oral triptans are effective and well tolerated. The triptans differ in their pharmacokinetic and pharmacodynamic profiles (Table 45-7). In general, triptans can be divided into those with a faster onset and higher efficacy and those with a slower onset and lower efficacy. A recent meta-analysis summarizes the efficacy and tolerability of the oral triptans across published and unpublished studies. Using 100 mg of sumatriptan as the reference dose and based on 2-hour response rates, at doses recommended by the manufacturer, most of the triptans evaluated had similar therapeutic gains; frovatriptan and naratriptan were the exceptions with lower efficacy. Compared with other triptans, frovatriptan and naratriptan have the longest half-lives, the slowest onset of action, and less headache recurrence. This may make them more suitable for patients who have migraine attacks of a slow onset and longer duration. Faster-acting triptans are more efficacious when a rapid onset is necessary. Subcutaneous, intranasal, or orally dissolving tablets may be useful in patients with prominent early nausea or vomiting or those who have difficulty in swallowing tablets. Despite the fact that oral absorption can be delayed during migraine attacks, most patients prefer oral formulations.14,20,25,28

TABLE 45-7 Pharmacokinetic Characteristics of Triptans

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Clinical response to the triptans can vary considerably among individual patients. Individual responses cannot be predicted, and if one triptan fails, a patient can be switched successfully to another triptan.14 Images After an effective agent and dose have been identified, subsequent treatments should begin with that same regimen. Combination therapy may also improve response rates and diminish migraine recurrence. A proprietary formulation of sumatriptan 85 mg plus naproxen 500 mg in a single tablet was more effective in clinical trials for headache relief and sustained pain-free response than either agent as monotherapy.14,18

Side effects to the triptans are common but usually mild to moderate in nature and of short duration. Adverse effects are consistent among the class and include paresthesias, fatigue, dizziness, flushing, warm sensations, and somnolence. Local side effects are reported with the subcutaneous (minor injection site reactions) and intranasal (taste perversion, nasal discomfort) routes. Up to 25% of patients receiving a triptan consistently report “triptan sensations,” including tightness, pressure, heaviness, or pain in the chest, neck, or throat. The mechanism of these symptoms is unknown, but a cardiac source of pain seems unlikely in most patients.28 However, all triptans are partial agonists of human 5-HT coronary artery receptors in vitro, resulting in a small but significant vasoconstrictor response. Adverse cardiac events are rare with only isolated cases of myocardial infarction and coronary vasospasm with ischemia reported. The triptans are contraindicated in patients with a history of ischemic heart disease (e.g., angina pectoris, Prinzmetal’s angina, or previous myocardial infarction), uncontrolled hypertension, and cerebrovascular disease. Patients at risk for unrecognized coronary artery disease should use triptans with caution. Postmenopausal women, men older than 40 years of age, and patients with uncontrolled risk factors should receive a cardiovascular assessment prior to triptan use and have initial doses administered under medical supervision. Triptans are also contraindicated in patients with hemiplegic and basilar migraine and should not be used routinely in pregnancy.18,28 The triptans should not be given within 24 hours of the ergotamine derivatives. Administration of sumatriptan, rizatriptan, and zolmitriptan within 2 weeks of therapy with monoamine oxidase inhibitors (MAOIs) is not recommended. Eletriptan should not be administered with cytochrome P450 3A4 inhibitors such as macrolide antibiotics, anti-fungals, and some antiviral therapies. Concomitant therapy with the selective serotonin reuptake inhibitors (SSRIs) or serotonin–norepinephrine reuptake inhibitors (SNRIs) (e.g., duloxetine, venlafaxine, and mirtazapine) can potentially cause 5-HT syndrome. Regulatory agencies caution against concurrent administration, although it appears the likelihood of CNS adverse events is extremely low. The potential risk of these combinations should be carefully considered and discussed with the patient.14,18,29 Frequent use of the triptans has been associated with the development of medication-misuse headache.17,28

Prophylactic Pharmacologic Therapy


Clinical Controversy…

To determine maximal clinical benefits, a therapeutic trial of 6 months is recommended when initiating treatment for episodic migraine prevention. Despite this recommendation, most migraine prevention studies have relatively brief treatment durations of only 12 to 16 weeks. Long-term scientifically sound assessments and evaluations of migraine preventive treatments are needed to further define their role in clinical care.21

β-Adrenergic Antagonists

β-Adrenergic antagonists are among the most widely used drugs for migraine prophylaxis. Metoprolol, propranolol, and timolol have established efficacy in controlled clinical trials, reducing the frequency of attacks by 50% in greater than 50% of patients.8,21 Atenolol and nadolol are also probably effective, while nebivolol and pindolol are possibly effective (Table 45-5).21 Because the relative efficacy of the individual agents has not been established, selection of a β-blocker can be based on β-selectivity, convenience of the formulation, and tolerability. β-Blockers with intrinsic sympathomimetic activity are typically ineffective for migraine prophylaxis.18 Although their precise mechanism of antimigraine action is unknown, β-blockers may raise the migraine threshold by modulating adrenergic or serotonergic neurotransmission in cortical or subcortical pathways. Although not first-line treatment for hypertension or anxiety, β-blockers may be useful along with other therapy in patients with comorbid hypertension or angina.7 Side effects can include drowsiness, fatigue, sleep disturbances, vivid dreams, memory disturbance, depression, impotence, bradycardia, and hypotension. β-Blockers should be used with caution in patients with congestive heart failure, peripheral vascular disease, atrioventricular conduction disturbances, asthma, depression, and diabetes.7,8,21

Antidepressants

The beneficial effects of antidepressants in migraine are independent of their antidepressant activity and may be related to down-regulation of central 5-HT2 receptors, increased levels of synaptic norepinephrine, and enhanced endogenous opioid receptor actions.30 The tricyclic antidepressant (TCA) amitriptyline and SNRI venlafaxine have demonstrated efficacy in placebo-controlled and comparative studies and are classified as probably effective for migraine prophylaxis (Table 45-5).8,21 Use of other antidepressants is based primarily on clinical and anecdotal experience. There are insufficient or conflicting data to support or refute the efficacy of other antidepressants, such as protriptyline, fluoxetine, or fluvoxamine, for migraine prophylaxis.21

Anticholinergic side effects are common with TCAs and limit use of these agents in patients with benign prostatic hyperplasia and glaucoma. Evening doses are preferred because of associated sedation. Increased appetite and weight gain can occur. Orthostatic hypotension and cardiac toxicity (slowed atrioventricular conduction) also are reported occasionally.8,21 The most common side effects reported with venlafaxine are nausea, vomiting, and drowsiness. Again, the potential risk of 5-HT syndrome should be considered in patients using SSRIs or SNRIs along with a triptan.21,29

MAOIs, such as phenelzine, have been used in the management of refractory headache, but their complex adverse effect profile limits their use to experienced prescribers. Strict adherence to a tyramine-free diet is necessary to avoid potentially life-threatening hypertensive crisis.8,16 The reader is referred to Chapter 51 for dietary and concurrent medication restrictions for patients taking MAOIs.

Anticonvulsants

Anticonvulsant medications have emerged as important therapeutic options for migraine prophylaxis with valproate, divalproex, and topiramate all having established efficacy.21 The beneficial effects of these agents are likely caused by multiple mechanisms of action, including enhancement of γ-aminobutyric acid (GABA)–mediated inhibition, modulation of the excitatory neurotransmitter glutamate, and inhibition of sodium and calcium ion channel activity.30Anticonvulsants are particularly useful in migraineurs with comorbid seizures, anxiety disorder, or bipolar illness.8,21 The efficacy of sodium valproate and divalproex sodium (a 1:1 molar combination of valproate sodium and valproic acid) has been demonstrated in multiple placebo-controlled studies. In most trials for headache prophylaxis, there were no significant differences in treatment-emergent side effects between these agents and placebo. Nausea and vomiting, the most common early side effects, are self-limited and appear to be less common with divalproex sodium and gradual titration of doses. Alopecia, tremor, asthenia, somnolence, and weight gain are also complaints.8,21,23 The extended-release formulation of divalproex sodium is administered once daily and is better tolerated than the enteric-coated formulation.22 Hepatotoxicity is the most serious side effect of valproate therapy, but the risk appears to be low in migraineurs (e.g., patients older than 10 years of age who are receiving monotherapy and have no underlying metabolic or neurologic disorder). Baseline liver function tests should be obtained, but routine followup studies are not necessary in asymptomatic adults on monotherapy. Regular followup is necessary, however, for dosage adjustments and monitoring of effects.8,21 Valproate is contraindicated in pregnant women (owing to potential teratogenicity) and patients with a history of pancreatitis or chronic liver disease.21,22

Topiramate is the most extensively studied medication to date for migraine prophylaxis. Efficacy and improvements in health-related quality of life including daily work, home, and social activities have been demonstrated in several placebo-controlled studies.8,16 To minimize adverse effects, topiramate should be initiated at a low dose and slowly titrated upward. The benefits of topiramate are observed as early as 2 weeks after initiation of therapy, with significant reductions in migraine frequency within the first month. Approximately 50% of patients treated to target doses are responders (50% or greater reduction in mean headache frequency). Treatment-emergent adverse events associated with topiramate include paresthesia, fatigue, anorexia, diarrhea, weight loss, hypesthesia, difficulty with memory, language problems, taste perversion, and nausea. Paresthesia is the most common adverse event, occurring in about half of patients at target doses. Weight loss, occurring in 9% to 12% of patients, is a unique adverse effect, as weight gain is a common reason to discontinue other preventive medications. Topiramate should be used with caution or avoided in patients with a history of kidney stones or cognitive impairment.8,21,23

Preliminary studies suggest a role for other anticonvulsants for migraine prevention. Carbamazepine is possibly effective, and a recent study evaluated gabapentin, but data are insufficient to determine efficacy. Lamotrigine is classified as possibly or probably ineffective.8,21

NSAIDs

NSAIDs are modestly effective for reducing the frequency, severity, and duration of migraine attacks, but potential GI and renal toxicity limit the daily or prolonged use of these agents.22 Consequently, NSAIDs have been used intermittently to prevent headaches that recur in a predictable pattern, such as menstrual migraine. Administration of NSAIDs in the perimenstrual period can be beneficial in women with true menstrual migraine. NSAIDs should be initiated 1 to 2 days prior to the expected onset of headache and continued during the period of vulnerability.7,23 If long-term NSAID therapy is initiated, monitoring of renal function and occult blood loss is necessary. For migraine prevention, the evidence for efficacy is strongest for naproxen and weakest for aspirin.21,23

Triptans

Triptans are also useful for the prevention of menstrual migraine. Frovatriptan has established efficacy, while naratriptan and zolmitriptan are probably effective. The triptan is usually started 1 or 2 days before the expected onset of headache and continued during the period of vulnerability.21,23 A separate indication for pure menstrual migraine is currently being deliberated by regulatory authorities.21

Miscellaneous Prophylactic Agents

At least two placebo-controlled studies show that petasites, an extract from the butterbur plant Petasites hybridus, is an effective preventive treatment for migraine.8,23,31 A double-blind, placebo-controlled study demonstrated the probable efficacy of riboflavin (vitamin B2) 400 mg daily in migraine prophylaxis. Riboflavin was well tolerated and associated with 50% or greater improvement in attack frequency in 54% of patients. However, the benefits of therapy became significant only after 3 months.8,23,31 The relatively stable extract of feverfew (Tanacetum parthenium), MIG-99, is the most studied herbal preparation for migraine prevention. MIG-99 is classified as probably effective, reducing migraine frequency by 1.9 attacks per month.8,23,31 Clinical trials evaluating various formulations of magnesium for migraine prevention have yielded mixed results, though overall probable efficacy.23,31 CNS levels of magnesium are known to be significantly low during migraine attacks. Magnesium supplementation may be particularly effective for prevention of menstrual migraine and in migraine patients with aura.8,23 Subcutaneous histamine has been compared with placebo, sodium valproate, and topiramate, with favorable results indicating probable efficacy in improving headache frequency, duration, and intensity. Transient burning and itching at the injection site were the only reported side effects with histamine administration.31

Other agents are possibly effective and may be considered for migraine prevention.21,31 The angiotensin-converting enzyme inhibitor lisinopril and the angiotensin II receptor blocker candesartan provided effective migraine prophylaxis in recent double-blind, placebo-controlled, crossover studies of these agents.21,23 Although use is limited by side effects, clonidine and guanfacine have also demonstrated possible efficacy.21 Coenzyme Q10 was effective for migraine prevention and well tolerated in a small, randomized, double-blind, controlled study.8,23,31 In one study, cyproheptadine (4 mg/day) was as effective as propranolol (80 mg/day) in reducing migraine frequency, duration, and severity, while the combination was more effective in attack frequency reduction.21,31

The calcium channel blockers, primarily verapamil, have been widely used for preventive treatment, although evidence supporting their use is inadequate or conflicting.8,21,23 Extensive clinical experience and the ease of use of verapamil suggest a possible role in migraine prevention. Side effects of verapamil can include constipation, hypotension, bradycardia, atrioventricular block, and exacerbation of congestive heart failure.8,21

Localized injections of botulinum toxin type A have been used for various conditions and pain syndromes, including migraine headache. However, no consistent, statistically significant benefits have been found with migraine. The American Academy of Neurology concludes that botulinum toxin is probably ineffective.23,32 Further study is needed to confirm the clinical utility and comparative efficacy for many of these miscellaneous agents in the prevention of migraine.

Personalized Pharmacotherapy

Although migraine is widely recognized as a disease that exacts an enormous toll on the sufferer, healthcare providers often do not recognize the degree and scope of functional impairment imposed by migraine on the individual.16 In 2004, only half of those surveyed with clear symptoms of migraine were diagnosed by a physician. Although most episodic migraine sufferers take medications for their headaches, 21% use opioids or compounds containing barbiturates, and only 24% use a triptan. Just 13% use medications specifically to prevent migraine, although 26% meet criteria to be offered prophylaxis, and an additional 13% should be considered for treatment.5 Because many migraineurs who receive inadequate care experience substantial levels of pain and disability, improvement in migraine diagnosis, care, and treatment potentially could result in lower direct and indirect costs of the disease.

Effective communication and education of headache patients regarding required behavior changes and appropriate use of acute and prophylactic pharmacotherapy is essential. Healthcare professionals should inquire about and address coexisting conditions that may contribute to headache presentation or successful acute and preventive management. Decisions for treatment should be individualized, with consideration for frequency and severity of headache episodes, level of disability, trigger factors, coexisting conditions, tolerability of the available agents, and the patient’s lifestyle and preferences.16,21

Medications with the highest level of efficacy should be used for treatment. Migraine management should be individualized on the basis of the patient’s clinical presentation and medical history. Therapy should usually be initiated with the lowest effective dose and then titrated upward until clinical benefits are achieved, in the absence of adverse events. Medications that increase headache frequency or severity should be avoided. Many patients try nonpharmacologic or nonprescription treatments for headache management either before or concurrently with other drug therapy. Patients may not know how to take these products optimally and often need instructions and dosing limits.

Analgesics and NSAIDs can be considered the drugs of choice if effective for infrequent mild to moderately severe attacks. The triptans or dihydroergotamine can be used if initial therapies prove ineffective or as first-line therapy in moderate to severe migraine headache. Abortive therapy should be instituted early in the course of the attack to optimize efficacy and minimize migraine-related pain and disability. Preventive therapy should be considered in the setting of recurring migraines that produce significant disability; frequent attacks requiring symptomatic medication more than twice per week; symptomatic therapies that are ineffective or contraindicated, or produce serious side effects; and uncommon migraine variants that cause risk of neurologic injury. Efficacy of a prescribed prophylactic regimen should be reassessed periodically. Therapeutic interventions require an adequate trial to achieve clinical benefit and often as long as 6 months for assessment of maximal benefit. A prolonged headache-free interval could allow for gradual dosage reduction and discontinuation of therapy.

A formal management plan and maintaining a headache diary are necessary for the patient and provider to evaluate therapy, headache impact, and medication consumption. Oversights can lead to decreased efficacy of medications resulting in repeat dosing and polypharmacy, decreased compliance, increased emergency visits, increased “doctor shopping,” and, perhaps, increased use of expensive diagnostic procedures and inpatient services. Patients with stratified care targeted to their needs have higher headache response rates, shorter disability times, less health service utilization, and less loss of productivity.18,23,31,32

TENSION-TYPE HEADACHE

Epidemiology

Tension-type headache is the most common type of primary headache, with an estimated 1-year prevalence ranging from 31% to 86%.3,33 Prevalence peaks in the fourth decade and is higher among women. The incidence decreases with age.33 Although an estimated 60% of tension-type headache sufferers experience some degree of functional impairment during their attacks, less than 15% of sufferers seek medical attention, likely because most have infrequent attacks. Infrequent episodic tension-type headache (defined as fewer than one episode per month) is experienced by 64% of sufferers, while 22% have frequent episodic tension-type headache (episodes on 1 to 14 days/mo). The prevalence of chronic tension-type headache (15 or more days/mo, perhaps without recognizable episodes) is estimated at 0.9% to 2.2%. Risk factors associated with a poor outcome in tension-type headache include coexisting migraine, sleep problems, not being married, and the presence of chronic tension-type headache.33,34

Pathophysiology

Although tension-type headache is the most common type of headache, it is the least studied of the primary headache disorders, and there is limited understanding of key pathophysiologic concepts.2,33 Some evidence supports that migraine and tension-type headaches represent a continuum of headache severity with similarities in mechanisms and pathophysiology. However, more recently, tension-type headache has been recognized as a distinct disorder.2 The mechanism of pain in chronic tension-type headache is thought to originate from myofascial factors and peripheral sensitization of nociceptors. Central mechanisms also are involved, with heightened sensitivity of pain pathways in the CNS.33 Mental stress, nonphysiologic motor stress, a local myofascial release of irritants, or a combination of these may be the initiating stimulus. Following activation of supra-spinal pain perception structures, a self-limiting headache results in most individuals owing to central modulation of the incoming peripheral stimuli. Chronic tension-type headache can evolve from episodic tension-type headache in predisposed individuals due to a change in central circuits and nociceptive processing along the brain stem reflex pathway and subsequent sensitization of the CNS.33,34 It is likely that other pathophysiologic mechanisms also contribute to the development of tension-type headache.

Clinical Presentation

Premonitory symptoms and aura are absent with tension-type headache. The pain usually is mild to moderate in intensity and often is described as a dull, nonpulsatile tightness or pressure.2,33 Bilateral pain is most common, but the location can vary (frontal and temporal pain are most common; occipital and parietal regions also may be affected).2 The pain is classically described as having a “hatband” pattern. Associated symptoms generally are absent, but mild photophobia or phonophobia may be reported. The disability associated with tension-type headache typically is minor in comparison with migraine headache, and routine physical activity does not affect headache severity.2,33Palpation of the pericranial or cervical muscles can reveal tender spots or localized nodules in some patients.2 Tension-type headache is classified as either episodic (infrequent or frequent) or chronic based on the frequency and duration of the attacks.2

TREATMENT

Tension-Type Headaches

General Approach to Treatment

The vast majority of episodic tension-type headache sufferers self-medicate with nonprescription medications and do not consult a healthcare professional. Although pharmacologic and nonpharmacologic treatments are available, simple analgesics and NSAIDs are the mainstay of acute therapy. Most agents used for tension-type headache have not been studied in controlled clinical trials.35

Nonpharmacologic Therapy

Psychophysiologic therapy and physical therapy have been used in the management of tension-type headache. Behavioral treatments can consist of cognitive-behavioral therapy (i.e., stress management), relaxation training, and biofeedback. These therapies (alone, in combination, or with pharmacotherapy) can result in a 33% to 64% reduction in headache activity. Relaxation training combined with biofeedback is more effective than other behavioral therapy options.36 Evidence supporting physical therapeutic options, such as heat or cold packs, ultrasound, electrical nerve stimulation, stretching, exercise, massage, acupuncture, manipulations, ergonomic instruction, and trigger point injections or occipital nerve blocks, is somewhat inconsistent. However, individual patients may benefit from selected modalities in reducing the frequency of tension-type headache or during an acute episode.35,36

Pharmacologic Therapy

Simple analgesics (alone or in combination with caffeine) and NSAIDs are effective for the acute treatment of most mild to moderate tension-type headaches. Acetaminophen, aspirin, diclofenac, ibuprofen, naproxen, ketoprofen, and ketorolac have demonstrated efficacy in placebo-controlled and comparative studies.35 Failure of nonprescription agents can warrant therapy with prescription drugs. High-dose NSAIDs and the combination of aspirin or acetaminophen with butalbital or, rarely, codeine are effective options. Use of butalbital and codeine combinations should be avoided when possible owing to the high potential for overuse and dependency. Acute medications should be taken for episodic tension-type headache no more than 3 days (butalbital-containing), 9 days (combination analgesics), or 15 days (NSAIDs) per month to prevent the development of chronic tension-type headache.35 There is no evidence to support the efficacy of muscle relaxants in the management of episodic tension-type headache.35Preventive treatment is appropriate for most patients with chronic tension-type headache and should be considered in those with frequent episodic tension-type headache if frequency (more than 2 per week), duration (greater than 3 to 4 hours), or severity results in medication overuse or substantial disability.36 The principles of preventive treatment for tension-type headache are similar to those for migraine headache. TCAs are prescribed most often for prophylaxis, but other drugs also can be selected after consideration of comorbid medical conditions and respective side effect profiles. SSRIs are not effective in patients with tension-type headache who do not have depression. Limited studies support the use of the SNRIs mirtazapine and venlafaxine in patients with chronic tension-type headache and without depression.34,36 Topiramate and gabapentin may have benefits in chronic tension-type headache; however, confirmation is needed from randomized clinical trials. Injection of botulinum toxin into pericranial muscles has demonstrated inconsistent efficacy in the prophylaxis of tension-type headache and because of this, it is not recommended for use.32,36

CLUSTER HEADACHE

Epidemiology

Cluster headache, the most severe of the primary headache disorders, is characterized by attacks of excruciating, unilateral head pain that occur in series lasting for weeks or months (i.e., cluster periods) separated by remission periods usually lasting months or years.2,37 Cluster headaches can be episodic or chronic.2 Cluster headache is relatively uncommon among the primary headache disorders, but the exact prevalence is uncertain. Estimates from pooled population studies show a lifetime prevalence of 124 per 100,000 or 0.12%.38 The male-to-female ratio for cluster headache is approximately 3:1 with age of onset typically in the third decade for men and at a slightly younger age for women. Greater than 65% of patients with cluster headache are tobacco smokers or have a history of smoking. Tobacco cessation does not, however, seem to improve the course of cluster headaches. Recent genetic epidemiologic surveys support a predisposition for cluster headache can exist in certain families.37,38

Pathophysiology

The etiologic and pathophysiologic mechanisms of cluster headache are not completely understood. Neuroimaging studies performed during acute attacks have demonstrated activation of the ipsilateral hypothalamic gray area, implicating the hypothalamus as a modulator of cluster headaches. The hypothalamus secondarily activates trigeminal-autonomic reflexes, leading to the ipsilateral pain and cranial autonomic features characteristic of cluster headache.37,39 The cyclic nature of attacks implicates a pathogenesis of hypothalamic dysfunction with resulting alterations in circadian rhythms.39 There is some evidence that cluster headache may result from inflammation of the nerves traversing the cavernous sinus resulting in injury to sympathetic fibers of the internal carotid artery.39

Clinical Presentation

One hallmark of cluster headaches is the circadian rhythm of painful attacks. Episodic cluster headaches are the most common cluster headache subtype in both men and women, occurring in 80% of patients.38 In episodic cluster headaches, attacks occur daily for 2 weeks to several months, followed by long pain-free intervals.37,39 Periods of remission average 2 years in length but have been reported to be from 2 months to 20 years in duration. Approximately 10% of patients have chronic symptoms with attacks recurring for over 1 year without remission or with remission periods of less than 1 month.37,39

Cluster headache attacks occur commonly at night and more commonly in the spring and fall. Attacks occur suddenly, with pain peaking quickly after onset and generally lasting 15 to 180 minutes.37 The pain is excruciating, penetrating, and of a boring intensity in orbital, supraorbital, and temporal unilateral locations.37,39 The headache is accompanied by cranial autonomic symptoms such as conjunctival injection, lacrimation, nasal stuffiness, rhinorrhea, eyelid edema, facial sweating, and miosis/ptosis, which resolve with resolution of the headache. Most sufferers of cluster headaches also describe restlessness or agitation. Whereas migraine patients retreat to a quiet, dark room, cluster headache patients generally sit and rock or pace about the room clutching their head.37 Auras are not present with cluster headaches. During the cluster period, attacks occur from once every other day to eight times per day.37,39 Specific diagnostic criteria for cluster headaches are provided within the IHS classification system.2

TREATMENT

Cluster Headaches

As in migraine, therapy for cluster headaches involves both abortive and prophylactic therapy. Abortive therapy is directed at managing the acute attack. Prophylactic therapies are started early in the cluster period in an attempt to induce remission. Patients with chronic cluster headache can require prophylactic medications indefinitely.

Abortive Therapy

Oxygen

The standard acute treatment of cluster headache is inhalation of 100% oxygen by nonbreather facial mask at a rate of at least 12 L/min for 15 to 30 minutes.40,42 Repeat administration can be necessary because of recurrence, as oxygen appears to merely delay, rather than abort, the attack in some patients.40 No side effects have been reported with the use of oxygen, but caution should be used for those who smoke or have chronic obstructive pulmonary disease.

Triptans

The quick onset of subcutaneous and intranasal triptans makes them safe and effective abortive agents for cluster headaches. Subcutaneous sumatriptan (6 mg) is the most effective agent. Nasal sprays are less effective but may be better tolerated in some patients. Adverse events reported in cluster headache patients are similar to those seen in migraineurs. Orally administered triptans have limited use in cluster attacks because of their relatively slow onset of action; oral zolmitriptan (10 mg), however, was beneficial in patients with episodic cluster headache, with 60% experiencing mild or no pain at 30 minutes.4042

Ergotamine Derivatives

All forms of ergotamine have been used in cluster headaches, although no controlled clinical trials support their use.41,42 In clinical use, IV dihydroergotamine results in the quickest response, and repeated administration for 3 to 7 days can break the cycle of frequent attacks.40 Ergotamine tartrate also has provided effective relief of cluster headache attacks when administered sublingually or rectally, but the pharmacokinetics of these preparations frequently limit their clinical utility.41 Dosing guidelines are similar to those for migraine headache therapy.

Prophylactic Therapy

Verapamil

The preferred first-line treatment for prevention of cluster headaches is verapamil, a calcium channel blocker with antianginal and anti-arrhythmic properties.40,42 The beneficial effects of verapamil often appear after 1 week of therapy. A typical suggested dosage range is from 360 to 720 mg/day. Rarely, patients with refractory cluster headaches are treated with doses as high as 1,200 mg/day. In such patients, an electrocardiogram should be obtained as the dose is increased, due to concerns for bradycardia or heart block.40,42

Lithium

Lithium carbonate is effective for episodic and chronic cluster headache attacks and can be used as an alternative to or in combination with verapamil.42 A positive response is seen in up to 78% of patients with chronic cluster headache, and in up to 63% of patients with episodic cluster headache.40 The usual dose is 600 to 1,200 mg/day, with a suggested starting dose of 300 mg twice daily.42 Optimal plasma lithium levels for prevention of cluster headache have not been established, but levels should be monitored and maintained between 0.6 and 1.2 mEq/L (0.6 and 1.2 mmol/L).40

Initial side effects are mild and include tremor, lethargy, nausea, diarrhea, and abdominal discomfort. Thyroid and renal function must be monitored during lithium therapy. Lithium should be administered with caution to patients with significant renal or cardiovascular disease, dehydration, pregnancy, or concomitant diuretic or NSAID use.42

Corticosteroids

Although there are few clinical trials evaluating the use of corticosteroids in cluster headache management, they have been used effectively for inducing remission.40 Therapy is initiated with 40 to 60 mg/day prednisone and tapered over approximately 3 weeks. Relief appears within 1 to 2 days of initiating therapy. To avoid steroid-induced complications, long-term use is not recommended. Headaches can recur when therapy is tapered or discontinued.

Miscellaneous Agents

Other therapies that have been used in the acute management of cluster headache include intranasal lidocaine, hyperbaric oxygen, and subcutaneous octreotide. Limited studies or case reports also support the use of divalproex sodium, topiramate, gabapentin, intranasal civamide, intranasal capsaicin, tizanidine, baclofen, melatonin, transdermal clonidine, leuprolide, and intramuscular botulinum toxin for cluster prophylaxis.41

Neurosurgical interventions to relieve chronic cluster headaches in patients refractory to pharmacologic therapy should be considered for some with debilitating headaches.37,42 Neurostimulation has gained attention in the last several years.43 Deep brain stimulation of the posterior hypothalamus and occipital nerve stimulation studies have shown positive results in small clinical trials.43

EVALUATION OF THERAPEUTIC OUTCOMES

Patients should be monitored for frequency, intensity, and duration of headaches, as well as any change in the headache pattern. To this end, patients should be encouraged to keep a headache diary to document the frequency, severity, and duration of attacks, as well as response to medication and potential trigger factors. Careful monitoring is essential to initiate the most appropriate pharmacotherapy, document therapeutic successes and failures, identify medication contraindications, and prevent or minimize adverse events. Patients using acute therapies should be monitored for frequency of use of prescription and nonprescription medications to identify potential medication-misuse headache. Patient counseling is necessary to allow for proper medication use (e.g., self-injection with sumatriptan), to encourage early use of medications in the headache cycle, and to enhance patient compliance. Strict adherence to dosing guidelines should be stressed to minimize potential toxicity. Patterns of abortive medication use can be documented to establish the need for prophylactic therapy. Prophylactic therapies also should be monitored closely for adverse reactions, abortive therapy needs, adequate dosing, and compliance. Consultation with other healthcare practitioners should be encouraged when changes in headache patterns or medication use occur.

ABBREVIATIONS

Images

REFERENCES

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