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Published: August 2010

Headache

Robert S. Kunkel

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Many causes of headache have been described in the medical literature. In 1988, the International Headache Society published a long, detailed classification of headache, which has proved helpful for research purposes because it has led to more reproducible and reliable studies in the field of headache. This classification was updated and revised in 2004. For practical clinical purposes, however, all headaches can be classified as one of the primary headache syndromes or as a headache that is caused by or secondary to an underlying disease process or medical condition. Because primary headaches are the most common, this discussion focuses on the diagnosis and management of those syndromes.

Definition

The primary headache syndromes are migraine, tension-type, and cluster headaches. Migraine and cluster headaches are episodic and recurring conditions. Tension-type headache is usually episodic but like migraine, it can become chronic, occurring daily or almost daily for more than 15 days a month.

None of these primary headaches is associated with demonstrable organic disease or structural neurologic abnormality. Laboratory and imaging test results are generally normal. Should an abnormality be found on testing, by definition, it most likely is not the cause of the headache. Similarly, the physical and neurologic examinations are also usually normal, but any abnormalities found are not related to the primary headache. During the headache attack however, cluster and migraine patients might have some abnormal clinical findings, and many patients with tension-type headache have demonstrable tightness in the cervical muscles, with limitation of neck motion, scalp tenderness, or both.

Secondary headaches are usually of recent onset and associated with abnormalities found on clinical examination. Laboratory testing or imaging studies confirm the diagnosis. Recognizing headaches related to an underlying condition or disease is critical not only because treatment of the underlying problem usually eliminates the headache but also because the condition causing the headache may be life-threatening.

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Prevalence

Primary headaches account for more than 90% of all headache complaints, and of these, episodic tension-type headache is the most common. Almost everyone has had a headache of this type. Although chronic tension-type headache occurs in only slightly more than 2% of the population, it accounts for a large number of visits to the physician's office and missed work days.

Several epidemiologic studies conducted in various areas of the world indicate that the prevalence of migraine headache ranges from 12% to 18% of the population. Migraine is three times more common in female patients.

The prevalence of cluster headache is less certain. This uncommon condition probably affects less than 0.5% of the population but is underdiagnosed and is often believed to be a sinus problem by both patients and physicians. Cluster headache affects men five to eight times more frequently than women.

Because the three primary headache syndromes tend to begin in persons younger than 50 years, anyone older than 50 years with a recent onset of headache should have a thorough examination and testing to look for an underlying cause.

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Pathophysiology

The pathophysiology of migraine, cluster, and tension-type headaches is not well understood. Migraine and cluster headaches are believed to initially begin in the brain as a neurologic dysfunction, with subsequent involvement of the trigeminal nerve and cranial vessels. In cluster headache, most, but not all, sufferers have overactivity of the parasympathetic nervous system. Tension-type headache can be primarily a central neurologic disturbance similar to migraine or can occur as the result of increased cervical and pericranial muscle activity, such as caused by flexion-extension injury of the neck, poor posture, or anxiety with increased clenching or grinding of the teeth.

Migraine is an inherited condition in which there appears to be an episodic instability of the neurovascular system (where serotonin and other neurotransmitters play roles). Available serotonin might be diminished or neuronal receptors for serotonin and other neuroactive substances might at times become less sensitive to these agents. Periodically, the nuclei of the trigeminal nerve appear to become hyperactive and excitable. Efferent impulses over branches of this nerve go to the innervated cranial vessels, causing the release of substances that promote perivascular inflammation and vascular dilation. Dysfunction of other areas of the brainstem and hypothalamus account for the other associated symptoms of migraine, such as nausea, photophobia, phonophobia, and osmophobia.

As the migraine attack progresses, the inflamed perivascular structures irritate nerve endings of the trigeminal nerve and cause afferent stimuli back into the trigeminal neurons of the brain, causing them to become sensitized, and they then continue to fire off. This process is called central sensitization. As this cyclic process continues, the scalp becomes sore and tender to ordinary nonpainful touching. This result is called cutaneous allodynia.

A few retrospective studies have suggested that closure of a patent foramen ovale is associated with a marked reduction of the frequency of migraine with aura. The foramen ovale does not close at birth in about 20% to 25% of persons. How this septal defect is associated with causing or triggering migraine with aura is unknown. Double-blind studies of catheter closure (or a sham procedure) of patent foramen ovales in migraineurs have been inconclusive.

Cluster headache also is an episodic neuronal dysfunction but more likely involves areas in the hypothalamus rather than the brainstem. There is also a marked increase in blood flow through the internal carotid artery on the headache side during the attack of pain.

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Signs and symptoms

Migraine

Most migraine patients do not have an aura; migraine with aura occurs in only 15% to 20% of sufferers. The aura is a well-defined visual or neurologic deficit lasting less than 1 hour and is followed by the headache within 1 hour. Most auras are visual, with photopsia (flashing lights) being most common. The aura is initially small, then enlarges or moves across the visual field. A typical migraine aura can occur without a headache. This phenomenon tends to occur later in life. Occasionally, a neurologic aura occurs, with a tingling or weakness that slowly spreads up or down an extremity.

Many patients with migraine have prodromal symptoms for many hours or even a day or so before the onset of an attack. These prodromal symptoms are generally changes in mood or personality. Fatigue also is common, and occasionally hyperactivity occurs.

The migraine attack lasts 6 to 72 hours. The pounding, throbbing pain of moderate to severe intensity is generally unilateral, but some patients experience bilateral pain. Pain caused by migraine worsens with physical activity. Photophobia and phonophobia are very common, and sensitivity to odors is a little less common. Migraine is a sick headache. Nausea occurs in most patients, and vomiting is very common. Dehydration can occur, which increases the pain and disability. Migraineurs want to be quiet, inactive, and in a darkened area during the attack. Approximately 60% of women experience their worst migraine attacks in conjunction with their menstrual period.

Tension-Type Headache

Tension-type headache is characterized by generalized pressure or a sensation of tightness in the head. The discomfort level is usually mild to moderate and does not worsen with activity. Although nausea and photophobia or phonophobia can occur, they generally are not prominent features. Tension-type headache is classified as episodic (<15 days a month) or chronic (>15 days a month).

Some patients with tension-type headache exhibit evidence of increased muscle tension, with prominent scalp tenderness, muscle tenderness in the temporomandibular joint muscles, or tight, tender cervical and trapezius muscles. Poor posture is often evident, which can play a role in causing tension-type headache. If there is no evidence of increased pericranial or cervical muscle tightness (no tenderness or limitation of motion in the neck) found during clinical examination, the pain likely originates centrally or is due to psychological factors.

Cluster Headache

Cluster headache causes intense pain that is generally steady and boring behind one eye. The pain can spread to the temple, face, and even into the upper neck. It is so intense that most sufferers pace the floor or do vigorous exercises during the attack. The attacks are short (usually less than 3 hours in duration) and often last only 30 to 45 minutes. They occur from one to several times a day for a period of several weeks or months, then remit, leaving the patient pain free for several months or years, only to recur.

During a cluster headache cycle, the attacks of pain often occur at the same time each day, most often waking the patient in the early morning hours. Eighty percent of cluster sufferers experience unilateral tearing, with conjunctival injection and ipsilateral nasal congestion. These symptoms clear as the attack leaves. Alcohol brings on an attack within a few minutes in a patient who is in a cluster headache cycle, but it does not induce an attack when the patient is in remission.

Chronic Daily Headache

Daily headache can occur as a chronic tension-type headache, but it is often a combination of tension-type and migraine (the type seen most often in headache clinics). This type of combination headache is not listed in the official classification, so one should diagnose both chronic tension-type headache and migraine in these patients. Most often, this type of combination or mixed headache develops in a person who initially had typical episodic migraine but in whom, over several years, a chronic daily or almost-daily headache develops. Many times, this daily headache seems to occur because of the frequent use of analgesics, especially opiate compounds and those combined with caffeine or butalbital. A daily or near-daily migraine headache can occur from the frequent use of ergotamine tartrate or any of the triptan drugs. This headache pattern has been called rebound headache or medication overuse headache.

Secondary Headache

Secondary headache may be caused by many different diseases. However, neurologic symptoms and signs are almost always present before there is significant headache in patients who have a mass lesion in the brain.

Temporal arteritis generally occurs in persons older than 50 years and may be associated with any type of headache. The pain of temporal arteritis is typically not throbbing and, although it is usually situated in the temples, can be nonlocalized. Fatigue and a low-grade fever are often present. The erythrocyte sedimentation rate is high, usually greater than 60 mm/hour. Diagnosis is confirmed by a temporal artery biopsy, which shows giant cell inflammation. Treatment should begin with 60 to 80 mg of prednisone per day as soon as the diagnosis is suspected, even before the confirmation by biopsy. One study suggested that methotrexate may be effective in allowing treatment with a lower dose of steroids, whereas another study did not show any benefit of adding this drug. If not treated, 20% to 30% of patients with this disease develop permanent partial or complete visual loss in the affected eye. Therefore, prompt treatment is essential.

Aneurysms do not cause chronic recurring headache unless they compress a cranial nerve. They manifest with a severe pain at the time of rupture. Occasionally, an arteriovenous malformation mimics migraine, particularly if it is located in the occipital lobe, but these lesions are more apt to cause seizures or to bleed. Headaches with a postural component need to be evaluated to exclude a lesion in the posterior fossa or a condition with low CSF pressure.

Pericranial inflammation such as a sinus infection, an ear infection, or dental disease should be evident on examination and is usually of a more recent, acute onset. Sleep apnea may be a factor in waking headaches. Systemic conditions such as endocrine disorders, anemia, sepsis, and hypertension can be associated with a non localized headache, but more often such conditions exacerbate an underlying migraine or tension-type headache.

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Diagnosis

The diagnosis of one of the primary headache syndromes is based on the history of the condition and the symptoms described by the patient. After talking with the patient, the clinician should have a fairly good idea of what type of headache the person is experiencing and whether it is one of the primary types or due to some underlying neurologic or medical condition.

Any abnormal physical or neurologic examination findings must be investigated. Laboratory studies may be useful in excluding metabolic or endocrine factors that might play a role. A high erythrocyte sedimentation rate in a patient older than 50 years with new headache onset suggests temporal arteritis. This diagnosis must be confirmed by temporal artery biopsy. Scans can be performed to exclude intracranial causes of headache or to rule out lesions that cause neurologic or visual abnormalities associated with headache. Computed tomography scanning of the paranasal sinuses is useful in evaluating the role of acute or chronic sinus infection as a cause of the headache. Magnetic resonance imaging is currently the best scan for viewing the posterior fossa and occipital areas of the brain.

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Summary

  • The diagnosis of the headache type is most often made by the history of symptoms.
  • Headaches caused by disease are usually of recent onset and usually manifest with abnormalities on examination and abnormal tests.
  • Look for an underlying condition in a headache that occurs for the first time in a patient older than 40 years.
  • Consider temporal arteritis in any new headache beginning after age 50 years.

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Treatment

Most patients with a primary headache require medication; however, other management methods also may be useful. Secondary headaches usually resolve when the underlying neurologic or systemic problem is treated.

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Migraine

Treatment

Some migraine headaches can be relieved with the use of cold packs, pressure on the temple, and sleep. However, most patients require abortive medication, and many are candidates for daily preventive medication.

Educating the migraine patient to recognize and avoid headache triggers helps to reduce the frequency of attacks. Common migraine triggers include weather changes, the estrogen cycle, bright lights, strong odors, stress, “let down” after stress, foods, food additives, and fasting or skipping meals. Migraineurs do better and have fewer headaches by following regular eating and sleeping patterns.

Preventive Medications

Daily prophylactic medication should be considered whenever migraine attacks occur several times a month or are very severe and do not respond well to abortive medication. Essentially six classifications of drugs are useful for migraine prophylaxis: beta blockers, calcium channel blockers, nonsteroidal anti-inflammatory drugs (NSAIDs), antidepressants, antiepileptic drugs, and the serotonin agonist methysergide maleate (Table 1). The beta blockers propranolol and timolol maleate, the anticonvulsants divalproex sodium and topiramate, and methysergide currently are the only drugs approved by the U.S. Food and Drug Administration for migraine prevention. (Methysergide is no longer available in the United States). A few other anticonvulsants such as gabapentin, tiagabine, and pregabalin are useful for neuralgic type of pain and are being evaluated for their effectiveness in preventing migraine but they seem to be less effective in migraine. They have been extensively used off label clinically for migraine prevention. Botulinum toxin type A injected into the scalp muscles has also been found to decrease the frequency and severity of migraine in about 50% of patients so treated. It has not been shown to be very effective in tension-type headaches.

Table 1: Prophylactic Migraine Drugs
Drug Usual Daily Dose
Beta Blockers
Atenolol 50-100 mg
Metoprolol succcinate or tartrate 50-150 mg
Nadolol 20-160 mg
Propranolol 80-240 mg
Timolol maleate 10-20 mg
Calcium Channel Blockers
Amlodipine besylate 10-20 mg
Diltiazem 80-240 mg
Nimodipine 60-120 mg
Verapamil 180-480 mg
Antiepileptic Drugs
Divalproex sodium 250-1500 mg
Gabapentin 300-1800 mg
Pregabalin 50-200 mg
Topiramate 25-150 mg
Zonisamide 100-200 mg
Antidepressants
Amitriptyline 25-150 mg
Citalopram 20-60 mg
Desipramine 25-100 mg
Doxepin 25-150 mg
Duloxetine 30-90 mg
Fluoxetine 20-60 mg
Nortriptyline 25-100 mg
Phenelzine 15-45 mg
Protriptyline 5-10 mg
Sertraline 50-150 mg
Venlafaxine 37.5-150 mg
Nonsteroidal Anti-inflammatory Drugs
Celecoxib 200-400 mg
Flurbiprofen 100-200 mg
Indomethacin 75-150 mg
Naproxen sodium 500-1000 mg
Serotonin Agonist
Methysergide maleate 2-8 mg
Antiserotonin/Antihistamine
Cyproheptadine 4-12 mg
Abortive Medications

All migraine patients with migraine need to take an abortive drug, whether or not they are taking a prophylactic agent (Table 2). For mild attacks, over-the-counter analgesics (especially those containing caffeine) may be useful. A large dose of a rapid-acting NSAID such as meclofenamate, ibuprofen, diclofenac, or naproxen sodium can also prove helpful in mild attacks.

Table 2: Migraine Abortive Agents
Drug Usual Dosage
Combination Drug
Isometheptene/dichloralphenazone/acetaminophen Two capsules at onset, then one or two in 1 hr
Anti-inflammatory Drugs
Ibuprofen 600-800 mg q 4 hr prn
Ketorolac tromethamine oral 10 mg, repeat once in 2 hr prn
Ketorolac tromathamine IV/IM 30 mg, repeat once in 1 to 2 hr prn
Meclofenamate sodium 200 mg, repeat once in 2 hr prn
Naproxen sodium 550 mg, repeat once in 2 hr prn
Triptan Drugs
Almotriptan 12.5 mg, repeat once in 2 hr prn
Eletriptan 40 mg, repeat once in 2 hr prn
Frovatriptan 2.5 mg, repeat once in 2 hr prn
Naratriptan 2.5 mg, repeat once in 3- 4 hr prn
Rizatriptan 10 mg, repeat once in 2 hrs prn
Sumatriptan, oral 50-100 mg, repeat once in 2 hr prn
Sumatriptan, nasal 20 mg (1 puff), repeat once in 2 hr
Sumatriptan, subcutaneous 6 mg, repeat once in 2 hr prn
Zolmitriptan, oral 2.5 mg or 5 mg, repeat once in 2 hr prn
Zolmitriptan, nasal 2.5 mg or 5 mg (1 puff), repeat in 2 hr prn
Triptan/NSAID
Sumatriptan/naproxen 85 mg/500mg at onset and repeat in 2 hs prn
Ergotamine Drugs
Dihydroergotamine mesylate, nasal 1 puff in each nostril, repeat in 15 min. This is the dose for 1 day
Dihydroergotamine mesylate, IV, IM, and SC 0.5-1 mg, repeat in 1 hr. Maximium dose is 3 mg in 24 hr
Ergotamine tartrate/caffeine, oral 2 tabs at onset, repeat once every 0.5 hr up to a maximum of 5 tabs
Ergotamine tartrate/caffeine, suppository 1/2 to 1 at onset, repeat once in 1 hr
Ergotamine tartrate, sublingual 1 at onset, repeat once in 0.5 hr prn

A revolutionary breakthrough in acute migraine treatment occurred with the development of sumatriptan succinate in the late 1980s. The triptan drugs are agonists that affect the 1B and 1D serotonin receptors located in neurons and cerebral vessels. Seven triptan agents are currently available in the United States: sumatriptan succinate (oral, nasal, and injectable), rizatriptan benzoate (oral), zolmitriptan (oral and nasal), naratriptan (oral), almotriptan (oral), frovatriptan (oral), and eletriptan (oral). All are very well tolerated by patients; however, like ergotamine, the triptans should not be used in patients with coronary artery disease, peripheral vascular disease, or uncontrolled hypertension. Triptan drugs are effective in 65% to 70% of patients, completely or significantly relieving migraine pain and associated symptoms within 2 hours of administration. The earlier they are taken in the attack, the more effective they seem to be. Side effects are generally mild, the most common being dizziness, sedation, or mild upper chest tightness that is noncardiac in origin. Unfortunately, headache recurs within 24 hours in up to 30% of users, necessitating an additional dose.

The triptans and other abortive agents are more effective when used early in the migraine attack before central sensitization and the subsequent cutaneous allodynia become established. Combined use of an NSAID with a triptan can offer better headache relief and may be associated with less-frequent recurrence of the migraine. A combination of sumatriptan and naproxen is now available.

Other effective agents available by prescription include a combination of isometheptene mucate, dichloralphenazone, and acetaminophen; ergotamine tartrate (sublingual) or ergotamine tartrate combined with caffeine (oral, suppository) and dihydroergotamine mesylate used parentally or as a nasal spray.

Several parenteral non-narcotic medications have been shown to be very useful in aborting severe migraine attacks. Intravenous dihydroergotamine, prochlorperazine, divalproex, magnesium, ketorolac tromethamine, and steroids can be very effective in stopping a migraine attack without resorting to narcotics.

At times, a rescue medication such as an opiate or a butalbital combination drug may be needed, but with the large number of nonhabituating preparations available, the need to use such drugs is much less now than in the past.

Oral abortive agents, especially the ergotamines, often aggravate nausea and vomiting, which can limit their use. However, taking metoclopramide before taking an abortive agent can control the nausea and enhance the effectiveness of the abortive drug. Other antinausea agents also may be helpful, including prochlorperazine, hydroxyzine pamoate, promethazine, or trimethobenzamide.

Tension-Type Headache

The occasional tension-type headache can be alleviated by a hot shower, massage, sleep, and patient recognition and avoidance of stress factors. Episodic tension-type headache is usually well treated with analgesics such as aspirin, acetaminophen, and NSAIDs or combinations of these agents with caffeine or sedating medications. Some patients, particularly those with tension-type headache caused by stress, benefit from learning relaxation techniques or biofeedback training. An active physical therapy program can decrease chronic neck pain caused by increased cervical muscle spasm or postural abnormalities. When tension-type headache becomes chronic, treatment can be challenging, especially if the patient overuses analgesics and opiates. Treatment will not be effective until the patient stops the frequent use of these acute pain-relieving agents. Patients suffering from chronic tension-type headache often need counselling and psychotherapy to help define and work through long-standing psychological issues.

The most effective group of drugs for the treatment of chronic tension-type headaches is the tricyclic antidepressants. Amitriptyline, doxepin, and nortriptyline are most commonly used. They are usually taken at bedtime because of their sedating effects. Morning sedation, weight gain, dry mouth, and constipation are common side effects. Less-sedating drugs in this group include desipramine and protriptyline. Selective serotonin reuptake inhibitors, such as fluoxetine, sertraline, paroxetine, and citalopram, are better tolerated and have fewer side effects than the tricyclics, but they do not appear to be as effective in easing headache unless the headache is a manifestation of underlying depression. Venlafaxine and duloxetine are both serotonin and norepinephrine uptake inhibitors and may be helpful in chronic pain conditions, including headache. Muscle relaxants such as cyclobenzaprine, orphenadrine citrate, and baclofen may be helpful at times, particularly if increased muscle spasm is present. The central-acting muscle relaxant tizanidine is often quite effective in treating chronic headache, either tension-type or coexisting migraine and tension-type, but it is very sedating.

Cluster Headache

Because the onset of cluster headache attacks is rapid and they can occur several times a day, the best approach to treatment is with daily preventive drugs. Effective prophylactic medications include verapamil, prednisone, lithium carbonate, methysergide, and the antiepileptic drugs divalproex and topiramate. High doses of verapamil (480-720 mg/day) may be necessary. A pretreatment EKG is recommended prior to starting a large dose of verapamil. Prednisone and methysergide work quickly and often are used with verapamil or lithium initially for a quick response and then tapered while the verapamil or lithium is continued. Prednisone is usually prescribed at 60 mg/day initially and then tapered over 2 to 3 weeks. There are a few reports that topiramate, divalproex, and baclofen are helpful in cluster headache, but no controlled studies have been published, and clinically these drugs do not appear to be effective very often.

Oxygen 100% by mask at a flow rate of 8 to 10 L/min for up to 10 minutes aborts an acute cluster headache in 50% to 60% of patients. Ergotamine tartrate, dihydroergotamine, and any of the triptans usually are very effective, but they are inappropriate in patients who suffer several attacks a day. Fortunately, cluster headache patients do not appear to develop rebound headaches from frequent use of ergotamine tartrate or the triptans, as do migraine sufferers.

Methysergide is the only drug approved in the United States for treating cluster headache, but it is no longer on the market. It is not used very often because of the possible development of retroperitoneal fibrosis or other fibrotic complications. Methysergide should not be used for longer than 4 to 6 months without giving the patient a 4- to 6-week drug holiday. Once the patient is free of cluster attacks for a few weeks, the prophylactic drugs should be tapered and discontinued. They can be restarted at the onset of the next cluster.

Summary

  • Help migraine sufferers identify and avoid possible triggers.
  • Prophylactic medications are underused in migraine. They can greatly reduce the frequency and severity of migraine attacks.
  • Migraine abortive drugs work best when taken early in the attack.
  • Cluster patients should take preventive medications early in the cluster.

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Outcomes

Although few long-term follow-up studies have been conducted, some studies indicate that inpatient treatment of chronic headache sufferers is associated with approximately a 50% improvement rate. Comprehensive outpatient treatment programs are now being used by many headache clinics; however, definitive outcome data are not yet available. Patients in these programs usually are suffering from chronic daily headaches and medication overuse. Most programs include detoxification from analgesics and narcotics and the initiation of preventive medicines as well as psychotherapy, physical therapy, and teaching relaxation and biofeedback techniques, along with educating patients to recognize triggers and be aware of possible factors involved in causing their headaches.

Studies have demonstrated that patients with acute migraine attacks treated with a triptan experience a reduction in visits to the doctor's office and emergency department as well as fewer days lost at work. Treatment of migraine with the newer, more-pecific drugs such as the triptans has greatly reduced the disability associated with this condition.

Comprising representatives of seven organizations, the U.S. Headache Consortium has published evidence-based guidelines for treating migraine headaches based on a review of the literature. These guidelines are an attempt to evaluate the validity of studies done with various abortive and preventive drugs and to rate the effectiveness of these drugs based on those studies in the literature. Non pharmacologic treatments of migraine are also evaluated and rated.

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Suggested Readings

  • American Academy of Neurology. Guideline summary for clinicians: Migraine headache. PDF available at http://www.aan.com/professionals/practice/guidelines/migraine/clinician_summary_migraine.pdf (accessed March 20, 2009)
  • Diamond S, Freitag FG, Maliszewski M. Inpatient treatment of headache: Long-term results. Headache. 1986, 26: 189-197.
  • Gillies JD, Lance JW. Pathophysiology of migraine. In: Tollison CD, Kunkel RS (eds): Headache: Diagnosis and Treatment. Baltimore: Williams & Wilkins, 1993, pp 77-84.
  • Hagen K, Zwart JA, Vatten L, et al: Prevalence of migraine and non-migrainous headache-head-HUNT, a large population-based study. Cephalalgia. 2000, 20: 900-906.
  • Headache Classification Subcommittee of the International Headache Society. The international classification of headache disorders. 2nd ed. Cephalalgia. 2004, 24: (Suppl 1): 1-160. PDF available at http://216.25.100.131/ihscommon/guidelines/pdfs/ihc_II_main_no_print.pdf (accessed December 12, 2007).
  • Jover JA, Hernandez-Garcia C, Morado IC, et al: Combined treatment of giant-cell arteritis with methotrexate and prednisone: A randomized, double-blind, placebo-controlled trial. Ann Intern Med. 2001, 134: 106-114.
  • Lofland JH, Johnson NE, Batenhorst AS, Nash DB. Changes in resource use and outcomes for patients with migraine treated with sumatriptan: A managed care perspective. Arch Intern Med. 1999, 159: 857-863.
  • Reisman M, Christofferson RD, Jesurum J, et al: Migraine headache relief after transcatheter closure of patent foramen ovale. J Am Coll Cardiol. 2005, 45: 493-495.
  • Schwartz BS, Stewart WF, Simon D, Lipton RB. Epidemiology of tension-type headache. JAMA. 1998, 279: 381-383.
  • Silberstein SD. Migraine pathophysiology and its clinical implications. Cephalalgia. 2004, 24: (Suppl 2): 2-7.
  • Silberstein SD. Practice parameter: Evidence-based guidelines for migraine headache (an evidence-based review): Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2000, 55: 754-762.
  • Silberstein S, Mathew N, Saper J, Jenkins S. Botulinum toxin type A as a migraine preventive treatment. Headache. 2000, 40: 445-450.
  • Stewart WF, Lipton RB, Celentano DD, Reed ML. Prevalence of migraine headache in the United States. Relation to age, income, race, and other sociodemographic factors. JAMA. 1992, 267: 64-69.

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