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Headaches and Other Head Pain
Definition
Headache, which is a very common symptom, can be secondary to an underlying abnormality but is usually a primary headache disorder such as migraine headache, tension-type headache, cluster headache, and paroxysmal hemicrania.
Epidemiology
About 90% of all adults experience headache at some time in their lives, and over 75% of children have complained of headaches by the age of 15 years. In the United States, the direct and indirect costs associated with migraine are over $27 billion annually. The World Health Organization lists migraine in the top 10 most disabling conditions. Patients at most risk for lost days of employment are those with chronic migraine and daily headache.
In large population-based studies, the relative risk of having migraine, tension-type headaches, or cluster headaches increases up to four times if a first-degree relative has the same kind of headaches. Studies of twins, especially identical twins, also show a similar susceptibility.
Pathobiology
Headache pain is initiated by primary trigeminal afferents that innervate the blood vessels, mucosa, muscles, and tissues. Fibers from these sources coalesce in the trigeminal ganglion, especially the first division. The trigeminal afferents terminate in the primary sensory nucleus of cranial nerve V and its spinal nucleus, which has several small subnuclei, the most important of which is the subnucleus caudalis. This subnucleus receives afferents from meningeal vessels, dura-sensitive neurons, and even the upper cervical cord and then projects them to the lateral and medial thalamus by way of the spinothalamic tract and to diencephalic and brain stem regions that are involved in the regulation of autonomic functions. Thalamic nociceptive information ascends to the sensory cortex, as well as to other areas of the brain.
Although secondary headaches may stimulate the pathway by way of processes such as inflammation and compression, primary headache disorders occur spontaneously by means of chemical mediators such as calcitonin gene–related peptide. The sequence of events commences with peripheral activation caused by neurogenic plasma extravasation activated spontaneously or by cortical spreading depression. The trigeminocervical complex, especially the nucleus caudalis, is then activated, and patients can experience allodynia, a condition in which a non-noxious stimulus is sensed as painful.
Aura is defined as a focal visual, sensory, or motor neurologic disturbance that may occur with or without headache. Aura is thought to occur when cortical spreading depression causes depolarization of membranes. Both neurons and glia can mediate both constriction and dilation of blood vessels. Migraine headache clearly has a genetic component. Familial hemiplegic migraine can be caused by mutations in the CACNA1A gene, which is located on chromosome 19p13.2-p13.1 and encodes for voltage-gated neuronal calcium channels. Mutations in the CACNA1A gene also cause episodic ataxia and epilepsy. Another mutation is in ATP1A2 , also called the familial hemiplegia migraine 2 ( FHM2 ) gene, which is located on chromosome 1q21-q23 and encodes for the sodium-potassium adenosine triphosphatase (Na + , K + -ATPase) transport protein. A third genetic locus is the SCN1A gene on chromosome 2q24.3, which is a voltage-gated sodium channel. In addition, many single-nucleotide polymorphisms have been associated with migraine. Although there are linkages to many genetic loci for more common forms of migraine, migraine and other headaches also probably have multiple epigenetic interactions with environmental factors, and it is clear that the genetic contributions are complex.
Clinical Manifestations
Patients with headache may describe the pain as throbbing, band-like, or aching. The pain is frequently unilateral but can be bilateral. Migraine headache is often associated with nausea, vomiting, photophobia, and phonophobia. It is invariably moderate to severe and interferes with activities. Other autonomic manifestations that can accompany migraine, cluster, and other headache variants include ptosis, conjunctival injection, tearing, rhinorrhea, Horner syndrome, and facial edema. Secondary headaches sometimes may appear to be similar to tension-type or migraine headaches, but “red flags” may suggest a secondary rather than a primary headache disorder ( Table 367-1 ). Particular attention should be paid to the sudden onset of severe thunderclap headaches ( Table 367-2 ), which frequently have an urgent underlying secondary cause.
TABLE 367-1
REASONS FOR FURTHER EVALUATION TO LOOK FOR SECONDARY HEADACHES
| Beginning of headaches at an older age, without a previous history or a positive family history Unexplainable and abnormal worsening of previously existing migraines Dramatic or unusual change in character of the prodrome or the headache previously present Headaches awakening the patient in the middle of the night (except for a cluster headache) Headaches much worse when recumbent, only when upright, or with coughing, sneezing, or the Valsalva maneuver Unusually severe headache of sudden onset (“worst headache of my life”) Focal deficits that do not disappear after the headache is over Any abnormal neurologic or new psychiatric finding on examination A new headache in a patient with human immunodeficiency virus infection, malignancy, or pregnancy |
TABLE 367-2
THUNDERCLAP HEADACHE
| Defined as sudden-onset severe headache reaching maximum intensity immediately or within 1 minute. Causes:
|
Diagnosis
Five elements of the history are key for evaluating headaches. The family history helps determine whether a person has a genetic predisposition to headache. The life history of headache determines whether the headache is new or has evolved over the course of a lifetime. The attack history provides the clinical features of the headache or headaches. The medical and psychiatric history determines whether there are comorbid conditions that can cause or worsen the headache. The medication and drug history determines whether the headache could be caused by or worsened by medications or drugs the person has ingested.
Diagnosis of the type of headache is based on the type of pain, the duration of headache, and accompanying features ( Table 367-3 ). Secondary headaches are usually due to an underlying condition such as a brain tumor ( Chapter 175 ), increased or low intracranial pressure, sinus disease ( Chapter 394 ), or a vascular malformation ( Chapter 377 ); on removing the cause, the headache generally improves. Headaches that occur at a frequency of less than 15 days a month are called episodic, whereas headaches that occur more than 15 days a month are considered chronic.
TABLE 367-3
DIFFERENTIAL DIAGNOSIS OF HEADACHE
| HEADACHE TYPE | GENETICS | EPIDEMIOLOGY | CHARACTERISTIC FEATURES | LENGTH | ACCOMPANYING SYMPTOMS |
|---|---|---|---|---|---|
| Migraine headache | Complex genetics but usually a family history | More frequent in women | Unilateral, bilateral; throbbing; moderate to severe; worsens with activity | Hours to days | Photophobia, phonophobia, nausea and/or vomiting |
| Tension-type headache | Usually a family history | Equal frequency in men and women | Tight band–like pain; bilateral; pain may be mild to moderate; improves with activity | Hours to days | No nausea or vomiting; small amount of light or sound sensitivity, but not both |
| Cluster headache | May have a family history | More frequent in men but also occurs in women | Unilateral severe pain in the face | Minutes to hours | Ipsilateral ptosis, miosis, rhinorrhea, eyelid edema, tearing |
| Paroxysmal hemicrania | Usually no family history | More frequent in women | Unilateral pain in the face | Minutes | Ipsilateral ptosis, miosis, rhinorrhea, eyelid edema, tearing; responds to indomethacin |
| Short unilateral headache with conjunctival injection, tearing | No family history | More frequent in men | Unilateral eye pain; orbit pain | Seconds to 240 seconds | Conjunctival injection, tearing |
| Hemicrania continua | No family history | More frequent in women | Unilateral continuous headache with episodic stabbing pains | Continuous | Ipsilateral autonomic features: ptosis, miosis, rhinorrhea, eyelid edema, tearing; responds to indomethacin |
The diagnostic evaluation for headache depends on the clinical findings. If the history is typical and if the neurologic examination is completely normal, no further evaluation is needed. The features of the history that are most likely to predict migraine headache without a secondary disorder include photophobia, nausea, and disabling nature. However, if there are atypical features of the history or any abnormality on neurologic examination, further evaluation is indicated. Patients with cluster headache types and headaches of undetermined cause need imaging to exclude secondary causes.
In patients with acute-onset headache, computed tomography (CT) is best for assessing possible acute hemorrhage as the cause of the headache. By comparison, magnetic resonance imaging (MRI) is best for assessing most persistent headaches to look for mass lesions, evidence of intracranial hypertension or hypotension, hemosiderin (old hemorrhage), and congenital abnormalities (e.g., Chiari malformation). If reversible cerebral vasoconstriction is a concern, either CT angiography or MR angiography should be obtained. In individuals older than 60 years with an unexplained new or unusual headache, the erythrocyte sedimentation rate (ESR) and/or C-reactive protein (CRP) level should be measured to evaluate for giant cell arteritis ( Chapter 63 ). Cerebrospinal fluid (CSF) analysis, including opening pressure, protein, glucose, cells, culture, and cytology, is indicated in patients with suspected intracranial hypertension or meningitis.
Treatment
Treatment of acute headache depends on the type and severity of the headache. For mild headaches, simple analgesics such as acetaminophen (500 to 1000 mg), acetaminophen with caffeine, aspirin (250 to 1000 mg), and nonsteroidal anti-inflammatory drugs ([NSAIDs]; e.g., ibuprofen, 400 to 800 mg; naproxen sodium, 220 to 500 mg, diclofenac 50 mg) will suffice.
Prevention
Preventive medications are recommended when headaches are frequent or severe enough to interfere with quality of life. The choice of medications should be based on the type of headache (migraine, tension-type), their side effect profiles, and the patient’s comorbid conditions ( Table 367-4 ). In general, treatments aimed at the calcitonin gene–related peptide are reserved for patients who have not responded to two to three other classes of medication.
TABLE 367-4
PREVENTIVE MEDICATIONS FOR HEADACHE
| DRUG | RATIONAL USE | DOSAGE | SIDE EFFECTS | CONTRAINDICATIONS/CAUTION |
|---|---|---|---|---|
| β-Blockers (e.g., propranolol, nadolol, timolol) | Migraine, anyone with elevated blood pressure | Propranolol, 20-80 mg; may increase | Lethargy, depression | Asthma, low blood pressure |
| Calcium-channel antagonists: verapamil, amlodipine | Cluster headache, elevated blood pressure | Verapamil, 120-480 mg/day | Low blood pressure | |
| Nonsteroidal anti-inflammatory drugs: | ||||
| naproxen, ibuprofen | Migraine, tension-type, and menstrual migraine | Naproxen, 200-600 mg/day; ibuprofen, 600-800 mg bid-tid |
Gastrointestinal | Ulcers, sensitivity, allergy |
| indomethacin | Paroxysmal hemicrania, hemicrania continua | Indomethacin, 25-50 mg tid | Gastrointestinal | Ulcers; renal insufficiency |
| Tricyclic antidepressants: amitriptyline, nortriptyline, imipramine | Migraine, tension-type headache, anyone with poor sleep | 10-25 mg qhs; may increase | Dry mouth, orthostatic hypotension, weight gain | Sensitivity to tricyclic anti-depressants |
| Anticonvulsants: topiramate valproate | Migraine, cluster headache | Topiramate, 25-50 mg bid; valproate, 250-500 mg bid | Topiramate: weight loss, kidney stones, intraocular hypertension Valproate: weight gain |
Pregnancy—both U.S. FDA classification D |
| Calcitonin gene–related peptide antibodies: eptinezumab, erenumab, fremanezumab, galcanezumab | Migraine, chronic migraine, cluster (galcanezumab) |
Eptinezumab 100-300 mg IV every 3 months; erenumab 70-140 mg SQ monthly; fremanezumab 225 mg SQ monthly; galcanezumab 240 mg SQ loading dose, then 120 mg SQ monthly | Injection site redness; nasal symptoms; constipation | Unknown pregnancy effect |
| Calcitonin gene–related peptide antagonists: rimegepant, atogepant | Migraine | Rimegepant 75 mg qod oral dissolving; atogepant 10-30 mg orally daily | Abdominal pain; indigestion | Unknown pregnancy effect |
bid = twice daily; FDA = Food and Drug Administration; IV = intravenously; qhs = at bedtime; qod = every other day; SQ = subcutaneously; tid = three times daily.
Prognosis
The natural history of headache depends on many factors, including the type of headache, comorbid conditions that accompany the headache, and success of treatment. Risk factors for chronic headache include female sex, migraine-type headaches, frequent headaches, obesity, low education and socioeconomic level, overuse of medication, depression, anxiety, stressful life events, and sleep apnea.
Migraine Headache
Definition
Migraine is an inherited headache disorder that is typically unilateral but sometimes bilateral, moderate to severe, worsens by routine physical activity, associated with nausea and/or vomiting, and accompanied by photophobia and phonophobia. The headache occurs anytime and persists from 4 to 72 hours. It may occur with an aura (a focal neurologic symptom that may be visual, sensory, motor, or language) or without an aura. Visual auras may have positive (photopsias) and negative (scotomas) features.
Epidemiology
The prevalence of migraine is 15 to 20% in women and 4 to 7% in men, and migraine headaches are estimated to afflict 1 billion people worldwide. In children the prevalence may be as high as 17% and is equal in boys and girls. At puberty, the prevalence rises in girls and remains higher throughout their lifespan. The highest prevalence occurs between the ages of 25 and 55 years, but migraines also affect older adults. Migraine with aura affects 5% of the adult population, and 90% of auras are visual. Migraine is more prevalent in White persons and in those with a lower socioeconomic status or income.
Comorbid conditions and lifestyle factors that may be associated with migraine headache include epilepsy, stroke, depression, anxiety, asthma, myocardial infarction, patent foramen ovale, Raynaud phenomenon, irritable bowel syndrome, and pain disorders such as fibromyalgia. Menstruation and ovulation may increase the frequency of headache.
Pathobiology
The aura of a migraine headache is thought to be due in part to cortical spreading depression, which is associated with a brief reduction in blood flow followed by hyperemia. These changes do not seem to correlate with the phase of the headache. Pain occurs when trigeminal afferents of the dura are stimulated.
Clinical Manifestations
Migraine headache often begins with a prodrome that may persist for hours to days, when patients note difficulty concentrating or fatigue without headache. An aura may or may not occur but is generally present before the headache begins. The headache may be unilateral or bilateral, throbbing, moderate to severe, and worsened with activity. Accompanying clinical features include nausea, vomiting, and sensitivity to light and sound. Other clinical features may include neck pain, dizziness, osmophobia (sensitivity to odors), and difficulty thinking clearly.
The migraine aura is generally visual but can be sensory or include aphasia or vertigo. Migraine aura without headache begins with a neurologic disturbance (e.g., a visual phenomenon) but without a subsequent headache. Although an aura is traditionally thought to precede the headache, it can be present during the headache phase.
Diagnosis
The diagnosis of migraine is based on the history. The differential diagnosis includes tension-type headache, but most moderate to severe headaches are migraine. In patients with a history suggestive of a secondary headache (see Table 367-1 ), further evaluation with an MRI should be considered ( Fig. 367-1 ). However, if the headache is typical of migraine and the findings on neurologic examination are normal, no further studies are needed.
Treatment
Treatment of migraine is divided into treatment of the acute headache and prevention of subsequent migraine attacks (see Fig. 367-1 and https://americanheadachesociety.org/flowchart/ ). Acute treatment is most effectively accomplished with migraine-specific care: a nonspecific analgesic agent or combination analgesic therapy for milder migraine and, most frequently, aggressive migraine-specific therapy for migraine. Stratification of care, including tailoring the treatment according to the type of headache, results in fewer days of disability and use of medications. Which migraine-specific drug will work for any individual patient depends on the patient. It is important to avoid overuse of analgesic and other medications (especially opiates) because overuse can cause chronic daily headache in susceptible individuals. Prompt treatment improves the outcome of headache when compared with late treatment.
Mild attacks can generally be treated successfully with over-the-counter analgesics such as acetaminophen (suggested dose, 650 to 1000 mg) or NSAIDs (aspirin, 250 mg to 1000 mg; ibuprofen, 400 to 600 mg; naproxen, 500 to 825 mg; diclofenac, 50 mg; or ketoprofen, 75 mg).
For moderate to severe migraine headaches, patients benefit from migraine-specific triptans (see Table 367-5 ), ergotamines (dihydroergotamine 1 to 2 mg intranasally or subcutaneously; ergotamine tartrate, 2 mg sublingually or 1 to 2 mg orally), the combination of naproxen and a triptan, or a formulary combination of isometheptene (65 mg), dichlorphenazone (100 mg), and acetaminophen (325 mg). Contraindications to use of triptans include uncontrolled hypertension, clinical evidence of ischemic heart disease, and Prinzmetal angina. Ergotamine given early in the migraine attack can be effective if the associated nausea and peripheral vasoconstriction are tolerable. Lasmitidan (50 to 200 mg) is a serotonin receptor agonist that does not have the vasoconstrictive side effects of triptans and that is safe and effective for patients who have contraindications to triptans ; however, it is sedating, so driving is contraindicated for at least 90 minutes and perhaps up to 8 hours after its administration. Small-molecule, calcitonin gene–related peptide receptor antagonists are also helpful for treating migraine attacks. Both rimegepant (75 mg orally) or ubrogepant (50 to 100 mg) can provide about a 10% absolute increase in pain freedom within 2 hours compared with placebo, , have few side effects, and are useful when triptans are not successful or are contraindicated.Ubrogepant is also effective when taken during a migraine prodrome. Another rapid-acting option is zavegepant (10 mg) nasal spray.
TABLE 367-5
SPECIFIC TRIPTAN MEDICATIONS FOR THE TREATMENT OF ACUTE MIGRAINE WITH GRADE A EVIDENCE FROM TWO OR MORE RANDOMIZED TRIALS
| SUMATRIPTAN | ZOLMITRIPTAN | NARATRIPTAN | RIZATRIPTAN | ALMOTRIPTAN | FROVATRIPTAN | ELETRIPTAN | |
|---|---|---|---|---|---|---|---|
| Trade name | Imitrex, Zecuity | Zomig | Amerge | Maxalt | Axert | Frova | Relpax |
| Forms | SQ, nasal (NS), oral | Oral: tablet/ZMT, NS | Oral | Oral: tablet/MLT | Oral | Oral | Oral |
| Dose | Oral: 50-100 mg (200 mg/24 hr max.) | 2.5-5 mg (10 mg/24 hr max.) | 1-2.5 mg (5 mg/24 hr max.) | 5-10 mg (30 mg/24 hr max.) | 6.25-12.5 mg (25 mg/24 hr max.) | 2.5 mg (7.5 mg/24 hr max.) | 20-40 mg (80 mg/24 hr max.) |
| SQ: 4-6 mg (12 mg/24 hr max.) | |||||||
| NS: 5-20 mg (40 mg/24 hr max.) Nasal delivery device (22 mg) |
5 mg (10 mg/24 hr max.) | ||||||
| Half-life | 2-3 hr | 3-4 hr | 6-8 hr | 2-3 hr | 3-4 hr | 26 hr | 4-6 hr |
| Crosses blood-brain barrier | − | + | + | + | + | + | + |
| Use with monoamine oxidase inhibitor (MAOI) | − | − | + | − | + | + | − |
| Good for recurrence | − | − | + | − | − | + | − |
| Rapid response | SQ, 10-15 min NS, 15-20 min Oral, 30 min |
30 min | 1-4 hr | 30 min | 60 min | 1-4 hr | 20-30 min |
| Other | In combination with naproxen (Treximet) | Decrease dose by half with propranolol | Do not use with CYP3A4 drugs (ketoconazole and some macrolide antibiotics) |
max. = maximum; MLT = rizatriptan melting tablet; NS = nasal spray; SQ = subcutaneous; ZMT = zolmitriptan melting tablet.
For very severe attacks, dihydroergotamine (1 mg subcutaneously or 0.5 to 1 mg intravenously [IV]) is usually effective but generally requires an antiemetic (e.g., promethazine, 25 mg) before intravenous use. Ketorolac (60 mg intramuscularly [IM] or 30 mg IV), prochlorperazine (10 to 25 mg IM or 10 mg IV delivered over a 5-minute period), metoclopramide (10 mg IV), or celecoxcib solution (120 mg orally) is useful for patients who are nonresponsive or have contraindications to vasoactive abortive agents.
Opioids should not be used except as a last resort. Nevertheless, opioids (e.g., acetaminophen [325 mg] with codeine [30 mg]; N-acetyl-p-aminophenol [APAP] with codeine [30 mg]; or butorphanol [1 mg per spray]) may benefit some patients who have contraindications to triptans and ergotamines. Meperidine is not effective. Oral opiates should not be used for chronic recurrent, primary headaches. When opiates are used, caution is required.
Noninvasive Neuromodulation
Noninvasive neuromodulation is an important new approach for treating acute migraine headaches. For example, randomized trials have supported FDA approval for electrical non-invasive vagus nerve stimulation, trigeminal nerve stimulation, occipital nerve stimulation, transcranial magnetic stimulation, and remote electrical neuromodulation via a smartphone-controlled wireless device. These devices should be avoided or used with great caution in patients who have cardiac pacemakers.
Pregnant Patients
During pregnancy, mild to moderate attacks can be treated with acetaminophen. Moderate headaches may respond to the combination of acetaminophen, isometheptene mucate (a mild vasoconstrictor, 65 mg), and dichloralphenazone (a mild sedative, 100 mg). Antinausea agents include prochlorperazine (10 to 25 mg) and metoclopramide (2.5 to 10 mg). The combination of metoclopramide (5 to 10 mg) with diphenhydramine (25 mg) is superior to codeine in pregnancy. In pregnant patients, noninvasive neuromodulation device therapy is an especially attractive alternative.
Prevention
Preventive treatment (see Table 367-3 ) is often recommended when headaches interfere with activities on 3 or more days per month or when the headaches are severe or prolonged. Prophylactic options include β-adrenergic blockers, calcitonin gene–related peptide antibodies and small-molecule inhibitors, calcium-channel antagonists, NSAIDs, tricyclic antidepressants, valproate, and topiramate. Other alternatives include the serotonergic drug cyproheptadine (4 to 20 mg) or the monoamine oxidase inhibitor phenelzine (30 to 60 mg).
Calcitonin gene–related peptide antibody options for prevention , include erenumab (70 to 140 mg subcutaneously monthly), fremanezumab (225 mg subcutaneously monthly or 675 mg quarterly), eptinezumab (100 to 300 mg intravenously at baseline and week 12), and galcanezumab (240 mg loading and 120 mg monthly). Small-molecule inhibitors include rimegepant (75 mg orally every other day) and atogepant (10 mg once daily to 60 mg once daily). ,
Acupuncture and biofeedback have been used successfully. OnabotulinumtoxinA injection is also effective for prophylaxis of chronic migraine. FDA-approved devices for the prevention of migraines include vagus nerve stimulation, transcutaneous direct current stimulation, trigeminal nerve stimulation, and transcranial magnetic stimulation. As with acute therapy, these devices should be avoided or used with great caution in patients with cardiac pacemakers.
Prognosis
The prognosis for patients with migraine is variable. In many patients, headaches decrease in severity with age, but migraine aura without headache becomes more frequent with older age. Modification of inciting factors such as avoiding dietary triggers (tyramine, phenylethylamine, ethanol), ameliorating or preventing insomnia, and averting environmental triggers (light, sound, odor) may improve outcome. Migraines may become chronic, defined as more than 15 days per month, especially when associated with obesity, snoring, depression, frequent headaches, and low socioeconomic status. Since there appears to be shared genetic susceptibility to migraine with aura and ischemic stroke, careful attention to cardiovascular risk factors is important. Closure of an associated patent foramen ovale ( Chapter 55 ) is of modest if any benefit.
Tension-Type Headache
Definition
Tension-type headache is defined as a mild or moderate holocranial headache without nausea or vomiting. Patients may have either photophobia or phonophobia but not both, and the headache does not worsen with activity.
Epidemiology
The 1-year prevalence is 14 to 93 per 100,000 individuals for episodic tension-type headache and 8.1 per 100,000 for chronic tension-type headache. Tension-type headaches are more common in women than in men, regardless of age, race, and educational level. Tension-type headaches are more common in Western countries and less frequent in Asian countries, and they are more common in White persons than in African Americans.
Pathobiology
The pathophysiology of tension-type headache is less well understood than that of the other types of headache. Myofascial tenderness is increased, especially in chronic tension-type headache. Genetic factors are uncertain. Migraine and tension-type headache often coexist. Although tension-type headaches are not due to emotion or muscle contraction, triggers of a tension-type headache are similar to those associated with migraine: stress, fatigue, and lack of sleep. Comorbid conditions in patients with tension-type headache include depression and anxiety in more than 50% of individuals.
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