1. The most common cause of episodic severe headache
a. Forty-three percent of women and 18% of men experience migraine during their lifetime.
b. Half of all cases begin before age 25; 75% begin before age 35.
c. Migraine is among the top 20 causes of disability worldwide; the disability is disproportionately concentrated in women of reproductive age.
2. When preceded by transient focal neurologic symptoms, the syndrome is termed “migraine with aura”; otherwise, it is known as “migraine without aura.” When occurring 15 or more days per month for at least 3 months, it is termed chronic migraine.
1. Positron emission tomography shows activation of the dorsal midbrain, including the periaqueductal gray matter and dorsal pons, during migraine.
2. The primary sensory nerve terminals that innervate dural vessels release substances that cause inflammation and dilation of meningeal arteries and sensitization of peripheral trigeminal neurons. Distension and pulsation of meningeal vessels is perceived as painful and throbbing by these sensitized neurons. Evidence suggests that the migrainous brain does not habituate to sensory signals in a normal way.
3. Pain-triggered activation of the sympathetic nervous system and ascending reticular arousal system probably cause associated autonomic symptoms.
1. Migraine is a condition of long duration. Frequency and severity commonly wax and wane, but over time, the disorder will follow one of three patterns:
a. Migraine may remit. Remission increases with age and in women is often attributed to menopause. Over a 1-year period, 10% of subjects in one study experienced complete remission, while 3% had partial remission.
b. Attacks of headache may become more frequent over time but lose characteristic migraine features such as vomiting and may no longer meet criteria for migraine.
c. In a small percentage of patients, migraine progresses and becomes chronic. Longitudinal studies suggest that roughly 3% of patients with baseline episodic headache progress to chronic headache over the course of a year. Risk factors for progression include medication overuse and obesity.
1. In episodic migraine, there are discrete episodes of headache lasting 4 to 72 hours if untreated, on average occurring once or twice a month.
2. Two of the following four features are present: the headache is unilateral, pulsating, has moderate or severe intensity, and is aggravated by or causes avoidance of routine physical activity.
3. At least one of the following must be present during headache: nausea and/or vomiting, photophobia, or phonophobia.
4. Headache is not attributed to another disorder.
5. In chronic migraine, headaches that meet these criteria occur 15 or more days per month for 3 or more months; milder headaches that do not fully meet criteria for migraine may be present as well.
6. When provoked by emotional stress, the headache typically comes afterward: so-called “letdown” headache. In women, migraine may be provoked by estrogen withdrawal and be more likely to occur in the pill-free week of combination oral contraceptive regimens or in the late luteal phase of the natural menstrual cycle.
7. Other common triggers of migraine headache in susceptible individuals are
a. Substances or their withdrawal
3) Phosphodiesterase inhibitors used to treat erectile dysfunction, such as sildenafil
4) Caffeine withdrawal
b. Chronobiologic challenges
1. Sufferers rarely go without acute treatment of some kind for individual attacks. Use of acute treatment should generally be limited to no more than 2 to 3 d/wk in order to avoid medication-overuse headache.
2. The goal of abortive therapy is to provide rapid, well-tolerated, complete relief of headache and associated symptoms with minimal impairment of functional ability.
3. The choice of abortive treatment depends upon headache characteristics and patient preference.
a. Oral therapies are convenient and preferred by most patients. They are appropriate for headaches that develop gradually and when nausea and vomiting are not prominent.
b. Nonoral therapies are more effective and reliable when headaches evolve rapidly or are accompanied by early nausea or vomiting. Gastric stasis may impair the efficacy of oral therapies, even in patients who do not experience nausea, so suboptimal results from an oral therapy should prompt a trial of nonoral treatment.
c. All forms of treatment are most effective when used early, while the headache is still mild.
4. The triptans (serotonin agonists with activity at 1B and 1D receptors) are first-line medications for the abortive therapy of migraine headache; seven available triptans are listed below, but not all are available in every country.
5. All triptans are available in oral formulations; rizatriptan and zolmitriptan are also available as orally disintegrating tablets that dissolve in the mouth but are absorbed intestinally. Sumatriptan and zolmitriptan are available as nasal sprays as well, and sumatriptan for subcutaneous (s.c.) injection is available in two fixed doses in an autoinjector. A sumatriptan-naproxen sodium combination tablet is also available. Sumatriptan is available without a physician prescription in some countries, a though interaction with a pharmacist is usually required.
6. The oral and orally disintegrating tablets are best administered at mild or mild to moderate headache intensity to secure their absorption. They should be administered in their optimum doses and may be repeated every 2 hours (for naratriptan every 4 hours), until headache is relieved or the maximum daily dose is reached.
7. Table 11-1 lists the tablet sizes and optimum, maximum single, and maximum daily doses of the oral triptans.
8. Almotriptan, eletriptan, rizatriptan, sumatriptan, and zolmitriptan, in their optimum doses, have similar 2-hour efficacy rates. They also have similar recurrence rates of approximately one-third.
9. Frovatriptan and naratriptan have 2-hour efficacy rates approximately half those of the other triptans. However, their duration of action is prolonged due to their longer plasma-elimination half-lives.
10. Triptans are generally well tolerated. The most common side effects of oral triptans are dizziness, paresthesias, and flushing. Neck or chest tightness can occur. These “triptan sensations” are usually mild and transient. If a particular triptan is not effective or tolerated, another should be tried.
TABLE 11-1 Oral Triptans
Tablet sizes (mg)
Optimum doses (mg)
Maximum single doses (mg)
Maximum daily doses (mg) or tablet
6.25 and 12.5
20 and 40
1 and 2.5
5 and 10
25, 50, and 100
Fixed-dose tablet with 80 mg sumatriptan and 500 mg naproxen sodium
2.5 and 5
a In patients on propranolol 5 and 15 mg, respectively.
11. Triptans are selective for the cranial circulation, but a small degree of coronary artery constriction can occur. Thus they are contraindicated in patients with known coronary artery disease or those at high risk for coronary artery disease. Uncontrolled hypertension is a contraindication to use. Rizatriptan, sumatriptan, and zolmitriptan are also contraindicated with the concomitant use of a monoamine oxidase inhibitor. The concomitant use of propranolol requires a 50% reduction in rizatriptan dose because of interference with the breakdown of the triptan. Eletriptan should not be used within 72 hours of taking medications that are inhibitors of CYP3A4 activity (mycin antibiotics, antifungal and antiviral medications).
12. The U.S. Food and Drug Administration has issued a safety alert about the risk of serotonin syndrome when triptans are used with selective serotonin or serotonin/norepinephrine reuptake inhibitors. It recommends weighing the potential risk of the syndrome with the expected benefit of using the combination, discussing this with patients, and following them closely during such treatment.
13. When oral medications do not reliably relieve headache within a reasonable time, nonoral routes of administration should be considered.
14. Parenteral, nasal, or rectal routes can be used to administer migraine medications.
a. The following nasal sprays are used to treat migraine:
1) Sumatriptan (5 and 20 mg)
2) Zolmitriptan (5 mg)
3) Dihydroergotamine (2 mg)
b. The following rectal suppositories are sometimes used:
1) Indomethacin (50 mg)
2) Ergotamine with caffeine
15. Dihydroergotamine and ergotamine are nonselective serotonin agonists with activity at a variety of other receptors including adrenergic and dopaminergic receptors. This accounts for their tendency to produce or aggravate nausea and
the possibility of more pronounced or prolonged vasoconstrictive effects. Thus, they are also contraindicated in patients with coronary artery disease or risk factors for coronary artery disease.
16. The sumatriptan and zolmitriptan nasal sprays can, if necessary, be repeated after 2 hours, with a maximum of 40 and 10 mg in 24 hours, respectively. The sumatriptan nasal spray is used in the dose of 20 mg and the zolmitriptan nasal spray in that of 5 mg. The dihydroergotamine nasal spray is given only once in 24 hours, in a dose of four times 0.5 mg. Side effects of the nasal sprays are nasal congestion, nasal irritation, and a bad taste in the mouth.
17. The indomethacin suppository is given in a dose of 50 or 100 mg, if necessary, repeated after one-half to 1 hour, with a maximum of 200 mg in 24 hours. Its most common side effect is orthostatic lightheadedness, due to a systemic vasodilator effect. The medication is contraindicated in peptic ulcer disease and bleeding disorders.
18. The ergotamine-caffeine suppository contains 2 mg ergotamine in combination with 100 mg caffeine to improve its absorption. Nausea and vomiting are its most common side effects and, therefore, it is important to administer the medication with care. Patients are advised to take only one-fourth or one-third of a suppository at a time and repeat it, if necessary, every 30 minutes to 1 hour, with a maximum of two suppositories a day.
19. Injection is another route through which a medication can be administered for the abortive therapy of migraine headache. The two medications that are available for parenteral administration are
a. Dihydroergotamine (1 mg/mL)
b. Sumatriptan (6 or 4 mg)
20. The usual dose of dihydroergotamine is 1 mg given s.c., intravenously (IV), or in-tramuscularly (IM). If given IV, the drug should be mixed with 5% dextrose in water (D5W) and not saline. Patients should be pretreated with an antiemetic drug to prevent worsening or precipitation of nausea or vomiting. Metoclopramide 10 mg, given IM or IV, is commonly used as pretreatment.
21. Sumatriptan is available for patient self-administration with an autoinjector. The injection is given s.c. in a dose of 6 or 4 mg, which can be repeated, if necessary, after 1 hour. Parenteral use of sumatriptan during aura does not prolong or worsen aura symptoms but has no effect on the subsequent headache. Thus patients with aura may wish to delay its use until just before or after the headache begins. The most common side effects of the sumatriptan injection are a hot, tight, or tingling sensation, generally in the upper chest, anterior neck, and face, and lightheadedness.
22. When abortive therapy is contraindicated, poorly tolerated, or ineffective, or when headaches occur more frequently than once a week, preventive therapy should be considered.
23. Preventive therapy does not have to mean drugs. There is some evidence of benefit from nonpharmacologic treatments such as biofeedback-assisted relaxation or lifestyle alterations.
24. The quality and quantity of evidence supporting the use of preventive medications varies considerably. Medications, herbal preparations, or vitamins that show benefit in at least one reasonably large, well-conducted, double-blind, randomized controlled trial include
c. Calcium-entry blockers
1) Divalproex sodium
e. Angiotensin-converting enzyme inhibitors
f. Angiotensin receptor blockers
g. Vitamin B2 (riboflavin)
h. Petasites (Butterbur)
25. Beta-blockers with intrinsic sympathomimetic activity are not effective in migraine. The mechanism of action of beta-blockers in migraine is unknown but probably is not due to blood pressure reduction.
26. Tricyclics such as amitriptyline and pizotifen may work by acting on the serotonergic system. The neurotransmitter serotonin inhibits the transmission of pain signals.
27. The calcium-entry blockers are a disparate group of drugs; not all show benefit in migraine. Those that do might work through effects on calcium-dependent processes involved in migraine, including synaptic transmission and neuronal membrane stability.
28. Divalproex sodium and topiramate are thought to be effective in part because they potentiate the inhibitory effects of γ-aminobutyric acid-ergic (GABA-ergic).
29. The choice of preventive medication depends on the features of the headaches and also on the risks, side effects, and possible benefits taking in consideration coexisting conditions.
30. When one preventive medication fails to provide relief or cannot be tolerated, another should certainly be tried. Clinical experience suggests that starting doses should be low and the dose gradually increased.
31. Headache activity normally waxes and wanes, so a treatment period of 2 to 3 months is necessary to be certain of a drug’s effect. This is best judged through the use of a headache diary or other objective measurements of headache activity.
32. Although single-drug therapy is preferred, some patients with resistant headache syndromes may benefit from combinations of two or even three preventive drugs.
33. Beta-blockers are contraindicated in sinus bradycardia, atrioventricular block, obstructive pulmonary disease (asthma), and diabetes mellitus.
34. Apart from sedation, amitriptyline can cause dry mouth, constipation, and weight gain; pizotifen can cause weight gain, and flunarizine occasionally causes depression. Amitriptyline is contraindicated in glaucoma, prostate hypertrophy, epilepsy, and cardiac disease; flunarizine and pizotifen do not have contraindications.
35. Verapamil in its sustained-release form can be given twice daily; its most common side effects are constipation and hypotension. Verapamil is contraindicated in atrioventricular block and sick sinus syndrome because it slows down atrioventricular conduction.
36. The anticonvulsants divalproex sodium and topiramate are often not well tolerated. Divalproex sodium can cause nausea, tremor, weight gain, and hair loss, and topiramate can cause sedation, cognitive dysfunction, paresthesias, weight loss, and kidney stones. Divalproex sodium is contraindicated in liver disease or when liver function is abnormal. Exposure during the first trimester of pregnancy can cause neural tube defects. It should thus be used with caution or avoided in women of childbearing age.
37. In the absence of clinical trial evidence guiding the length of treatment, most experts continue the medications for 4 to 6 months and then taper them slowly. They can be resumed if headaches recur. The medications should be prescribed for at least 6 months, after which the dose is gradually decreased and the medication, if possible, discontinued.
1. Migraine with aura is also known as classic migraine. It is headache preceded by transient focal neurologic symptoms, generally referred to as aura symptoms. The majority of patients who have migraine with aura also have attacks of migraine without aura.
2. When the aura symptoms occur by themselves, not followed by headache, the condition is called migraine aura without headache. In the older patient, this condition is an important differential diagnostic consideration in transient ischemic attack (TIA).
3. Occurrence in the general population
a. Lifetime prevalence is 5%; male-to-female ratio is 1 to 2.
b. One-year prevalence is 3%; male-to-female ratio is 3 to 4.
1. Aura is caused by cortical spreading depression (CSD), which is a wave of neuronal and glial depolarization that spreads across the cortex at a rate of 3 mm/min.
2. Modest reductions in cerebral blood flow occur in the wake of CSD, but they do not correlate with aura symptoms and are unlikely to be their cause. It is more likely that both the blood flow reductions and aura symptoms are due to CSD-triggered electrophysiologic changes.
3. A variety of genetic mutations may increase susceptibility to CSD by affecting the stability of neuronal membranes.
4. A causal link between aura and headache is uncertain. Some believe that “silent” CSD can trigger headache in the absence of clinically apparent aura; others believe that aura and headache are independent, though often parallel, processes.
1. Migraine with aura is a risk factor for ischemic stroke, but the attributable risk is small. The relationship is particularly strong in the posterior circulation as evidenced by a 15-fold increased risk of cerebellar lesions in migraine patients both with and without aura.
2. Migraine with aura is a contraindication to the use of estrogen-containing contraceptives. Migraine with aura may increase the risk of cardiovascular disease.
3. Migrainous infarction is uncommon; when it occurs, it usually consists of ischemic infarction of an occipital lobe, resulting in homonymous hemianopia.
1. The symptoms of typical migraine aura are visual or sensory. When aura consists of weakness, it is called hemiplegic migraine. Three mutations associated with hemiplegic migraine have been identified.
2. A common presentation of typical visual aura is the scintillating scotoma, also known as teichopsia or fortification spectra. Digitolingual paresthesias, also called cheiro-oral syndrome, represent the typical presentation of the somatosensory aura.
3. The aura symptoms usually last approximately 20 minutes, with a range from 10 to 30 minutes. When they last longer than 60 minutes, they are referred to as prolonged aura, and when they last longer than 24 hours, they are called migraine aura status.
4. The scintillating scotoma usually begins near the center of vision as a twinkling star that develops into a circle of bright, and sometimes colorful, flickering zigzag lines. The circle opens up on the inside to form a semicircle or horseshoe that further expands into the periphery of one visual field or the other. On the inside of the visual disturbance, a band of dimness follows in the wake of the crescent of flickering zigzag lines. The disturbance of vision ultimately disappears as it fades away in, or moves outside of, the visual field in which it developed.
5. The digito-lingual paresthesias typically start in the fingers of one hand, extending upward into the arm and, at a certain point, also involving the nose/mouth area on the same side. The progression of the somatosensory disturbance, similar to that of the scintillating scotoma, is slow and usually takes 10 to 30 minutes.
6. A progressing somatosensory disturbance similar to the digito-lingual paresthesias of migraine can occur with stroke, although this is rare. What differentiates one from the other is the resolution of the disturbed sensation, to which the first-last rule applies: in migraine, what is involved first, resolves first, whereas in stroke, what is involved first resolves last.
7. When the aura symptoms are fixed in their lateralization, neurologic illness should be suspected, especially when occurring with contralateral headache. Occipital arteriovenous malformation is a notorious cause of symptomatic migraine with aura.
1. Migraine with aura is treated as migraine in general, except that in its preventive therapy beta-blockers are often avoided because of theoretical worry that they may aggravate the neurologic symptoms.
2. There is no well-validated, practical acute treatment for aura symptoms. Experimentally, ketamine seems to abort aura in about half the cases. Anecdotal accounts suggest benefit from furosemide, compazine suppositories, or rebreathing into a paper bag. When frequent auras are troublesome, some experts suggest preventive therapy with aspirin and/or a calcium-entry blocker.
1. Tension-type headache is sometimes called muscle-contraction or tension headache.
2. In its episodic form (fewer than 15 d/mo) it is among the most common pain syndromes, with a lifetime prevalence of 69% in men and 88% in women. Chronic tension-type headache is diagnosed when headaches occur 15 or more days a month for at least 3 months.
3. Episodic tension-type headache is often self-treated; patients with chronic forms of the disorder are more likely to seek medical attention.
4. Although the burden of tension-type headache may be modest at the level of the individual, its prevalence means that it is the largest single cause of headache-related disability at the population level.
1. Mild or moderate intermittent headaches occur, lasting hours to days.
2. Headaches are generally bilateral and diffuse in location.
3. Pain is described as tightness or pressure and is usually not associated with other symptoms.
4. Migraine is commonly misdiagnosed as tension-type headache. Neck or muscle pains are common in both disorders and are not specific to tension-type headaches. Typical associated symptoms and features of migraine may not develop if attacks are treated early or do not progress. Confusion between these two headache types is minimized when diagnosis is based on records from headache diaries in which patients have recorded associated symptoms and other headache features.
1. Headaches generally respond to simple nonprescription analgesics. Evidence is best for nonsteroidal anti-inflammatory drugs (NSAIDs) but acetaminophen may also be effective. If this treatment is helpful, well tolerated, and infrequent, no additional treatment is needed.
2. In episodic tension-type headache that responds well to simple analgesics, the main role of the doctor is to monitor the frequency of use of abortive medication. As a general rule, this should be limited to no more than 2 to 3 days of use per week, to prevent development of medication-overuse headache.
3. The use of opioids or sedative medications, while effective, is generally discouraged because of concerns about the development of tolerance or addiction.
4. Preventive treatment should be considered if headaches are troublesome or disabling despite optimal abortive therapy, or if headache frequency exceeds twice a week on a regular basis.
5. Effective preventive treatments include
6. Amitriptyline and doxepin are particularly helpful when there is also insomnia because the medications are sedating. Imipramine is less sedating and otherwise better tolerated. It causes less weight gain and has fewer anticholinergic side effects, including dry mouth and constipation.
7. A good starting dose is 25 mg at bedtime, after which the dose is gradually increased until some dryness of the mouth develops. The dose of a tricyclic usually required to achieve a beneficial effect in tension headache lies between 25 and 75 mg/d.
1. Mild headache is common with acute sinusitis but chronic sinusitis is thought to be an uncommon cause of chronic headache or facial pain.
2. The prevalence is unknown but probably high since mild, acute episodes may resolve spontaneously and sufferers may self-treat.
1. Headache is caused by underpressure in the sinuses due to obstruction of the orifices, in particular the ostiomeatal complexes (maxillary sinuses) and nasofrontal ducts (frontal sinuses).
2. Obstruction is generally caused by swelling of the nasal mucosa, often on the basis of anatomically relatively narrow orifices, and it involves all sinuses.
1. Acute sinusitis can be caused by cold viruses and noninfectious conditions such as allergies. Bacterial sinusitis is also a possibility, particularly if symptoms persist beyond 10 days or worsen after initial improvement.
2. Headache is generally located in the frontal or maxillary region and described as pressure. If the sphenoid sinus is involved, pain may be occipital, frontal, temporal, or periorbital.
3. Symptoms are characteristic of a prolonged upper respiratory infection but last less than 4 weeks in acute sinusitis, 4 to 8 weeks in subacute sinusitis, and longer than 8 weeks in the chronic form. Facial tenderness, congestion, anosmia, purulent nasal discharge, fever, cough, or halitosis may occur.
4. The pain of sphenoid sinusitis may be aggravated by bending, standing, and walking, and nausea and vomiting may occur.
5. Sinus computed tomography (CT) scan with coronal cuts is recommended when episodes are recurrent or chronic bacterial sinusitis is suspected.
1. Observation and symptomatic treatment without the use of antibiotics are appropriate in mild cases for up to 2 weeks, since many episodes resolve spontaneously.
2. The choice of antibiotic is based on the likely pathogen, cost, and adverse effects. A common treatment for acute sinusitis in adults is a 10- to 14-day course of amoxicillin 250 to 500 mg t.i.d.
3. Nasal corticosteroid sprays, saline irrigation, antihistamines, decongestants, and other symptom-relieving drugs may be helpful. Improvement with any treatment may take up to 7 days.
4. The use of antibiotics for chronic sinusitis is controversial, and referral to an allergist or otolaryngologist should be considered.
1. Cluster headache is also known as migrainous neuralgia or alarm clock headache.
2. It is relatively rare, with a population prevalence of less than 1%. The male-to-female ratio is roughly 14 to 1.