28 Headache

28 Headache
The Massachusetts General Hospital Handbook of Pain Management


F. Michael Cutrer and Pramit Bhasin

I have a pain upon my forehead here.
—Othello Act 3, Scene 3, by William Shakespeare (1564–1616)

I. Anatomy of head pain
II. Pathogenic theories of headache

1. Vasogenic theory

2. Neurogenic theory

3. Peripheral sensitization

4. Central sensitization
III. Clinical approach to acute headache

1. Important questions to ask

2. Important physical findings

3. When to order laboratory tests or imaging studies
IV. Differential diagnosis of secondary headaches
V. Differential diagnosis of primary headaches

1. Migraine

2. Tension-type headache

3. Cluster headache

4. Miscellaneous benign headaches
VI. Refractory headaches

1. Chronic daily headache

2. Status migrainosus
VII. Rational approach to pharmacologic treatment of primary headaches

1. Treatment of migraine

2. Treatment of tension-type headache

3. Treatment of cluster headache

4. Indomethacin-sensitive headaches
VIII. Nonpharmacologic treatment
IX. Hints for successful headache management
Selected Readings

Headache descriptions and treatments can be found in pre-Christian Sumerian and Egyptian writings. Aretaeus of Cappadocia in second-century Turkey wrote of headache sufferers who “hid from the light and wished for death.” Headache is still a common affliction; in 1985, a large-scale survey-based study reported the prevalence of headache in the United States to be 78% of women and 68% of men. It is estimated that 40% of adults in North America have experienced a severe debilitating headache at least once in their lives.
Despite its long history and great prevalence in the population, the complaint of recurrent headache is still met with widespread indifference and suspicion among many health care providers. As a result, headache patients must often contend with haphazard and sometimes even inappropriate treatment. This is unnecessary and can even be tragic because not only can headache be the presenting symptom for a serious and even life-threatening abnormality, but also the majority of patients with recurrent headache show a good response to therapy.
Over 50 years ago, epilepsy surgery performed on the brains of awake patients under local anesthesia indicated that brain tissue itself was relatively insensate to electrical or mechanical stimulation, whereas electrical stimulation of the meninges or meningeal blood vessels produced a severe boring headache. The meninges and meningeal vessels are richly supplied with C fibers (small fibers) and are the key structures involved in the generation of headache. The C fibers from the meninges converge into the trigeminal nerve and project to the trigeminal nucleus caudalis in the lower medulla, where they synapse. From the caudal brainstem, fibers carrying nociceptive signals project to more-rostral trigeminal subnuclei and the thalamus (ventral posterior medial, medial, and intralaminar nuclei). Projections from the thalamus ascend to the cerebral cortex, where painful information is localized and reaches consciousness.
Head pain results from the activation of the pain fibers that innervate intracranial structures regardless of the activating stimulus. In a small number of patients, an identifiable structural or inflammatory source for the headache can be found using neuroimaging or other laboratory investigations. However, the overwhelming majority of patients encountered in clinical practice suffer from primary headache disorders such as migraine or tension headache in which physical examinations and laboratory studies are unrevealing. Research into the pathophysiology of headache has been limited by the subjective nature of the complaints and the paucity of animal models with which to test hypotheses. Theories of migraine pathogenesis fall roughly into two categories, vasogenic and neurogenic. Since the duration of headache frequently exceeds the duration of the initiating stimulus, it is likely that sensitization within the trigeminal and upper cervical pain pathways contributes to the prolongation of headaches. Sensitizing events may occur in both the peripheral and central portions of these pathways.
1. Vasogenic theory
In the late 1930s, investigators observed that cranial vessels appear to be important in the generation of headache. They found that in many patients extracranial vessels became distended and pulsated during a migraine attack, and that vasoconstrictive substances such as ergots could abort the headache, whereas vasodilatory substances such as nitrates tended to provoke the headache. Based on these observations, they theorized that intracranial vasoconstriction is responsible for the aura of migraine, that the headache results from a rebound dilation and distention of cranial vessels. Later, it was postulated that head pain is enhanced by vasoactive polypeptides.
2. Neurogenic theory
The alternative hypothesis holds that migraine is caused by a dysfunction of the brain itself, involving a lowered cerebral thresh old to migraine attacks. According to this hypothesis, when precipitating factors exceed this threshold, a migraine attack occurs, and although vascular changes may occur during a migraine attack, they occur as a result rather than the cause of the attack. Proponents of the neurogenic theory point to the broad range of neurologic symptoms associated with a migraine attack that cannot be explained on the basis of vasoconstriction within a single cerebrovascular distribution, as well as the prodromal symptoms such as euphoria, hunger, thirst, or fluid retention that precede the headache, in some individuals by as much as 24 hours.

Figure 1. Schematic overview of the mechanism leading to headache pain perception after activation of trigeminovascular nociceptive neurons. VPM, ventral posterior medical.

3. Peripheral sensitization
There is increasing experimental evidence that once activated, C fibers release neuropeptides (e.g., substance P, neurokinin A, calcitonin gene-related peptide) that generate a neurogenic inflammatory response within the meninges. This response consists of increased plasma leakage from meningeal vessels, vasodilation, and activation of mast cells and endothelial cells. Once set into motion, this process may act to lower the threshold of the C fibers to further activation and, as a result, prolong and intensify the headache attack. Drugs known to be effective in ending a migraine attack, such as dihydroergotamine or sumatriptan, have been shown to act at serotonin (5HT) receptor subtypes to block the release of neuropeptides and the development of neurogenic inflammation.
4. Central sensitization
Animal studies indicate that inflammatory or chemical C-fiber activation results in expansion of receptive fields and recruitment of previously non-nociceptive neurons into the transmission of painful information. The changes are clinically reflected as hyperalgesia (lowered pain threshold) and allodynia (the generation of a painful response by normally nonpainful stimuli). Analogous clinical phenomena are seen in headache disorders. For example, minor head movements, bending, or coughing, which normally do not cause pain, are perceived as painful during or in the hours following a migraine attack. Recent studies by Burstein and coworkers have demonstrated that stimulation of meningeal nociceptors causes a lowering of the activation thresholds for convergent, previously nonpainful skin stimulation. Subsequent studies of human subjects during migraine attacks have also demonstrated the development of cutaneous allodynia both within the areas innervated by the trigeminal nerve and in extratrigeminal areas.
When faced with a patient in the emergency department whose primary complaint is that of a severe headache, the first question to ask is whether the headache is symptomatic of a potentially serious underlying abnormality requiring rapid and appropriate treatment. In the vast majority of cases, the headache represents a particularly severe episode in a primary headache disorder. However, the distinction between primary and secondary (symptomatic of another cause) headache must be made as rapidly and accurately as possible. It is crucial to use the history and physical exam to decide whether the patient is at high or low risk, to order diagnostic tests, and to provide therapy accordingly. Laboratory tests and imaging studies ordered without good clinical indication are usually unhelpful and always expensive.
1. Important questions to ask
Is this headache the first of its kind? If the headache is unlike anything experienced previously, the risk increases. If it is similar (even if of greater intensity) to attacks experienced over many months or years, the likelihood that it is a benign process increases. This question becomes increasingly important for patients over 40 years, as the incidence of the first attack of migraine decreases and the incidence of neoplasm and other intracranial pathology increases.
Was this headache of sudden onset? A persistent headache that begins and reaches maximal intensity within a few seconds or minutes is more suggestive of an ominous vascular cause.
Has there been any alteration in mental status during the course of the headache? Generally a family member or friend who has been with the patient must answer this question. Although migraineurs can appear fatigued, especially after prolonged vomiting or analgesic use, obtundation and confusion are more suggestive of meningitis, encephalitis, or subarachnoid hemorrhage.
Has there been recent or coexistent infectious disease? Infection in other locations (e.g., lungs, paranasal or mastoid sinuses) may precede meningitis. Fever is not a feature of migraine or a primary headache disorder. Fever may also occur in association with subarachnoid hemorrhage, although usually 3 to 4 days after the actual hemorrhage.
Did the headache begin in the context of vigorous exercise or seemingly trivial head or neck trauma? Although effort-induced migraine or coital migraine certainly exist, the rapid onset of headache with strenuous exercise, especially when minor trauma has occurred, increases the possibility of carotid artery dissection or intracranial hemorrhage.
Does the head pain tend to radiate posteriorly? Pain radiation between the shoulders or lower is not typical of migraine and may indicate meningeal irritation from subarachnoid blood or infection.
Other important points not to be overlooked in a careful history include the following:
Do other family members have similar headache? Migraine has a strong familial tendency.
What medications does the patient take? Certain medications can cause headache. Anticoagulants and oral antibiotics place the patient in a higher risk group for hemorrhage or partially treated central nervous system (CNS) infection.
Does the patient have any other chronic illness or a history of neurologic abnormality? These may confuse the neurologic examination.
Is the headache consistently in the same location or on the same side? Benign headache disorders tend to change sides and locations at least occasionally.
2. Important physical findings
It is crucial to examine each patient carefully, especially when there are atypical elements in the history. A basic neurologic examination should be performed that addresses the following six components:
Mental status: What is the patient’s level of consciousness? Is the patient able to maintain normal attention during the examination? Are language and memory normal?
Cranial nerves: Each cranial nerve should be tested separately. Are there asymmetries? Is there papilledema?
Motor: Are motor strength and muscle tone symmetrical and within the normal range? Are there any abnormal involuntary movements?
Sensory: Are there asymmetries of pain, temperature, or proprioceptive sensation?
Coordination: Is there dysmetria or gait ataxia?
Reflexes: Is there asymmetry of reflexes in either the upper or lower extremities?
Three findings on examination should be considered signs of possible serious pathology:
Nuchal rigidity: This can be an indicator of either meningitis or subarachnoid hemorrhage.
Toxicity: Is there a low-grade fever or persistent tachycardia? Does the patient appear more acutely ill than most migraine patients?
Previously unnoticed neurologic abnormality: Subtle findings such as slight pupillary asymmetry, unilateral pronator drift, or an extensor plantar response are significant and should lead to further investigation.
3. When to order laboratory tests or imaging studies
Laboratory tests should be obtained to confirm the presence of abnormalities suspected from the history and physical examination and should be appropriate for the pathology suspected. Laboratory, electroencephalographic, or neuroimaging “fishing trips” are discouraged because they rarely provide useful information, can delay treatment, and can divert attention away from more relevant findings. At the present time computed tomography (CT) is the imaging study most likely to be available in the acute setting. There are three major indications for an urgent CT scan:

The presence of papilledema

Any impairment of consciousness or orientation

The presence of localizing or lateralizing findings on neurologic examination
CT is most useful for identifying recent intracerebral and extracerebral hemorrhages, hydrocephalus, brain abscesses, and other space occupying lesions.
Headache can be symptomatic of many underlying abnormalities. The frequency of secondary headaches is smaller than that of primary headache disorders. However, it is vital that these headaches be diagnosed quickly and treated appropriately. The most common causes are listed in Table 1.

Table 1. Secondary headache etiologies

In clinical practice, the vast majority of patients investigated because of head pain ultimately prove to have a primary headache disorder (i.e., recurrent headaches for which no underlying structural, infectious, or other systemic abnormality can be found). Migraine and tension-type headaches form the bulk of this population, but cluster headache and other less common syndromes are occasionally seen. To classify and investigate primary headaches, the International Headache Society (IHS) has developed classification and diagnostic criteria for headache and facial pain (Table 2), which are invaluable for clinical research, with the caveat that many patients do not fall neatly into a diagnostic category.

Table 2. Diagnostic criteria for common headache types

1. Migraine
It is estimated that approximately 16% of women and 6% of men in the United States meet the diagnostic criteria for migraine. Migraine sufferers frequently have family members who also have recurrent headaches. Migraine falls into two categories: migraine without aura (previously called common migraine) and migraine with aura (previously called classic migraine). Patients with migraine often report prodromal symptoms that begin 24 to 48 hours before a headache attack. These symptoms can include hyperactivity, mild euphoria, lethargy, depression, cravings for certain foods, frequent yawning, and other atypical symptoms. Prodromal symptoms should not be confused with the migraine aura, which occurs within 1 hour of the onset of the headache and consists of specific neurologic symptoms. Typical migraine aura symptoms include the following:

Homonymous visual disturbance, classically a scintillating scotoma

Unilateral paresthesias and or numbness, often affecting the distal extremities or the perioral region of the face

Unilateral weakness

Aphasia or other language disturbance
The aura symptoms in some patients localize to the brainstem. These include visual symptoms in the temporal and nasal fields of both eyes, dysarthria, vertigo, tinnitus, decreased hearing, double vision, ataxia, bilateral paresthesias, bilateral weakness, and decreased level of consciousness.
Basilar migraine
Patients in whom brainstem symptoms predominate are generally given the diagnosis of basilar migraine. Many of these symptoms are subject to misinterpretation, as they can occur with anxiety and hyperventilation. In many patients, basilar attacks are intermingled with typical attacks. Dizziness is frequently reported as a feature of an otherwise typical attack of migraine with aura.
Migraine with prolonged aura, or complicated migraine
Migraine attacks in which the aura symptoms persist for more than 1 hour, but less than 1 week, and in which neuroimaging studies are normal are diagnosed as complicated migraines.
Familial hemiplegic migraine
Patients who have migraine with aura including hemiparesis, and who have at least one first-degree relative who experiences identical attacks, are given a diagnosis of familial hemiplegic migraine. This form of migraine has been localized to chromosome 19 in several families.
2. Tension-type headache
Tension-type headache is probably the most common primary headache disorder. It has been referred to by many names in the past including muscle contraction headache, essential headache, stress headache, and psychomyogenic headache. The exact pathogenesis of tension-type headache and the importance of muscle contraction to its generation are still poorly understood. Pericranial muscle spasm or tenderness may or may not be present. Tension type headache occurs in both episodic and chronic forms.
3. Cluster headache
Cluster headaches are much less common than migraine or tension-type headaches. They afflict men five to six times more often than women, and the age of onset is typically 20 to 40 years. The syndrome derives its name from the fact that attacks occur in series lasting for weeks or months (the so-called cluster periods), separated by remissions that usually last for months or years. During cluster periods, headache attacks might be provoked by alcohol, histamine, or nitroglycerine. The pain is very severe, with a throbbing, at times sharp, quality. During a cluster headache, a patient is often agitated and frequently paces, unlike a migraine patient who prefers to avoid movement in a quiet dark room. In some instances, the clustering pattern of the episodic form can change into the chronic form in which there is no remission.
4. Miscellaneous benign headaches
There are several headache syndromes that are unassociated with a structural cause but are distinct from migraine, tension type, or cluster headaches. The following is a brief listing and description of these syndromes.
Chronic paroxysmal hemicrania is a relatively rare syndrome in which attacks occur that are similar to those of cluster headache. It differs from cluster headache in that attacks occur with greater frequency (>5 per day for more than half the time) and tend to be very brief (5 to 20 minutes), prolonged remissions do not occur, women are affected more frequently than men, and attacks are very responsive to low-dose indomethacin.
Paroxysmal hemicrania is a relatively uncommon syndrome characterized by brief (2 to 45 minutes) and multiple (five or more per day) episodes of unilateral orbital throbbing or stabbing pain of severe intensity. The attacks are associated with ipsilateral autonomic signs (e.g., conjunctival injection, rhinorrhea, tearing, eyelid edema, and ptosis).
Hemicrania continua is a rare headache syndrome in which unilateral orbital or temporal pain is present almost constantly.
Idiopathic stabbing headache, a series of icepick-like jabbing pains, frequently occurs in migraineurs on the side frequently affected by migraine attacks. These attacks often respond to oral indomethacin (25 mg three times per day).
Benign exertional headache can be precipitated by any form of exercise. It is generally bilateral in location and can last from several minutes to 24 hours.
Cold-induced headaches can result from either exposure of the head to low ambient temperatures or passage of a cold liquid or solid material over the palate or posterior pharynx (e.g., “ice cream headache”).
Orgasm-induced headache can occur in susceptible individuals with masturbation or sexual intercourse.
Benign cough headache may be diagnosed only after a structural lesion has been excluded with neuroimaging.
1. Chronic daily headache
The IHS classifies headaches that are present for at least 15 days per month during at least 6 months per year as chronic. Patients usually describe these headaches as being tension-type in quality, although more severe attacks similar to migraine may be interspersed. Prophylactic therapy in patients taking daily analgesics or ergotamine-containing medications is frequently ineffective. Discontinuation of daily analgesic or ergotamine use often results in improvement.
2. Status migrainosus
Migraine attacks that persist for longer than 72 hours despite treatment are classified as status migrainosus. In-patient treatment is necessary (see section VII, 1, iii).
Pharmacologic treatment of patients with headache can be divided into two broad categories: acute therapy given during an attack to end it, and prophylactic treatment given daily to decrease the frequency and severity of future attacks. The reader is referred to Appendix VIII or to the Physicians Desk Reference (PDR) for more detailed descriptions of the drugs used in the management of headache.
1. Treatment of migraine
(i) Acute therapy for mild or moderate attacks
Acetaminophen. Occasionally, patients have mild attacks that, when caught early, respond to over-the-counter analgesics like acetaminophen (650 to 1,000 mg). Mild to moderate attacks during pregnancy should be treated with acetaminophen in the first instance.
Nonsteroidal anti-inflammatory drugs (NSAIDs) including aspirin (900 to 1,000 mg), ibuprofen (1,000 to 1,200 mg), Naprosyn (500 to 825 mg) and ketoprofen (100 to 200 mg) can be used to treat mild to moderate attacks.
Midrin is a combination medication containing acetaminophen, isometheptene mucate (a mild vasoconstrictor), and dichloralphenazone (a mild sedative). Two tablets should be taken at the onset of headache followed by one each hour until relief occurs or up to a maximum of five capsules within a 12-hour period. Anecdotally, Midrin is less likely than many of the other combination medications to generate a rebound headache syndrome, although daily use of any of these treatments is not recommended.
(ii) Acute therapy for severe attacks
Butalbital is a barbiturate combined with caffeine, acetylsalicylic acid, and/or acetaminophen in several medications (including Fiorinal, Fioricet, Phrenilin, and Esgic). The recommended dosage is two tablets every 4 hours, not to exceed six per day. These medications are best suited for treatment of moderate to severe, infrequent headaches. If used to treat headaches occurring more than twice per month, patients may develop rebound headaches. If prescribing these drugs, physicians should ensure that they are not prescribed in escalating doses.
Oral opioid-containing medications have little place in the treatment of chronic recurrent primary headaches and should be avoided until all other treatment alternatives have been considered. Under certain conditions they are the only viable option, (e.g., pregnancy, severe vascular disease). Physicians should discuss the risks of rebound headache and dependency before prescribing.
Ketorolac is a potent NSAID that is available in injectable form. It can be given intramuscularly (IM) or intravenously (IV) for the treatment of severe migraine attacks with early and prominent vomiting. Although ketorolac is expensive and not clearly superior to cheaper medications, some patients respond well. Because of its potency, the risk of side effects is actually greater than with other NSAIDs, and the manufacturers recommend short-term usage only (see Chapter 8).
Ergotamine-containing medications are available in oral, sublingual, and suppository formulations in the United States. Ergotamines are the classical antimigraine agents and can be effective if patients tolerate the side effects of nausea and peripheral vasoconstriction. They are typically most effective if given early in the migraine attack. A potential problem is overuse, which can result in a chronic daily headache syndrome and in extreme cases the gangrene-like complications of ergotism. If prescribing the suppository, patients should be instructed to cut the suppository in half or into quarters to find the lowest effective dose and thereby reduce ergotamine-induced nausea. Contraindications include coronary artery disease, angina, peripheral vascular disease, Raynaud’s phenomenon, uncontrolled hypertension, and severely impaired renal or hepatic function.
Dihydroergotamine (DHE) is a hydrogenated ergot that until recently was the mainstay of nonopioid treatment of acute severe headache attacks. It has fewer potent peripheral arterial vasoconstrictive effects and can be effective even when given well into the attack. It is associated with less nausea than ergotamine, but an antiemetic given prior to treatment is usually required. DHE is available in injectable and intranasal formulations. To give DHE in the acute setting, early in the attack, administer 1 to 2 mg IM or subcutaneously (SC), repeated up to a further 3 mg in 24 hours. Well into a severe attack, administer prochlorperazine 5 mg IV, or metoclopramide 10 mg IV, followed in 5 to 10 minutes by DHE 0.75 to 1 mg IV over 2 to 3 minutes. If the attack has not subsided after 30 minutes, an additional 0.5 mg of DHE may be given IV.
Sumatriptan (Imitrex) and the “triptans.” Sumatriptan is the prototype of the new triptan class of drugs that selectively bind to 5HT1B/D/F receptors. It exerts both direct vasoconstrictor and antineurogenic inflammatory effects on dural vessels. Sumatriptan treatment is also associated with improvement in the nausea, vomiting, photophobia, and phonophobia that accompany many migraine attacks. It has been shown to be effective when given up to 4 hours after the onset of a headache attack. Sumatriptan is available in injectable (6 mg SC) oral (25 and 50 mg) and intranasal (20 mg) as well as oral formulations.
Newer 5HT1B/D/F receptor agonists that have recently become available include naratriptan (Amerge), zolmitriptan (Zomig), and rizatriptan (Maxalt). The overall efficacy and side-effect profiles of these new agents do not vary greatly from those of sumatriptan. However, there are differences in half-life, relative affinity for the h5HTID and h5HTIB receptor subtypes, and blood–brain barrier penetrance. Naratriptan (2.5-mg tablets) has been reported to have an overall lower incidence of side effects than sumatriptan, but the onset appears to be somewhat slower. Duration may be longer, however. The side-effect profiles of both zolmitriptan (2.5 and 5-mg tablets) and rizatriptan (5- and 10-mg tablets and rapidly dispersible wafers) are similar to sumatriptan, but trials suggest that the onset of action may be slightly faster than oral sumatriptan. Three more triptans, eletriptan, frovatriptan, and almotriptan, await approval from the U.S. Food and Drug Administration (FDA). These drugs are now widely available and have become the de facto drugs of choice in the outpatient treatment of moderate to severe migraine attacks in patients without risk factors for coronary disease or prolonged neurologic symptoms.
Neuroleptics, including chlorpromazine, prochlorperazine, and droperidol, have been used as an alternative to meperidine or vasoactive medications in the emergency department for the treatment of severe migraine attacks. Droperidol given by repeated IV injection is frequently effective in the treatment of status migrainosus. The protocol for patients with intractable migraine attacks is as follows: Give 2.5 mg IV and repeat twice at 30-minute intervals if the headache persists (total dose, 7.5 mg). To avoid akathisia, pretreat with benztropine (Cogentin), 1 mg PO (orally), followed by 1 mg PO twice daily. The risks of hypotension, sedation, and akathisia limit the use of neuroleptics.
Opioids. Meperidine is the opioid most frequently chosen by emergency department physicians for the treatment of severe migraine headache. It is commonly given in combination with an antiemetic. The choice of meperidine, or in fact any opioid, is questionable for this indication, and there is no evidence in the literature to support this practice. In fact, in one double-blind comparison study, meperidine was found to be inferior to chlorpromazine for aborting a migraine attack. Its main beneficial effect may be that of induction of sleep with resultant resolution of the attack. The use of parenteral opioids should be limited to patients with infrequent attacks, or patients in whom other treatments are contraindicated. The use of meperidine is generally discouraged because of the toxicity of its metabolite normeperidine, and because of the preference of addicts for this particular opioid (see Chapter 9). Suitable alternatives would be morphine or hydromorphone.
(iii) Treatment of status migrainosus
If efforts to end a migraine attack in the emergency department are unsuccessful and the patient requires hospitalization, IV treatment with DHE is the treatment of choice if there are no contraindications. The following protocol is recommended:

Metoclopramide 10 mg IV plus DHE 0.5 mg IV is given over 2 to 3 minutes.

If the headache stops but nausea develops, no DHE is given for 8 hours, then 0.3 or 0.4 mg DHE plus 10 mg metoclopramide is given every 8 hours for 3 days.

If the head pain persists and no nausea develops, 0.5 mg DHE is repeated in 1 hour. If headache is relieved but nausea develops, DHE 0.75 mg IV every 8 hours for 3 days plus metoclopramide 10 mg is given. If headache is relieved and no nausea develops, DHE 1.0 mg every 8 hours plus metoclopramide 10 mg for 3 days is given.

If headache stops and no nausea develops, DHE 0.5 mg plus metoclopramide 10 mg IV is given every 8 hours for 3 days.
The DHE should be given undiluted through an IV Hep-Lock. Metoclopramide may be discontinued after six DHE doses.
Diarrhea is a common side effect of the DHE protocol and can be controlled with oral diphenoxylate (Lomotil). Contraindications to IV DHE include Prinzmetal’s angina, pregnancy, coronary artery disease or uncontrolled hypertension, peripheral vascular disease, and severe renal or hepatic disease.
When patients are hospitalized and given IV DHE, special attention should be given to the amount of analgesic medications they were taking prior to admission. Status migrainosus is frequently associated with overuse of abortive medications, and patients should be watched carefully for evidence of barbiturate or opiate withdrawal. If no prophylactic regimen is in place in a patient with episodes status migrainosus, then initiation of prophylactic therapy is appropriate.
(iv) Prophylactic therapy
Acute drug treatment of headache is largely to relieve symptoms and has no benefit beyond the single attack. In the many patients who have infrequent attacks, an effective abortive agent is sufficient. However, the frequent use of abortive agents rapidly becomes a part of the problem. Once a patient has slid into the insidious cycle of analgesic rebound, prophylactic therapy may be futile and the headaches just keep on getting worse.
If attacks occur more than once or twice per month and are sufficiently severe to prohibit normal activities, or the patient’s dread of the attacks is intrusive, then prophylactic therapy should be considered (Table 3). The regimen should be individualized to the patient. Concurrent medical problems may contraindicate certain prophylactic medications, or occasionally the prophylactic medicine can be used to treat migraine as well as a preexistent illness. Prophylactic medications are empiric treatments, and to date, their mechanism of action is unknown. Most of these medications were originally used for other indications and their antimigraine effects were found coincidentally. It is likely that in many cases their effect in migraine is unrelated to the action for which they were originally prescribed. Most prophylactic agents are associated with increased appetite and patients should be warned about potential weight gain.

Table 3. Prophylactic medications useful in migraine

Prophylactic medications fall into a two-tiered hierarchy. First line agents are those that are likely to be effective without intolerable side effects. Second-line agents may be effective when the first-line agents have failed, but they carry the risk of more frequent or potentially serious side effects.
First-Line Agents
Adrenoceptor blockers. Beta-blockers shown to be effective migraine prophylactic agents in clinical trials include propranolol, nadolol, atenolol, timolol, and metoprolol. The antimigraine activity of these medications does not depend on CNS penetration, cardioselectivity, or 5HT binding. The only common pharmacologic property that separates the beta-blockers effective in migraine prophylaxis from those that are ineffective is the lack of partial sympathomimetic activity. Because of differences in pharmacologic properties among the various agents, failure of one agent is not an indicator of failure of others. Side effects occur in 10% to 15% of patients and include hypotension, fatigue, dizziness, gastrointestinal (GI) disturbance (diarrhea, constipation), depression, insomnia, and memory disturbance. Contraindications include asthma, congestive heart failure, chronic obstruction pulmonary disease, peripheral vascular disease, cardiac conduction defects, and brittle diabetes.
NSAIDs. Although NSAIDs inhibit platelet function as part of their spectrum of activities (see Chapter 8), it has been difficult to correlate prophylactic efficacy with inhibition of platelet function. NSAIDs that have been shown to exhibit prophylactic effects in controlled clinical trials include aspirin, naproxen/naproxen sodium, tolfenamic acid, ketoprofen, mefenamic acid, and fenoprofen.
There have been no trials comparing different NSAIDs for migraine prophylaxis. The only agent shown to be effective in controlled studies for treatment of menstruation-associated migraine is naproxen sodium. This, coupled with its proven efficacy in double-blind studies, makes it the first choice among the NSAIDs for migraine prophylaxis.
Antidepressants. The only antidepressant with significant evidence of efficacy in migraine prophylaxis is the tricyclic antidepressant amitriptyline, which inhibits reuptake of both norepinephrine and 5HT. However, reuptake inhibition does not appear to correlate with efficacy in migraine. Clinical trials also indicate that the antimigraine activity of amitriptyline is unrelated to its antidepressant activity. In fact, the doses generally useful in the treatment of migraine are well below those required to treat depression. The tricyclic antidepressants are described in detail in Chapter 11 .
Calcium channel blockers prevent the transmembrane influx of calcium ions through slow voltage-dependent channels. They were first introduced for use in the treatment of migraine on the basis of their presumed blockade of the vasospastic phase in a migraine attack, although vasospasm is now considered an unlikely cause of migraine. Of the available blockers, only verapamil has sufficient evidence of efficacy to warrant its use in migraine.
Anticonvulsants are the most recent addition to the migraine prophylactic armamentarium. Valproic acid, an anticonvulsant known to inhibit gamma-aminobutyric acid (GABA) aminotransferase, reduces headache frequency and severity. It should be reserved for use as a second-line agent because of its association with birth abnormalities (neural tube defects) in the offspring of women taking it during the first trimester of pregnancy, and with polycystic ovarian syndrome. Gabapentin, a GABA analog, has recently shown efficacy in migraine prophylaxis, and is generally well tolerated, although it may be associated with dizziness and sedation. Although gabapentin has a very favorable side-effect profile, the general experience is that it is less efficacious in the treatment of recurrent headaches than valproic acid. However, until information from head-to-head trials is available, any definitive statement as to relative effectiveness is premature. The anticonvulsants are fully described in Chapter 10 .
Second-Line Agents
Methysergide, an ergot derivative, was one of the first drugs used for migraine prophylaxis. It was thought to have an effect via inhibition of 5HT2 receptors. However, recent evidence indicates that potent selective 5HT2 antagonists are weak or ineffective in migraine. Double-blind clinical trials have shown methysergide to be effective in reducing the frequency, severity, and duration of migraine attacks. Unfortunately, it is associated with the serious complication of retroperitoneal, pericardial, or pleural fibrosis. Because of the risk of this potentially fatal side effect, methysergide should be reserved for severe cases that are refractory to other prophylactic regimens. Since the fibrotic complications are reversible early in the process, methysergide should be discontinued for 6 to 8 weeks every 6 months. The early symptoms of retroperitoneal fibrosis include decreased urine output and leg or back pain.
Phenelzine is a monoamine oxidase inhibitor that has been shown to be effective in patients with severe migraine. The potential for the generation of a hypertensive crisis after dietary intake of tyramine-containing foods should limit its use to patients with severe migraine who have been refractory to other treatments and who are committed to strict dietary monitoring.
2. Treatment of tension-type headache
(i) Acute treatment
The majority of tension-type headaches are of mild to moderate severity, and many patients use nonprescription medications quite effectively. NSAIDs are the mainstay of treatment (see Chapter 8 ). Those commonly used are listed in Table 4. Acetaminophen in both 650- and 1,000-mg doses has been reported to be superior to placebo in the treatment of headache.

Table 4. NSAIDs commonly used in tension-type headache

Muscle relaxants are sometimes used to treat tension-type headache. Such agents include diazepam, baclofen, dantrolene sodium, and cyclobenzaprine hydrochloride. There are no clinical trials of these medications in the treatment of acute tension-type headaches; therefore, their use is largely empiric. The one exception is tizanidine, which has recently been shown to be effective in chronic tension-type headache. In our experience, doses of 4 to 16 mg may be effective.
(ii) Prophylactic treatment
Tricyclic antidepressants are generally considered the first-line agents for prophylaxis. Amitriptyline is the drug of choice. Other medications that are sometimes selected for prophylaxis include NSAIDs, atypical antidepressants, and valproate, although evidence supporting their use in this situation is scanty.
Amitriptyline has been shown to affect headache improvement in double-blind placebo-controlled studies. Dosage ranges from 10 to 100 mg per day or higher if tolerated. In some patients, its use is somewhat limited by its anticholinergic side effects (i.e., sedation, dry mouth, tachycardia, constipation, or urinary retention). To minimize sedation, the drug can be given in a single dose 1 to 2 hours before bedtime. It should be started at a low dose (10 mg per day) and slowly increased over several weeks (10-mg increments at intervals of 1 to 2 weeks).
3. Treatment of cluster headache
(i) Acute treatment
Oxygen inhalation is a safe and effective treatment for individual attacks of cluster headache in many patients. The patient most likely to respond to oxygen treatment is one with episodic-type cluster headaches who is under the age of 50 years.
Oxygen is delivered at a rate of 8 liters per minute for 15 minutes via a loose-fitting facemask. Nasal biprongs are less effective because of greater air entrainment and lower oxygen concentration delivered. Patients who respond to oxygen do so usually within 10 minutes. The mechanism of effect of oxygen is unknown.
Ergotamine has been used since the 1940s to treat cluster headache attacks. The sublingual and inhalational routes appear to be superior to oral tablets. Ergotamines are effective and well tolerated in many patients with cluster headaches. DHE may also be of use in the acute treatment of cluster headaches.
Sumatriptan has been found to be effective in reducing both the pain and conjunctival injection of cluster headache within 15 minutes. It is well tolerated in patients with cluster headache. However, sumatriptan is contraindicated in patients with coronary artery disease, which is quite common among middle-aged men who make up the majority of cluster headache sufferers.
(ii) Prophylactic treatment
In general, prophylactic treatment for cluster headache is given only during the cluster period. Once a remission is established, in most cases within 3 to 6 weeks, the prophylactic agents is tapered and withdrawn.
Verapamil is frequently used in cluster headache, and in many patients it has a good effect with few side effects. The recommended dose is 240 to 480 mg/day.
Ergotamine tartrate is the traditional agent used in the prophylactic treatment of cluster headache. In doses of 2 to 4 mg/day in either oral or suppository form, ergotamine is an effective, well-tolerated medication for many of these patients.
Methysergide prophylaxis is efficacious in about 70% of patients with episodic cluster headache. The development of retroperitoneal, pleural, or pericardial fibrosis, which limits its use in migraine, is not as likely to occur in these patients because the length of use is considerably shorter. In patients with cluster headache, methysergide should be discontinued for 4 to 6 weeks after 2 to 3 months of treatment.
Lithium carbonate has been shown in over 20 open clinical trials to be effective in the treatment of chronic cluster headache. Because of its rather narrow therapeutic window, it is important to monitor serum lithium levels during periods of treatment. The serum level should be obtained 12 hours after the last dose and should not exceed 1.0 mmol/L (therapeutic range is usually from 0.3 to 0.8 mmol/L). Certain medications can interact with lithium to increase the serum level, including the NSAIDs and the thiazide diuretics. Average daily doses range from 600 to 900 mg but should be titrated according to serum concentrations.
Steroids are widely used in the treatment of both the episodic and chronic forms of cluster headache, even though documentation of their effect is largely limited to open trials.
4. Indomethacin-sensitive headaches
There are several headache syndromes that frequently respond to prophylactic treatment with indomethacin. Indomethacin, a potent NSAID, is not effective in migraine and has significant GI side effects. The syndromes for which indomethacin can be effective include chronic paroxysmal hemicrania, hemicrania continua, benign cough headache, effort and coital migraine, and idiopathic jabbing headaches. It is not known why these headaches respond to indomethacin when others do not. Clinical features that indomethacin-sensitive headaches share include a tendency to be provoked by certain movements or activities, relatively brief duration, and severe intensity.
To treat these syndromes, an initial dose of 25 mg twice a day is increased over several days until the attacks cease (sometimes requiring up to 150 mg to 250 mg per day). After relief is stable for several days, the dose should be titrated downward to the lowest effective maintenance dose (usually 25 to 100 mg daily). There is great variation between individuals in the maintenance dose required.
Indomethacin can have potentially serious GI side effects when given over long periods of time. These include dyspepsia, peptic ulcer, and GI bleeding. Other potential side effects include dizziness, nausea, and purpura.
Nonpharmacologic treatments include very old treatments such as application of pressure, heat, or cold directly to the head, as well as electrical stimulation, dental treatment, acupuncture, hypnosis, relaxation training, biofeedback, and cognitive therapy. All of these techniques have proponents, but the inherent difficulties in designing and carrying out blinded, unbiased studies make it almost impossible to make strong statements regarding their efficacy. At this point, it is impossible to predict whether an individual patient will benefit.
Less is More
In prescribing prophylactic therapy, start with a small dose and titrate upward using small increments at 1- to 2-week intervals. This will allow you to determine the lowest effective dose.
Don’t Abandon Ship
If a prophylactic medication does not work at a modest dose, titrate upward slowly and systematically. Listen to the patient, and let side effects be your guide.
Pregnancy and Prophylaxis Potentially Precipitate Problems
Women who intend to become pregnant should be withdrawn from prophylactic treatment because the effects of many of these drugs on the fetus (especially in the first trimester) are not known. In many cases, pregnancy induces a remission in migraine attacks.
All Headaches are not Created Equal
Just because a patient has intermittent severe migraine attacks does not mean that every headache is a migraine requiring aggressive abortive therapy. Many migraineurs have frequent simple tension-type headaches intermixed, and the frequent use of ergotamines, analgesics, or barbiturate-containing medications can result in an iatrogenic rebound syndrome.
Prophylaxis is not a Life Sentence
Once a patient has been headache free for several months, begin discussions about tapering down the medications.

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