lecture8 headache

8/8/2019 Lecture8 Headache

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Headache (HA)

1. History

Includes nature of headache, family history, psychosocial history, and current medications. Inquire

about inciting factors such as smoking, alcohol, vasodilators, or ingestion of tyramine-containing

food (such as chocolate or red wine). Oral contraceptive pills and pregnancy can alleviate or

intensify headaches. Analgesic overuse can cause "rebound headache."2. Characteristics of Various Types of Headaches

1. Primary headaches.

1. Migraine without aura (common migraine). Must have at least 5 attacks that meet

the following criteria:

1. Headache attacks last 4 to 72 hours.

2. Headache has at least 2 of the following:

*0 Unilateral location

*1 Pulsating quality

*2 Moderate or severe intensity (inhibits daily activity)

*3 Aggravation by routine physical activity

3. During the headache, at least 1 of the following:

*4 Nausea or vomiting

*5 Photophobia and phonophobia

4. No organic cause found by history, PE, neurologic exam.

2. Migraine with aura (classical migraine). Must have at least 2 attacks fulfilling the

following criteria:

1. At least 3 of the following are present:

*6 One of more fully reversible aura symptoms indicating focal cerebral cortical or brainstem

dysfunction.

*7 At least one aura symptom develops gradually over more than 4 minutes.

*8 No aura symptom lasts more than 60 minutes (duration proportionally increases if >1 aura symptompresent).

*9 HA follows aura with free interval of less than 60 minutes (may begin before or with the aura). HA

usually lasts 4 to 72 hours but may be absent.


3. Tension type.

1. Headache with at least 2 of the following:

*10 Pressing or tightening quality

*11 Mild or moderate intensity

*12 Bilateral location

*13 No aggravation by routine physical activity

2. No organic cause found by history, PE, neurologic exam.3. Tension headache is separated into two subtypes based on frequency:

1. Episodic

*14 Headache lasting 30 minutes to 7 days

*15 No nausea or vomiting with headache

*16 Photophobia and phonophobia are absent, or one but

not the other is present

*17 At least 10 previous headaches as above, with number

of headache days


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4. Cluster (episodic or chronic).

1. Severe unilateral orbital, supraorbital, or temporal pain lasting 15 to 180

minutes untreated.

2. Headache is associated with at least 1 of the following on the pain side:

*21 Conjunctival injection

*22 Lacrimation

*23 Nasal congestion

*24 Forehead and facial sweating*25 Rhinorrhea

*26 Miosis

*27 Ptosis

*28 Eyelid edema

3. Frequency of attacks ranges from 1 to 8 daily.

4. At least 5 attacks occur as above.

5. Chronic paroxysmal hemicrania.

1. Severe unilateral orbital, supraorbital, or temporal pain always on the same

side, lasting 2 to 45 minutes.

2. Attack frequency >5 a day for more than half the time (periods of lower

frequency may occur).3. Headache is associated with at least 1 of the following on the pain side:

*29 Conjunctival injection

*30 Lacrimation

*31 Nasal congestion

*32 Rhinorrhea

*33 Eyelid edema

*34 Ptosis

4. Absolute effectiveness of indomethacin (150 mg/day or less).

5. At least 50 attacks occur as above.


2. Secondary headaches.

1. Increased intracranial pressure (pseudotumor cerebri). Idiopathic, 19 of 100,000

in obese young females. Has been associated with tetracycline use. Often presents

with chronic retrobulbar HA exacerbated by eye movements. Also visual changes,

diplopia, meningeal signs, and paresthesias. Exam may reveal papilledema and

cranial nerve VI palsy. CSF normal except for elevated opening pressure (250 to 450

mm H2O). Treatment: weight loss, serial LPs to remove 20 to 40 ml, diuretics,

acetazolamide 500 to 1000 mg QD, prednisone 40 to 60 mg QD, and rarely a shunt.

2. Tumor. HA most common only complaint, though only 50% of tumors present with

HA. 17% have "typical" tumor HA (worse in morning, nausea, vomiting, worse

bending over). Usually other neurologic signs or symptoms help localize tumor.Obtain head CT with contrast or MRI for patients with chronic HA presenting with

new symptoms or abnormal neurologic signs. Treatment: neurosurgical

consultation.

3. Arteritis (giant cell, temporal). Most common symptom is nonspecific headache

often with scalp or temporal artery tenderness. Jaw claudication pathognomic.

Elderly females at increased risk. Sedimentation rate elevated. Biopsy reveals

arteritis.

4. Acute effects of substance use. Occurs within a discrete period after substance use

and disappears with elimination of use.

5. Substance withdrawal. Occurs after >3 months of high daily dose of substance.

Occurs within hours after elimination and relieved by renewed intake. Disappearswith withdrawal of substance. This includes caffeine use.

6. Meningitis and herpes encephalitis..


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7. Drug-rebound headache. Aggravating factors: ergotamine induced, analgesic

abuse (such as >50 g/month ASA or equivalent mild analgesic, >300 mg/month

diazepam.) Treatment: stop drug.

8. Carbon monoxide poisoning.

9. Subarachnoid hemorrhage (SAH). Generally have acute onset of worst headache

of life. May have nausea, vomiting, mental status changes, or loss of consciousness.

Most (59%) have a "warning leak" before severe event and may have antecedent

headaches for weeks. Since mortality is 50% for each bleed, if one can pick up thewarning leak, one can prevent death and illness.

1. May have mental status changes and meningeal signs but may not (39%

initially free of CNS symptoms or signs).

2. Only 10% have initially focal exam.

3. May have fever and leukocytosis from meningeal irritation.

4. CT scan will find only about 90% of SAH (98% in third-generation

scanners). All those who need a CT also need an LP. CT should be done on

those with severe headache that is different from their usual headache or new

onset of headache. In one study, 33% of those with new onset of severe

headache and no CNS signs or symptoms and no other obvious cause of

headache had SAH.5. Response to nonnarcotic and narcotic analgesia does not rule out SAH.

6. Nimodipine reduces the risk of cerebral vasospasm, which may contribute to

mortality. Dose is 60 mg Q4h for 21 days.

3. Physical examination. Vitals (BP and temperature), neurologic deficits, papilledema,

retinal hemorrhage, cranial bruit, thickened tender temporal arteries, trigger point for fascial

pain, ptosis, dilated pupils, and stiff neck.

4. Ancillary tests not necessary if physical exam is negative. Routine CT scanning has low

yield except when headaches are severe - an indication that subarachnoid hemorrhage or a

neurologic deficit may be present.

1. CT should be done to rule out mass lesion.

2. An LP should be done if CT negative and suspect SAH (CT will miss about 10%).

3. Be sure to rule out meningitis, temporal arteritis by the clinical setting. Obtaining a

sedimentation rate in elderly patients with new-onset headaches is prudent.

4. Remember simple causes such as sinusitis, toothache, temporomandibular joint

syndrome.

3. Treatment for Migraine Headache

1. General. Taper off analgesics to prevent rebound HA and start preventive medications.

Depression (if identified) needs to be treated.

2. Nonpharmacologic prophylaxis for migraine.

1. Dietary changes.

1. Avoid monosodium glutamate, nitrates, and alcohol.2. Spread out caffeine evenly.

2. Lifestyle changes. Regular eating, sleeping, and exercise patterns.

3. Behavioral therapies. Biofeedback, stress management, and self-help groups.

3. Acute therapy (outpatient).

1. Acetaminophen or ASA usually are not effective in severe headaches because of

delayed gastric emptying. The uses of metoclopramide 10 mg PO may enhance

the efficacy of oral medication.

2. NSAIDs. Such as ibuprofen 400 to 800 mg PO TID or QID or naproxen sodium 550

mg PO BID or TID with food.

3. Fiorinal 1 or 2 tablets Q4-6h up to 4 per day and twice per week. Avoid overuse.

4. Abortive therapy for migraines. Ergotamine derivatives contraindicated inperipheral or coronary artery disease. Do not use sumatriptan in those who

have had an ergot preparation within the last 24 hours and vice versa.

1. Midrin 2 caps PO initially and then 1 capsule Q1h up to 5 in 12 hours.


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3. Valproic acid 250 to 1500 mg PO daily dose divided BID to QID titrated up

to effective blood levels (50 to 100 mg/L).

9. Fluoxetine 10-30 mg PO Qa.m. Other SSRIs are also effective.

4. Treatment for Severe Tension Headache

1. Symptomatic treatment. Simple analgesics, NSAIDs, or TCAs as above.

2. Preventive treatment. TCAs, beta-blockers, or calcium-channel blockers as above.

5. Treatment for Cluster Headache

1. Acute treatment is by any of the following:1. Oxygen inhalation through a nonrebreathing mask at a flow rate of 6 to 8 L/min for

15 minutes is 70% effective.

2. Nasal lidocaine 4% solution (15 drops) or 5% ointment (3 swabs) intranasally on

ipsilateral side may be abortive.

3. Sumatriptan is especially effective for cluster headache because by definition they

last


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For many years, headache pain during a migraine attack was thought to be a reactive hyperemiain response to vasoconstriction-induced ischemia during aura. This explained the throbbingquality of the headache, its varied localization, and the relief obtained from ergots; however, it didnot explain the prodrome and associated features, the efficacy of some drugs used to treatmigraines that have no effect on blood vessels, and the fact that most patients do not have anaura.Also, intracarotid and single-photon emission computed tomography (SPECT) studies revealed

that the headache is dissociated from hyperperfusion at its onset and termination in patientssuffering from migraine headache with aura. They also revealed that regional cerebral blood flow(rCBF) decreases in the posterior area of the relevant cerebral hemisphere even before the aurais noted and that headache occurred while rCBF remained decreased; rCBF gradually increasedthroughout the remainder of the headache phase. No consistent flow changes have beenidentified in patients suffering from migraine headache without aura, but rCBF remains normal inthe majority. However, bilateral decrease in rCBF beginning at the occipital cortex and spreadinganteriorly has been reported.Cortical spreading depressionThe spread of hypoperfusion propagates at a speed similar to that of cortical spreadingdepression (CSD) and migraine aura. This suggests not only that CSD is the disturbance

resulting in the clinical manifestation of migraine aura but also that this spreading oligemia can beclinically silent (ie, migraine without aura). Perhaps a certain threshold is required to producesymptoms in patients having aura but not in those without aura. CSD with or without clinicalmanifestation (aura) may be a key trigger for the headache of migraine. Although this question isunsettled, CSD has been postulated to directly excite trigeminovascular afferents by promotingrelease of nociceptive substances from neocortex into the interstitial space, causing direct firingof the nociceptive stimulus.Vasoactive substances and neurotransmittersPerivascular nerve activity also results in release of substances such as substance P (SP),neurokinin A (NKA), calcitonin gene-related peptide (CGRP), and nitric oxide (NO), which interactwith the blood vessel wall to produce dilatation, protein extravasation, and sterile inflammation,

stimulating the trigeminocervical complex as shown by induction of c-fos antigen by positronemission tomography (PET) scan. Information then is relayed to the thalamus and cortex forregistering of pain. Involvement of other centers may explain the associated autonomicsymptoms and affective aspects of this pain.Is the neurologically mediated sterile plasma extravasation the cause of this pain? Neurogenicplasma extravasation is inhibited by 5-HT1 agonists, GABA agonists, neurosteroids,prostaglandin inhibitors, SP antagonists, and the endothelin antagonist bosentan; the latter 2 areineffective as antimigraine drugs, showing that blockade of neurogenic plasma extravasation isnot completely predictive of antimigraine efficacy in humans. Neurogenically induced plasmaextravasation may play a role in expression of pain in migraine, but whether this in itself is

sufficient to cause pain is not clear; the presence of other stimulators may be required. Also, thepain process needs not only the activation of nociceptors of pain-producing intracranial structuresbut also reduction in the normal functioning of endogenous pain control pathways that gate thepain.Migraine centerWhat generates a migraine episode? A potential "migraine center" in the brain stem has beenproposed based on findings on PET of persistently elevated rCBF in the brain stem (ie,periaqueductal gray, midbrain reticular formation, locus caeroleus) even after sumatriptanproduced resolution of headache and related symptoms in 9 patients who had experiencedspontaneous attack of migraine without aura. This increased rCBF was not observed outside ofthe attack, suggesting that this activation is not due to pain perception or increased activity of the

endogenous antinociceptive system.That sumatriptan reversed the concomitant increased rCBF in the cerebral cortex but not thebrainstem centers suggests dysfunction in the regulation involved in antinociception and vascularcontrol of these centers. Thalamic processing of pain is known to be gated by ascending


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serotonergic fibers from the dorsal raphe nucleus and from aminergic nuclei in the pontinetegmentum as locus caeroleus and that the latter can alter brain flow and blood-brain barrierpermeability. Perhaps when these modulatory controls are timed to dysfunction, the migrainousprocess ensues.Frequency:

*35 In the US: More than 23 million people in the United States suffer from migraine.This roughly corresponds to 17.6% of females and 6.0% of males.

Mortality/Morbidity: Headaches may serve as a warning: not all severe headaches are due tomigraine; they can be a warning sign of more serious conditions. Headache characteristics thatshould raise concern include the following:

*36 Headaches associated with other neurological signs or symptoms (eg, diplopia, lossof sensation, weakness, ataxia) or those of unusually abrupt onset*37 Headaches that are persistent (especially beyond 72 hours), that first occur after theage of 55 years, or that develop after head injury or major trauma*38 Headaches that are associated with stiff neck or fever*39 Headaches without a clear family history of migraine headache

Race: The prevalence of migraine appears to be lower among African Americans and AsianAmericans than among whites.

Sex:*40 Migraine headaches are reported to affect women more than men.*41 Approximately 75% of all migraineurs are women.

Age:*42 The prevalence of migraine appears to be similar for boys and girls in theprepubescent years.*43 The prevalence of migraine is higher in adolescent girls than in boys of similar age.*44 By early adulthood, migraine is 3 times as frequent in women as it is in men.

History: The typical headache of migraine is throbbing or pulsatile. It is initially unilateral andlocalized in the frontotemporal and ocular area, then builds up over a period of 1-2 hours,progressing posteriorly and becoming diffuse. It typically lasts from several hours to a whole day.Pain intensity is moderate to severe, prompting the patient to remain still as it intensifies evenwith routine physical activity.

*45 The attack commonly occurs when the patient is already awake, although it mayhave already started upon awakening and less commonly may awaken the patient atnight.*46 Nausea and vomiting usually occur later in the attack in about 80% and 50% ofpatients, respectively, along with anorexia and food intolerance.*47 Some patients have been noted to be pale and clammy, especially if nauseadevelops.

*48 Photophobia and/or phonophobia also commonly are associated with the headache.*49 The headache usually subsides gradually within a day and after a period of sleep; amajority of patients report being tired and weak afterwards.*50 About 60% of migraineurs report a prodrome, often occurring hours to days beforeheadache onset. Patients describe a change in mood or behavior that may includepsychological, neurological, constitutional, or autonomic features.

*51 These symptoms may be difficult to diagnose as part of the migraine complexif they occur in isolation from the headache or if they are mild. The prodrome ofmigraine has yet to receive significant investigational attention.*52 Because of the set periodicity of migraine, linkage to the suprachiasmaticnucleus of the hypothalamus that governs circadian rhythm has been proposed.

Discovering the central trigger for migraine would help identify better prophylacticagents.

*53 The migraine aura is a complex of neurological symptoms that may precede oraccompany the headache phase or may occur in isolation.


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*54 It usually develops over 5-20 minutes and lasts less than 60 minutes.*55 The aura can be visual, sensory, motor, or any combination of these.*56 The most characteristic visual aura of migraine is a scintillating scotoma(occurring in about 64% of cases), beginning as a hazy spot from the center of avisual hemifield followed by shimmering light of different patterns expandingperipherally to involve a greater part of the hemifield with scotoma.*57 Paresthesias, occurring in 40% of cases, constitute the next most common

aura; they are often cheiro-oral with numbness starting in the hand then migratingto the arm and then jumping to involve the face, lips, and tongue.*58 As with visual auras, positive symptoms typically are followed by negativesymptoms; paresthesias may be followed by numbness.

*59 Sensory aura rarely occurs in isolation and usually follows visual aura.*60 The rate of spread of sensory aura is helpful in distinguishing it from transientischemic attack (TIA) or a sensory seizure.*61 Just as a visual aura spreads across the visual field slowly, the paresthesiasmay take 10-20 minutes to spread, which is slower than the spread of sensorysymptoms of TIA.*62 The migrainous aura generally resolves within a few minutes and then is

followed by a latent period before the onset of headache, although merging of the 2also is reported.

*63 Motor symptoms may occur in 18% of patients and usually are associated withsensory symptoms.

*64 Motor symptoms often are described as a sense of heaviness of the limbsbefore a headache but without any true weakness.*65 Speech and language disturbances have been reported in 17-20% ofpatients, commonly associated with upper extremity heaviness or weakness.

*66 Whether migraine with and without aura (prevalences, 36% and 55%, respectively)represent 2 distinct processes remains debatable; however, the similarities of theprodrome, headache, and resolution phases of the attacks, similarity in therapeutic

response, and the fact that 9% of patients experience both suggest that they are the sameentity.*67 When an aura is not followed by a headache, it is called a migraine equivalent oracephalic migraine. This is reported most commonly in patients older than 40 years whohave a history of recurrent headache. Scintillating scotoma has been considered to bediagnostic of migraine even in the absence of a headache; however, paresthesias,weakness, and other transient neurological symptoms are not. In the absence of a priorhistory of recurrent headache and first occurrence after age 45 years, TIA should beconsidered and must be investigated fully.*68 Although headache is a very common reason for physician visits, the majority of

headache complaints are benign in origin. However, migraine with its proteanmanifestation may simulate or be simulated by primary and secondary headachedisorders. Also, it can co-exist with a secondary headache disorder. When headache isepisodic, recurrent, and with a well-established pattern, a primary headache disorder islikely. Differentiating between migraine, tension-type, and cluster headaches is important,as optimal treatment may differ.*69 Any of the following features suggest a secondary headache disorder and warrantfurther investigation:

*70 Atypical history or unusual character that does not fulfill the criteria formigraine*71 Occurrence of a new, different, or truly "worst" headache

*72 Change in frequency of episodes or major characteristics of the headache*73 Abnormal neurological examination*74 Inadequate response to optimal therapy


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*75 When patients are seen shortly after the initial headache and their level of anxiety issuch that more than reassurance is needed, further diagnostic studies may be necessary.*76 Severe headache of sudden onset is a concern despite its occurrence in primaryheadache disorders. Typically, migraine is gradual in onset, peaking within 2 hours,although some have abrupt onset; these are termed "crash" migraine and are similar to a"thunderclap" headache.

*77 Cluster headache also may be sudden and excruciating, but it lasts only 15-

180 minutes and is recognized easily if the patient has had previous attacks.Exertional headache builds in intensity over minutes and occurs with sustainedphysical exertion. Coital headache can develop at the height of orgasm or it maybuild up through intercourse.*78 Despite these possibilities, a ruptured intracranial aneurysm is the primaryconsideration if the headache is severe with sudden onset and reaches maximumintensity in minutes. The classical presentation of an aneurysmal subarachnoidhemorrhage (SAH) is a severe headache with sudden, explosive onset, stiff neck,photophobia, nausea and vomiting, and possibly alteration of consciousness. Anextensive evaluation is indicated in this case, including initial CT scan of the headwithout contrast. Lumbar puncture (LP) should be considered if CT scan is

negative, as 25% of cases are missed by CT.*79 The question persists of whether an angiogram should be performed afternormal findings of neurological examination, cerebrospinal fluid (CSF) examination,and CT or MRI. In one study, acute severe thunderclap headache comparable tothat of SAH without the nuchal rigidity occurred in 6.3% of patients with unrupturedaneurysm. Other studies have revealed that in patients with severe thunderclapheadache with normal CT and CSF findings, none developed SAH, leading to moreconfusion. If the CT scan and LP are performed late after symptom onset, so thatnegative results are unreliable, and if clinical features such as family history or pastmedical history, classic SAH-like symptoms, or the presence of neurological signs(in particular a third cranial nerve palsy affecting the pupil) suggest that the patient

is at risk, such patients probably should undergo angiography if an experiencedangiographer is available. In patients with unrevealing studies in whom thediagnosis of aneurysmal SAH is possible but veryunlikely, MRI and magnetic resonance angiography (MRA) are screening tests, andclose follow-up is appropriate if the findings of these tests are negative.

*80 Another concern is the possibility of a space-occupying lesion mimicking migraine.In a series of 111 patients with primary (34%) or metastatic (66%) brain tumor, headachewas reported in 48%; the headache had characteristics similar to migraine in 9% and totension-type headache in 77%, while the so-called classic brain tumor headache occurredin only 17%. Headache was intermittent in 62%, usually lasting a few hours, and was

constant in 36%. It was bilateral in 72% and was moderate to severe in intensity in mostpatients. All patients with headaches similar to migraine had other neurological symptomsor abnormal signs. Of note is that 32% had history of headache; in 36% of those, theheadache was of identical character to prior headaches but was more severe or frequentand was associated with other symptoms such as seizures, confusion, prolonged nausea,and hemiparesis. These data indicate that patients with a history of headache should havefurther diagnostic workup if the headache is accompanied by newsymptoms or abnormal signs or differs in any way from their usual headache. With new-onset headache, imaging should be obtained if headache is severe or occurs with nausea,vomiting, or abnormal signs.*81 Other space-occupying lesions must be considered in the appropriate clinical

setting. Large intraparenchymal hemorrhage presents dramatically with headache andneurological symptoms or signs shortly after onset. Of patients with chronic, subacute, oracute subdural hematoma, 81%, 53%, and 11%, respectively, have headaches. In brain


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abscesses, a progressive, severe, intractable headache is common, and headache isreported in 70-90% of patients.*82 Cerebral venous thrombosis involves the sagittal sinus in about 70% of cases;these patients present with signs and symptoms of increased intracranial pressure (ICP),such as headache and papilledema. Should the thrombus extend to the superficial corticalveins, then focal findings may be noted. In the appropriate setting with known risk factors,cerebral venous thrombosis must be considered and evaluated with MRI, MRA, or

magnetic resonance venography (MRV).*83 Spontaneous internal carotid artery dissection is an uncommon cause of headacheand acute neurological deficit, but it must be considered in the younger individuals whohave unilateral, severe, persistent head pain of sudden onset preceding neurologicalsigns, most commonly Horner syndrome, differentiating it from traumatic causes, in whichcerebral ischemic symptoms are more common.*84 Other secondary causes of alarming headaches should be sought in the presenceof the "red flags" mentioned above and must be sought in the appropriate clinical setting.Other features needing further diagnostic workup include positional headaches, which mayoccur in colloid cysts or other ventricular tumors such as ependymomas, Chiarimalformations, and low CSF pressure headache. Headaches after age 50 years must be

investigated to consider temporal or giant cell arteritis. Headaches associated withsystemic disease require consideration of infectious and non-infectious inflammatoryprocesses.*85 Bear in mind that sumatriptan and related compounds, by virtue of being able toblock expression of c-fos by their action on 5-HT1 receptors, decrease headaches withdiverse pathogenesis. These agents may be effective in decreasing headache painassociated with meningovascular irritation, such as viral and bacterial infections andsubarachnoid hemorrhage. Hence, response to 5-HT1 agonists is not diagnostic of amigraine headache.

Physical:*86 Most patients with headache have a normal neurological examination.

*87 Some abnormal findings suggest a secondary cause, which would necessitate adifferent diagnostic and treatment approach.*88 The presence of papilledema suggests increased ICP and warrants a diagnosticimaging study to rule out a mass lesion.*89 Nuchal rigidity due to meningeal irritation is seen with meningitis and subarachnoidor intraparenchymal hemorrhage.

Arteriovenous MalformationsAtypical Facial Pain

Cerebral AneurysmsChildhood Migraine VariantsChronic Paroxysmal HemicraniaCluster HeadacheCraniopharyngiomaDissection SyndromesGlioblastoma MultiformeHeadache: Pediatric PerspectiveHerpes Simplex EncephalitisIntracranial HemorrhageMeningioma

Meningococcal MeningitisMigraine Headache: Pediatric PerspectiveMigraine VariantsMuscle Contraction Tension Headache
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OligodendrogliomaPituitary TumorsPolyarteritis NodosaPostherpetic NeuralgiaSubarachnoid HemorrhageSystemic Lupus ErythematosusTemporal/Giant Cell Arteritis

Tolosa-Hunt SyndromeViral EncephalitisViral Meningitis

Other Problems to be Considered:Cerebral venous thrombosis

Lab Studies:*90 Diagnostic investigations are performed for the following reasons:

*91 Exclude structural, metabolic, and other causes of headache that can mimicor co-exist with migraine

*92 Rule out comorbid diseases that could complicate headache and itstreatment*93 Establish a baseline for treatment and exclude contraindications to drugadministration*94 Measure drug levels to determine compliance, absorption, or medicationoverdose

Imaging Studies:*95 Neuroimaging is indicated for any of the following:

*96 First or worst headache of the patient's life*97 Change in frequency, severity, or clinical features of the headache*98 Abnormal neurological examination

*99 Progressive or new daily, persistent headache*100 Neurological symptoms that do not meet the criteria for migraine with typicalaura or that themselves warrant investigation*101 Persistent neurological deficit*102 Hemicrania that is always on the same side and associated with contralateralneurological symptoms*103 Inadequate response to routine therapy*104 Atypical clinical presentation

*105 Neuroimaging studies that may be appropriate include CT scan and MRI. Otherstudies such as angiography, MRA, and MRV also may be indicated. See History for more

information on selection of imaging studies.Procedures:*106 Indications for LP include the following:

*107 First or worst headache of a patient's life*108 Severe, rapid-onset, recurrent headache*109 Progressive headache*110 Atypical chronic intractable headache

*111 Neuroimaging (CT scan or MRI) should precede LP to rule out a mass lesion and/orincreased ICP.

Medical Care: Approach to migraine treatment involves acute (abortive) and preventive

(prophylactic) therapy; patients with frequent attacks usually require both. Acute treatment aimsto stop or prevent the progression of a headache or reverse a headache that has started.Preventive treatment, which is given even in the absence of a headache, aims to reduce the
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frequency and severity of the migraine attack, make acute attacks more responsive to abortivetherapy, and perhaps also improve the patient's quality of life.Numerous abortive medications are used for migraine, and the choice for each patient dependsupon the severity of the attacks, associated symptoms such as nausea and vomiting, comorbidproblems, and the patient's treatment response. A stratified approach based on the patient'stherapeutic needs has been advanced, as has a step-care approach. Simple analgesics alone orin combination with other compounds have provided relief for mild to moderately severe and even

at times severe headaches. 5-HT1 agonists and/or opioid analgesics alone or in combination withdopamine antagonists are used for more severe pain. The use of abortive medications must belimited to 2-3 days a week to prevent development of a rebound headache phenomenon.Table 1. Abortive Medication Stratification by Severity

Moderate Severe Extremely Severe

NSAIDsIsometheptheneErgotamineNaratriptanRizatriptan

SumatriptanZolmitriptanDopamineantagonists

NaratriptanRizatriptanSumatriptan (SC,NS)Zolmitriptan

DHE (NS/IM)ErgotamineDopamineantagonists

DHE (IV)Opioids

Dopamineantagonists

*112 Rebound headache has been defined as perpetuation of head pain in chronicheadache sufferers secondary to frequent and excessive use of symptomatic medication.Analgesic overuse may be responsible in part for the transformation of episodic migraineor tension-type headache into daily headache and for the perpetuation of the syndrome;

however, it is not the absolute cause of transformed migraine or chronic tension-typeheadache. Although the actual doses and duration of analgesic overuse needed todevelop rebound headache have not been defined clearly, the use of abortive medicationsmore than 2 days a week often is cited. Also, no major difference is known among varioustypes of analgesics used in the treatment of headache in producing analgesic reboundheadache.*113 In some US headache centers, 50-80% of patients with chronic daily headachesreported analgesic overuse. In a survey, 40% of responders reported that 20% ofheadache patients experience analgesic rebound. The following are clinical features ofanalgesic rebound:

*114 Headache occurs daily or near daily

*115 Occurs in a patient with primary headache disorder who uses immediaterelief medications very frequently, often in excessive quantities*116 Headache varies in intensity, type, severity, and location from time to time*117 Slight physical or intellectual effort bring on headaches; threshold for pain low*118 Headache accompanied by asthenia, nausea and other GI symptoms,restlessness, anxiety, irritability, memory problems, difficulty in intellectualconcentration, and depression*119 Drug-dependent rhythmicity of headaches*120 Evidence of tolerance to analgesics over a period of time*121 Withdrawal symptoms when taken off the medications abruptly*122 Spontaneous improvement of headache on discontinuing the medications

*123 Concomitant prophylactic medications relatively ineffective while the patientis consuming excessive amounts of immediate relief medications. Its pathogenesisis not understood clearly, but it may be partly due to a defective mechanism of 5-HTuptake caused by analgesic overuse.


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*124 To facilitate understanding of the mechanisms of action of the various medications,the relationship between serotonin and migraine is reviewed here briefly, as some of thesestudies partly define the current understanding of migraine. Stimulation of the trigeminalnerve releases SP, CGRP, and NKA from the sensory C-fibers, resulting in neurogenicinflammation that then interacts with the blood vessel wall, producing dilatation, plasmaextravasation, and sterile inflammation. Plasma extravasation has been shown to beblocked by ergots, sumatriptan, and the newer 5-HT1B/D agonists, indomethacin,

acetylsalicylic acid, GABA agonists such as valproic acid and benzodiazepines,neurosteroids, substance P antagonists, and the endothelin antagonist bosentan.*125 Immunohistochemical studies have detected 5-HT1D receptors in trigeminalsensory neurons, including peripheral projections to the dura and within the trigeminalnucleus caudalis (TNC) and solitary tract, while 5-HT1B receptors are present on smoothmuscle cells in meningeal vessels; however, both can be found in both tissues to someextent and even in coronary vessels. These findings suggest that sumatriptan and otherselective 5-HT1 agonists decrease headache by abolishing neuropeptide release in theperiphery and blocking neurotransmission by acting on second-order neurons in thetrigeminocervical complex. All the currently available "triptans" are selective 5-HT1B/D fullagonists. The major differences among these agents lie in their pharmacokinetic

properties, which may affect onset of action (eg, rizatriptan with lesser tmax leading to fasteronset), duration of action (eg, naratriptan with longer half-life leading to lower recurrencerate), bioavailability (eg, naratriptan with higher oralbioavailability leading to more consistent response), and CNS penetration (eg, sumatriptannot shown to cross the intact blood-brain barrier).*126 GABA-A receptor is suggested to reside on the parasympathetic fibers emanatingfrom the sphenopalatine ganglia, as the effects of valproic acid, benzodiazepines, andsteroids are abolished when these projections are sectioned. The possible relationship ofdopamine and migraine has been shown by a direct relationship between dopamineconcentration and migraine symptomatology and the demonstrated efficacy of dopamineantagonists in the acute treatment of migraine.*127 Prophylactic therapy can be considered under the following conditions:

*128 Two or more attacks each month with significant disability that lasts 3 ormore days*129 Contraindication to or ineffectiveness of symptomatic medications*130 Use of abortive medications more than twice a week*131 Migraine variants such as hemiplegic migraine or rare headache attacksproducing profound disruption or risk of permanent neurological injury

*132 Currently, the major prophylactic medications for migraine work via one of thefollowing mechanisms:

*133 5-HT2 antagonism - Methysergide

*134 Regulation of voltage-gated ion channels - Calcium channel blockers*135 Modulation of central neurotransmitters - Beta-blockers, tricyclicantidepressants*136 Enhancing GABAergic inhibition - Valproic acid, gabapentin*137 Another notable mechanism is through alteration of neuronal oxidativemetabolism by riboflavin and reducing neuronal hyperexcitability by magnesiumreplacement.

*138 Like that of abortive medications, the selection of a preventive medication must takeinto consideration comorbid conditions and side effect profile. The majority of preventivemedications have modest efficacies and have therapeutic gains less than 50% whencompared to placebo. The latency between initiation of therapy and onset of positive

treatment response can be quite prolonged. Furthermore, the scientific bases for usingmost of these medications is wanting. Only propranolol, timolol, methysergide, andvalproic acid currently are approved by the US Food and Drug Administration (FDA) formigraine prophylaxis, and only valproic acid has been proven to prevent migraine.


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Table 2. Preventive Drugs

First line High efficacy Beta-blockersTricyclic antidepressantsDivalproex

Low efficacyVerapamilNSAIDs

SSRIs

Second line

High efficacyMethysergideFlunarizineMAOI's

Unproven efficacyCyproheptadineGabapentinLamotrigine

Table 3. Preventive Medication for Comorbid Conditions

Hypertension Beta-blockers

Angina Beta-blockers

Stess Beta-blockers

Depression Tricyclic antidepressants, SSRIs

Underweight Tricyclic antidepressants

Epilepsy Valproic acid

Mania Valproic acid

Diet:

*139 A fraction of migraineurs have dietary triggers. Common triggers include chocolate,aged cheeses and meats, wine and beer (ie, sulfites), and citrus fruits.*140 Obviously, the avoidance of dietary triggers plays an important role in the treatmentof these patients.

Pharmacologic agents used for the treatment of migraine can be classified as abortive (ie,symptomatic) drugs and prophylactic (ie, preventive) agents.

Drug Category:Abortive medications/Selective serotonin receptor (5-HT1) agonists-- The following serotonin receptor (5-HT1) agonists/triptans are used as abortive medications formoderately severe to severe migraine headaches.

Drug Name

Sumatriptan (Imitrex), zolmitriptan (Zomig), naratriptan (Amerge), rizatriptan --Efficacy of SC sumatriptan is 82% at 20 min, that of inhaled is 62% at 2 h, andthat of PO is 60-70% at 4 h.Zolmitriptan at initial dose of 2.5 mg PO has efficacy of 62% at 2 h and 75-78%within 4 h.Naratriptan at 2.5 mg PO has higher bioavailability and longer half-life thansumatriptan, which may contribute to lower rate of headache recurrences. Painrelief experienced by 60-68% of patients within 4 h of treatment and maintainedup to 24 h in 49-67% of patients.Rizatriptan 10 mg PO has reported early onset of action (30 min) and efficacy of71% at 2 h.

Adult Dose Sumatriptan25-100 mg PO; second dose up to 100 mg may be taken after 2 h; additionaldoses may be taken at 2-h intervals; not to exceed 300 mg/d5-20 mg NS inhaled into 1 nostril; second dose may be given after 2 h if


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headache returns or if response is partial; not to exceed 40 mg in 24 h6 mg SC; not to exceed 2 6-mg injections separated by minimum interval of 1 hZolmitriptan2.5-5 mg PO; if headache returns after initial dose, second dose may be givenany time after 2 h of first dose; not to exceed 10 mg/dNaratriptan2.5 mg PO; may be repeated after 4 h if headache recurs or if only partial relief

with initial doseRizatriptan5-10 mg PO disintegrating tab initially; may be repeated every 2 h; not to exceed30 mg within 24 h

Pediatric Dose Not established

Contraindications

Documented hypersensitivity; angina or other signs or symptoms of ischemicheart disease or coronary vasospasm; uncontrolled hypertension; stroke of anytype; peripheral vascular disease; severe renal or hepatic impairment; concurrentergotamine-containing preparations or MAOIs; hemiplegic or basilar migraine

InteractionsTheoretical interactions with ergotamine-containing drugs, MAOIs, and SSRIs;propranolol increases plasma concentration of rizatriptan by 70%

Pregnancy C - Safety for use during pregnancy has not been established.

Precautions

Safety and efficacy in patients >65 y have not been established.Limited data available concerning use during breastfeeding.None of these agents should be used within 24 h of treatment with other 5-HT1agonist or ergotamine-containing or ergot-type medication (eg,dihydroergotamine, methysergide)Tingling, sensation of heat, dizziness, flushing, sensation of burning, pressure,and heaviness are common adverse effects.In patients receiving propranolol, rizatriptan single dose should not exceed 5 mgand total daily dose should not exceed 15 mg in 24 h

Drug Category:Abortive medications/Ergot alkaloids-- These are nonselective 5-HT1agonists that have a wider spectrum of receptor affinities outside of the 5-HT1 system, includingdopamine receptors. They can be used for the abortive treatment of moderately severe to severemigraine headache.

Drug Name

Ergotamine tartrate (Cafatine, Cafergot, Cafetrate), Dihydroergotamine (DHE-45)-- Counteract episodic dilation of extracranial arteries and arterioles.DHE differs from ergotamine tartrate in that it is weaker arterial constrictor, hasless emetic and less uterine effects, and is less likely to produce drug-reboundheadache. DHE 1 mg IM yielded 72% improvement of symptoms (ie, mild pain orno pain) after 1 h.

Adult Dose

Ergotamine tartrate

1 mg PO initially; every 30 min prn; not to exceed 6 mg per attack1-2 mg SL initially; every 30 min prn; not to exceed 6 mg per attack1-2 mg PR initially; every 30 min prn; not to exceed 4 mg per attackDHE1 spray (0.5 mg) NS inhaled in each nostril, repeated after 15 min; not to exceed2 mg0.5-1 mg IM/SC, repeat dose at 1-h intervals; not to exceed 3 mgIV route used when more rapid results desired: 1 mg IV q8h with or withoutmetoclopramide is safe and effective for treatment of status migrainosus


Contraindications

Documented hypersensitivity; peripheral vascular disease; coronary arterydisease; thrombophlebitis; severe hypertension; bradycardia; hepatic or renalimpairment; hyperthyroidism; malnutrition; sepsis; pregnancy; breastfeeding; age>60 y


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wk, except around menses, to prevent drug-induced headacheHepatotoxicity possible in chronic alcoholics following various dose levels ofacetaminophen; severe or recurrent pain or high or continued fever may indicatea serious illness; acetaminophen is contained in many OTC products andcombined use with these products may result in cumulative acetaminophen dosesexceeding recommended maximum dose

Drug Category:Abortive medications/Nonsteroidal anti-inflammatory drugs

(NSAIDs)-- Generally used as abortive therapy in mild to moderately severe type of migraineheadaches; however, they also may be effective for severe headaches, especially ketorolac.

Drug Name Aspirin (Bayer Aspirin, Anacin), Ibuprofen (Motrin, Ibuprin) -- Mild analgesics thatcan be used to treat infrequent migraine episodes.

Adult Dose

Aspirin900-1000 mg PO initially; repeat same dose after 1-2 h prnIbuprofen400-1200 mg/attack PO; may be repeated at dose of 400-800 mg in 1-2 h; not toexceed 3200 mg/dNaproxen sodium

Up to 825 mg PO initially; may give 550 mg after 1-2 h prnKetorolac10 mg PO q4h prn; not to exceed 40 mg/d; limit use to 5 consecutive days30-60 mg IM initially; repeat q6h prn; not to exceed 120 mg/d; limit use to 3consecutive daysIV administration similar to IM but dose used is 30 mg

Pediatric Dose Not recommended

Contraindications

Documented hypersensitivity; active peptic ulcer disease; renal or hepaticimpairment; concomitant or recent use of anticoagulants; hemophilia or otherhemorrhagic conditions

Interactions

Aspirin: Activated charcoal, ammonium chloride, ascorbic acid, methionine,

antacids, urinary alkalizers, carbonic anhydrase inhibitors, corticosteroids,nizatidine, alcohol, ACE inhibitors, oral anticoagulants, beta-blockers, heparin,loop diuretics, methotrexate, nitroglycerin, other NSAIDs, probenecid,sulfinpyrazone, spironolactone, sulfonylureas, insulin, valproic acidIbuprofen: ACE inhibitors, anticoagulants, beta-blockers, cimetidine, cyclosporine,digoxin, dipyridamole, hydantoins, lithium, loop diuretics, methotrexate,penicillamine, probenecid, salicylates, sympathomimetics, thiazide diureticsNaproxen: Other NSAIDs, anticoagulants, thrombolytic agents, probenecid,glucocorticoids, methotrexate and other antineoplastic agents, cephalosporins,insulin and oral hypoglycemic agents


Precautions

Aspirin: The elderly may be more susceptible to CNS effects; should not be usedin last trimester of pregnancyNSAIDs: GI effects such as dyspepsia, nausea, and vomiting are commonadverse effects

Drug Category:Abortive medications/Combination analgesics-- Combinationanalgesics may be used when simple analgesics are not effective and the patient is not acandidate for treatment with 5-HT1 agonists or when the patient needs an alternative drug.

Drug Name Butalbital (Fiorinal), Isometheptene and dichloralphenazone (Midrin) --Combination drugs effective for mild to moderately severe migraine headache.

Adult Dose

Butalbital: 1-2 tab PO q4h prn; not to exceed 6 tabs/d

Isometheptene and dichloralphenazone: 2 caps PO initially then 1 capsule q1huntil symptoms relieved; not to exceed 5 capsules in 12-h period

Pediatric DoseButalbital: Not established in patients


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Contraindications

Butalbital: Documented hypersensitivity; porphyriaIsometheptene and dichloralphenazone: Documented hypersensitivity; glaucoma;severe renal or hepatic impairment or disease; organic heart disease;concomitant MAOIs

Interactions

Butalbital: Effects decreased by coadministration of phenothiazines, quinidine,tricyclic antidepressants, theophylline, haloperidol, chloramphenicol,ethosuximide, corticosteroids, warfarin, doxycycline, and beta-blockers; effects

are increased with coadministration of CNS depressants, methylphenidate,valproic acid, propoxyphene, and benzodiazepinesIsometheptene and dichloralphenazone: Concurrent use of MAOIs withisometheptene may result in severe headache, hypertension and hyperpyrexia,which in turn may result in hypertensive crisis


Precautions

Butalbital: Not recommended for prolonged use because of potential for drugdependency; limit use to not more than 2 d per wk, except around menses, toprevent drug-induced headacheIsometheptene and dichloralphenazone: Use with caution in patients withhypertension, peripheral vascular disease, or recent cardiovascular episodes;

safety in pregnancy not known for isometheptene and dichloralphenazone

Drug Category:Abortive medications/Antiemetics-- As dopamine antagonists, theseagents are effective if nausea and vomiting are prominent features and also may act asprokinetics to increase gastric motility and enhance absorption.

Drug Name

Droperidol (Inapsine), chlorpromazine (Thorazine), metoclopramide (Reglan) --Used alone or in combination with other analgesics as adjuncts, especially ifmigraine attack associated with significant nausea and vomiting. Its role inmigraine based on findings that increased dopamine concentration is associatedwith prominent migraine symptomatology.

Adult Dose

Droperidol: 2.5-10 mg (alone or with an antihistamine) given IM or slow IV

Chlorpromazine: 10-25 mg PO q4-6h prn; 50-100 mg PR q6-8h prn; 25-50 mg IMq3-4h; 5-50 mg IVMetoclopramide: 10-20 mg PO/IM

Pediatric Dose

Droperidol: 1-1.5 mg/9-11 kg for children aged 2-12 yChlorpromazine: 0.55 mg/kg PO/IM q6-8h; not to exceed 75 mg/d for childrenaged 5-12 yMetoclopramide: Not established

Contraindications

Documented hypersensitivity; concurrent drugs that are likely to causeextrapyramidal reactions

InteractionsAnticholinergic drugs, narcotic analgesics, alcohol, sedatives, hypnotics,tranquilizers, MAOIs, and barbiturates


Precautions

Sedation, hypotension, tachycardia, extrapyramidal reactions, hyperactivity,anxiety, and dizziness are common adverse effects, which must be givenconsideration especially for very young and elderly patientsMetoclopramide classified as category B for use in pregnancy

Drug Category: Prophylactic therapy/Antiepileptics-- These drugs are effective inprophylaxis of migraine headache.

Drug Name

Divalproex sodium/valproate (Depakote, Depacon, Depakene) -- Now consideredfirst-line preventive medication for migraine. Believed to enhance GABAneurotransmission, which may suppress events related to migraine that occur in

cortex, perivascular sympathetics, or trigeminal nucleus caudalis. Has beenshown to reduce migraine frequency by 50%.

Adult Dose125-250 mg/d PO initially; titrate dose prn; not to exceed 1500 mg/d; doses higherthan 250 mg/d should be divided bid


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Pediatric Dose Limit use in children


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diabetes; severe depression

Interactions

Decreases effect of diuretics and increases toxicity of methotrexate, lithium, andsalicylates; may diminish reflex tachycardia, resulting from nitroglycerin use,without interfering with hypotensive effects; cimetidine may increase labetalolblood levels; glutethimide may decrease labetalol effects by inducing microsomalenzymes


Precautions

May cause bradycardia, dizziness, nausea, fatigue, depression, memorydisturbance, impotence, and diminished exercise tolerance; caution in impairedhepatic function; discontinue therapy if there are signs of liver dysfunction; inelderly patients, a lower response rate and higher incidence of toxicity may beobserved

Drug Category: Prophylactic therapy/Tricyclic antidepressants-- Amitriptyline,nortriptyline, doxepin, and protriptyline have been used for migraine prophylaxis, but onlyamitriptyline has proven efficacy and appears to exert its antimigraine effect independent of itseffect on depression.

Drug NameAmitriptyline (Elavil), doxepin (Adapin), nortriptyline (Aventyl), protriptyline --Migraine prophylaxis that is effective (independent of antidepressant effect).Mechanism of action is unknown. Inhibits activity of such diverse agents ashistamine, 5-HT, and acetylcholine.

Adult Dose

Amitriptyline, doxepin, nortriptyline: 10-25 mg PO qhs initially; increase by 10-25mg every 1-2 weeks based on efficacy and tolerance; not to exceed 150-175mg/dProtriptyline: 15 mg/d PO initially; titrate prn; not to exceed 40 mg/d given tid orqid

Pediatric Dose12 years: Administer as in adults

Contraindicatio

ns

Documented hypersensitivity; pregnancy or lactation; narrow-angle glaucoma;

urinary retention; cardiac arrhythmias or defects in bundle-branch conduction;concomitant MAOIs

Interactions

Phenobarbital may decrease effects; coadministration with CYP2D6 enzymesystem inhibitors (e.g., cimetidine and quinidine) may increase tricyclicantidepressant levels; tricyclic antidepressants inhibit hypotensive effects ofguanethidine; may interact with thyroid medications, alcohol, CNS depressants,barbiturates, and disulfiram

Pregnancy D - Unsafe in pregnancy

Precautions

Concurrent MAOIs may cause hypertension, hyperpyrexia, seizures, and deathshould not be given within 2 wk of using MAOIsAdverse effects are dose related and include sedation, agitation, tremor, seizures,

anticholinergic effects such as dry mouth, constipation, delayed micturition,blurred vision, increased appetite with weight gain, decreased libido, andexcessive sweating

Drug Category: Prophylactic therapy/Calcium channel blockers-- This group iscommonly used as prophylactic medication, although studies of their effectiveness have shownmixed results. Flunarizine has the best-documented efficacy but is not available in the UnitedStates. The efficacy of verapamil is supported by studies.This group is particularly useful in patients with comorbid hypertension and in those withcontraindications to beta-blockers such as asthma and Raynaud disease. This group may haveparticular advantage in patients with prolonged aura, vertebrobasilar migraine, or hemiplegic

migraine.Drug Name Verapamil (Calan, Covera) -- During depolarization, inhibits calcium ion fromentering slow channels or voltage-sensitive areas of vascular smooth muscle.

Adult Dose 120 mg/d PO qd (sustained release) initially or 40 mg tid; increase gradually; not


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to exceed 480 mg/d


Contraindications

Documented hypersensitivity; bradycardia; second-and third-degree heart block;sick-sinus syndrome; concomitant beta-blockers

Interactions

Phenobarbital may decrease effects; coadministration with CYP2D6 enzymesystem inhibitors (e.g., cimetidine and quinidine) may increase tricyclicantidepressant levels; amitriptyline inhibits hypotensive effects of guanethidine;

may interact with thyroid medications, alcohol, CNS depressants, barbiturates,and disulfiram


Precautions

Patients may report an initial increase in headache, which improves after weeksof treatment; hypotension and dizziness also reported secondary tovasodilatation; increase in peripheral edema may be associated with nifedipineand decrease with nimodipine and verapamil

Drug Category: Prophylactic therapy/Selective serotonin reuptake inhibitors-- Thesemay be considered first-line drugs, but they have low efficacy.

Drug Name

Fluoxetine (Protac), Sertraline (Zoloft), Paroxetine (Paxil) -- Fluoxetine has been

shown by anecdotal reports and small, double-blind, placebo-controlled study tobe of benefit in migraine prophylaxis. Atypical, nontricyclic antidepressant withpotent specific 5-HT-uptake inhibition with fewer anticholinergic andcardiovascular side effects than TCAs.

Adult Dose

Fluoxetine: 10 mg/d PO on waking initially; can be increased every 2 wk; not toexceed 60 mg/dSertraline: 50 mg/d PO initially; increase at weekly interval over several wk; not toexceed 200 mg/dParoxetine: 10 mg/d PO initially; titrate prn; not to exceed 50 mg/d


Contraindicatio

ns

Documented hypersensitivity; pregnancy and lactation; severe renal or hepatic

disease

Interactions

Increases toxicity of MAO inhibitors, diazepam, tolbutamide, and warfarin;serotonin syndrome (ie, myoclonus, rigidity, confusion, nausea, hyperthermia,autonomic instability, coma, eventual death) occurs with simultaneous use ofother serotonergic agents (eg, anorectic agents, tramadol, buspirone, trazodone,clomipramine, nefazodone, tryptophan), discontinue other serotonergic agents atleast 2 wk prior to SSRIs


Precautions

Concurrent MAOIs may cause serious, potentially fatal reactions such asautonomic instabilityAnxiety, insomnia or drowsiness, tremor, anorexia, anorgasmia and other sexual

dysfunctions reported; nausea, flulike symptoms, and agitation also noted, whichresolve within 1-2 wk

Drug Category: Prophylactic therapy/NSAIDs-- These are used as prophylactic agents,but they are associated with a higher risk of adverse effects, particularly gastropathy ornephropathy, than when used as abortive medications. In controlled clinical trials, naproxensodium demonstrated better efficacy than placebo and efficacy similar to propranolol. Tolfenamicacid has also been tried for migraine prophylaxis, but the clinical efficacy is not as good as that ofbeta-blockers, valproate, or methysergide.

Drug NameNaproxen sodium (Anaprox, Naprelan, Naprosyn) -- Inhibits inflammatoryreactions and pain by decreasing activity of cyclooxygenase, enzyme responsible

for prostaglandin synthesis.Adult Dose 275 mg PO tid or 550 mg bid

Pediatric Dose


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ns impairment; concomitant or recent anticoagulants

Interactions

Probenecid may increase toxicity; ibuprofen may decrease effects of loopdiuretics; anticoagulants may prolong PT (watch for signs of bleeding); mayincrease serum lithium levels and risk of methotrexate toxicity (eg, stomatitis,bone marrow suppression, nephrotoxicity)

Pregnancy B - Usually safe but benefits must outweigh the risks.

Precautions

Category D in third trimester of pregnancy; acute renal insufficiency, interstitial

nephritis, hyperkalemia, hyponatremia, and renal papillary necrosis may occur;patients with preexisting renal disease or compromised renal perfusion risk acuterenal failure; leukopenia occurs rarely, is transient, and usually returns to normalduring therapy; persistent leukopenia, granulocytopenia, or thrombocytopeniawarrants further evaluation and may require discontinuation of drug

Drug Category: Prophylactic therapy/Serotonin antagonists-- Reported to provideeffective migraine prophylaxis.

Drug Name

Methysergide (Sansert) -- 5-HT2 antagonist with effective 5-HT1A agonist activityproviding effective migraine prophylaxis in 60% or more of patients, which may begreater in migraineurs with aura.Adverse effects may be severe; should be used only in patients who have notresponded to other preventive agents.

Adult Dose 2 mg/d PO initially; increase dose gradually; not to exceed 8 mg/d

Pediatric Dose Not recommended

Contraindications

Documented hypersensitivity; peripheral vascular disease; severearteriosclerosis; severe hypertension; coronary artery disease; phlebitis orcellulitis of lower extremities; pulmonary disease; collagen disease or fibroticprocesses; impaired renal or hepatic function; valvular heart disease

InteractionsPotentiates effects of CNS depressants; MAO inhibitors may prolong and intensifyanticholinergic and sedative effects


PrecautionsContinuous administration should not exceed 6 mo; retroperitoneal fibrosis andrelated conditions have occurred with uninterrupted use; Allow for 3- to 4-wk drug-free interval after each 6-mo course

Drug Name

Cyproheptadine (Periactin) -- Acts primarily as antagonist of cerebral vascular 5-HT2 receptors and has been used traditionally for pediatric migraine preventiondespite minimal objective evidence of its efficacy.Pizotifen has been shown to be effective for migraine, especially when used incombination with sumatriptan, but is not available in US.

Adult Dose2 mg PO initial dose; increase every third day until beneficial effect demonstratedor until adverse effects occur

Usual maintenance dose: 8-32 mg in 3-4 divided doses

Pediatric Dose2-6 years: 2 mg PO q8-12h; not to exceed 12 mg/d6-14 years: 2-4 mg q8-12h; not to exceed 16 mg/d

Contraindications

Documented hypersensitivity; glaucoma; acute asthmatic attack

InteractionsPotentiates effects of CNS depressants; MAO inhibitors may prolong and intensifyanticholinergic and sedative effects of antihistamines

Pregnancy B - Usually safe but benefits must outweigh the risks.

PrecautionsCommon adverse effects include drowsiness, dizziness, blurred vision, drymouth, increased appetite, and weight gain

Further Inpatient Care:*141 Inpatient care for migraine may be indicated for the following:

*142 Treatment of severe nausea, vomiting, and subsequent dehydration


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*171 Pituitary adenomas*172 Nasopharyngeal carcinoma*173 Vertebral artery aneurysms*174 Metastatic carcinoma of the lung

Medical Care: Pharmacologic management of CH may be classified as abortive/symptomatic orpreventive/prophylactic.

Surgical Care:*175 Invasive nerve blocks and ablative neurosurgical procedures (eg, percutaneousradiofrequency, trigeminal gangliorhizolysis, rhizotomy) all have been implementedsuccessfully in cases of refractory CH.*176 More recently, gamma-knife radiosurgery has provided a less invasive alternativefor pervasive CH.

The pharmacologic management of CH may be divided into abortive/symptomatic andpreventive/prophylactic strategies. Abortive therapy is directed at stopping or reducing theseverity of an acute attack, while prophylactic agents are used to reduce the frequency and

intensity of individual headache exacerbations. Due to the fleeting, short-lived nature of theattacks, effective prophylactic therapy should be considered the cornerstone of treatment. Theprophylactic therapy should start at the onset of a CH cycle and continue until the patient isheadache free for at least 2 weeks. The agent then may be tapered slowly to preventrecurrences.

Drug Category:Abortive agents-- These agents are administered to abort an attack of CH.Because of the duration of the attacks, they must provide immediate relief.

Drug Name

High-flow oxygen -- Inhalation of high-flow,concentrated oxygen extremely effective foraborting CH attack. Precise mechanism of

action poorly understood. Effectivealternative to ergotamine. Despite immediateavailability of oxygen in ED, its widespreaduse in outpatient setting limited byimpracticality.

Adult Dose6-8 L/min concentrated (100%) oxygen byface mask for no longer than 15 min

Contraindications None reported

Interactions None reported

Pregnancy A - Safe in pregnancy

Drug Category: Ergot alkaloids-- These agents are highly effective in relieving acute CHpain.

Drug Name

Ergotamine (Cafatine, Cafergot, Cafetrate,Ercaf) -- Vasoconstrictor of smooth muscle incranial blood vessels, alpha-adrenergicblocker, and nonselective 5-HT agonist. PRor SL preparations of ergotamine tartratepreferred to PO because of immediate onsetof action. Avoid exceeding maximum dosageguidelines to prevent rebound headaches.

Adult Dose 2 tabs PO at first sign of onset, followed by 1

tab q30min prn; not to exceed 6 tabs/attackor 10 tabs/wk 1 tab SL at first sign of onset,followed by 1 tab q30min prn; not to exceed3 tabs/24h or 5 tabs/wk 1 supp PR at first


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sign of onset, followed by second dose prnafter 1 h; not to exceed 2 supp/attack or 5supp/wk

Contraindications Documented hypersensitivity

InteractionsErythromycin, troleandomycin, and othermacrolide antibiotics may increase toxicity

Pregnancy X - Contraindicated in pregnancy

Precautions

Use caution in patients with history ofhypertension or coronary or peripheralarterial insufficiency; use caution in elderly,as may precipitate angina or MI or aggravateintermittent claudication; avoid prolongedadministration or excessive dosage, sinceincreases danger of ergotism or gangrene;patients who take for extended periods maybecome dependent

Drug Name Dihydroergotamine (D.H.E.-45 injection,Migranal) -- Available in IV or intranasalpreparations, tends to cause less arterialvasoconstriction than ergotamine tartrate.

Adult Dose

Up to 2 mg IV; not to exceed 2 mg/dose or 6mg/wk 1 mg IM/SC at first sign of onset; notto exceed 3 mg total 1 spray (0.5 mg) intoeach nostril; not to exceed 6 sprays/d or 8sprays/wk

Contraindications

Documented hypersensitivity; do not usewithin 24 h of sumatriptan, zolmitriptan, other

serotonin agonists, or ergotlike agents; useof MAOIs within last 2 wk

Interactions

May increase effects of heparin;erythromycin, clarithromycin, nitroglycerin,propranolol, and troleandomycin mayincrease toxicity

Pregnancy X - Contraindicated in pregnancy

PrecautionsUse caution in patients with hypertension,angina, peripheral vascular disease, orimpaired renal or hepatic function

Drug Name

Sumatriptan (Imitrex), Zolmitripan (Zomig) --As selective agonists of serotonin 5HT1receptors in cranial arteries, causevasoconstriction and reduce inflammationassociated with antidromic neuronaltransmission in CH. Can reduce severity ofheadache within 15 min of SC injection.Intranasal form recently introduced in US,offering attractive alternative to self-injections. However, slower onset of action

could affect widespread use of newer POselective serotonin receptor agonists(zolmitriptan, naratriptan, rizatriptan) inabortive therapy.


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adverse GI reactions most commonly affectcompliance; use caution in renal or hepaticimpairment; adverse effects include legcramps, paresthesias, edema, and skindiscoloration

Drug Category:Anesthetics-- Local anesthetics stabilize the neuronal membrane so theneuron is less permeable to ions. This prevents initiation and transmission of nerve impulses,

thereby producing the local anesthetic action.

Drug Name

Intranasal lidocaine (4%) -- An experimentaltherapy in CH, blocks conduction of nerveimpulses by decreasing neuronalmembrane's permeability of sodium ions,which results in inhibition of depolarizationand blockade of conduction. Effective in 2separate clinical trials. Intranasaladministration of lidocaine drops requiresspecific and, for many patients, difficulttechnique.

Adult Dose4% solution intranasally; actual dose notestablished

Contraindications Documented hypersensitivity

Interactions May enhance effects of succinylcholine

PregnancyB - Usually safe but benefits must outweighthe risks.

PrecautionsUse extreme caution in patients with markedhypoxia, severe respiratory depression, orbradycardia

Drug Category: Oral opioids and other analgesics-- The short-lived and unpredictablecharacter of CH precludes the effective use of oral narcotics or analgesics. Despite their lack ofefficacy, these substances are abused by some CH sufferers.

Drug Name

Intranasal capsaicin -- This experimentaltherapy successfully tested in clinical trials.Derived from chili peppers, induces releaseof substance P, principal chemomediator ofpain impulses from periphery to CNS. Afterrepeated applications, depletes neuron ofsubstance P and prevents reaccumulation.

Adult DoseFew drops of capsaicin solution applied to

ipsilateral nostrilContraindications Documented hypersensitivity

Interactions None reported

PregnancyC - Safety for use during pregnancy has notbeen established.

Precautions

Avoid contact with eyes; irritant to mucosalmembranes, should be used with caution;warn patients about nasal cavity irritation,burning, congestion, drainage, and sneezingwhile using

Drug Category: Calcium channel blockers-- These agents inhibit the initialvasoconstrictive phase of CH.

Drug Name Verapamil (Calan, Verelan, Covera-HS) --Perhaps most effective calcium channel


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blocker for CH prophylaxis, inhibits calciumions from entering slow channels, selectvoltage-sensitive areas, or vascular smoothmuscle, thereby producing vasodilation.

Adult DoseImmediate release: 120-360 mg/d POdivided tid/qidExtended release form may be given qd

Contraindications

Documented hypersensitivity, sinusbradycardia, cardiogenic shock, advancedheart block, ventricular tachycardia,congestive heart failure, atrial fibrillation orflutter associated with accessory conductionpathways

Interactions

Phenobarbital, hydantoins, vitamin D,sulfinpyrazone, and rifampin may decreaseserum concentrations by increasing hepaticmetabolism; amiodarone may increasetoxicity; beta blockers may increase cardiacdepressant effects on AV conduction;cimetidine may increase serum levels; mayincrease cyclosporine, doxorubicin,theophylline, carbamazepine, vecuronium,and digoxin serum levels


Precautions

Use caution in patients with sick-sinussyndrome, severe left ventriculardysfunction, hepatic or renal impairment, or

hypertrophic cardiomyopathy; monitor ECGand blood pressure closely in patients withsupraventricular tachycardia receiving IVtherapy; adverse effects include constipationand water retention; patients intolerant ofverapamil should try nimodipine, diltiazem,or nifedipine

Drug Category: Mood stabilizers-- Mechanism of action of lithium in CH is unclear,although preliminary evidence suggests that it may interfere with substance P and vasoactiveintestinal peptideinduced arterial relaxation.

Drug Name Lithium carbonate (Eskalith, Lithane,

Lithobid, Lithonate, Lithotabs) -- Effectivelyprevents CH (particularly in its more chronicforms) and treats bipolar mood disorder,another cyclic illness. Responses variable,but still recommended first-line agent in CH.Narrow therapeutic window requires closemonitoring of levels and adverse effects.Plasma lithium level of 0.6-1.2 mEq/Lmeasured at steady state, 12 h after lastdose (ie, just before next dose), usually

sought, but optimal plasma levels forprevention of CH not established. Thoughteffective in CH at serum concentrationslower than those required in bipolar disorder


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(0.3-0.8 mEq/L).

Adult Dose600-900 mg/d PO in divided doses; increaseto 600-1200 mg/d divided bid/qid prn

ContraindicationsDocumented hypersensitivity, severecardiovascular or renal disease

Interactions

Thiazide diuretics, NSAIDs, haloperidol,phenothiazines, neuromuscular blockers,

carbamazepine, fluoxetine, and ACEinhibitors may increase serum levels andtoxicity; theophylline, caffeine, and otherxanthines decrease effects


Precautions

Lithium toxicity can occur at therapeuticdoses; use caution in patients withcardiovascular or thyroid disease, severedebilitation, dehydration, or sodiumdepletion, or in patients taking diuretics;adverse effects include tremor, polyuria,diarrhea, nausea, fatigue, weight gain, andthyroid dysfunction; renal toxicity with tubulardamage and interstitial fibrosis may occur;CNS toxicity manifested by confusion andataxia

Drug Category: Corticosteroids-- These agents are extremely effective in terminating a CHcycle and in preventing immediate headache recurrence. High-dose prednisone is prescribed forthe first few days, followed by a gradual taper. The simultaneous use of standard prophylacticagents (eg, verapamil) is recommended. The mechanism of action in CH is still subject tospeculation.

Drug Name

Prednisone (Deltasone) -- Effective fortreatment of CH not responsive to lithium ormethysergide. Effects in CH may occur viainhibition of prostaglandin synthesis. Long-term use not recommended.

Adult Dose40-60 mg/d PO in divided doses for 5 d,followed by slow taper over 2-4 wk

ContraindicationsDocumented hypersensitivity; systemicfungal infections or serious infections, exceptseptic shock or tuberculous meningitis

InteractionsBarbiturates, phenytoin, and rifampindecrease effects; may decrease effects ofsalicylates


Precautions

Use cautiously in patients with diabetes,hypothyroidism, cirrhosis, congestive heartfailure, thromboembolic disorders, orulcerative colitis; chronic use may lead togastric ulceration, immunosuppression,electrolyte disturbances, weight gain, and

osteopenia

Prognosis:*177 Eighty percent of patients with episodic CH tend to maintain the episodic form.


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*178 Episodic CH eventually transforms into chronic CH in 4-13% of patients.Intermediate (mixed) forms may occur.*179 Prolonged, spontaneous remissions have been described in up to 12% of patientsin some series, particularly in episodic CH. Chronic CH is more relentless and may persistin this form in up to 55% of cases. Less frequently, chronic CH may remit into an episodicform.*180 Generally, CH is a lifelong problem.

*181 Pharmacologic intervention may play a part in the transformation of chronic CH intothe episodic form; otherwise, it does not influence outcome.*182 Late onset of this disorder, along with male sex and a previous history of episodicCH, predict a less favorable course.

lecture8 headache

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