Lecture8 Headache

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 symptom
present).
*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
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 <180/year and <15/month
2. Chronic
*18 Headache averages 15 days/month (180 days/year), 6
months
*19 No vomiting
*20 No more than 1 of the following: nausea, photophobia,
or phonophobia
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. Disappears
with withdrawal of substance. This includes caffeine use.
6. Meningitis and herpes encephalitis..
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 the
warning 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 in
peripheral 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.
2. Sumatriptan (Imitrex) 6 mg SQ; may repeat in 1 hour; maximum 12 mg/24
hours. Contraindicated if concomitant CAD or uncontrolled hypertension. Do
not use if patient is given an ergot alkaloid in the last 24 hours. Many (up to
50%) will require rescue medicine because of sumatriptan's 2-hour halflife.
Oral sumatriptan available but not so effective.
3. Cafergot 1 or 2 tablets PO; may repeat up to 4 tabs/attack or 10/week.
4. Ergotamine 2 mg PO or SL; may repeat in 30 minutes up to 6 mg/24 hours or
10 mg/week.
5. Prochlorperazine 25 mg PR BID PRN can be used to abort the migraine at
home.
4. Acute therapy (emergency room): migraine.
1. Antiemetics may in themselves abort the headache.
1. Prochlorperazine (Compazine) 10 mg IV or chlorpromazine 25 to 75 mg IV.
Chlorpromazine has fallen out of favor because of hypotension, which can be
treated with IV NS.
2. Metoclopramide 5 to 10 mg IV Q8h. Often given with dihydroergotamine
(DHE) to prevent DHE-induced nausea. May be combined orally with ASA.
2. NSAIDs (ketorolac [Toradol] 60 mg IM, indomethacin [Indocin] 50 mg PR BID or
TID). Not so effective in migraines.
3. Dihydroergotamine (DHE) 0.75 mg IV over a few minutes preceded by
prochlorperazine or metoclopramide 10 mg IV. Another 0.5 mg of DHE may be
given in 30 minutes. Contraindicated in peripheral or coronary artery disease or
those who are >60 years of age or those who have had sumatriptan.
4. Meperidine (Demerol) 50 to 100 mg IM Q3h PRN.
5. Dexamethasone 4 mg IM or a short course of prednisone (40 to 60 mg PO QD),
combined with analgesics above, if migraine continues >24 hours.
6. Sumatriptan (Imitrex); see above for dose. Oral sumatriptan also available but less
effective.
7. Lidocaine 100 mg IV once for intractable headache. Patient should not drive after
treatment. Risk for seizures, arrhythmia, confusion.
8. Transnasal butorphanol 1 mg (1 spray in 1 nostril) repeated if necessary in 60 to 90
minutes.
5. Prophylaxis.
1. Amitriptyline 10 to 200 mg PO QHS. Other tricyclic antidepressants (TCAs) also
effective.
2. Propranolol 20 to 60 mg PO BID to QID. Long-acting form can be used. Consider
switching to a second beta-blocker if first one fails after adequate trial period (6 to 8
weeks). Contraindicated in asthma, heart failure, and diabetes.
3. Verapamil 40 to 80 mg PO TID (80 to 240 mg/day). Diltiazem and nifedipine are
less effective. More beneficial in migraine with aura or cluster headache. Trial
should be .2 months. Contraindicated in heart failure and heart block. Constipation is
a common side effect.
4. NSAIDs, especially useful for menstrual migraine.
5. Cyproheptadine 2 to 4 mg PO QID. Less effective than methysergide but safe.
6. Methysergide (Sansert) 1 to 2 mg PO QID. Should not use longer than 6 months
without a 1-month drug holiday to avoid fibrosis. Contraindicated in peripheral or
coronary artery disease.
7. Ergotamine (low dose) 1 mg PO BID, not to exceed 10 mg/week (2 days/week
skipped), contraindicated in ischemic diseases.
8. Anticonvulsants.
1. Carbamazepine 200 to 800 mg PO daily dose divided BID to QID.
2. Phenytoin 300 to 800 mg PO daily dose divided QD to TID. Efficacy not
shown for migraine with aura.
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 <3 hours. However, this is not an approved usage.
4. Parenteral therapy as above.
2. Prophylactic treatment. Low-dose oral ergotamine, methy-sergide, prednisone (60 mg QD
for 1 week with a rapid tapering off), verapamil (80 to 160 mg TID), lithium carbonate 300
mg BID or TID, with or without valproate 250 to 1500 mg total daily dose divided BID to
QID.
Table 14-1 Characteristics of Various Types of Primary Headaches
Headache Quality Location Duration Associated symptoms

Migraine Throbbi Unilateral or 6-48 hours Nausea, vomiting, photophobia
without aura ng bilateral
Migraine Throbbi Unilateral 3-12 hours Visual prodrome, nausea, vomiting, photophobia
with aura ng
Tension Dull Diffuse Unremitting Depression
type bilateral
Cluster Boring Unilateral 15-120 Ipsilateral tearing, Horner's syndrome, nasal
(M:F = 5:1) especially minutes stuffiness
orbital
Subarachnoi Throbbi Variable Variable May have focal neurologic symptoms or
d ng, decreased level of consciousness but may be alert
hemorrhage severe with nonfocal exam
Chronic Severe Unilateral,
paroxysmal orbital, or
hemicrania temporal
Migraine Headache
Synonyms, Key Words, and Related Terms: complex migraine, migraine equivalent
Background: Although migraine is a term applied to certain headaches with a vascular quality,
overwhelming evidence suggests that migraine is a dominantly inherited disorder characterized
by varying degrees of recurrent vascular-quality headache, photophobia, sleep disruption, and
depression.
Pathophysiology: The mechanisms of migraine remain not completely understood. However,
the advent of new technologies has allowed formulation of current concepts that may explain
parts of the migraine syndrome.
Vascular theory
For many years, headache pain during a migraine attack was thought to be a reactive hyperemia
in response to vasoconstriction-induced ischemia during aura. This explained the throbbing
quality of the headache, its varied localization, and the relief obtained from ergots; however, it did
not explain the prodrome and associated features, the efficacy of some drugs used to treat
migraines that have no effect on blood vessels, and the fact that most patients do not have an
aura.
Also, intracarotid and single-photon emission computed tomography (SPECT) studies revealed
that the headache is dissociated from hyperperfusion at its onset and termination in patients
suffering 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 aura
is noted and that headache occurred while rCBF remained decreased; rCBF gradually increased
throughout the remainder of the headache phase. No consistent flow changes have been
identified in patients suffering from migraine headache without aura, but rCBF remains normal in
the majority. However, bilateral decrease in rCBF beginning at the occipital cortex and spreading
anteriorly has been reported.
Cortical spreading depression
The spread of hypoperfusion propagates at a speed similar to that of cortical spreading
depression (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 be
clinically silent (ie, migraine without aura). Perhaps a certain threshold is required to produce
symptoms in patients having aura but not in those without aura. CSD with or without clinical
manifestation (aura) may be a key trigger for the headache of migraine. Although this question is
unsettled, CSD has been postulated to directly excite trigeminovascular afferents by promoting
release of nociceptive substances from neocortex into the interstitial space, causing direct firing
of the nociceptive stimulus.
Vasoactive substances and neurotransmitters
Perivascular 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 interact
with 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 positron
emission tomography (PET) scan. Information then is relayed to the thalamus and cortex for
registering of pain. Involvement of other centers may explain the associated autonomic
symptoms and affective aspects of this pain.
Is the neurologically mediated sterile plasma extravasation the cause of this pain? Neurogenic
plasma extravasation is inhibited by 5-HT1 agonists, GABA agonists, neurosteroids,
prostaglandin inhibitors, SP antagonists, and the endothelin antagonist bosentan; the latter 2 are
ineffective as antimigraine drugs, showing that blockade of neurogenic plasma extravasation is
not completely predictive of antimigraine efficacy in humans. Neurogenically induced plasma
extravasation 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, the
pain process needs not only the activation of nociceptors of pain-producing intracranial structures
but also reduction in the normal functioning of endogenous pain control pathways that gate the
pain.
Migraine center
What generates a migraine episode? A potential "migraine center" in the brain stem has been
proposed based on findings on PET of persistently elevated rCBF in the brain stem (ie,
periaqueductal gray, midbrain reticular formation, locus caeroleus) even after sumatriptan
produced resolution of headache and related symptoms in 9 patients who had experienced
spontaneous attack of migraine without aura. This increased rCBF was not observed outside of
the 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 the
brainstem centers suggests dysfunction in the regulation involved in antinociception and vascular
control of these centers. Thalamic processing of pain is known to be gated by ascending
serotonergic fibers from the dorsal raphe nucleus and from aminergic nuclei in the pontine
tegmentum as locus caeroleus and that the latter can alter brain flow and blood-brain barrier
permeability. Perhaps when these modulatory controls are timed to dysfunction, the migrainous
process 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 to
migraine; they can be a warning sign of more serious conditions. Headache characteristics that
should raise concern include the following:
*36 Headaches associated with other neurological signs or symptoms (eg, diplopia, loss
of sensation, weakness, ataxia) or those of unusually abrupt onset
*37 Headaches that are persistent (especially beyond 72 hours), that first occur after the
age 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 Asian
Americans 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 the
prepubescent 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 and
localized 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 even
with routine physical activity.
*45 The attack commonly occurs when the patient is already awake, although it may
have already started upon awakening and less commonly may awaken the patient at
night.
*46 Nausea and vomiting usually occur later in the attack in about 80% and 50% of
patients, respectively, along with anorexia and food intolerance.
*47 Some patients have been noted to be pale and clammy, especially if nausea
develops.
*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; a
majority of patients report being tired and weak afterwards.
*50 About 60% of migraineurs report a prodrome, often occurring hours to days before
headache onset. Patients describe a change in mood or behavior that may include
psychological, neurological, constitutional, or autonomic features.
*51 These symptoms may be difficult to diagnose as part of the migraine complex
if they occur in isolation from the headache or if they are mild. The prodrome of
migraine has yet to receive significant investigational attention.
*52 Because of the set periodicity of migraine, linkage to the suprachiasmatic
nucleus of the hypothalamus that governs circadian rhythm has been proposed.
Discovering the central trigger for migraine would help identify better prophylactic
agents.
*53 The migraine aura is a complex of neurological symptoms that may precede or
accompany the headache phase or may occur in isolation.
*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 a
visual hemifield followed by shimmering light of different patterns expanding
peripherally 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 migrating
to the arm and then jumping to involve the face, lips, and tongue.
*58 As with visual auras, positive symptoms typically are followed by negative
symptoms; 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 transient
ischemic attack (TIA) or a sensory seizure.
*61 Just as a visual aura spreads across the visual field slowly, the paresthesias
may take 10-20 minutes to spread, which is slower than the spread of sensory
symptoms 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 2
also is reported.
*63 Motor symptoms may occur in 18% of patients and usually are associated with
sensory symptoms.
*64 Motor symptoms often are described as a sense of heaviness of the limbs
before a headache but without any true weakness.
*65 Speech and language disturbances have been reported in 17-20% of
patients, 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 the
prodrome, 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 same
entity.
*67 When an aura is not followed by a headache, it is called a migraine equivalent or
acephalic migraine. This is reported most commonly in patients older than 40 years who
have a history of recurrent headache. Scintillating scotoma has been considered to be
diagnostic of migraine even in the absence of a headache; however, paresthesias,
weakness, and other transient neurological symptoms are not. In the absence of a prior
history of recurrent headache and first occurrence after age 45 years, TIA should be
considered 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 protean
manifestation may simulate or be simulated by primary and secondary headache
disorders. Also, it can co-exist with a secondary headache disorder. When headache is
episodic, recurrent, and with a well-established pattern, a primary headache disorder is
likely. 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 warrant
further investigation:
*70 Atypical history or unusual character that does not fulfill the criteria for
migraine
*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
*75 When patients are seen shortly after the initial headache and their level of anxiety is
such 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 primary
headache 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 sustained
physical exertion. Coital headache can develop at the height of orgasm or it may
build up through intercourse.
*78 Despite these possibilities, a ruptured intracranial aneurysm is the primary
consideration if the headache is severe with sudden onset and reaches maximum
intensity in minutes. The classical presentation of an aneurysmal subarachnoid
hemorrhage (SAH) is a severe headache with sudden, explosive onset, stiff neck,
photophobia, nausea and vomiting, and possibly alteration of consciousness. An
extensive evaluation is indicated in this case, including initial CT scan of the head
without 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 after
normal findings of neurological examination, cerebrospinal fluid (CSF) examination,
and CT or MRI. In one study, acute severe thunderclap headache comparable to
that of SAH without the nuchal rigidity occurred in 6.3% of patients with unruptured
aneurysm. Other studies have revealed that in patients with severe thunderclap
headache with normal CT and CSF findings, none developed SAH, leading to more
confusion. If the CT scan and LP are performed late after symptom onset, so that
negative results are unreliable, and if clinical features such as family history or past
medical 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 experienced
angiographer is available. In patients with unrevealing studies in whom the
diagnosis of aneurysmal SAH is possible but very
unlikely, MRI and magnetic resonance angiography (MRA) are screening tests, and
close 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, headache
was reported in 48%; the headache had characteristics similar to migraine in 9% and to
tension-type headache in 77%, while the so-called classic brain tumor headache occurred
in 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 most
patients. All patients with headaches similar to migraine had other neurological symptoms
or abnormal signs. Of note is that 32% had history of headache; in 36% of those, the
headache was of identical character to prior headaches but was more severe or frequent
and was associated with other symptoms such as seizures, confusion, prolonged nausea,
and hemiparesis. These data indicate that patients with a history of headache should have
further diagnostic workup if the headache is accompanied by new
symptoms 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 and
neurological symptoms or signs shortly after onset. Of patients with chronic, subacute, or
acute subdural hematoma, 81%, 53%, and 11%, respectively, have headaches. In brain
abscesses, a progressive, severe, intractable headache is common, and headache is
reported 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 cortical
veins, 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 headache
and acute neurological deficit, but it must be considered in the younger individuals who
have unilateral, severe, persistent head pain of sudden onset preceding neurological
signs, most commonly Horner syndrome, differentiating it from traumatic causes, in which
cerebral ischemic symptoms are more common.
*84 Other secondary causes of alarming headaches should be sought in the presence
of the "red flags" mentioned above and must be sought in the appropriate clinical setting.
Other features needing further diagnostic workup include positional headaches, which may
occur in colloid cysts or other ventricular tumors such as ependymomas, Chiari
malformations, and low CSF pressure headache. Headaches after age 50 years must be
investigated to consider temporal or giant cell arteritis. Headaches associated with
systemic disease require consideration of infectious and non-infectious inflammatory
processes.
*85 Bear in mind that sumatriptan and related compounds, by virtue of being able to
block expression of c-fos by their action on 5-HT1 receptors, decrease headaches with
diverse pathogenesis. These agents may be effective in decreasing headache pain
associated with meningovascular irritation, such as viral and bacterial infections and
subarachnoid hemorrhage. Hence, response to 5-HT1 agonists is not diagnostic of a
migraine headache.
Physical:
*86 Most patients with headache have a normal neurological examination.
*87 Some abnormal findings suggest a secondary cause, which would necessitate a
different diagnostic and treatment approach.
*88 The presence of papilledema suggests increased ICP and warrants a diagnostic
imaging study to rule out a mass lesion.
*89 Nuchal rigidity due to meningeal irritation is seen with meningitis and subarachnoid
or intraparenchymal hemorrhage.
Arteriovenous Malformations
Atypical Facial Pain
Cerebral Aneurysms
Childhood Migraine Variants
Chronic Paroxysmal Hemicrania
Cluster Headache
Craniopharyngioma
Dissection Syndromes
Glioblastoma Multiforme
Headache: Pediatric Perspective
Herpes Simplex Encephalitis
Intracranial Hemorrhage
Meningioma
Meningococcal Meningitis
Migraine Headache: Pediatric Perspective
Migraine Variants
Muscle Contraction Tension Headache
Oligodendroglioma
Pituitary Tumors
Polyarteritis Nodosa
Postherpetic Neuralgia
Subarachnoid Hemorrhage
Systemic Lupus Erythematosus
Temporal/Giant Cell Arteritis
Tolosa-Hunt Syndrome
Viral Encephalitis
Viral 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 mimic
or co-exist with migraine
*92 Rule out comorbid diseases that could complicate headache and its
treatment
*93 Establish a baseline for treatment and exclude contraindications to drug
administration
*94 Measure drug levels to determine compliance, absorption, or medication
overdose
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 typical
aura or that themselves warrant investigation
*101 Persistent neurological deficit
*102 Hemicrania that is always on the same side and associated with contralateral
neurological symptoms
*103 Inadequate response to routine therapy
*104 Atypical clinical presentation
*105 Neuroimaging studies that may be appropriate include CT scan and MRI. Other
studies 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/or
increased ICP.
Medical Care: Approach to migraine treatment involves acute (abortive) and preventive
(prophylactic) therapy; patients with frequent attacks usually require both. Acute treatment aims
to 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
frequency and severity of the migraine attack, make acute attacks more responsive to abortive
therapy, and perhaps also improve the patient's quality of life.
Numerous abortive medications are used for migraine, and the choice for each patient depends
upon the severity of the attacks, associated symptoms such as nausea and vomiting, comorbid
problems, and the patient's treatment response. A stratified approach based on the patient's
therapeutic needs has been advanced, as has a step-care approach. Simple analgesics alone or
in 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 with
dopamine antagonists are used for more severe pain. The use of abortive medications must be
limited 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

NSAIDs
Naratriptan
Isomethepthene
Rizatriptan
Ergotamine
Sumatriptan (SC,NS) DHE (IV)
Naratriptan
Zolmitriptan Opioids
Rizatriptan
DHE (NS/IM) Dopamine
Sumatriptan
Ergotamine antagonists
Zolmitriptan
Dopamine
Dopamine
antagonists
antagonists
*112 Rebound headache has been defined as perpetuation of head pain in chronic
headache sufferers secondary to frequent and excessive use of symptomatic medication.
Analgesic overuse may be responsible in part for the transformation of episodic migraine
or 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-type
headache. Although the actual doses and duration of analgesic overuse needed to
develop rebound headache have not been defined clearly, the use of abortive medications
more than 2 days a week often is cited. Also, no major difference is known among various
types of analgesics used in the treatment of headache in producing analgesic rebound
headache.
*113 In some US headache centers, 50-80% of patients with chronic daily headaches
reported analgesic overuse. In a survey, 40% of responders reported that 20% of
headache patients experience analgesic rebound. The following are clinical features of
analgesic rebound:
*114 Headache occurs daily or near daily
*115 Occurs in a patient with primary headache disorder who uses immediate
relief 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 intellectual
concentration, 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 patient
is consuming excessive amounts of immediate relief medications. Its pathogenesis
is not understood clearly, but it may be partly due to a defective mechanism of 5-HT
uptake caused by analgesic overuse.
*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 these
studies partly define the current understanding of migraine. Stimulation of the trigeminal
nerve releases SP, CGRP, and NKA from the sensory C-fibers, resulting in neurogenic
inflammation that then interacts with the blood vessel wall, producing dilatation, plasma
extravasation, and sterile inflammation. Plasma extravasation has been shown to be
blocked 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 trigeminal
sensory neurons, including peripheral projections to the dura and within the trigeminal
nucleus caudalis (TNC) and solitary tract, while 5-HT1B receptors are present on smooth
muscle cells in meningeal vessels; however, both can be found in both tissues to some
extent and even in coronary vessels. These findings suggest that sumatriptan and other
selective 5-HT1 agonists decrease headache by abolishing neuropeptide release in the
periphery and blocking neurotransmission by acting on second-order neurons in the
trigeminocervical complex. All the currently available "triptans" are selective 5-HT1B/D full
agonists. The major differences among these agents lie in their pharmacokinetic
properties, which may affect onset of action (eg, rizatriptan with lesser tmax leading to faster
onset), duration of action (eg, naratriptan with longer half-life leading to lower recurrence
rate), bioavailability (eg, naratriptan with higher oral
bioavailability leading to more consistent response), and CNS penetration (eg, sumatriptan
not shown to cross the intact blood-brain barrier).
*126 GABA-A receptor is suggested to reside on the parasympathetic fibers emanating
from the sphenopalatine ganglia, as the effects of valproic acid, benzodiazepines, and
steroids are abolished when these projections are sectioned. The possible relationship of
dopamine and migraine has been shown by a direct relationship between dopamine
concentration and migraine symptomatology and the demonstrated efficacy of dopamine
antagonists 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 or
more 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 attacks
producing profound disruption or risk of permanent neurological injury
*132 Currently, the major prophylactic medications for migraine work via one of the
following mechanisms:
*133 5-HT2 antagonism - Methysergide
*134 Regulation of voltage-gated ion channels - Calcium channel blockers
*135 Modulation of central neurotransmitters - Beta-blockers, tricyclic
antidepressants
*136 Enhancing GABAergic inhibition - Valproic acid, gabapentin
*137 Another notable mechanism is through alteration of neuronal oxidative
metabolism by riboflavin and reducing neuronal hyperexcitability by magnesium
replacement.
*138 Like that of abortive medications, the selection of a preventive medication must take
into consideration comorbid conditions and side effect profile. The majority of preventive
medications have modest efficacies and have therapeutic gains less than 50% when
compared to placebo. The latency between initiation of therapy and onset of positive
treatment response can be quite prolonged. Furthermore, the scientific bases for using
most of these medications is wanting. Only propranolol, timolol, methysergide, and
valproic acid currently are approved by the US Food and Drug Administration (FDA) for
migraine prophylaxis, and only valproic acid has been proven to prevent migraine.
Table 2. Preventive Drugs
First line High efficacy Beta-blockers

Tricyclic antidepressants
Divalproex
Verapamil
Low efficacy NSAIDs
SSRIs
Methysergide
High efficacy Flunarizine
MAOI's
Second line
Cyproheptadine
Unproven efficacy Gabapentin
Lamotrigine
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 treatment
of 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 for
moderately severe to severe migraine headaches.
Sumatriptan (Imitrex), zolmitriptan (Zomig), naratriptan (Amerge), rizatriptan --
Efficacy of SC sumatriptan is 82% at 20 min, that of inhaled is 62% at 2 h, and
that 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.
Drug Name
Naratriptan at 2.5 mg PO has higher bioavailability and longer half-life than
sumatriptan, which may contribute to lower rate of headache recurrences. Pain
relief experienced by 60-68% of patients within 4 h of treatment and maintained
up to 24 h in 49-67% of patients.
Rizatriptan 10 mg PO has reported early onset of action (30 min) and efficacy of
71% at 2 h.
Adult Dose Sumatriptan
25-100 mg PO; second dose up to 100 mg may be taken after 2 h; additional
doses may be taken at 2-h intervals; not to exceed 300 mg/d
5-20 mg NS inhaled into 1 nostril; second dose may be given after 2 h if
headache returns or if response is partial; not to exceed 40 mg in 24 h
6 mg SC; not to exceed 2 6-mg injections separated by minimum interval of 1 h
Zolmitriptan
2.5-5 mg PO; if headache returns after initial dose, second dose may be given
any time after 2 h of first dose; not to exceed 10 mg/d
Naratriptan
2.5 mg PO; may be repeated after 4 h if headache recurs or if only partial relief
with initial dose
Rizatriptan
5-10 mg PO disintegrating tab initially; may be repeated every 2 h; not to exceed
30 mg within 24 h
Pediatric Dose Not established
Documented hypersensitivity; angina or other signs or symptoms of ischemic
Contraindicatio heart disease or coronary vasospasm; uncontrolled hypertension; stroke of any
ns type; peripheral vascular disease; severe renal or hepatic impairment; concurrent
ergotamine-containing preparations or MAOIs; hemiplegic or basilar migraine
Theoretical interactions with ergotamine-containing drugs, MAOIs, and SSRIs;
Interactions
propranolol increases plasma concentration of rizatriptan by 70%
Pregnancy C - Safety for use during pregnancy has not been established.
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-HT1
agonist or ergotamine-containing or ergot-type medication (eg,
Precautions 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 mg
and total daily dose should not exceed 15 mg in 24 h
Drug Category: Abortive medications/Ergot alkaloids -- These are nonselective 5-HT1
agonists that have a wider spectrum of receptor affinities outside of the 5-HT1 system, including
dopamine receptors. They can be used for the abortive treatment of moderately severe to severe
migraine headache.
Ergotamine tartrate (Cafatine, Cafergot, Cafetrate), Dihydroergotamine (DHE-45)
-- Counteract episodic dilation of extracranial arteries and arterioles.
Drug Name DHE differs from ergotamine tartrate in that it is weaker arterial constrictor, has
less emetic and less uterine effects, and is less likely to produce drug-rebound
headache. DHE 1 mg IM yielded 72% improvement of symptoms (ie, mild pain or
no pain) after 1 h.
Ergotamine tartrate
1 mg PO initially; every 30 min prn; not to exceed 6 mg per attack
1-2 mg SL initially; every 30 min prn; not to exceed 6 mg per attack
1-2 mg PR initially; every 30 min prn; not to exceed 4 mg per attack
DHE
Adult Dose
1 spray (0.5 mg) NS inhaled in each nostril, repeated after 15 min; not to exceed
2 mg
0.5-1 mg IM/SC, repeat dose at 1-h intervals; not to exceed 3 mg
IV route used when more rapid results desired: 1 mg IV q8h with or without
metoclopramide is safe and effective for treatment of status migrainosus
Documented hypersensitivity; peripheral vascular disease; coronary artery
Contraindicatio disease; thrombophlebitis; severe hypertension; bradycardia; hepatic or renal
ns impairment; hyperthyroidism; malnutrition; sepsis; pregnancy; breastfeeding; age
>60 y
Increase effects of heparin; increase toxicity of nitroglycerin, propranolol,
Interactions
erythromycin, vasoconstrictors, 5-HT1 agonists, and clarithromycin
Pregnancy X - Contraindicated in pregnancy
Ergotamine tartrate not recommended for prolonged use and may cause
significant rebound headache
Precautions
Avoid using prolonged regimens due to danger of causing gangrene as well as
dependency
Drug Category: Abortive medications/analgesics -- These agents are used as initial
abortive therapy for patients with infrequent migraines.
Acetaminophen (Tylenol), propoxyphene (Darvon), oxycodone (OxyContin),
morphine -- Used as ‘rescue’ medications if migraine headache not controlled
Drug Name
with standard treatment, or if 5-HT1 agonists contraindicated.
Acetaminophen (with or without metoclopramide) in particular is the first choice
for treatment of migraine attacks during pregnancy and breastfeeding.
Acetaminophen
650-1000 mg PO initially, may be repeated after 1-2 h prn
Propoxyphene
Propoxyphene HCl: 65 mg PO q4h prn; not to exceed 390 mg/d
Propoxyphene napsylate: 100 mg PO q4h prn; not to exceed 600 mg/d
(Propoxyphene napsylate 100 mg = propoxyphene HCl 65 mg)
Oxycodone
5 mg PO q6h prn
Morphine
Adult Dose 10-30 mg PO q4h prn
5-20 mg/70 kg IM/SC q4h prn
Meperidine
50-150 mg PO/IM/SC q3-4h prn
Hydromorphone
2-4 mg PO q4-6h prn
1-4 mg IM/SC q4-6h prn
Butorphanol
1 mg NS inhaled into 1 nostril; if sufficient relief not obtained in 60-90 min, give
additional 1 mg; repeat initial 2-dose sequence in 3-4 h prn
Acetaminophen: 10 mg/kg/dose PO; not to exceed 720 mg/d (children aged 3-6 y)
or 2.6 g/d (children aged 6-12 y)
Pediatric Dose Meperidine: 1-1.8 mg/kg PO/IM/SC q3-4h; not to exceed recommended adult
dosage
Other drugs: Not established
Documented hypersensitivity; intracranial lesion associated with impaired
Contraindicatio intracranial pressure (hydromorphone); recent or concurrent MAOIs; depressed
ns respiration; COPD; cor pulmonale; emphysema; status asthmaticus;
kyphoscoliosis
Increase CNS depressant properties of other drugs including alcohol,
antihistamines, antidepressants, sedative/hypnotics, and MAOIs
Interactions Rifampin can reduce analgesic effects of acetaminophen; coadministration with
barbiturates, carbamazepine, hydantoins, and isoniazid may increase
acetaminophen hepatotoxicity
Precautions Common adverse effects are dose related and include respiratory depression,
sedation, confusion, nausea, vomiting, constipation, urinary retention, multifocal
myoclonus, and seizures
Long-term administration associated with pharmacological effects of tolerance
and physical and psychological dependence; limit use to not more than 2 d per
wk, except around menses, to prevent drug-induced headache
Hepatotoxicity possible in chronic alcoholics following various dose levels of
acetaminophen; severe or recurrent pain or high or continued fever may indicate
a serious illness; acetaminophen is contained in many OTC products and
combined use with these products may result in cumulative acetaminophen doses
exceeding recommended maximum dose
Drug Category: Abortive medications/Nonsteroidal anti-inflammatory drugs
(NSAIDs) -- Generally used as abortive therapy in mild to moderately severe type of migraine
headaches; however, they also may be effective for severe headaches, especially ketorolac.
Drug Name Aspirin (Bayer Aspirin, Anacin), Ibuprofen (Motrin, Ibuprin) -- Mild analgesics that
can be used to treat infrequent migraine episodes.
Aspirin
900-1000 mg PO initially; repeat same dose after 1-2 h prn
Ibuprofen
400-1200 mg/attack PO; may be repeated at dose of 400-800 mg in 1-2 h; not to
exceed 3200 mg/d
Naproxen sodium
Adult Dose
Up to 825 mg PO initially; may give 550 mg after 1-2 h prn
Ketorolac
10 mg PO q4h prn; not to exceed 40 mg/d; limit use to 5 consecutive days
30-60 mg IM initially; repeat q6h prn; not to exceed 120 mg/d; limit use to 3
consecutive days
IV administration similar to IM but dose used is 30 mg
Pediatric Dose Not recommended
Documented hypersensitivity; active peptic ulcer disease; renal or hepatic
Contraindicatio
impairment; concomitant or recent use of anticoagulants; hemophilia or other
ns
hemorrhagic conditions
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 acid
Interactions Ibuprofen: ACE inhibitors, anticoagulants, beta-blockers, cimetidine, cyclosporine,
digoxin, dipyridamole, hydantoins, lithium, loop diuretics, methotrexate,
penicillamine, probenecid, salicylates, sympathomimetics, thiazide diuretics
Naproxen: Other NSAIDs, anticoagulants, thrombolytic agents, probenecid,
glucocorticoids, methotrexate and other antineoplastic agents, cephalosporins,
insulin and oral hypoglycemic agents
Aspirin: The elderly may be more susceptible to CNS effects; should not be used
in last trimester of pregnancy
Precautions
NSAIDs: GI effects such as dyspepsia, nausea, and vomiting are common
adverse effects
Drug Category: Abortive medications/Combination analgesics -- Combination
analgesics may be used when simple analgesics are not effective and the patient is not a
candidate 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.
Butalbital: 1-2 tab PO q4h prn; not to exceed 6 tabs/d
Adult Dose Isometheptene and dichloralphenazone: 2 caps PO initially then 1 capsule q1h
until symptoms relieved; not to exceed 5 capsules in 12-h period
Butalbital: Not established in patients <12 years
Pediatric Dose
Isometheptene and dichloralphenazone: Not established
Butalbital: Documented hypersensitivity; porphyria
Contraindicatio Isometheptene and dichloralphenazone: Documented hypersensitivity; glaucoma;
ns severe renal or hepatic impairment or disease; organic heart disease;
concomitant MAOIs
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,
Interactions
valproic acid, propoxyphene, and benzodiazepines
Isometheptene and dichloralphenazone: Concurrent use of MAOIs with
isometheptene may result in severe headache, hypertension and hyperpyrexia,
which in turn may result in hypertensive crisis
Butalbital: Not recommended for prolonged use because of potential for drug
dependency; limit use to not more than 2 d per wk, except around menses, to
prevent drug-induced headache
Precautions
Isometheptene and dichloralphenazone: Use with caution in patients with
hypertension, peripheral vascular disease, or recent cardiovascular episodes;
safety in pregnancy not known for isometheptene and dichloralphenazone
Drug Category: Abortive medications/Antiemetics -- As dopamine antagonists, these
agents are effective if nausea and vomiting are prominent features and also may act as
prokinetics to increase gastric motility and enhance absorption.
Droperidol (Inapsine), chlorpromazine (Thorazine), metoclopramide (Reglan) --
Used alone or in combination with other analgesics as adjuncts, especially if
Drug Name
migraine attack associated with significant nausea and vomiting. Its role in
migraine based on findings that increased dopamine concentration is associated
with prominent migraine symptomatology.
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 IM
Adult Dose
q3-4h; 5-50 mg IV
Metoclopramide: 10-20 mg PO/IM
Droperidol: 1-1.5 mg/9-11 kg for children aged 2-12 y
Chlorpromazine: 0.55 mg/kg PO/IM q6-8h; not to exceed 75 mg/d for children
Pediatric Dose
aged 5-12 y
Metoclopramide: Not established
Contraindicatio Documented hypersensitivity; concurrent drugs that are likely to cause
ns extrapyramidal reactions
Anticholinergic drugs, narcotic analgesics, alcohol, sedatives, hypnotics,
Interactions
tranquilizers, MAOIs, and barbiturates
Sedation, hypotension, tachycardia, extrapyramidal reactions, hyperactivity,
anxiety, and dizziness are common adverse effects, which must be given
Precautions
consideration especially for very young and elderly patients
Metoclopramide classified as category B for use in pregnancy
Drug Category: Prophylactic therapy/Antiepileptics -- These drugs are effective in
prophylaxis of migraine headache.
Divalproex sodium/valproate (Depakote, Depacon, Depakene) -- Now considered
first-line preventive medication for migraine. Believed to enhance GABA
Drug Name
neurotransmission, which may suppress events related to migraine that occur in
cortex, perivascular sympathetics, or trigeminal nucleus caudalis. Has been
shown to reduce migraine frequency by 50%.
125-250 mg/d PO initially; titrate dose prn; not to exceed 1500 mg/d; doses higher
Adult Dose
than 250 mg/d should be divided bid
Pediatric Dose Limit use in children <10 y because of increased risk of fatal hepatotoxicity
Contraindicatio Documented hypersensitivity; children aged <10 y (because of risk of fatal
ns hepatotoxicity); hepatic disease; thrombocytopenia
Coadministration with cimetidine, salicylates, felbamate, and erythromycin may
increase toxicity; rifampin may significantly reduce valproate levels; in pediatric
patients, protein binding and metabolism of valproate decrease when taken
concomitantly with salicylates; coadministration with carbamazepine may result in
variable changes of carbamazepine concentrations with possible loss of seizure
Interactions
control; valproate may increase diazepam and ethosuximide toxicity (monitor
closely); valproate may increase phenobarbital and phenytoin levels while either
one may decrease valproate levels; valproate may displace warfarin from protein
binding sites (monitor coagulation tests); may increase zidovudine levels in HIV
seropositive patients
Pregnancy D - Unsafe in pregnancy
Common adverse effects include nausea and/or vomiting and indigestion, which
are usually self-limited; tremor, hair loss, weight gain, and hepatic toxicity also
Precautions have been reported; periodic clinical assessment and occasional blood tests to
evaluate hematopoietic, renal, and hepatic systems should accompany prolonged
therapy
Gabapentin (Neurontin) -- Initial open study showed efficacy in migraine and

Drug Name transformed migraine. Randomized, double-blind, placebo-controlled trial showed
lower migraine headache rate in gabapentin group than in placebo group; more
patients in gabapentin group had >50% reduction in frequency.
Adult Dose 300 mg PO tid; titrate gradually prn; not to exceed 2400 mg/d
<12 years: Not established
Pediatric Dose
>12 years: Administer as in adults
Contraindicatio
Documented hypersensitivity
ns
Antacids may significantly reduce bioavailability of gabapentin (administer at least
Interactions
2 h following antacids); may increase norethindrone levels significantly
Precautions Somnolence, fatigue, dizziness, and coordination problems reported
Drug Category: Prophylactic therapy/Beta-blockers -- Propranolol and timolol are both
FDA-approved prophylactic agents, but propranolol has more scientific evidence of efficacy than
timolol. Atenolol, metoprolol, and nadolol are not FDA-approved preventive agents. Significant to
their activity as migraine prophylactic agents is the lack of partial agonistic activity. Latency from
initial treatment to therapeutic results may be as long as 2 months.
Propranolol (Inderal), timolol (Blocadren), nadolol (Corgard), atenolol -- Are
Drug Name effective in prophylactic therapy possibly by blocking vasodilators, decreasing
platelet adhesiveness and aggregation, stabilizing the membrane, and increasing
the release of oxygen to tissues.
Propranolol: Start with low dose, 60 mg PO qd (sustained release) or 40 mg in
divided doses; titrate prn; not to exceed 320 mg/d
Timolol: 10 mg/d PO initially; titrate prn; not to exceed 30 mg/d
Adult Dose
Nadolol: 20 mg/d PO qd initially; titrate prn; not to exceed 240 mg/d
Atenolol: 50 mg/d PO qd initially; titrate prn; not to exceed 200 mg/d
Metoprolol: 50 mg PO qd or bid initially; titrate prn; not to exceed 200 mg/d
Only propranolol has been used for children
Pediatric Dose 0.5 mg/kg PO bid initially; may be increased every 3-5 d; not to exceed 1 mg/kg
bid
Contraindicatio Documented hypersensitivity; asthma; COPD; CHF; partial or complete AV
ns conduction defects; Raynaud disease; peripheral vascular disease; brittle
diabetes; severe depression
Decreases effect of diuretics and increases toxicity of methotrexate, lithium, and
salicylates; may diminish reflex tachycardia, resulting from nitroglycerin use,
Interactions without interfering with hypotensive effects; cimetidine may increase labetalol
blood levels; glutethimide may decrease labetalol effects by inducing microsomal
enzymes
May cause bradycardia, dizziness, nausea, fatigue, depression, memory
disturbance, impotence, and diminished exercise tolerance; caution in impaired
Precautions hepatic function; discontinue therapy if there are signs of liver dysfunction; in
elderly patients, a lower response rate and higher incidence of toxicity may be
observed
Drug Category: Prophylactic therapy/Tricyclic antidepressants -- Amitriptyline,
nortriptyline, doxepin, and protriptyline have been used for migraine prophylaxis, but only
amitriptyline has proven efficacy and appears to exert its antimigraine effect independent of its
effect on depression.
Amitriptyline (Elavil), doxepin (Adapin), nortriptyline (Aventyl), protriptyline --
Drug Name Migraine prophylaxis that is effective (independent of antidepressant effect).
Mechanism of action is unknown. Inhibits activity of such diverse agents as
histamine, 5-HT, and acetylcholine.
Amitriptyline, doxepin, nortriptyline: 10-25 mg PO qhs initially; increase by 10-25
mg every 1-2 weeks based on efficacy and tolerance; not to exceed 150-175
Adult Dose mg/d
Protriptyline: 15 mg/d PO initially; titrate prn; not to exceed 40 mg/d given tid or
qid
<12 years: Not recommended
Pediatric Dose
>12 years: Administer as in adults
Documented hypersensitivity; pregnancy or lactation; narrow-angle glaucoma;
Contraindicatio
urinary retention; cardiac arrhythmias or defects in bundle-branch conduction;
ns
concomitant MAOIs
Phenobarbital may decrease effects; coadministration with CYP2D6 enzyme
system inhibitors (e.g., cimetidine and quinidine) may increase tricyclic
Interactions antidepressant levels; tricyclic antidepressants inhibit hypotensive effects of
guanethidine; may interact with thyroid medications, alcohol, CNS depressants,
barbiturates, and disulfiram
Concurrent MAOIs may cause hypertension, hyperpyrexia, seizures, and death—
should not be given within 2 wk of using MAOIs
Adverse effects are dose related and include sedation, agitation, tremor, seizures,
Precautions
anticholinergic effects such as dry mouth, constipation, delayed micturition,
blurred vision, increased appetite with weight gain, decreased libido, and
excessive sweating
Drug Category: Prophylactic therapy/Calcium channel blockers -- This group is
commonly used as prophylactic medication, although studies of their effectiveness have shown
mixed results. Flunarizine has the best-documented efficacy but is not available in the United
States. The efficacy of verapamil is supported by studies.
This group is particularly useful in patients with comorbid hypertension and in those with
contraindications to beta-blockers such as asthma and Raynaud disease. This group may have
particular advantage in patients with prolonged aura, vertebrobasilar migraine, or hemiplegic
migraine.
Drug Name Verapamil (Calan, Covera) -- During depolarization, inhibits calcium ion from
entering 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
to exceed 480 mg/d
Contraindicatio Documented hypersensitivity; bradycardia; second-and third-degree heart block;
ns sick-sinus syndrome; concomitant beta-blockers
Phenobarbital may decrease effects; coadministration with CYP2D6 enzyme
system inhibitors (e.g., cimetidine and quinidine) may increase tricyclic
Interactions antidepressant levels; amitriptyline inhibits hypotensive effects of guanethidine;
may interact with thyroid medications, alcohol, CNS depressants, barbiturates,
and disulfiram
Patients may report an initial increase in headache, which improves after weeks
of treatment; hypotension and dizziness also reported secondary to
Precautions
vasodilatation; increase in peripheral edema may be associated with nifedipine
and decrease with nimodipine and verapamil
Drug Category: Prophylactic therapy/Selective serotonin reuptake inhibitors -- These
may be considered first-line drugs, but they have low efficacy.
Fluoxetine (Protac), Sertraline (Zoloft), Paroxetine (Paxil) -- Fluoxetine has been
shown by anecdotal reports and small, double-blind, placebo-controlled study to
Drug Name
be of benefit in migraine prophylaxis. Atypical, nontricyclic antidepressant with
potent specific 5-HT-uptake inhibition with fewer anticholinergic and
cardiovascular side effects than TCAs.
Fluoxetine: 10 mg/d PO on waking initially; can be increased every 2 wk; not to
exceed 60 mg/d
Adult Dose Sertraline: 50 mg/d PO initially; increase at weekly interval over several wk; not to
exceed 200 mg/d
Paroxetine: 10 mg/d PO initially; titrate prn; not to exceed 50 mg/d
Contraindicatio Documented hypersensitivity; pregnancy and lactation; severe renal or hepatic
ns disease
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 of
Interactions
other serotonergic agents (eg, anorectic agents, tramadol, buspirone, trazodone,
clomipramine, nefazodone, tryptophan), discontinue other serotonergic agents at
least 2 wk prior to SSRIs
Concurrent MAOIs may cause serious, potentially fatal reactions such as
autonomic instability
Precautions Anxiety, insomnia or drowsiness, tremor, anorexia, anorgasmia and other sexual
dysfunctions reported; nausea, flulike symptoms, and agitation also noted, which
resolve 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 or
nephropathy, than when used as abortive medications. In controlled clinical trials, naproxen
sodium demonstrated better efficacy than placebo and efficacy similar to propranolol. Tolfenamic
acid has also been tried for migraine prophylaxis, but the clinical efficacy is not as good as that of
beta-blockers, valproate, or methysergide.
Naproxen sodium (Anaprox, Naprelan, Naprosyn) -- Inhibits inflammatory
Drug Name
reactions and pain by decreasing activity of cyclooxygenase, enzyme responsible
for prostaglandin synthesis.
Adult Dose 275 mg PO tid or 550 mg bid
Pediatric Dose <12 years: Not recommended
Contraindicatio Documented hypersensitivity, active peptic ulceration; renal or hepatic
ns impairment; concomitant or recent anticoagulants
Probenecid may increase toxicity; ibuprofen may decrease effects of loop
diuretics; anticoagulants may prolong PT (watch for signs of bleeding); may
Interactions
increase serum lithium levels and risk of methotrexate toxicity (eg, stomatitis,
bone marrow suppression, nephrotoxicity)
Pregnancy B - Usually safe but benefits must outweigh the risks.
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 acute
Precautions
renal failure; leukopenia occurs rarely, is transient, and usually returns to normal
during therapy; persistent leukopenia, granulocytopenia, or thrombocytopenia
warrants further evaluation and may require discontinuation of drug
Drug Category: Prophylactic therapy/Serotonin antagonists -- Reported to provide
effective migraine prophylaxis.
Methysergide (Sansert) -- 5-HT2 antagonist with effective 5-HT1A agonist activity
providing effective migraine prophylaxis in 60% or more of patients, which may be
Drug Name
greater in migraineurs with aura.
Adverse effects may be severe; should be used only in patients who have not
responded to other preventive agents.
Adult Dose 2 mg/d PO initially; increase dose gradually; not to exceed 8 mg/d
Pediatric Dose Not recommended
Documented hypersensitivity; peripheral vascular disease; severe
Contraindicatio arteriosclerosis; severe hypertension; coronary artery disease; phlebitis or
ns cellulitis of lower extremities; pulmonary disease; collagen disease or fibrotic
processes; impaired renal or hepatic function; valvular heart disease
Potentiates effects of CNS depressants; MAO inhibitors may prolong and intensify
Interactions
anticholinergic and sedative effects
Continuous administration should not exceed 6 mo; retroperitoneal fibrosis and
Precautions related conditions have occurred with uninterrupted use; Allow for 3- to 4-wk drug-
free interval after each 6-mo course
Cyproheptadine (Periactin) -- Acts primarily as antagonist of cerebral vascular 5-

HT2 receptors and has been used traditionally for pediatric migraine prevention
Drug Name
despite minimal objective evidence of its efficacy.
Pizotifen has been shown to be effective for migraine, especially when used in
combination with sumatriptan, but is not available in US.
2 mg PO initial dose; increase every third day until beneficial effect demonstrated
Adult Dose or until adverse effects occur
Usual maintenance dose: 8-32 mg in 3-4 divided doses
2-6 years: 2 mg PO q8-12h; not to exceed 12 mg/d
Pediatric Dose
6-14 years: 2-4 mg q8-12h; not to exceed 16 mg/d
Contraindicatio
Documented hypersensitivity; glaucoma; acute asthmatic attack
ns
Potentiates effects of CNS depressants; MAO inhibitors may prolong and intensify
Interactions
anticholinergic and sedative effects of antihistamines
Pregnancy B - Usually safe but benefits must outweigh the risks.
Common adverse effects include drowsiness, dizziness, blurred vision, dry
Precautions
mouth, 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
*143 Treatment of severe refractory migraine pain (ie, status migrainosus)
*144 Detoxification from overuse of combination analgesics, ergots, or opioids
In/Out Patient Meds:
*145 For recommended medications in comorbid conditions,
Deterrence/Prevention:
Complications:
*146 Ischemic stroke may occur as a rare but serious complication of migraine. Risk
factors for stroke include migraine with aura, female sex, cigarette smoking, and estrogen
use.
Cluster Headache
Synonyms, Key Words, and Related Terms: Bing-Horton syndrome, histaminic cephalalgia,
cluster migraine, paroxysmal nocturnal cephalalgia, red migraine, erythromelalgia of the head,
sphenopalatine neuralgia, migrainous neuralgia
Background: Cluster headache (CH) is an idiopathic syndrome consisting of recurrent brief
attacks of sudden, severe, unilateral periorbital pain.
Pathophysiology: The pathophysiology of CH is not understood entirely. Its typical periodicity
has been attributed to hypothalamic (particularly suprachiasmatic nuclei) hormonal influences.
CH pain is thought to be generated at the level of the pericarotid/cavernous sinus complex. This
region receives sympathetic and parasympathetic input from the brain stem, possibly mediating
occurrence of autonomic phenomena during an attack. The exact roles in CH of immunologic and
vasoregulatory factors, as well as the influence of hypoxemia and hypocapnia, are still
controversial.
Frequency:
*147 In the US: Exact prevalence is unknown. Kudrow estimated 0.4% in men and
0.08% in women.
*148 Internationally: In an extensive study of 100,000 inhabitants of the republic of San
Marino, the prevalence was 0.07%.
Sex:
*149 CH is more common in men; the male-to-female ratio is 5:1.
Age: CH affects middle-aged persons.
History:
*150 Attacks of CH are typically short in duration (5-180 min) and occur with a frequency
from once every other day to 8 times a day, particularly during sleep. As opposed to
migraine, CH is not preceded by aura, affording patients little or no warning.
*151 Pain generally is described as excruciating, penetrating, and not throbbing.
*152 It may radiate to other areas of the face and neck but is typically periorbital.
*153 It may be triggered by stress, relaxation, extreme temperatures, glare,
allergic rhinitis, and sexual activity.
*154 CH rarely is triggered by ingestion of specific foods, although tobacco or
alcohol products may precipitate an attack.
*155 An attack of CH is a dramatic event during which the patient may be extremely
restless. In desperation, CH patients may rock, sit, pace, or bang themselves against a
hard surface.
*156 Classification of cluster headache: The International Headache Society (IHS)
classifies CH by duration as episodic or chronic.
*157 Episodic CH occurs in periods (clusters) lasting from 7 days to 1 year;
clusters are separated by pain-free intervals lasting at least 2 weeks. Typically, a
cluster lasts 2 weeks to 3 months.
*158 Chronic CH is defined as that occurring for more than 1 year without
remission or with remissions lasting less than 2 weeks. It is subdivided into chronic
CH from onset and chronic CH evolving from episodic.
*159 Chronic CH is notoriously difficult to treat and resistant to standard
prophylactic agents.
*160 Symptomatic clusterlike headache should be suspected if the presentation is
atypical. Atypical features may include the following:
*161 Absence of a periodic pattern
*162 Residual headache between exacerbations
*163 Incomplete or minimal response to standard therapy
*164 Presence of lateralizing findings on exam (except for those of CH-related
Horner syndrome)
Physical: The association of prominent autonomic phenomena is a hallmark of CH. Such signs
include ipsilateral nasal congestion and rhinorrhea, lacrimation, conjunctival hyperemia, facial
diaphoresis, palpebral edema, and complete or partial Horner syndrome (which may persist
between attacks). Tachycardia is a frequent finding.
*165 A distinctive CH face is described as follows: leonine facial appearance,
multifurrowed and thickened skin with prominent folds, a broad chin, vertical forehead
creases, and nasal telangiectasias.
*166 CH sufferers are typically tall and rugged-looking.
Causes: Cases of CH affecting multiple members within a single family have been reported,
suggesting that a genetic predisposition may exist in some individuals.
Anisocoria
Atypical Facial Pain
Basilar Artery Thrombosis
Brainstem Gliomas
Cavernous Sinus Syndromes
Chronic Paroxysmal Hemicrania
Craniopharyngioma
Headache: Pediatric Perspective
Intracranial Hemorrhage
Migraine Headache
Migraine Variants
Pituitary Tumors
Postherpetic Neuralgia
Subarachnoid Hemorrhage
Temporomandibular Joint Syndrome
Tolosa-Hunt Syndrome
Trigeminal Neuralgia
Other Problems to be Considered:

Arteriovenous malformations
Brainstem syndromes
Cyclical migraine
Hemicrania continua
Metastatic lung carcinoma
Nasopharyngeal carcinoma
Malignant and nonmalignant pain syndromes
Raeder paratrigeminal syndrome
Vertebral artery aneurysm
Imaging Studies:
*167 CH is strictly a clinical diagnosis. On rare occasions, structural lesions may mimic
its presentation, prompting the need for neuroimaging study (CT scan or MRI).
*168 The following conditions can present with findings suggestive of CH:
*169 Meningiomas of the cavernous sinus
*170 Arteriovenous malformations
*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 or

preventive/prophylactic.
Surgical Care:
*175 Invasive nerve blocks and ablative neurosurgical procedures (eg, percutaneous
radiofrequency, trigeminal gangliorhizolysis, rhizotomy) all have been implemented
successfully in cases of refractory CH.
*176 More recently, gamma-knife radiosurgery has provided a less invasive alternative
for pervasive CH.
The pharmacologic management of CH may be divided into abortive/symptomatic and

preventive/prophylactic strategies. Abortive therapy is directed at stopping or reducing the
severity 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 the
attacks, effective prophylactic therapy should be considered the cornerstone of treatment. The
prophylactic therapy should start at the onset of a CH cycle and continue until the patient is
headache free for at least 2 weeks. The agent then may be tapered slowly to prevent
recurrences.
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.
High-flow oxygen -- Inhalation of high-flow,
concentrated oxygen extremely effective for
aborting CH attack. Precise mechanism of
Drug Name action poorly understood. Effective
alternative to ergotamine. Despite immediate
availability of oxygen in ED, its widespread
use in outpatient setting limited by
impracticality.
6-8 L/min concentrated (100%) oxygen by
Adult Dose
face 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 CH
pain.
Ergotamine (Cafatine, Cafergot, Cafetrate,
Ercaf) -- Vasoconstrictor of smooth muscle in
cranial blood vessels, alpha-adrenergic
Drug Name blocker, and nonselective 5-HT agonist. PR
or SL preparations of ergotamine tartrate
preferred to PO because of immediate onset
of action. Avoid exceeding maximum dosage
guidelines 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/attack
or 10 tabs/wk 1 tab SL at first sign of onset,
followed by 1 tab q30min prn; not to exceed
3 tabs/24h or 5 tabs/wk 1 supp PR at first
sign of onset, followed by second dose prn
after 1 h; not to exceed 2 supp/attack or 5
supp/wk
Contraindications Documented hypersensitivity
Erythromycin, troleandomycin, and other
Interactions
macrolide antibiotics may increase toxicity
Use caution in patients with history of
hypertension or coronary or peripheral
arterial insufficiency; use caution in elderly,
as may precipitate angina or MI or aggravate
Precautions intermittent claudication; avoid prolonged
administration or excessive dosage, since
increases danger of ergotism or gangrene;
patients who take for extended periods may
become dependent
Dihydroergotamine (D.H.E.-45 injection,

Drug Name Migranal) -- Available in IV or intranasal
preparations, tends to cause less arterial
vasoconstriction than ergotamine tartrate.
Up to 2 mg IV; not to exceed 2 mg/dose or 6
mg/wk 1 mg IM/SC at first sign of onset; not
Adult Dose to exceed 3 mg total 1 spray (0.5 mg) into
each nostril; not to exceed 6 sprays/d or 8
sprays/wk
Documented hypersensitivity; do not use
within 24 h of sumatriptan, zolmitriptan, other
Contraindications
serotonin agonists, or ergotlike agents; use
of MAOIs within last 2 wk
May increase effects of heparin;
erythromycin, clarithromycin, nitroglycerin,
Interactions
propranolol, and troleandomycin may
increase toxicity
Use caution in patients with hypertension,
Precautions angina, peripheral vascular disease, or
impaired renal or hepatic function
Sumatriptan (Imitrex), Zolmitripan (Zomig) --

As selective agonists of serotonin 5HT1
receptors in cranial arteries, cause
vasoconstriction and reduce inflammation
associated with antidromic neuronal
transmission in CH. Can reduce severity of
Drug Name headache 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 PO
selective serotonin receptor agonists
(zolmitriptan, naratriptan, rizatriptan) in
abortive therapy.
Sumatriptan 6 mg SC, followed by second
injection prn at least 1 h after first; not to
exceed 2 injections/d
25-100 mg PO, followed by second dose 2 h
later prn; not to exceed 300 mg/d 1 spray (5-
20 mg) in 1 nostril or 1 spray (5 mg) in each
Adult Dose
nostril; may repeat in 2 h prn; not to exceed
40 mg/d
Zolmitriptan: 2.5-5 mg PO; repeat after 2 h
prn; not to exceed 10 mg/d
Naratriptan: 2.5 mg PO
Rizartriptan: 10 mg PO
Documented hypersensitivity, ischemic heart
Contraindications disease, uncontrolled hypertension, use of
MAOIs in last 2 wk
MAOIs, ergot-containing drugs, and selective
Interactions serotonin reuptake inhibitors (SSRIs) may
increase toxicity
C - Safety for use during pregnancy has not
Pregnancy
been established.
May cause facial flushing, numbness,
paresthesias, and chest pain of noncardiac
origin; significant elevation in blood pressure,
including hypertensive crisis, has been
Precautions
reported in patients without history of
hypertension; peripheral vascular ischemia,
colonic ischemia with abdominal pain, and
bloody diarrhea have occurred
Methysergide (Sansert) -- Useful in patients

unresponsive to lithium. Although of
ergotamine chemical class, actions differ,
since has minimal ergotaminelike
vasoconstrictive properties and significantly
greater serotoninlike properties. Plays
Drug Name
important role in CH prophylaxis. Often
effective in reducing pain frequency,
particularly in younger patients with episodic
CH. If no improvement after 3 wk, unlikely to
be beneficial. Do not give continuously for >6
mo. Drug-free interval of 3-4 wk must follow
each 6-mo course.
Adult Dose 2-8 mg/d PO
Documented hypersensitivity, peripheral
vascular disease, severe arteriosclerosis,
Contraindications
pulmonary disease, severe hypertension,
phlebitis, serious infections
Precautions Use >6 mo discouraged, since long-term
therapy may cause retroperitoneal fibrosis
and fibrotic thickening of cardiac valves; drug
holiday recommended to avoid these effects;
adverse GI reactions most commonly affect
compliance; use caution in renal or hepatic
impairment; adverse effects include leg
cramps, paresthesias, edema, and skin
discoloration
Drug Category: Anesthetics -- Local anesthetics stabilize the neuronal membrane so the
neuron is less permeable to ions. This prevents initiation and transmission of nerve impulses,
thereby producing the local anesthetic action.
Intranasal lidocaine (4%) -- An experimental
therapy in CH, blocks conduction of nerve
impulses by decreasing neuronal
membrane's permeability of sodium ions,
Drug Name which results in inhibition of depolarization
and blockade of conduction. Effective in 2
separate clinical trials. Intranasal
administration of lidocaine drops requires
specific and, for many patients, difficult
technique.
4% solution intranasally; actual dose not
Adult Dose
established
Interactions May enhance effects of succinylcholine
B - Usually safe but benefits must outweigh
Pregnancy
the risks.
Use extreme caution in patients with marked
Precautions hypoxia, severe respiratory depression, or
bradycardia
Drug Category: Oral opioids and other analgesics -- The short-lived and unpredictable
character of CH precludes the effective use of oral narcotics or analgesics. Despite their lack of
efficacy, these substances are abused by some CH sufferers.
Intranasal capsaicin -- This experimental
therapy successfully tested in clinical trials.
Derived from chili peppers, induces release
Drug Name
of substance P, principal chemomediator of
pain impulses from periphery to CNS. After
repeated applications, depletes neuron of
substance P and prevents reaccumulation.
Few drops of capsaicin solution applied to
Adult Dose
ipsilateral nostril
Pregnancy
been established.
Avoid contact with eyes; irritant to mucosal
membranes, should be used with caution;
Precautions warn patients about nasal cavity irritation,
burning, congestion, drainage, and sneezing
while using
Drug Category: Calcium channel blockers -- These agents inhibit the initial
vasoconstrictive phase of CH.
Drug Name Verapamil (Calan, Verelan, Covera-HS) --
Perhaps most effective calcium channel
blocker for CH prophylaxis, inhibits calcium
ions from entering slow channels, select
voltage-sensitive areas, or vascular smooth
muscle, thereby producing vasodilation.
Immediate release: 120-360 mg/d PO
Adult Dose divided tid/qid
Extended release form may be given qd
Documented hypersensitivity, sinus
bradycardia, cardiogenic shock, advanced
heart block, ventricular tachycardia,
Contraindications
congestive heart failure, atrial fibrillation or
flutter associated with accessory conduction
pathways
Phenobarbital, hydantoins, vitamin D,
sulfinpyrazone, and rifampin may decrease
serum concentrations by increasing hepatic
metabolism; amiodarone may increase
toxicity; beta blockers may increase cardiac
Interactions
depressant effects on AV conduction;
cimetidine may increase serum levels; may
increase cyclosporine, doxorubicin,
theophylline, carbamazepine, vecuronium,
and digoxin serum levels
Pregnancy
been established.
Use caution in patients with sick-sinus
syndrome, severe left ventricular
dysfunction, hepatic or renal impairment, or
hypertrophic cardiomyopathy; monitor ECG
and blood pressure closely in patients with
Precautions
supraventricular tachycardia receiving IV
therapy; adverse effects include constipation
and water retention; patients intolerant of
verapamil 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 vasoactive
intestinal peptide–induced arterial relaxation.
Drug Name Lithium carbonate (Eskalith, Lithane,
Lithobid, Lithonate, Lithotabs) -- Effectively
prevents CH (particularly in its more chronic
forms) and treats bipolar mood disorder,
another cyclic illness. Responses variable,
but still recommended first-line agent in CH.
Narrow therapeutic window requires close
monitoring of levels and adverse effects.
Plasma lithium level of 0.6-1.2 mEq/L
measured at steady state, 12 h after last
dose (ie, just before next dose), usually
sought, but optimal plasma levels for
prevention of CH not established. Thought
effective in CH at serum concentrations
lower than those required in bipolar disorder
(0.3-0.8 mEq/L).
600-900 mg/d PO in divided doses; increase
Adult Dose
to 600-1200 mg/d divided bid/qid prn
Documented hypersensitivity, severe
Contraindications
cardiovascular or renal disease
Thiazide diuretics, NSAIDs, haloperidol,
phenothiazines, neuromuscular blockers,
carbamazepine, fluoxetine, and ACE
Interactions
inhibitors may increase serum levels and
toxicity; theophylline, caffeine, and other
xanthines decrease effects
Lithium toxicity can occur at therapeutic
doses; use caution in patients with
cardiovascular or thyroid disease, severe
debilitation, dehydration, or sodium
depletion, or in patients taking diuretics;
Precautions adverse effects include tremor, polyuria,
diarrhea, nausea, fatigue, weight gain, and
thyroid dysfunction; renal toxicity with tubular
damage and interstitial fibrosis may occur;
CNS toxicity manifested by confusion and
ataxia
Drug Category: Corticosteroids -- These agents are extremely effective in terminating a CH
cycle and in preventing immediate headache recurrence. High-dose prednisone is prescribed for
the first few days, followed by a gradual taper. The simultaneous use of standard prophylactic
agents (eg, verapamil) is recommended. The mechanism of action in CH is still subject to
speculation.
Prednisone (Deltasone) -- Effective for
treatment of CH not responsive to lithium or
Drug Name
methysergide. Effects in CH may occur via
inhibition of prostaglandin synthesis. Long-
term use not recommended.
40-60 mg/d PO in divided doses for 5 d,
Adult Dose
followed by slow taper over 2-4 wk
Documented hypersensitivity; systemic
Contraindications fungal infections or serious infections, except
septic shock or tuberculous meningitis
Barbiturates, phenytoin, and rifampin
Interactions decrease effects; may decrease effects of
salicylates
Pregnancy
been established.
Use cautiously in patients with diabetes,
hypothyroidism, cirrhosis, congestive heart
failure, thromboembolic disorders, or
Precautions ulcerative colitis; chronic use may lead to
gastric ulceration, immunosuppression,
electrolyte disturbances, weight gain, and
osteopenia
Prognosis:
*177 Eighty percent of patients with episodic CH tend to maintain the episodic form.
*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 patients
in some series, particularly in episodic CH. Chronic CH is more relentless and may persist
in this form in up to 55% of cases. Less frequently, chronic CH may remit into an episodic
form.
*180 Generally, CH is a lifelong problem.
*181 Pharmacologic intervention may play a part in the transformation of chronic CH into
the episodic form; otherwise, it does not influence outcome.
*182 Late onset of this disorder, along with male sex and a previous history of episodic
CH, predict a less favorable course.

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Headache (HA)

Table 14-1 Characteristics of Various Types of Primary Headaches

Headache Quality Location Duration Associated symptoms

Other Problems to be Considered:

Moderate Severe Extremely Severe

First line High efficacy Beta-blockers

Table 3. Preventive Medication for Comorbid Conditions

Gabapentin (Neurontin) -- Initial open study showed efficacy in migraine and

Cyproheptadine (Periactin) -- Acts primarily as antagonist of cerebral vascular 5-

Further Inpatient Care:

Other Problems to be Considered:

Medical Care: Pharmacologic management of CH may be classified as abortive/symptomatic or

The pharmacologic management of CH may be divided into abortive/symptomatic and

Dihydroergotamine (D.H.E.-45 injection,

Sumatriptan (Imitrex), Zolmitripan (Zomig) --

Methysergide (Sansert) -- Useful in patients

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