ISSUES IN MIGRAINE
| IDENTIFYING AND TREATING MIGRAINE HEADACHE —Alan Rapoport, MD, Clinical Professor of Neurology,
Columbia University College of Physicians & Surgeons, New York City; Director and Founder, New England
Center for Headache, Stamford, Connecticut
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| General considerations: migraine headache occurs in 12% of general population; 3 times more common in women
than men; tension-type headache— 90% of people have it from time to time; generally not seen clinically because
over-the-counter (OTC) treatment effective; cluster headache—type of trigeminal autonomic cephalgia; rare; severe;
often confused with sinus headache; secondary headache disorder—headache symptom of another disorder,
eg, temporomandibular joint (TMJ) syndrome, tooth problem, brain tumor or hemorrhage, giant cell arteritis, anemia,
chronic disease
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| Neuroanatomy of migraine: electric phenomena— start in cortex of brain in occipital lobe, moving slowly forward; believed
to be cause of visual aura occurring before headache in ≈30% of people with migraine; inflammation—occurs in
meninges; meningeal vessels dilate, causing pain; brainstem—pons significantly involved in migraine; first branch of
trigeminal nerve connects pons with meninges; presynaptic vessels contain neuropeptides, eg, calcitonin gene-related
peptide (CGRP) that, when released, causes vasodilation and inflammation around blood vessels; CGRP antagonist administered
intravenously (IV) almost as effective against migraine as triptans; when serotonin 1D receptor (inhibitory;
prevents release of CGRP) stimulated, inflammation stopped and release of CGRP prevented; all triptans stimulate serotonin
1D receptor; central sensitization of brainstem—migraine left untreated worsens; cutaneous allodynia indication
of brainstem abnormality; instruct patient to take triptan early in pain cycle; if taken late, brainstem becomes
abnormal and triptan not as effective
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| Clinical work-up: history—often all required for diagnosis; imaging studies—magnetic resonance imaging (MRI)
provides more information than computed tomography (CT); noncontrast CT if acute bleeding suspected; blood
work—no significant value; assess for anemia, inflammation, Lyme disease, or thyroid dysfunction; cardiac risk
factors—screen for before prescribing triptan; electroencephalography, lumbar puncture, or angiography of no diagnostic
value
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| Red flag symptoms: headache in patient >50 yr of age (more likely vascular disease or brain tumor); symptoms that do
not fit diagnostic criteria; patient reports headache as first or worst; rapidly accelerating headache that worsens in 5
min; headache that develops over 2 or 3 wk (migraine develops over 1 to 2 hr); headache from exertion; headache associated
with any neurologic symptom, even visual aura; exercise high index of suspicion with unusual headache
symptoms
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| Diagnostic criteria for migraine without aura: at least 5 previous attacks (migraine repetitive disease) lasting 4 to 72
hr (cluster headache lasts 90 min); 2 of 4 criteria: unilateral location, pounding, throbbing quality, moderate or severe
intensity, worsened by simple activity; during headache, need: nausea and/or vomiting, both photophobia and phonophobia;
only ≈50% of people with migraine accurately diagnosed; patients with stable pattern of recurrent severe
headache 2 or 3 times monthly associated with significant disability who are better or partially better next day considered
to have migraine until proven otherwise (do neurologic history and examination and appropriate tests if warranted)
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| Sinus disease: most people complaining of sinus headache have migraine headache; success rate 94% when patient
treated with triptan
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| Stroke and headache: concern about migraine with aura, birth control pills, and stroke; small increased chance people
who have migraine with aura at risk for stroke (≈4 in 10,000)
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| Patent foramen ovale (PFO) and migraine with aura: prospective double-blind studies under way looking at people who
have migraine with aura and PFO with right-to-left shunt
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| Treatment: triggers—patient should attempt to identify triggers (eg, foods, stress, altitude, menstruation) and avoid if
possible; triggers must be avoided for optimum effectiveness of medication; behavioral therapies—biofeedback
training, relaxation techniques; refer anxious or depressed patient for counseling; OTC agents—high doses of vitamin
B2 , high doses of magnesium, feverfew, butterbur (Petasites hybridus), melatonin, and coenzyme Q10 ; physical
techniques—acupuncture, chiropractic (sudden twisting of neck by manipulation dangerous to great vessels and
should be avoided), physical therapy, and exercise helpful for migraine, but do not prevent it; analgesic rebound—
caused by frequent and excessive use of immediate-relief headache medications; do not use opiates to treat migraine
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| Triptans: early intervention important in treatment; 30% of patients have visual aura, and ≈40% have prodrome (may
report “something funny in head”, “don’t feel right”, irritability, frequent urination, or food cravings); definitive
treatment of prodrome unclear; speaker recommends nonsteroidal anti-inflammatory drugs (NSAIDs); instruct patient
to take triptan during aura or as soon as aura ends at start of headache; delay in treating migraine may lead to
central sensitization, and triptan may become less effective; triptans work by stimulating serotonin 1B receptors,
causing dilated blood vessels to constrict; stop release of CGRP, which prevents inflammation; may be necessary to
try different triptans until effective one found; melt-on-tongue formulations absorbed in small bowel (not mucous
membranes of mouth) convenient; injection of sumatriptan works rapidly but associated with more side effects; nasal
sprays (sumatriptan and zomatriptan) effective in 10 to 15 min; speaker recommends nasal spray or injection formulation
for patient with nausea (avoids gastrointestinal [GI] tract); triptan therapy contraindicated if patient suspected
of having ischemic heart or brain disease, peripheral vascular disease, uncontrolled high blood pressure, or cardiac
risk factors until work-up done
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| Prophylactic therapy: considerations in implementing— if migraine affects patient’s functioning, patient nonresponsive
to acute care medications, acute care medications contraindicated, patient has adverse effects from acute care
medications, or patient cannot afford triptan medication; β-blockers —propranolol and timolol; antiepileptics —
divalproex (Depakote) and topiramate (Topamax); speaker recommends Topamax (start low and go slow to avoid
side effects); calcium channel blockers—not as effective as β-blockers, but have fewer side effects;
antidepressants— migraine can have comorbidity with depression, anxiety, and sleep problems; speaker recommends
amitriptyline and nortriptyline; selective serotonin reuptake inhibitors (SSRIs) not as effective and can
worsen migraine; unclear about selective norepinephrine receptor inhibitors (SNRIs, eg, venlafaxine, duloxetine);
buproprion can cause headache; other options—methysergide (Sansert) no longer on market; methylergonovine
(Methergine); angiotensin receptor blockers (eg, candesartan [Atacand]; data show 16 mg daily superior to placebo),
leukotriene antagonists, eg, montelukast (Singulair), may be helpful in treating children; botulinum toxin type A
(Botox)—off-label use; speaker opines it works not only in people with migraine, but also those with frequent severe
headache
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| MENSTRUAL MIGRAINE —Beverly S. Tozer, MD, Instructor in Medicine, Mayo Clinic College of Medicine, Scottsdale,
Arizona
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| General considerations: migraine headache more common than diabetes, osteoarthritis, or asthma; 28 million migraineurs
in United States, of whom 20 million women; prevalent in women of reproductive age; 3 times more common
in women than men 25 to 55 yr of age; 1 in 4 women 30 to 49 yr of age have migraine; >50% of migraineurs
report impairment severe enough to require bed rest; 31% report missing at least some work because of migraine; economic
burden ≈$13 billion annually; before puberty, incidence greater in boys than in girls; ≈4% to 10% of school-
aged children have migraine; incidence in girls begins to rise at menarche and continues to rise until ≈40 yr of age; cyclical
hormonal changes account for some but not all differences seen between men and women; about two thirds of
people with migraine seek care from primary care physicians, and 16% consult headache specialists
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| Menstrual migraine: hormonal fluctuations most commonly reported trigger; ≈55% of all migraineurs have migraine
without aura, 36% have migraine with aura, ≈9% have both; menstrual migraine not recognized as separate entity in
second edition of International Classification of Headache Disorders; pure menstrual migraine—occurs exclusively
during 5-day perimenstrual period extending from 2 days before onset of menstrual flow through 3 days after onset
in at least 2 of 3 cycles; menstrual-related migraine— occurs during perimenstrual period in at least 2 of 3 cycles
and at other times of month; 60% of women who have migraine without aura report some association with menses;
14% have pure menstrual migraine (headaches only with menses); 46% have menstrual-related migraine; 40% of
women with migraine without aura report no association of migraine with menses; menstrual migraine believed more
severe, more disabling, of longer duration, to have more associated symptoms, and more resistant to treatment
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| Approach to treatment: headache diary—helps patient and clinician identify triggers and monitor response to therapy
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 | Acute treatment: necessary for all patients with migraine; goal to stop pain and progression of migraine attack
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| Preemptive therapy: initiated before exposure to time-limited trigger, eg, exercise; menstrual migraine has typically
slower onset; ≈80% of patients report mild headache phase before progressing to moderate-to-severe headache;
may be confused with other symptoms of menses; leads to “wait and see approach”; may progress to more severe
headache if acute medication not taken in effective window of time (within ≈2 hr of onset of headache); same medications
and doses used in acute therapy of migraine also used in menstrual migraine; NSAIDs helpful in decreasing
some prostaglandin-mediated symptoms of premenstrual syndrome; ergotamines, ergot derivatives, and
triptans first-line treatment for acute moderate-to-severe migraine; narcotics reserved for severe refractory headache
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| Preventive treatment: goal is decrease in migraine frequency and severity; consider preventive treatment if acute
therapy fails to provide adequate relief from pain or if attacks frequent; considered effective if migraine frequency
decreased by at least 50%
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| Short-term or “mini” prophylaxis: preferred initial approach to patient with “pure” menstrual migraine (migraine occurring
exclusively around menses); data show medications effective when used this way (no medications approved
to be used in this manner); medication taken only around vulnerable period (menses); headaches must have
predictable relationship to menses; use ovulation kit if menses irregular; medication should be used for 3 cycles
before deemed ineffective; NSAIDs—data show 550 mg of naproxen bid taken 1 wk before expected menses and
continued 1 wk after menses superior to placebo in preventing menstrual migraine; inexpensive and easily obtained;
may help with other symptoms associated with menses; ergots and dihydroergotamine nasal spray—given
for 5 days but started 2 days before anticipated headache; magnesium— given tid for 2 wk before anticipated
menses; hormonal manipulation—also used; long-acting triptans—started 2 days before expected headache; expensive;
avoid in patient with coronary artery disease (CAD); naratriptan 1 mg bid for 5 days shown superior to placebo,
but at 2.5 mg, no different from placebo
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| Long-term prophylaxis: medication used daily to prevent headache; may need to increase dose around menses; consider
comorbidities in selecting medications, eg, β-blocker in patient with hypertension; any preventive medication
used in long-term migraine prophylaxis can be used; divalproex, topiramate, propanolol, and timolol only approved
medications; Botox used, but currently not widely accepted
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| Combined oral contraceptives (OCs): may improve, worsen, or have no effect on migraine; International Headache Society
(IHS) Task Force on Combined OCs and Hormone Replacement Therapy concluded use acceptable for women
who have migraine without aura and those with aura who have no risk factors for stroke; smoking doubles patient’s
risk for stroke and risk increases with age; 6-fold increased risk for stroke in woman who smokes and takes OCs; addition
of migraine increases risk 34-fold; combined OC use in migraineurs—35-µg combined OC produces greater
than physiologic premenstrual decline and may increase migraine potential; physiologic fall in ethinyl estradiol concentration
in natural menstrual cycle equivalent to 20 µg decline in ethinyl estradiol; best to start OC with lowest dose
of ethinyl estradiol, especially if patient has headaches throughout cycle; monophasic OCs preferable to avoid fluctuating
hormone levels; consider long cycle of use with withdrawal every 10th to 13th week (shown to reduce frequency
of menstrual migraine from estrogen withdrawal by 50%); consider add-back estrogen on placebo week (using gel,
patch, or oral preparations)
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Educational Objectives
| The goal of this program is to educate the listener about the diagnosis and treatment of migraine headache. After hearing
and assimilating this program, the clinician will be better able to:
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| 1. Distinguish migraine from other headache disorders and rule out other possible causes of headache.
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| 2. Discuss the neuroanatomy of migraine.
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| 3. List the diagnostic criteria for migraine and red flag symptoms that indicate a serious underlying medical problem.
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| 4. Define pure menstrual migraine.
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| 5. Summarize current options for treatment of migraine and menstrual migraine.
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Discussed on This Program
Amitriptyline HCl [Elavil]
Botulinum toxin type A [Botox, Botox Cosmetic]
Bupropion HCl [Wellbutrin, Wellbutrin SR, Wellbutrin XL, Zyban]
Butterbur (Petasites vulgaris, Petasites hybridus)
Candesartan cilexetil [Atacand]
CoEnzyme Q10 Dihydroergotamine mesylate [D.H.E. 45, Migranal]
Duloxetine [Cymbalta]
Ethinyl estradiol and levonorgestrel [Alesse, Aviane, Empressa, Lessina, Levite, Levlen, Levlite, Levora, Nordette,
Portia, Preven, Seasonale, Triphasil, Tri-Levlen, Trivora]
Feverfew (Tanacetum parthenium, Chrysanthemum parthenium)
Melatonin
Methylergonovine maleate [Methergine]
Methysergide maleate [Sansert] (discontinued)
Montelukast sodium [Singulair]
Nortriptyline HCl [Aventyl HCl, Aventyl HCl Pulvules, Pamelor]
Propranolol HCl [Inderal, Inderal LA, InnoPran XL]
Riboflavin (B2 )
Sumatriptan succinate [Imitrex]
Timolol maleate [Betimol, Blocadren, Isatol, Timoptic, Timoptic-XE]
Topiramate [Topamax]
Valproic acid [Depacon, Depakene, Depakote, Depakote ER]
Venlafaxine HCl [Effexor, Effexor XR]
Zolmitriptan [Zomig, Zomig-ZMT]
Suggested Reading
Bousser MG: International Headache Society (HIS) Task Force on oral contraceptives (OCs) and hormone replacement
therapy (HRT) used in migraine sufferers. Cephalalgia 20(3):147;discussion 145-6, 2000; Calhoun AH: A novel
specific prophylaxis for menstrual-associated migraine. South Med J 97(9):819, 2004; Loder E: Menstrual migraine:
clinical considerations in light of revised diagnostic criteria. Neurol Sci 26 Suppl2:s121, 2005; Silberstein SD et al:
Botulinum toxin type A for the prophylactic treatment of chronic daily headache: a randomized, double-blind, placebo-
controlled trial. Mayo Clin Proc 80(9):1126, 2005; Siberstein SD et al: The International Classification of Headache
Disorders, 2nd Edition (ICHD-11)—revision of criteria for 8.2 Medication-overuse headache. Cephalalgia 25(6):460,
2005.
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial
relationship with the manufacturer or provider of any commercial product or service discussed. The following
has been disclosed: Dr. Rapoport has been or is currently involved with the following pharmaceutical companies: Allergan,
AstraZeneca, Eisai Pharmaceuticals, Endo Pharmaceuticals, Forest Laboratories, GlaxoSmithKline, Janssen
Pharmaceuticals, Johnson & Johnson, Merck, Ortho-McNeil, Pfizer Inc., Pozen, UCB Pharma, Vernalis, and Winston
Pharmaceuticals.
Dr. Rapoport was recorded at the 21st Annual Update in Clinical Medicine, sponsored by New Britain General Hospital,
and held on November 7-10, 2005 in Scottsdale, Arizona. Dr. Tozer was recorded at Women’s Health 2006,
sponsored by Mayo Clinic College of Medicine, and held on March 9-11, 2006, in Phoenix, Arizona. The Audio-Digest
Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.
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