MIGRAINE
| MIGRAINE PREVENTION STRATEGIES —Paru S. David, MD, Clinical Instructor, Mayo Clinic, Scottsdale, Arizona
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| Introduction: diagnosis of migraine increased from 1989 to 1999; 1999 statistics show ≈28 million people suffer from migraine;
majority of patients not properly diagnosed as having migraine
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| International Headache Society criteria: patient must have ≥5 attacks lasting 4 to 72 hr and ≥2 of following, unilateral,
pulsating, moderate or severe intensity, and aggravated by routine physical activity; symptoms must include nausea and/
or vomiting, and patient must have both photophobia and phonophobia; symptoms must not be attributable to another disorder;
tension headache—most common primary headache disorder; most poorly understood and least distinctive; debatable
whether tension headache variant of mild migraine; patient can have tension headache that transforms into migraine;
strategies for migraine treatment—acute, preventive, and preemptive (use of medication before known headache trigger,
eg, start of menses)
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| Preventive treatment: when to implement therapy—pain interferes significantly with patient’s daily routine despite acute
treatment, causing increased disability; medications for acute attacks contraindicated, ineffective, have intolerable side
effects, or overused (overuse causes daily headache or daily migraine); >2 attacks weekly and use of medication >2 times
weekly; patient has uncommon migraine conditions; patient preference; goals of preventive treatment—decrease frequency
of attacks 50%; decrease intensity and duration; improve responsiveness to acute treatment; improve functioning
and decrease disability
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| Patient counseling: counsel patient no cure for migraine, but control of attacks possible (50% reduction considered good);
side effects with all medications; 50% of patients noncompliant with medication regimen; writing out medication regimen
for patient and keeping copy in patient’s medical record good way to establish accountability; headache diary—
enables clinician to design appropriate treatment plan; stratifies care to headache type; determines whether acute treatment
adequate or if prophylaxis required; instruct patient to record headache triggers, symptoms, duration of symptoms,
relieving or exacerbating factors, severity of attack, and medications used; triggers—changes in sleep habits, weather
changes, hormonal changes, glare or flickering light, stress; establishing regular sleep pattern and having regular meals
can decrease frequency of migraine; stress significant factor in development of migraine; Migraine Disability Assessment
Questionnaire (MIDAS)—assesses headache-related disability (work and social); can be downloaded from Web site
(www.midas-migraine.net); patient with moderate disability good candidate for preventive treatment
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| General principles of preventive treatment: involve patients in their care to maximize compliance; start with low dose
and increase slowly (reduces side effects); use long-acting formulation if compliance is issue; 2 to 3 mo at appropriate
dosage necessary to evaluate effectiveness of medication; reevaluate therapy in 2 to 3 mo (improves compliance); counsel
patient about how and when to use medication and possible side effects; instruct patient that over-the-counter (OTC)
acute medications containing caffeine can promote continuous daily headache; evaluate therapy using patient’s headache
diary; attempt to taper and discontinue medication when headaches well controlled (≈1 yr)
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| Prohylactic medications: approved for off-label use—propranolol, timolol, and valproic acid; consider medication that
will treat comorbid conditions, eg, depression (significant comorbidity), anxiety, stroke, coronary artery disease
(CAD); do not use migraine medication if contraindicated for another condition, eg, β-blocker if person asthmatic; do
not use medications that can exacerbate migraine headache, eg, nitrates used for CAD; be aware of drug interactions
and pregnancy in reproductive-age women
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 | Anticonvulsants: divalproex (Depakote)—approved for migraine; efficacy 4+; some side effects; topiramate—efficacy
4+; few side effects; gabapentin (Neurontin)
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| Antidepressants: tricyclic antidepressants (TCAs)— efficacy 4+; few side effects; amitriptyline or nortriptyline recommended
(at hs if patient has difficulty sleeping; low dosage, ie, 10 mg titrated to 50 mg recommended; selective serotonin reuptake inhibitors
(SSRIs)— efficacy 2+; monoamine oxidase inhibitors (MAOIs)— efficacy 2+; numerous side effects; refractory depression
relative indication; speaker does not prescribe MAOIs; methysergide— efficacy 4+; numerous side effects; not
available in United States
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| Others: β-blockers—efficacy 4+; calcium channel blockers—efficacy 2+; few side effects; nonsteroidal anti-inflammatory
drugs (NSAIDs)—naproxen; used perimenstrually; riboflavin, feverfew, botulinum toxin, and petasites extract (butterbur;
herbal agent); MigraHealth—400 mg magnesium, 400 mg riboflavin, and 10 mg feverfew; available OTC
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| Acute medications: preventive agents cannot be used to treat acute migraine; limit acute medications to prevent drug-induced
headache; preventive medications enhance effectiveness of acute medications; certain medications require caution
or cannot be used together, eg, methysergide and MAOIs; risk for gastrointestinal (GI) bleeding with NSAIDs; butalbital
with divalproex increases sedation
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| Nonpharmacologic treatment: indications— patient preference, poor tolerance, poor response or contraindications to drug
therapy, pregnancy, anticipation of pregnancy, breastfeeding, history of medication abuse, significant life stresses, deficient
stress-coping skills; shown effective— relaxation training, thermal biofeedback (hand warming) with relaxation training,
electromyographic biofeedback, and cognitive behavioral therapy; insufficient evidence to recommend—acupuncture, transcutaneous
electrical nerve stimulation (TENS), cervical manipulation, occlusal adjustment, hyperbaric O2 , and hypnosis; behavioral
therapy can enhance preventive therapy; counseling patients—educate and reassure patients that headaches can be
treated and managed; counsel about potential headache triggers; suggest self-help books for stress reduction and relaxation
techniques; suggest headache support group
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| Sex-specific issues: 70% of women have worsening headaches associated with menstrual cycle; 60% report relief from headaches
during pregnancy; 40% have first migraine during pregnancy or shortly after delivery; 70% have few migraines after
menopause, but many women report worsening headaches around perimenopausal transition; prevalence—of 28 million
people experiencing migraine, 20 million are women; before puberty, prevalence about equal between men and women;
prevalence increases in women with onset of menarche; prevalence highest in women 25 to 55 yr of age; true menstrual
migraine—not actual diagnosis, but subset of migraine; occurs exclusively during perimenstrual period; attack occurs
within 5-day window (2 days before onset of menses through first 3 days of menses); menstrually associated migraine— migraines
during menstrual window, ovulation, and premenstrually; most women experience menstrually associated migraine;
hormonally associated headache— occurs with abrupt withdrawal of estrogen; continuous use of oral contraceptives (OCs)
recommended; if unacceptable to patient, prescribe add-back estrogen during placebo week (0.05-mg or 0.1-mg patch,
weekly or biweekly); therapy with OCs can be used in patients not normally using OCs if attacks occurring around menstrual
cycle; instruct patient to start patch 3 days before onset of menses and continue at least 3 days after onset of menses;
cyclic prophylaxis— dihydroergotamine (Migranal) 1 to 2 times daily perimenstrually; rizatriptan (Maxalt) 10 mg shown to
relieve 79% of attacks; with frovatriptan (Frova) 5 mg, 52% of patients achieved relief; 41% achieved relief with 2.5-mg
dose compared to placebo (26%); given for 6 days (3 days before onset of menses and 3 days after menses)
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| ISSUES IN MIGRAINE —Julia A. Files, MD, Chair, Division of Women’s Health-Internal Medicine, Mayo Clinic Arizona;
Assistant Professor, Mayo Clinic College of Medicine, Scottsdale, Arizona
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| Pathophysiology: migraine primary brain disorder; originates from dysfunction in trigeminal nuclear complex (located in
brainstem); familial disorder with significant genetic influence; migraineurs more susceptible to brain dysfunction than
nonmigraineurs (reason unknown); V1 of trigeminal nerve innervates pain-sensitive areas in brain; migraine generator in
brainstem; excitation of trigeminal nuclear complex leads to firing of V1 , activation of nerves, and release of “toxic soup”
around blood vessels, leading to vasodilation; calcitonin gene-related peptide (CGRP)—potent vasodilator; released at
level of blood vessels when V1 of trigeminal nuclear complex activated; causes problems with blood vessel dilation, ie,
stretching and activation of pain fibers; loop of intensifying pain and cortical dysfunction leads to migraine phenomenon;
treatment options no longer limited to masking of pain associated with migraine, but directed at pathophysiologic targets
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| Triptans: concern about cardiovascular (CV) safety barrier to prescribing; American Headache Society consensus statement:
cardiovascular safety profile of triptans (5-HT1B/1D agonists) in acute treatment of migraine—chest symptoms occurring
during therapy with triptans usually not serious and usually not attributed to ischemia; while serious CV adverse events occurred
after use of triptans, their incidence in clinical trials and clinical practice extremely low; CV risk-benefit profiles of
triptans favor their use in absence of contraindications; most clinical trials and clinical practice data on triptans derived from
patients without known CAD; safety profile in women—safety in women enhanced because migraines generally occur at
time of life when most women do not have significant CV disease; assess patient’s risk factors for CAD using Adult Treatment
Panel (ATP) III guidelines—low risk, triptan therapy can be used; intermediate risk, evaluate patient for CV disease;
high risk (CAD or CAD equivalent), triptan therapy contraindicated; frovatriptan use in migraineurs with or at high risk for
CAD—data showed placebo group had more electrocardiography (ECG) changes at 2 hr than treatment group; no significant
negative outcomes, ie, myocardial infarctions, deaths; mechanism of action—migraine-specific therapy; serotonin agonists;
work at variety of targets through 5-HT1B/1D receptors (serotonin receptors); 5-HT1B/1D receptors responsible
for vasoconstriction; work at trigeminal nerve endings to inhibit release of toxic neuropeptides; may have some mild
central effects in cutaneous allodynia; sumatriptan (Imitrex) in clinical use since 1991; 5-HT1B/1D receptor agonist;
6 second-generation triptans currently available; individual variability in response not predictable; factors in choosing
triptan— time of onset, time to peak pain intensity, severity of symptoms, presence of GI symptoms, and frequency and pattern
of attacks; survey shows patients want complete pain relief within 2 hr, no headache recurrence, rapid onset of action,
no adverse effects, and relief of associated symptoms; route of administration not significant; sumatriptan soon to be marketed
in all forms of administration; meta-analysis showed best treatment for acute migraine most likely almotriptan, eletriptan,
or rizatriptan
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| Topiramate (Topamax): data show significant efficacy in prevention within first month of treatment; neuromodulator
agent; structurally unique anticonvulsant; γ-aminobutyric acid (GABA)-agonist and glutamate inhibiting properties;
blocks sodium and calcium channels; inhibits carbonic anhydrase; inhibits neuronal excitability; recommendations—start
low, go slow; 15 to 25 mg daily; increase weekly to 200 mg daily; data show 3.3% to 4.1% weight loss; side effects—
distal paresthesias, cognitive dysfunction, reversible acute angle closure glaucoma (refer patient for eye pressure screening),
and kidney stones
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| Botulinum toxin type A (Botox): approved in United States for cervical dystonia, blepharospasm, and forehead wrinkles;
some open-label, uncontrolled studies suggest benefits for migraine and tension-type headache; limited randomized controlled
trial (RCT) data suggest benefit; arguments in favor—used for 2 decades with no permanent muscle weakness or
paralysis; evidence growing; long duration of action (interval between injections ≈3 mo); excellent response reported;
few systemic side effects; evolving understanding of mechanism involving CGRP; arguments against—mechanism of
action does not justify use (Botox paralyzes muscles, migraine not related to muscle contraction); lack of substantive evidence
(trials open-label); RCTs show effect with 25 units, but no effect with 75 units; other evidence not as strong or
supportive
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| Calcitonin gene related peptide: release of CGRP from trigeminal nerve after nerve activation known to occur; potent dilator
of intracranial vessels; causes degranulation and release of inflammatory agents from meningeal mast cells; involved
in transmission of painful stimuli from intracranial vessels to cerebrospinal fluid; BIBN 4096 BS—potential new
treatment; potent receptor agonist for CGRP; data show significant improvement in 2-hr pain relief from acute migraine
attack over placebo in all dosing groups; few side effects; unlike serotonin receptor agonists or triptans, has no vasoconstrictor
activity; Botox decreases release of CGRP from trigeminal neurons; Botox’s mechanism of action biologically
plausible and may account for efficacy in prevention of migraine (however, RCT in Cephalalgia showed no effect)
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| More on Botox: most headache centers in United States using off label; held to higher standard than other drugs used for
prevention; injectable and expensive; questions surrounding use include which subgroup of migraine patients, whether to
use standardized or tailored therapy, and optimal therapeutic dose
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| Feverfew: parthenolide believed to be active component; whole leaf preparations may have effects beyond parthenolide;
used throughout history for migraine prevention; recent RCT of feverfew in combination with riboflavin and magnesium
showed no response beyond placebo; high placebo response in study possibly due to use of 25 mg of riboflavin as placebo
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| Lisinopril: various pharmacologic effects may be important; RCT showed moderate response, but statistically significant
compared to placebo
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| Candesartan: shown to be effective in double-blind RCT; decreased number of headache days; angiotensin-receptor blocker
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| Conclusion: migraine may not be benign intermittent brain disorder; may lead to long-term effects and damage at level of
brain; understanding of migraine pathophysiology evolving; acute and preventive treatment options expanding
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Educational Objectives
| The goal of this program is to educate the listener about the prevention and treatment of migraine headache. After hearing
and assimilating this program, the clinician will be better able to:
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| 1. List the diagnostic criteria for migraine headache as set forth by the International Headache Society.
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| 2. Recognize when preventive treatment for migraine should be implemented, and discuss counseling issues about the
treatment of migraine.
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| 3. Discuss hormonal influences on migraine.
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| 4. Discuss the pathophysiology of migraine and why botulinum toxin type A may be a potential option for the treatment of
migraine.
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| 5. Prescribe the appropriate medication for a patient suffering from migraine headache.
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Discussed on This Program
Almotriptan malate [Axert]
Amitriptyline HCl [Elavil]
Botulinum toxin type A [Botox, Botox Cosmetic, Dysport]
Butalbital (several formulations and trade names)
Butterbur (Petasites vulgaris, Petasites hybridus)
Candesartan cilexetil [Atacand]
Dihydroergotamine mesylate [D.H.E. 45, Migranal]
Divalproex sodium [Depakote, Depakote ER]
Eletriptan HBr [Relpax]
Feverfew (Tanacetum parthenium, Chrysanthemum parthenium)
Frovatriptan succinate [Frova]
Gabapentin [Neurontin]
Lisinopril [Prinivil, Zestril]
Methysergide maleate [Sansert] (discontinued)
Naproxen [Aleve, Anaprox, Anaprox DS, EC-Naprosyn, Naprosyn, Naprelan]
Nortriptyline HCl [Aventyl HCl, Aventyl HCl Pulvules, Pamelor]
Propranolol HCl [Inderal, Inderal LA]
Riboflavin (B2 )
Rizatriptan benzoate [Maxalt, Maxalt-MLT]
Sumatriptan succinate [Imitrex]
Timolol maleate [Betimol, Blocadren, Istalol, Timoptic, Timoptic-XE]
Topiramate [Topamax]
Valproic acid [Depacon, Depakene, Depakote, Depakote ER]
Suggested Reading
Adelman JU et al: Current options for the prevention and treatment of migraine. Clin Ther 23(6):772, 2001; Arulmani U
et al: Calcitonin gene-related peptide and its role in migraine pathophysiology. Eur J Pharmacol 500(1-3):315, 2004; Bigal
ME et al: Prophylactic migraine therapy: emerging treatment options. Curr Pain Headache Rep 8(3):178, 2004; Elkind AH
et al: Frovatriptan use in migraineurs with or at high risk of coronary artery disease. Headache 44(5):403, 2004; Evers S et
al: Botulinum toxin A in the prophylactic treatment of migraine—a randomized, double-blind, placebo-controlled study.
Cephalalgia 24(10), 2004; Gladstone JP et al: Migraine in special populations. Treatment strategies for children and adolescents,
pregnant women, and the elderly. Postgrad Med 115(4):39, 2004; Goadsby PJ et al: Migraine—current understanding
and treatment. N Engl J Med 346(4):257, 2002; Kruit MC et al: Migraine as a risk factor for subclinical brain
lesions. JAMA 291(4):427, 2004; Lipton RB et al: Medical consultation for migraine: results from the American Migraine
Study. Headache 38(2):87, 1998; Olesen J et al: Calcitonin gene-related peptide receptor antagonist BIBN 4096 BS for the
acute treatment of migraine. N Engl J Med 350(11):1104, 2004; Tepper SJ et al: Safety profile of the triptans. Expert Opin
Drug Saf 2(2):123, 2003; Silberstin SD: The rise and fall of estrogen levels. Cephalalgia 17(7), 1997; Silberstein SD et al:
Migraine: preventive treatment. Cephalagia 24(10):908, 2004; Stewart WF et al: Migraine disability assessment (MIDAS)
score: relation to headache frequency, pain intensity, and headache symptoms. Headache 43(3):258, 2003
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. For this issue, the faculty reported
nothing to disclose.
Drs. David and Files were recorded at the Mayo Clinic’s Women’s Health 2004 sponsored by the Mayo Clinic College of
Medicine, held on October 28-30, 2004 in Scottsdale, Arizona. The Audio-Digest Foundation thanks the speakers and the
sponsor for their cooperation in the production of this program.
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