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Migraine in Women
Deborah Friedman, MD, MPH
Professor, Neurology and Ophthalmology
University of Texas Southwestern Medical
Center
Dallas, Texas
Disclosure:
Consultant: Iroko, MAP Pharmaceuticals, Zogenix
Grant Support: AGA Pharmaceuticals, Merck, Pfizer, MAP Pharmaceuticals, Quark Pharmaceuticals
Honoraria: Allergan
Other: Neurology News Editorial Board
Migraine is a Female Disorder
Average lifetime percent of population with migraine:
22.6% women (range 13-32%)
10.5% men (range 5.7-9%)
Women are roughly 3 times as likely as men to have migraine
Hormonally associated migraine affect 12 million women in the U.S.
Is it Migraine? Migraine without Aura
At least 5 attacks
Headache lasts 4-72 hours (untreated) in adults,
1-72 hours in children
At least 2 of the following:
Unilateral location
Pulsating quality
Moderate or severe intensity
Aggravated by routine physical activity
During the headache, at least 1 of the following:
Nausea and/or vomiting
Photophobia and phonophobia
Migraine with Aura
At least 2 attacks Scintillating scotoma
At least 3 of the following:
Fully reversible aura symptoms explained by focal brain dysfunction
At least one aura symptoms evolving over at least 4 minutes or two or more symptoms in succession
Each symptom lasts less than 60 minutes
Headache usually begins during or follows the aura
Sensory
Paresthesias (tongue; hand-mouth)
Motor
Unilateral or bilateral weakness (spreads)
Olfactory
Gustatory hallucinations
Vertigo/dizziness
Common (50%) but does not distinguish migraine with/without aura
Fortification spectra
Speech
Dysarthria
Aphasia
Behavioral
Depersonalization
Automatic behavior
Transient global amnesia
Emotional (anxiety, euphoria)
Déjà vu (strange things look familiar) Jamais vu (familiar things look strange)
Other
Diplopia
Ptosis
Altered level of consciousness
Ataxia
Unilateral episodic mydriasis
Auditory
What’s not aura
Blurred vision
Premonitory photophobia, phonophobia, nausea
Quick and Easy Migraine Diagnosis:“I.D. Migraine”
1. Headache related disability
2. Photophobia3. Nausea
93% of migraineurs have 2 of 3 features81% sensitivity, 75% specificityAura 100% sensitive
Phases of Migraine
*Yawning, mood change, sleepiness,
food cravings, excessive thirst or
urination
Pre-HeadachePremonitory symptoms*
AuraHeadache Post-Headache
Postdrome
Mild Moderate Severe
Taking the History: The American Migraine Communication Study
60 visits (approximately 12 minutes each) between healthcare professionals (primary care, neurologists, NP) and patients were video and audio-recorded
Post-visit interviews were conducted separately with patients and healthcare professionals
All interviews were transcribed and analyzed looking for discordance
Findings
91% of the questions asked were closed-ended or short-answer
90% of visits did not address impairment in any way (60% were severely impaired during attacks; average frequency 5/month)
Of the 50 patients, 35 were not on a preventive medication after the first visit
Prevention was only mentioned in 50% of the 25 patients who would qualify for one based on standard guidelines
Suggestions for Improving Communication
Patient-centered interviewing focused on disability:
“How do migraines affect your daily life?”“How does migraine affect your work and
family?”“How does migraine make you feel – even
when you aren’t having one?”
Other General Features
Migraine changes throughout life
Migraine may change with hormones
You can have a migraine without a headache
Children get migraines too
People with migraine often get other kinds of headaches as well
It runs in the family
Occurs in the peak productive years
Migraine affects:18% of women6.5% of men
7% of children
Estrogen Paradox
Being female increases the likelihood of having migraine (estrogen)
Sudden decreases in estrogen can trigger migraine headaches
Fall in estrogen
Prior to menses
Pill free week of oral contraceptives
Perimenopause
Postpartum
Migraine Throughout the (Hormonal) Life CycleChildren
Adolescence – Puberty
Menstruation
Pregnancy
Menopause
Other:
Hormone replacement therapy
Oral contraceptives
Migraine in Children
Boys=girls prior to puberty Peak incidence of migraine with aura
Boys – age 5
Girls – age 12-13
Peak incidence of migraine without aura
Boys – age 10-11
Girls – age 14-17
After puberty ratio is 3 to 1
(girls to boys)
Boys often outgrow them
Migraine in Childhood
Under-diagnosed
Young children may not be
able to describe pain or associated features
Nausea, vomiting, sensitivity
to light and noise is inferred
Headaches are often shorter than in adults
Think about migraine in children with:
Episodes of unexplained vomiting and abdominal pain lasting an hour or more
Attacks of imbalance or dizziness lasting minutes
Recurring attacks of head tilt, vomiting, imbalance lasting hours to days
Alternating one-sided weaknessHeadaches followed by droopy eyelid and
double vision (lasting days to weeks)
Migraine and Menstruation60-70% of women with migraine have
them with menstruationPure Menstrual Migraine
2 days prior to menses to 4th day of menses only (14% of women) for 2 of 3 cycles
Menstrually-Related MigraineWithin the above window and at other times of the month
Perimenstrual MigraineAttacks 2-7 days prior to menses
Keep a diary! Compare menstrual and non-menstrual attacks.
May Be Associated with Other Features of PMS
(DSM-4: 5 days before to 4 days into menses, interfere with activities)
Affective
Depression
Angry outbursts
Irritability
Anxiety
Confusion
Social withdrawal
Food cravings
Increased appetite
Sexual disinterest
Physical
Breast tenderness
Abdominal bloating
Headache
Peripheral edema
Acne
Cramping
What’s Different During Menses?
No difference in sex hormones between migraineurs and controls (testosterone, LH, FSH)
Headaches more severe, more
nausea and vomiting
Treatments may not
be as effective during
menses (?)
Loder E. Neurol Sci 2005;26:S121-124
Treatment of Menstrual MigraineAcute symptomatic treatment
Migraine specific, anti-inflammatoriesStandard preventive treatmentShort-term preventive treatment (“mini-
prevention”)Non-steroidal anti-inflammatoriesLong-acting triptans (frova) or ergots MagnesiumHormonal therapy (estradiol gel)Increase usual preventative
Non-pharmacologic therapy
**Pringsheim T, et al. Acute treatment and prevention of menstrually related migraine headache. Neurology 2008;70:1555-1563
Use of Oral Contraceptives to Prevent Menstrual Migraine
1. Extended cycle OCsSuppress ovulation for monthsMay have breakthrough bleeding in first few
months (accompanied by migraine)
2. Reduce monthly decline in estrogenUse low-dose estrogen instead of 7 placebo pills
each month
3. Contraceptive patch + vaginal ringLess daily fluctuation in estrogen level
Migraine and Pregnancy
Better (50-60+%)
Worse (15-%)
The Same (25%)
May worsen during the first trimester
May only occur during pregnancy
May be headache free in last trimester
New Onset of Headaches During Pregnancy
Increased intracranial pressure
Tension-type headache
Cerebral venous sinus thrombosis
Stroke
Tumor
Vasculitis
Intracranial hemorrhage
Reversible cerebrovasoconstrictive syndrome (RCVS)
Headache Medications and Pregnancy – General Concepts
Pharmakokinetics vary during gestation
Increased plasma volume – increase unbound drug
Decreasing albumin – increase free fraction (total assays unreliable)
Increased renal clearance
Changes in CYP and glucuronidation
**Lucas S. Medication Use in the Treatment of Migraine During Pregnancy and Lactation. Curr Pain Headache Rep 2009;13:392-398.
Symptomatic Treatment of Migraine During Pregnancy (Category B – no evidence of risk but no studies)
AcetaminophenCaffeineIbuprofen*Indomethacin*Naproxen*MeperidineMorphinePrednisone
*Avoid in third trimester
Barbiturates, opioids, benzodiazepines
Neonatal withdrawal syndrome
Opioids are category B
Beware medication overuseTriptans are all category CErgots are contraindicated
Treatment of Migraine-Related Nausea (Category B)
Dimenhydramine Meclizine
Metoclopramide
Ondansetron
Anticholinergics – meconium ileus
Migraine Prevention During Pregnancy (Category B/C)
Avoid migraine triggers
Beta blockers (C)
Fluoxetine (C)
Venlafaxine (C)
Vitamin B2 (B)
Coenzyme Q-10 (B)
Magnesium (B)
Avoid valproate, topiramate, AEDs, lithium (D)
Breast Feeding – General Principles
No evidence that lactation worsens migraine
Safe in pregnancy ≠ safe in lactation
Amount passed to breast milk depends on:
• average plasma concentration
• amount excreted into breast milk
• volume of milk ingested
Is the drug necessary?
Use the safest one
Consider measuring blood levels in the infant
Take medication after completing a breast feeding to minimize exposure to the baby
Symptomatic Treatment While Breast Feeding
Compatible
Acetaminophen, caffeine, NSAID
Caution
Aspirin, barbiturates
Triptans
Concern
Benzodiazepines
Contraindicated
Antihistamines
Ergotamine/DHE
Preventive Treatment While Breast Feeding
CompatibleBeta blockersCalcium blockersValproateCorticosteroidsAmitriptyline
CautionSSRI
ConcernTricyclic antidepressantsVerapamil
ContraindicatedBromocriptine
**Hale TW. Medications and Mother’s Milk. Amarillo, TX, Hale Publishing, 2008.
Perimenopause
Women with a history of menstrual migraine (“hormonally sensitive”) may have worsening of migraines in peri-menopause
Treatment:Hormone replacement therapy
Low dose OC (without placebo week)
Standard migraine therapies
MenopauseMigraine and natural
menopause:
20-40% worsen
20-30% improve
30-50% unchanged
Effect of surgical menopause:
(hysterectomy, oophorectomy)
38-87% worsen
Some women develop migraines for the first time at menopause
Hormone Replacement Therapy?
Conflicting data regarding migraineConsiderations:
Delivery (patch*, cream, pill, injection)Need for continuous useType and dosage
Natural estrogens (estradiol) are better tolerated than conjugated estrogen
One size does not fit allRisk-benefit ratio
Migraine and Stroke
Women under 45
Posterior circulation strokes and white matter lesions more likely in MWA and high attack frequency of migraine than controls
Women 45 years and older
MWA twice as likely to develop ischemic stroke and MI over 10 years of follow-up
Ferrari M, et al. Brain 2005
Migraine and Stroke
Numerous studies document increase risk:
National Health and Nutrition Examination Survey – prospective (11,777 men and women; RR 2.1)
Meta-analysis of 14 observational studies
Risk among all migraineurs, OR = 2
MWA, OR = 2.9
MWOA, OR = 1.6
Women’s Health StudyProspective cohort study of 39,754 health
professionals ages 45 and olderNo migraine or MWOA – no increased risk
MWA – Adjusted hazards ratio
1.53 for total stroke
1.71 for ischemic stroke
No increased risk for hemorrhagic stroke
Women < 55 with MWA had greatest risk:
1.75 for total stroke
2.25 for ischemic stroke
Stroke Risk: Low Dose OCs
Meta analysis of 16 studies (Gillum)RR = 1.92 (1.4-2.7) controlling for smoking and hypertension = 1 additional stroke per 24,000
Meta analysis of 14 studies (Baillargeon)RR 1.84 (1.4-2.4) with low dose OC useAlso risk of 2nd and 3rd generation OC use
Risk of Stroke Varies by Age: Women
9 per 100,000 in 20-year-old MWA
3 per 100,000 in 20-year-old w/o migraine
80 per 100,000 in 40-year-old MWA
11 per 100,000 in 40 year-old w/o migraine
Summary of Risk
Migraine increases risk of stroke, OR = 2-3Aura, female sex, age > 45, high frequency,
migraine duration – higher risk > 12 attacks/year, > 12 years of migraine)
OC increases risk of ischemic stroke, OR = 2OC increase risk of venous sinus thrombosis, OR = 22OC increase risk of subarachnoid hemorrhage, OR = 1.6
Recommendations (ACOG, WHO, IHS)
Women with migraine should minimize other vascular risks
Women with MWOA on hormone therapy should stop if aura develops or headache worsens
Women with migraine over 35 who smoke should not use OCs
Women with a history of stroke or venous clot should not use OCs
Controversy: Women with MWA should not use hormonal therapy
Migraine and Cardiovascular Disease (Women’s Health Study)
580 major CVD events occurredActive MWA: hazard ratio 2.15 overall
1.91 for ischemic stroke2.08 for MI1.74 for coronary revascularization1.71 for angina2.33 for ischemic CVD death
18 additional major CVD events/10,000 women per year, after adjusting for age
MWOA: No increased risk
Migraine as a Clinically Progressive Disorder
Episodic migraine evolves over time in some patients, AKA “transformed migraine”
Attacks increase in frequency (medication overuse)
Chronic daily headache (>180 days yearly) with superimposed migraine
Development of allodynia
Risk Factors for Development of Chronic Daily Headache
Definition: Headache on more days than not (> 15 days monthly X 3 months
Case-control, cross sectional population study
Longitudinal follow-up for progression
800 people with episodic headache
3% developed CDH
6% developed 105-179 HA days
Predictors of Progression
Medication overuse
Especially OTC with caffeine combinations, narcotic combinations, barbiturate combinations
Weight: Overweight = 2X, Obesity = 5X!!
Baseline headache frequency (>1/wk)
Low socioeconomic status
Head injury
Lipton RB, Bigal M. Headache 2005; 45 (suppl 1) S3-S13Goadsby PJ. Med J Austr 2005;182(3):103-4
Stressful life events (moving, death in family, work-related changes)
Snoring
Risk Factors and Development of CDH
Not readily modifiable
Migraine as a disorder
(predisposition)
Female sex
Low SES
Head injury
Modifiable
Attack frequency
Obesity
Medication overuse
Stressful life events
Snoring (OSA and other sleep disorders)
Central Sensitization and Allodynia
Allodynia – a normally non-painful stimulus becomes painful
Occurs in 75% of migraineurs during migraine
Usually takes years to develop
Allodynia – Taking the HistoryPositive in 70%
Peripheral sensitizationThrobbing qualityHair / eye glasses / earrings hurtHurts to touch: shave, sleep, wash
Central sensitizationPain is worse with coughing, sneezingTriptans less likely to work when central allodynia is present
Implications for Treatment
Stratified care based on disability
Reduce environmental triggers, if present
Weight management
Investigate for sleep disorder when appropriate
Prophylaxis
Reduce modifiable cardiovascular risk
Stratified Care by Overall DisabilityLittle to none “Low end” Triptans
Moderate Combination treatments
Triptans Anti-emetics
Prophylaxis
Severe “High end” Triptans
Prophylaxis Narcotics
Anti-emetics Ergots
Refer to specialist
Summary
Women are different.Migraines change throughout the reproductive cycle.Estrogen is important.Migraine may be progressive – consider preventive treatment.
Additional Recommended Reading
Dodick DW. Chronic daily headache. NEJM 2008;354:158-165
Elliott D. Migraine and stroke: current perspectives. Curr Pain Headache Rep 2008;30(8):801-12
Ferrante E, Tassorelli C, Rossi P, et al. Focus on the management of thunderclap headache: from nosography to treatment. J Headache Pain 2011;12:251-258
Klein AM, Loder E. Postpartum headache. Int J Obstet Anesth. 2010;19:422-30
Kurth T, Gaziano JM, Cook NR, et al. Migraine and risk of cardiovascular disease in women. JAMA 2006;296;283-291
Lipton RB, Bigal ME. Ten lessons on the epidemiology of migraine. Headache 207;46(Suppl1):S2-S9
McGregor EA. Prevention and treatment of menstrual migraine. Drugs 2010;70:1799-818
Sullivan E, Bushnell C. Management of menstrual migraine: a review of current abortive and prophylactic therapies. Curr Pain Headache Rep 2010;14:376-84
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