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A. Types of Migraine Headache (HA)navigator

  1. Migraine without aura (common migraine)
    1. Attacks lasting 4-72 hours (untreated)
    2. At least 2 of: unilateral, pulsating, moderate to severe, aggrevated by movement
    3. At least 1 of: nausea or vomiting, photophobia, phonophobia
  2. Migraine with aura (classic migraine)
    1. One or more transient focal neurological aura symptoms
    2. Gradual development of aura symptom over >4 minutes, or several symptoms in a row
    3. Aura symptoms last 4-60 minutes (untreated)
    4. HA follows or accompanies aura within 60 minutes
  3. Ophthalmoplegic migraine
  4. Retinal migraine
  5. Childhood periodic syndromes
  6. Complicated migraine
  7. Familial Hemiplegic Migraine
  8. Transformed Migraine [3]
    1. Head pain for >15 days/month for >1 month
    2. Average HA >4 hours if untreated
    3. History of migraine or migrainous HA for at least 3 months
  9. Menstrual Migraine [4]
    1. Includes pure menstrual and menstrually related migraine
    2. Usually occurs without aura and longer duration than non-menstrual migraine
    3. Usually more resistant to treatment than non-menstrual migraine
  10. Migraine patients are defined as having either:
    1. Two attacks with aura
    2. Five attacks without aura
  11. If new onset "migraine" occurs in patient >40 years old, strongly consider CT or MRI scan

B. Epidemiologynavigator

  1. Very common condition
  2. Marked female predominance (75%) except in earliest years
  3. Age related prevalence rates are:
    1. Age 5: male = female 0.05%
    2. Age 10: female 0.16%, male 0.12%
    3. Age 20-30: female ~0.25%, male 0.05%
    4. Age 35: female (peak) 0.35%, male 0.10%
    5. Age 40-55: female 0.30%, male 0.10%
    6. Overall: rates in women are ~3 fold higher than men (~18% of women, 6% of men)
  4. New migraine patients are very rare after the age of 40-45 years
    1. Peak prevalence in women is age 35
    2. Peak prevalence in men is age 50
  5. Therefore, presentation of new HA in persons >40 years old is cause for concern

C. Migraine Triggersnavigator

  1. Trigger foods
    1. Chocolate - role has been questioned
    2. Caffeine - usually as a withdrawal syndrome
    3. Alcohol (EtOH)
    4. Monosodium glutamate (MSG)
    5. Nitrites
    6. Sulfites
  2. Tobacco Smoke
  3. Estrogens [4]
    1. Very high estrogen levels may reduce attacks
    2. Decreased frequency and severity of migraines during pregnancy
    3. Fall in estrogen levels triggers migraine, particularly around menstrual period
    4. High frequency of migraines in perimenopausal period
  4. Fumes and Vapors
  5. Dehydration
  6. High Altitudes
  7. Decompression Illness (scuba divers)
  8. Patent foramen ovale with right to left shunt [7]
  9. Genetic mutations: unclear what percentage of migraine suffers have genetic cause

D. Symptoms (see above)navigator

  1. Throbbing HA is always present, often one side worse than other
  2. Migraine with or without aura will have different symptoms
  3. Nausea and vomiting
    1. Apparently due to decreased grastric motility
    2. Vomiting sometimes releives HA
  4. Photophobia or phonophobia
  5. Feeling of doom occurs more in "Classic Migraine" as an "aura"
  6. Visual auras are usually one sided
  7. Suggestive of Migraine Versus "Serious" HA Cause [31]
    1. Pulsating
    2. Duration 4-72 hours
    3. Unilateral
    4. Nausea
    5. Disabling
    6. Presence of 4 of these 5 gives likelihood ratio (LR) for migraine of 24
    7. Presence of 3 of these 5 gives LR for migraine of 3.5
    8. Presence of 1 or 2 of these 5 gives LR of 0.4
  8. Neuroimaging Recommended for [31]:
    1. Cluster-type headache: LR ~11
    2. Abnormal neurological examination: LR ~5
    3. Undefined HA: LR ~4
    4. HA with aura: LR ~3

E. Pathogenesis [1] navigator

  1. Primary disorder of the brain with vascular dysfunction
    1. Neurologic changes initiate secondary vasodilation [2]
    2. Migraine is not a primary vascular event
    3. Subclinical brain lesions have been found in subsets of patients with migraine [5]
    4. Group of familial disorders with some genetic component
    5. Specific familial migraine syndromes have been defined (see below)
    6. Mutations in a the alpha2 subunit of the Na/K pump have also been implicated [1]
  2. Vascular Changes and Pain
    1. Migraine involves both vasoconstriction and vasodilatation
    2. Likely due to dysfunction of brainstem or diencephalic nuclei
    3. These nuclei control sensory (nociceptive) modulation of craniovascular afferents
    4. Brainstem is activated during migraine
    5. Such activation may be restricted in the brain to the trigeminal nerve region
    6. Depolarization of trigeminal ganglion or perivascular nerve terminals involved
    7. Trigeminaocervical (C2 spinal region) complex is involved
    8. Depolarization of these neurons leads to neuropeptide release, vasodilation
    9. Parasympathetic and serotonergic neurons also involved
  3. Specific Neurotransmitters
    1. Pain may be due to release of Substance P and Calcitonin Gene Related Peptide (CGRP)
    2. CGRP causes dural vasodilation (A-delta fibers)
    3. Trigeminal type C-fibers release neurokinin A and substance P
    4. This leads to dural plasma extravasation, inflammation, and increased pain
    5. Leukotrienes and Neuropeptide Y are then released from sympathetic nerves
    6. Nitric oxide, a potent vasodilator, is released directly from the artery itself
    7. Migraine patients also have systemic disturbances of serotonin metabolism (vomiting)
    8. Low levels of serotonin in such patients are permissive for migraines
    9. One central problem appears to be serotonin regulation mediated through HT-1D receptor
    10. Stimulation of the 5-HT1 receptor can abort migraines (see below)
    11. Blockade of CGRP can abort migraines [9]
  4. Aura
    1. Originally believed to be caused by vasoconstriction
    2. Now thought to be caused by cortical spreading depression (CSD)
    3. CSD is a depolarization wave that propagates across brain cortex 2-3mm/min
    4. CSD associated with transient depression and spontaneous and evoked neuronal activity
    5. CSD is assocated with profound ion channel activity and cerebral blood flow changes
    6. These changes in cerebral blood flow likely give rise to visual and aural symptoms
    7. Migraine with aura is a ~2X risk factor for cardiovascular events (MI and stroke) [30]
    8. Serotonin and glutamate have also been implicated in initiating the aura
    9. Most efficacious treatments alter serotonin actions and decreases glutamate levels
  5. Familial Hemiplegic Migraine (FHM) [17]
    1. Type 1 FHM: mutation in brain calcium channel P/Q type subunit (chromosome 19p13)
    2. Mutation in CACNA1A (gene for P/Q calcium channel alpha subunit) causes disease
    3. Patients develop migraine with hemiparesis, epilepsy
    4. Ataxia and frank cerebellar atrophy occur in a subset of patients
    5. Abnormal serotonin regulation
    6. Mutations in CACNA1A also cases episodic type 2 ataxia
    7. Type 2 FHM: missense mutation in ATP1A2, encodes alpha2 subunit of Na+/K+ pump
    8. Third locus for FHM identified on chromsome 2q24 at the SCN1A gene
    9. SCN1A gene coding for neuronal sodium channel, is mutated Gln1489Lys in some FHM [15]

F. Therapeutic Intervention [1,2,8]navigator

  1. Acute goal is obviously control of pain [16]
    1. Strongly advocate use of stratified care regimen versus usual step care
    2. Thus, moderate and severe migraines should be treated aggressively [16]
    3. For moderate to severe migraines, serotonin agonists are first line
    4. These agents should be used under medical supervision for the first 1-2 doses
    5. Parenteral opiates (such as meperidine) and anti-nausea agents may be used as well
  2. More dangerous causes of HA must be ruled out (see above)
  3. Prevention of Migraines
    1. Initially, try elimination diet: eliminate implicated foods and add back one at a time
    2. Discontinue vasoconstrictor (usually sympathomimetic) medications
    3. Add prophylactic agents (see below)
    4. Many patients would prefer continuing normal lifestyle and adding preventive agents
    5. Acupuncture has not been effective for prevention of migraine in randomized trials [29]

G. Treatment of Acute Exacerbations [8]navigator

  1. Non-Steroidal Anti-Inflammatory Drugs (NSAID)
    1. Mainly for mild to moderate HA
    2. Generally poorer control of concurrent migraine symptoms than other agents
    3. Ketorolac (Toradol®): potent agent; im or iv initial dose, lower oral followup doses
    4. Indomethacin (Indocin®): 25mg po bid-qid activity appears superior to many NSAIDs
    5. Flurbiprofen (Ansaid®): 200-400mg po qd
    6. Naproxen sodium (Anaprox®): 550-1100mg po
    7. Naproxen combined with sumatriptan is more effective than either alone [32]
    8. GI distress and bleeding is a concern
    9. Renal dysfunction can occur, particularly with other nephrotoxins
    10. Acetaminophen (paracetamol) is an alternative particularly in pregnancy
  2. Triptans [19,22]
    1. Triptans stimulate 5HT-1B and -1D receptors, and probably -1F receptors
    2. 5HT1-R agonists and induce cerebral vasoconstriction
    3. Triptans can also cause coronary artery vasoconstriction through 5HT-1B R
    4. Thus, triptans are generally contraindicated in cases of coronary artery disease
    5. Side effects of triptans include chest pain, vasocontstriction, wheezing, flushing
    6. 5HT-1F R agonist LY334370 has antimigraine activity without vasoconstriction [18]
    7. Specific triptans are discussed in detail below
  3. Dihydroergotamine (DHE; see also below) [22]
    1. Derivative of ergotamine with less vasoconstriction and adverse effects
    2. Can be given sc, im, iv, and newer intranasal therapy
    3. ~70% of patients will have relief within 2 hours of injection
    4. DHE Nasal Spray (Migranal®) - one spray (0.5mg)/nostril x 1, repeat in 15 minutes
    5. Generally well tolerated
    6. May cause hypertension or cardiac valvular lesions
    7. Nasal form may be safer, more effective
    8. Often as effective as (more expensive) serotonin agonists
    9. Ergots cause potent peripheral vasoconstriction that can lead to ischemia [14]
    10. Ischemia leading to gangrene due to ergotism was called Saint Anthony's fire
  4. Dopamine Antagonists
    1. Primarily improve nausea and vomiting and may cause sedation
    2. Metoclopramide (Reglan®) - also improves gastric emptying; 10mg IV usually given [27]
    3. Prochlorperazine (Compazine®) 10mg iv
    4. Chlorpromazine 25mg iv
    5. Often given with benadryl or hydroxyzine 25mg iv or im
    6. Side effects of dopamine antagonists: dystonia, tardive dyskinesia
  5. Opiates
    1. Meperidine (Demerol® 25-100mg) im or iv (with hydroxyzine 25mg)
    2. May be repeated q30-60 minutes
    3. Dilaudid® (Hydromorphone)
    4. Butorphanol (Stadol®) nasal spray
    5. Addiction is a major concern
  6. Other Ergot Alkaloids (3rd line therapy)
    1. Non-specific 5-HT (serotonin) receptor agonist
    2. Ergotamine tartrate (Ergostat®)
    3. Give 1-2mg iv q 30-60 minutes; do not give with sumatriptan
    4. Also made with Caffeine (Cafergot®) - effective rectally
    5. Limiting dosages: 6mg / 24 hours and 10mg / week
    6. Side effects: GI distress, muscle cramps, vascular occlusion with gangrene
  7. Other Agents
    1. Dexamethasone 4mg iv
    2. Fiorinal®: Caffeine + ASA + Butalbital (not recommended)
    3. Intranasal lidocaine (4%) - patients must be supine, overall not very effective
    4. CGRP antagonist BIBN4096 effective in early or later migraine [9]

H. Triptans: 5HT-1B / 5HT-1D Agonists [22] navigator

  1. These are first line agents for control of moderate to severe migraines
  2. Agents [13]
    1. Sumatriptan (Imitrex®) [11]
    2. Zolmitriptan (Zomig®) [25,26]
    3. Naratriptan (Amerge®) [13]
    4. Rizatriptan (Maxalt®) [13]
    5. Eletriptan (Relpax®)
    6. Almotriptan (Axert®) [21]
    7. Frovatriptan (Frova®) [21]
  3. Actions [20]
    1. Serotonin agonists are selective for 5HT-1B and 5HT-1D receptors
    2. Also have weaker agonist effects at 5HT-1F and somewhat 5HT-1A
    3. Potent cerebral vessel constrictors particularly in trigeminal region
    4. Efficacy in HA likely due to 5HT-1B/1D effects, possibly 5HT-1F
    5. Cause minimal constriction of cardiac vessels
    6. Coronary vessels express 5HT-1B recpetors
    7. Very low incidence of cardiac ischemia or frank myocardial infarction
    8. Safer than many other potent antimigraine agents
  4. Sumatriptan (Imitrex®) [11,12,13]
    1. Sumatriptan 100mg po is the reference standard for acute migraine treatments
    2. Oral 50mg po is usual starting dose; repeat in 60 minutes
    3. Also available for subcutaneous dosing: 6mg, may repeat in 15 minutes
    4. Effective in reducing HA in ~65% of cases with single dose
    5. Headache reduced up to 80% with two doses, ~33% headache free at 2 hours
    6. Nasal spray is also effective with 60% response at 2 hours
    7. Sumatriptan 85mg po combined with naproxen 500mg po (Treximet®) was superior to either agent alone and to placebo across most aspects of migraine symptoms, and on rebound [32,33]
    8. Alternatively, sumatriptan 100mg can be combined with generic naproxen [33]
  5. Zolmitriptan (Zomig®) [25,26]
    1. Oral or nasal spray (more rapid onset) 5-HT1-R agonist
    2. Similar efficacy to sumatriptan
    3. Some patients who do not respond to sumatriptan may respond to zolmitriptan
    4. Oral dose is 1/2 or 1 tablet (2.5mg) initially, repeated in 2 (and 4) hours
    5. Maximum oral dose is 10mg in 24 hours
    6. Nasal spray 5mg dose (~30% absorbed in <5 minutes); onset in as little as 15 minutes
  6. Naratriptan (Amerge®) [13]
    1. Dose 1mg or 2.5mg tablet, repeated in 4 hours
    2. May repeat to maximum of 5mg per 24 hours
    3. Longer half life than others, with slower onset of action
    4. Only 50% of patients improved at 2 hours; 15% pain free at 24 hours
    5. May be used in patients taking MAO inhibitors
    6. For prevention of menstrual-associated migraine, 1mg po bid two days before initiation of menstruation reduced migraine rates from 50% to 25% [4]
  7. Rizatriptan (Maxalt®)
    1. 5mg or 10mg tablet or wafer (MLT) which can dissolve on tongue
    2. May repeat in 2 hours to maximum dose 30mg per 24 hours
    3. Rapid onset of action similar to zolmitriptan
    4. Propranolol increases levels of rizatriptan
    5. Probably the best agent for acute complete headache eradication within 2 hours [2,19]
  8. Almotriptan (Axert®) [21]
    1. 12.5mg po dose initially; may be repeated after 2 hours
    2. Excellent eradication of headache at 2 hours
    3. Lowest cost compared with other agents
  9. Frovatriptan (Frova®) [21]
    1. 2.5mg orally; may be repeated after 2 hours
    2. Lowest acute efficacy rate of any of the triptans
    3. For prevention of menstrual-associated migraine, 5mg loading dose day 1, then 2.5mg po qd or bid through day 5 of period significantly reduces migraines [4]
    4. Frovatriptan 2.5mg bid is superior to 2.5mg once daily for menstrual migraines [4]
  10. Eletriptan (Relpax®)
    1. Dose initially 20mg to maximum of 40mg
    2. 80mg dose most effective but is not labelled
  11. Drug Interactions
    1. Should not be used with other serotonergic agents
    2. This includes selective serotonin reuptake inhibitors
    3. Should not be used within 2 weeks of MAO inhibitor (except naratriptan)
    4. Reduce dose in presence of liver dysfunction
  12. Contraindications
    1. Coronary artery disease - use with extreme caution but generally well tolerated [20]
    2. Bronchospasm
    3. Moderately severe and/or uncontrolled hypertension
    4. History of allergic reaction
    5. Use of monoamine oxidase (MAO) inhibitors
    6. Use within 24 hours of ergotamines (such as dihydroergotamine, methysergide)
  13. Efficacy [19]
    1. Migraine reduction within 30-60 in majority of patients using parenteral sumatriptan
    2. Most agents show ~30% of patients headache free at 2 hours
    3. All agents have 30-40% migraine recurrence rate within 24 hours
    4. Eletriptan 80mg, rizatriptan 10mg, almotriptan 12.5mg provide highest success rates overall [19]
    5. Sumatriptan is useful in cluster HA [12]
  14. Side Effects
    1. Rare precipitation of angina, likely due to coronary vasospasm or vasoconstriction
    2. Flushing
    3. Bronchoconstriction - rare
    4. Allergic reactions including anaphylaxis with shortness of breath
    5. Allergic reactions usually reversed with iv diphenhydramine

I. Migraine Prophylaxis [1,2,13,22]navigator

  1. Usually for >3 months migraine or migraines >1 / week
    1. ß-adrenergic blockers first line
    2. Amitriptyline usually second line
    3. Topiramate (preferred), gabapentin (Neurontin®) are reasonable second line alternatives and also effective for transformed migraine [3,28]
    4. Divalproex (valproate) usually third line
    5. Candesartan (an angiotensin II receptor blocker) - particularly in hypertensive persons
    6. Methysergide only for recurrent, refractory migraines
    7. Other agents as described below
  2. ß-Blocking Agents
    1. Extremely effective agents, should be 1st or 2nd line prophylaxis
    2. Propranolol (Inderal and Inderal LA®) non-selective; 20-240mg po qd
    3. Naldolol (Corgaurd®) non-selective, also effective
    4. Atenolol (50mg qd) and Metoprolol (100mg bid), ß1-selective, moderately effective
    5. Timolol (Blocadren®) 10-15mg po bid
    6. Side effects include bradycardia, hypotension, heart failure, bronchospasm, impotence
  3. Topiramate (Topamax®) [6,10]
    1. Significant reductions (35-45%) in migraine frequency with 100-200mg po qd
    2. Reductions in migraine days per month 25-35% at 100-200mg po qd
    3. Initiate Dose 25 mg po qd and increase weekly (by 25mg qd) to maximum 200mg po qd
    4. Minimal side effects: cognitive impairment, fatigue, anorexia, diarrhea, some weight loss
  4. Tricyclic (TCA) and other Antidepressants
    1. Excellent choice for prophylaxis; also improves sleep and mood
    2. Amitriptyline (Elavil®) has proven efficacy 10-150mg po qhs (causes drowsiness)
    3. No evidence for benefit with nortriptyline (Pamelor®) or other TCAs
    4. Modest effect for fluoxetine (Prozac®) 20mg qod to 40mg qd
    5. Efficacy may improve with addition of Ca channel blocker (such as verapamil) or ß-blocker
    6. Side effects include dry mouth, slow urination, constipation, rare cardiac anomalies
  5. Gapapentin (Neurontin®)
    1. Gabapentin - 300-750mg po tid may be effective in some patients
    2. Generally fewer side effects than valproate; no need for blood chemistry monitoring
  6. NSAIDs
    1. Generally not indicated for prophylaxis
    2. COX-2 selective agents may be considered (celecoxib, valdecoxib, others)
    3. Side effects prominent in long term usage with GI distress, renal problems, diarrhea
  7. Candesartan (Atacand®) [23,24]
    1. Angiotensin II receptor blocker approved for hypertension
    2. 16mg po qd candesartan reduced severity, duration, sick leave versus placebo
    3. Appears effective for migraine prophylaxis, and well tolerated
  8. Calcium Channel Blockers
    1. Verapamil (120-240mg/d) has no demonstrated efficacy in controlled trials
    2. May use in conjunction with TCA and may potentiate action
    3. Side effects include bradycardia, hypotension, heart failure, constipation
    4. Nimodipine may also be useful (very expensive)
    5. Consider particularly in migraine with aura and in patients with hypertension, asthma
  9. Valproate
    1. Generally reserved for patients who fail ß-blockers, topiramate and TCA
    2. Dose 800-1000mg po qd in 2-3 divided doses (goal serum level 70-120mg/L)
    3. Begin dosing of divalproex sodium at 250mg per day to dose above
    4. Side effects include hair loss, weight gain, hepatic dysfunction
    5. Carbamazepine and vigabatrin not effective
  10. Lithium: 300mg po qid (monitor renal function and thyroid function tests)
  11. Specific Serotonin Reuptake Inhibitors (SSRI's)
    1. Fluoxetine (Prozac®): 20mg po qam
    2. Sertraline (Zoloft®): 50mg po qam
    3. Unclear if these agents are effective for migraine prophylaxis
  12. Cyproheptadine (Periactin®)
    1. Anti-histamine with antiserotonin and calcium antagonism
    2. Limited efficacy in controlled trials
    3. Side effects: drowsiness and weight gain
  13. Methysergide (Sansert®)
    1. Ergot Alkaloid, now reserved for recurrent, refractory, severe migraines
    2. Dose 1-2mg po tid for 4-6 months then discontinue agent for 1 month
    3. Discontinuation is critical due to risk for retroperitoneal and other fibrosis
    4. High rate of side effects: weight gain, peripheral edema, retroperitoneal fibrosis
    5. Drug interactions with ß-blockers, macrolides, dopamine, other ergot alkyloids
    6. Timed release DHE also effective for migraine prevention
  14. Avoid addictive medications
    1. Opiates
    2. Barbiturates - including Fiorinal® (ASA + caffeine + butalbital), Fioracet®
    3. Benzodiazapines
  15. Generally carry out at least a 1 month trial of specific agent before switching agents

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