eMedicine Specialties > Neurology > Headache and Pain
Migraine Headache: Treatment & Medication
Updated: Sep 4, 2008
- Overview
- Differential Diagnoses & Workup
- Treatment & Medication
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Treatment
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.
Abortive Therapy
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 (see Table 1 below), 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 Headache SeverityOpen table in new window
Table
| Moderate | Severe | Extremely Severe |
| NSAIDs | Naratriptan | DHE (IV) |
| Isometheptene | Rizatriptan | Opioids |
| Ergotamine | Sumatriptan (SC,NS) | Dopamine antagonists |
| Naratriptan | Zolmitriptan | |
| Rizatriptan | Almotriptan | |
| Sumatriptan | Frovatriptan | |
| Zolmitriptan | Eletriptan | |
| Almotriptan | DHE (NS/IM) | |
| Frovatriptan | Ergotamine | |
| Eletriptan | Dopamine antagonists | |
| Dopamine antagonists |
| Moderate | Severe | Extremely Severe |
| NSAIDs | Naratriptan | DHE (IV) |
| Isometheptene | Rizatriptan | Opioids |
| Ergotamine | Sumatriptan (SC,NS) | Dopamine antagonists |
| Naratriptan | Zolmitriptan | |
| Rizatriptan | Almotriptan | |
| Sumatriptan | Frovatriptan | |
| Zolmitriptan | Eletriptan | |
| Almotriptan | DHE (NS/IM) | |
| Frovatriptan | Ergotamine | |
| Eletriptan | Dopamine antagonists | |
| Dopamine antagonists |
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.
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:
- Headache occurs daily or near daily
- Occurs in a patient with primary headache disorder who uses immediate relief medications very frequently, often in excessive quantities
- Headache varies in intensity, type, severity, and location from time to time
- Slight physical or intellectual effort bring on headaches; threshold for pain low
- Headache accompanied by asthenia, nausea and other GI symptoms, restlessness, anxiety, irritability, memory problems, difficulty in intellectual concentration, and depression
- Drug-dependent rhythmicity of headaches
- Evidence of tolerance to analgesics over a period of time
- Withdrawal symptoms when taken off the medications abruptly
- Spontaneous improvement of headache on discontinuing the medications
- Concomitant prophylactic medications are 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.
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.
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).
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.
Prophylactic Therapy
Prophylactic therapy can be considered under the following conditions:
- Two or more attacks each month with significant disability that lasts 3 or more days
- Contraindication to or ineffectiveness of symptomatic medications
- Use of abortive medications more than twice a week
- Migraine variants such as hemiplegic migraine or rare headache attacks producing profound disruption or risk of permanent neurological injury
Currently, the major prophylactic medications for migraine work via one of the following mechanisms:
- 5-HT2 antagonism - Methysergide
- Regulation of voltage-gated ion channels - Calcium channel blockers
- Modulation of central neurotransmitters - Beta-blockers, tricyclic antidepressants
- Enhancing GABAergic inhibition - Valproic acid, gabapentin
- Another notable mechanism is through alteration of neuronal oxidative metabolism by riboflavin and reducing neuronal hyperexcitability by magnesium replacement.
Like that of abortive medications, the selection of a preventive medication must take into consideration comorbid conditions and side effect profile (see Table 2 and Table 3). Most 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 basis for using most of these medications are wanting. Propranolol, timolol, methysergide, and valproic acid have been approved by the US Food and Drug Administration (FDA) in the past, and recently topiramate has also been approved for migraine prophylaxis. Refer to Medication for further information on prophylaxis.
Table 2. Preventive Drugs
Open table in new window
Table
| First line | High efficacy | Beta-blockers Tricyclic antidepressants Divalproex Topiramate |
Low efficacy | Verapamil NSAIDs SSRIs | |
| Second line | High efficacy | Methysergide Flunarizine MAOIs |
Unproven efficacy | Cyproheptadine Gabapentin Lamotrigine |
| First line | High efficacy | Beta-blockers Tricyclic antidepressants Divalproex Topiramate |
Low efficacy | Verapamil NSAIDs SSRIs | |
| Second line | High efficacy | Methysergide Flunarizine MAOIs |
Unproven efficacy | Cyproheptadine Gabapentin Lamotrigine |
Table 3. Preventive Medication for Comorbid Conditions
Open table in new window
Table
| Comorbid Condition | Medication |
| Hypertension | Beta-blockers |
| Angina | Beta-blockers |
| Stress | Beta-blockers |
| Depression | Tricyclic antidepressants, SSRIs |
| Underweight | Tricyclic antidepressants |
| Epilepsy | Valproic acid, Topiramate |
| Mania | Valproic acid |
| Comorbid Condition | Medication |
| Hypertension | Beta-blockers |
| Angina | Beta-blockers |
| Stress | Beta-blockers |
| Depression | Tricyclic antidepressants, SSRIs |
| Underweight | Tricyclic antidepressants |
| Epilepsy | Valproic acid, Topiramate |
| Mania | Valproic acid |
Surgical Care
Besides the medical management, surgical treatments have also been tried for the prevention of migraines. Guyuron and colleagues have shown that surgical deactivation of migraine headache trigger sites can help eliminate or significantly reduce the symptoms of migraine.5
Corrugator muscle resection has a much better chance for improvement with the mild form of migraine headache compared with worse forms as shown by Dirnberger and Becker.6
- Botulinum toxin-A (BOTOX ®) has been used in multiple trials for the prophylaxis of migraine headaches. Some mixed results have occurred on the use of botulinum toxin-A for the migraine headaches.7
- Pericranial injection of 50-U botulinum toxin-A has shown good efficacy and tolerability as a prophylactic agent. Botulinum toxin-A therapy has been tried for refractory chronic migraine in those who previously have failed to respond to at least 3 prophylactic medications.
- A recent report from Schulte-Mattler and Martinez-Castrillo has shown no evidence for a beneficial effect of botulinum toxin and thus, they have not supported the widespread use of botulinum toxin therapy in headaches.8
Diet
- A fraction of persons who experience migraines have dietary triggers. Common triggers include chocolate, aged cheeses and meats, wine and beer (ie, sulfites), and citrus fruits.
- Obviously, the avoidance of dietary triggers plays an important role in the treatment of these patients.
Medication
Pharmacologic agents used for the treatment of migraine can be classified as abortive (ie, symptomatic) drugs and prophylactic (ie, preventive) agents.
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); naratriptan (Amerge, Naramig); zolmitriptan (Zomig, Zomig-ZMT); rizatriptan (Maxalt, Maxalt-MLT); almotriptan (Axert); frovatriptan (Frova)
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.
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.
Almotriptan induces cranial vessel constriction, inhibition of neuropeptide release, and reduces pain transmission in trigeminal pathways.
Frovatriptan possesses long half-life (ie, 26-30 h), thus, decreases recurrence of migraine within 24 h after treatment.
Eletriptan's onset is within 1 h, and the half-life is 18 h.
Adult
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
Almotriptan:
6.25-12.5 mg PO at onset of migraine; may repeat once, not to exceed 25 mg/d
Frovatriptan:
2.5 mg PO once at onset of migraine attack
Eletriptan:
20-40 mg PO at onset of migraine; if initial dose ineffective, may repeat dose once after 2 h; not to exceed 80 mg/d
Pediatric
Sumatriptan:
Tab: 12.5-25 mg PO prn; not to exceed 100 mg qd
Nasal spray: 5 mg NS prn
Injection: 0.02 mg/kg SC prn
Zolmitriptan: 2.5 mg PO prn; not to exceed 10 mg qd
Naratriptan: 1 mg PO prn; not to exceed 5 mg qd
Rizatriptan: 5 mg PO prn; not to exceed 30 mg qd
Almotriptan: Not established
Frovatriptan: <18 years: Not established
>18 years: Administer as in adults
Eletriptan: <18 years: Not established
>18 years: Administer as in adults
Theoretical interactions with ergotamine-containing drugs, MAOIs, and SSRIs; propranolol increases plasma concentration of rizatriptan by 70%; concurrent administration with ergot-containing drugs or other 5-HT1 agonists may increase vasospastic reactions
Eletriptan: Potent CYP450 3A4 inhibitors (eg, ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, nelfinavir) may increase toxicity
Documented hypersensitivity; age >65 y; angina or other signs or symptoms of ischemic heart disease or coronary vasospasm; uncontrolled hypertension; stroke of any type; peripheral vascular disease; severe renal or hepatic impairment; concurrent ergotamine-containing preparations or MAOIs; hemiplegic or basilar migraine
Additionally, for eletriptan: severe hepatic impairment; administration within 72 h of potent CYP450 3A4 inhibitors
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Limited data available concerning use during breastfeeding
Patients with known or suspected coronary artery disease may have increased risk of myocardial ischemia, infarction, or other cardiac or cerebrovascular events (5-HT1 agonists may cause coronary vasospasm)
May cause tingling, sensation of heat, dizziness, flushing, sensation of burning, pressure, and heaviness; in patients receiving propranolol, rizatriptan single dose should not exceed 5 mg and total daily dose should not exceed 15 mg in 24 h
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.
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.
Adult
Ergotamine tartrate
1 mg PO initially; q30min prn; not to exceed 6 mg per attack
1-2 mg SL initially; q30min prn; not to exceed 6 mg per attack
1-2 mg PR initially; q30min prn; not to exceed 4 mg per attack
DHE
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
Pediatric
Not established
Increase effects of heparin; increase toxicity of nitroglycerin, propranolol, erythromycin, vasoconstrictors, 5-HT1 agonists, and clarithromycin
Documented hypersensitivity; peripheral vascular disease; coronary artery disease; thrombophlebitis; severe hypertension; bradycardia; hepatic or renal impairment; hyperthyroidism; malnutrition; sepsis; pregnancy; breastfeeding; age >60 y
Pregnancy
X - Contraindicated; benefit does not outweigh risk
Precautions
Ergotamine tartrate not recommended for prolonged use and may cause significant rebound headache
Avoid using prolonged regimens due to danger of causing gangrene as well as dependency
Abortive medications/analgesics
These agents are used as initial abortive therapy for patients with infrequent migraines.
Acetaminophen (Tylenol), propoxyphene (Darvon), oxycodone (OxyContin), morphine (Duramorph, MS Contin), meperidine (Demerol), hydromorphone (Dilaudid), butorphanol (Stadol)
Used as ‘rescue' medications if migraine headache not controlled 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.
Adult
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
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
Pediatric
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)
Meperidine: 1-1.8 mg/kg PO/IM/SC q3-4h; not to exceed recommended adult dosage
Other drugs: Not established
Increase CNS depressant properties of other drugs including alcohol, antihistamines, antidepressants, sedative/hypnotics, and MAOIs
Rifampin can reduce analgesic effects of acetaminophen; coadministration with barbiturates, carbamazepine, hydantoins, and isoniazid may increase acetaminophen hepatotoxicity
Documented hypersensitivity; intracranial lesion associated with impaired intracranial pressure (hydromorphone); recent or concurrent MAOIs; depressed respiration; COPD; cor pulmonale; emphysema; status asthmaticus; kyphoscoliosis
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
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
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.
Aspirin (Bayer Aspirin, Anacin), ibuprofen (Motrin, Ibuprin), naproxen (Naprosyn, Naprelan), ketorolac (Toradol)
Mild analgesics that can be used to treat infrequent migraine episodes.
Adult
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
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
Not recommended
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
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
Ketorolac: Coadministration with aspirin increases risk of inducing serious NSAID-related adverse effects; probenecid may increase concentrations and, possibly, toxicity of NSAIDs; may decrease effect of hydralazine, captopril, and beta-blockers; may decrease diuretic effects of furosemide and thiazides; may increase PT when taking anticoagulants (instruct patients to watch for signs of bleeding); may increase risk of methotrexate toxicity; phenytoin levels may be increased when administered concurrently
Documented hypersensitivity; active peptic ulcer disease; renal or hepatic impairment; concomitant or recent use of anticoagulants; hemophilia or other hemorrhagic conditions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Aspirin: The elderly may be more susceptible to CNS effects; should not be used in last trimester of pregnancy
NSAIDs: GI effects such as dyspepsia, nausea, and vomiting are common adverse effects
Abortive medications/Combination analgesics
The first combination product of a 5HT receptor agonist and an NSAID, Treximet, was approved by the US Food and Drug Administration in April 2008. Efficacy was demonstrated in 2 randomized, double-blind, multicenter, parallel-group trials comparing the combination product to placebo and each individual active component (ie, sumatriptan and naproxen sodium). The percentage of patients remaining pain free without use of other medications through 24 hours postdose was significantly greater (p<0.01) among patients receiving a single dose of Treximet (25% and 23%) compared with placebo (8% and 7%) or either sumatriptan (16% and 14%) or naproxen sodium (10%) alone.9
Other combination products that contain ergots, sedatives, and 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.
Sumatriptan and naproxen (Treximet)
Combination product containing sumatriptan, a selective 5-hydroxytryptamine (5-HT1) receptor agonist, and naproxen sodium, an arylacetic acid nonsteroidal anti-inflammatory drug (NSAID). Fixed combination contains sumatriptan 85 mg and naproxen sodium 500 mg. Indicated for acute migraine. Sumatriptan mediates vasoconstriction of the basilar artery and vasculature of dura mater, which correlates with migraine relief. Naproxen provides analgesic, anti-inflammatory, and antipyretic properties. Decreases activity of cyclooxygenase, thereby interrupting prostaglandin synthesis.
Adult
1 tab PO at onset of migraine; do not exceed 2 tab/24 h; if second dose administered, do not administer until at least 2 h after first dose
Pediatric
Not established
Do not split, crush, or chew tab
Sumatriptan: Do not administer within 24 h of ergotamine-containing or ergot-type drugs (eg, dihydroergotamine, methysergide); coadministration with selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) may increase risk for serotonin syndrome; coadministration with MAOIs or within 2 wk of discontinuing MAOIs may increase sumatriptan levels (see Contraindications)
Naproxen: Coadministration with aspirin increases risk of inducing serious NSAID-related adverse effects; probenecid may increase concentrations and, possibly, toxicity of NSAIDs; may decrease effect of hydralazine, captopril, and beta-blockers; may decrease diuretic effects of furosemide and thiazides; may increase PT when taking anticoagulants (instruct patients to watch for signs of bleeding); may increase risk of methotrexate toxicity; phenytoin levels may be increased when administered concurrently
Documented hypersensitivity; ischemic heart disease (eg, stable angina, vasospastic forms of angina, myocardial infarction, silent myocardial ischemia); uncontrolled hypertension; cerebrovascular or peripheral vascular disease; history of coronary artery bypass graft (CABG) surgery; peptic ulcer disease; recent GI bleeding or perforation; renal (CrCl <30 mL/min) or hepatic insufficiency; coadministration with MAOIs or within 2 wk of discontinuing MAOI; hemiplegic or basilar migraine; patients in whom aspirin or other NSAIDs induce asthma, rhinitis, nasal polyps, or urticaria
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Sumatriptan may increase risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke
Naproxen may increase risk of serious GI adverse events (eg, bleeding, ulceration, stomach or intestinal perforation); acute renal insufficiency, interstitial nephritis, hyperkalemia, hyponatremia, and renal papillary necrosis may occur; patients with preexisting renal disease or compromised renal perfusion risk acute 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; preexisting asthma
Butalbital (Fiorinal), Isometheptene and dichloralphenazone (Midrin)
Combination drugs effective for mild to moderately severe migraine headache.
Adult
Butalbital: 1-2 tab PO q4h prn; not to exceed 6 tabs/d
Isometheptene and dichloralphenazone: 2 caps PO initially then 1 capsule q1h until symptoms relieved; not to exceed 5 capsules in 12-h period
Pediatric
Butalbital: Not established in patients <12 years
Isometheptene and dichloralphenazone: Not established
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, 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: Documented hypersensitivity; porphyria
Isometheptene and dichloralphenazone: Documented hypersensitivity; glaucoma; severe renal or hepatic impairment or disease; organic heart disease; concomitant MAOIs
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
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
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
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 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.
Adult
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 q3-4h; 5-50 mg IV
Metoclopramide: 10-20 mg PO/IM
Pediatric
Droperidol: 1-1.5 mg/9-11 kg IM for children aged 2-12 y
Chlorpromazine: 0.55 mg/kg PO/IM q6-8h; not to exceed 75 mg/d for children aged 5-12 y
Metoclopramide: Not established
Anticholinergic drugs, narcotic analgesics, alcohol, sedatives, hypnotics, tranquilizers, MAOIs, and barbiturates
Documented hypersensitivity; concurrent drugs that are likely to cause extrapyramidal reactions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Sedation, hypotension, tachycardia, extrapyramidal reactions, hyperactivity, anxiety, and dizziness are common adverse effects, which must be given consideration especially for very young and elderly patients
Metoclopramide classified as category B for use in pregnancy
Prophylactic therapy/Antiepileptics
These drugs are effective in prophylaxis of migraine headache.
Divalproex sodium/valproate (Depakote, Depacon, Depakene), topiramate (Topamax)
Valproic acid: Now considered first-line preventive medication for migraine. Believed to enhance GABA 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%.
Topiramate: Indicated for migraine headache prophylaxis. Precise mechanism unknown, but the following properties may contribute to its efficacy: (1) electrophysiological and biochemical evidence showing blockage of voltage-dependent sodium channels, (2) augments activity of the neurotransmitter GABA at some GABA-A receptor subtypes, (3) antagonizes AMPA/kainate subtype of the glutamate receptor, and (4) inhibits the carbonic anhydrase enzyme, particularly isozymes II and IV.
Adult
Valproic acid: 125-250 mg/d PO initially; titrate dose prn; not to exceed 1500 mg/d; doses higher than 250 mg/d should be divided bid
Topiramate: Slowly titrate upward at a minimum of 1-wk
intervals as follows:
Week 1: 25 mg PO qhs
Week 2: 25 mg PO bid
Week 3: 25 mg PO qam
and 50 mg PO qhs
Week 4: 50 mg PO bid
Pediatric
Valproic acid: Limit use in children <10 y because of increased risk of fatal hepatotoxicity
Topiramate: Not established
Valproic acid: 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 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
Topiramate: Phenytoin, carbamazepine, and valproic acid can significantly decrease topiramate levels; topiramate reduces digoxin and norethindrone levels, when administered concomitantly; concomitant use with carbonic anhydrase inhibitors may increase risk of renal stone formation and should be avoided; use topiramate with extreme caution when administering concurrently with CNS depressants since may have an additive effect in CNS depression, as well as other cognitive or neuropsychiatric adverse events
Valproic acid: Documented hypersensitivity; children aged <10 y (because of risk of fatal hepatotoxicity); hepatic disease; thrombocytopenia
Topiramate: Documented hypersensitivity
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Valproic acid: Common adverse effects include nausea and/or vomiting and indigestion, which are usually self-limited; tremor, hair loss, weight gain, and hepatic toxicity also have been reported; periodic clinical assessment and occasional blood tests to evaluate hematopoietic, renal, and hepatic systems should accompany prolonged therapy
Topiramate: Risk of developing a kidney stone formation is increased 2-4 times that of untreated population; risk may be reduced by increasing fluid intake; caution in renal or hepatic impairment; patients taking topiramate should seek immediate medical attention if they experience blurred vision or periorbital pain; continued usage after symptoms develop, can lead to glaucoma; primary treatment is discontinuation of topiramate; if left untreated, serious sequelae, including permanent vision loss, may occur; oligohidrosis and hyperthermia has been reported predominantly in children during vigorous exercise or exposure to warm environmental temperatures (ensure proper hydration prior and during activity and warm temperatures);
May cause hyperchloremic, nonanion gap metabolic acidosis acute or chronic metabolic acidosis resulting in hyperventilation, and nonspecific symptoms, such as fatigue and anorexia, or more severe adverse effects including cardiac arrhythmias or stupor; chronic, untreated metabolic acidosis may increase nephrolithiasis or nephrocalcinosis risk, osteomalacia (ie, rickets in pediatric patients), or osteoporosis with an increased risk for bone fractures; chronic metabolic acidosis in pediatric patients may also reduce growth rates; measure baseline and periodic serum bicarbonate; sprinkle cap should be swallowed whole, or carefully open cap and sprinkle contents on soft food immediately before ingestion, do not chew or crush
Gabapentin (Neurontin)
Initial open study showed efficacy in migraine and 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
300 mg PO tid; titrate gradually prn; not to exceed 2400 mg/d
Pediatric
<12 years: Not established
>12 years: Administer as in adults
Antacids may significantly reduce bioavailability of gabapentin (administer at least 2 h following antacids); may increase norethindrone levels significantly
Documented hypersensitivity
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Somnolence, fatigue, dizziness, and coordination problems reported
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 (Tenormin)
Are effective in prophylactic therapy possibly by blocking vasodilators, decreasing platelet adhesiveness and aggregation, stabilizing the membrane, and increasing the release of oxygen to tissues.
Adult
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
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
Pediatric
Only propranolol has been used for children
0.5 mg/kg PO bid initially; may be increased every 3-5 d; not to exceed 1 mg/kg bid
Decreases effect of diuretics and increases toxicity of methotrexate, lithium, and salicylates; may diminish reflex tachycardia, resulting from nitroglycerin use, without interfering with hypotensive effects; cimetidine may increase labetalol blood levels; glutethimide may decrease labetalol effects by inducing microsomal enzymes
Documented hypersensitivity; asthma; COPD; CHF; partial or complete AV conduction defects; Raynaud disease; peripheral vascular disease; brittle diabetes; severe depression
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
May cause bradycardia, dizziness, nausea, fatigue, depression, memory disturbance, impotence, and diminished exercise tolerance; caution in impaired 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
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 (Vivactil)
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.
Adult
Amitriptyline, doxepin, nortriptyline: 10-25 mg PO qhs initially; increase by 10-25 mg q1-2wk based on efficacy and tolerance; not to exceed 150-175 mg/d
Protriptyline: 15 mg/d PO initially; titrate prn; not to exceed 40 mg/d given tid or qid
Pediatric
<12 years: Not recommended
>12 years: Administer as in adults
Phenobarbital may decrease effects; coadministration with CYP2D6 enzyme system inhibitors (eg, cimetidine, quinidine) may increase tricyclic antidepressant levels; tricyclic antidepressants inhibit hypotensive effects of guanethidine; may interact with thyroid medications, alcohol, CNS depressants, barbiturates, and disulfiram
Documented hypersensitivity; pregnancy or lactation; narrow-angle glaucoma; urinary retention; cardiac arrhythmias or defects in bundle-branch conduction; concomitant MAOIs
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
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, anticholinergic effects such as dry mouth, constipation, delayed micturition, blurred vision, increased appetite with weight gain, decreased libido, and excessive sweating
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.
Verapamil (Calan, Covera)
During depolarization, inhibits calcium ion from entering slow channels or voltage-sensitive areas of vascular smooth muscle.
Adult
120 mg/d PO qd (sustained release) initially or 40 mg tid; increase gradually; not to exceed 480 mg/d
Pediatric
Not established
Phenobarbital may decrease effects; coadministration with CYP2D6 enzyme system inhibitors (e.g., cimetidine and quinidine) may increase tricyclic antidepressant levels; amitriptyline inhibits hypotensive effects of guanethidine; may interact with thyroid medications, alcohol, CNS depressants, barbiturates, and disulfiram
Documented hypersensitivity; bradycardia; second-and third-degree heart block; sick-sinus syndrome; concomitant beta-blockers
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Patients may report an initial increase in headache, which improves after weeks of treatment; hypotension and dizziness also reported secondary to vasodilatation; increase in peripheral edema may be associated with nifedipine and decrease with nimodipine and verapamil
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 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.
Adult
Fluoxetine: 10 mg/d PO on waking initially; can be increased every 2 wk; not to exceed 60 mg/d
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
Pediatric
Not established
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 other serotonergic agents (eg, anorectic agents, tramadol, buspirone, trazodone, clomipramine, nefazodone, tryptophan), discontinue other serotonergic agents at least 2 wk prior to SSRIs
Documented hypersensitivity; pregnancy and lactation; severe renal or hepatic disease
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Concurrent MAOIs may cause serious, potentially fatal reactions such as autonomic instability
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
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 reactions and pain by decreasing activity of cyclooxygenase, enzyme responsible for prostaglandin synthesis.
Adult
275 mg PO tid or 550 mg bid
Pediatric
<12 years: Not recommended
>12 years: Administer as in adults
Probenecid may increase toxicity; ibuprofen may decrease effects of loop diuretics; anticoagulants may prolong PT (watch for signs of bleeding); may increase serum lithium levels and risk of methotrexate toxicity (eg, stomatitis, bone marrow suppression, nephrotoxicity)
Documented hypersensitivity, active peptic ulceration; renal or hepatic impairment; concomitant or recent anticoagulants
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Acute renal insufficiency, interstitial nephritis, hyperkalemia, hyponatremia, and renal papillary necrosis may occur; patients with preexisting renal disease or compromised renal perfusion risk acute 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
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 greater in persons who experience migraines with aura.
Adverse effects may be severe; should be used only in patients who have not responded to other preventive agents.
Adult
2 mg/d PO initially; increase dose gradually; not to exceed 8 mg/d
Pediatric
Not recommended
Potentiates effects of CNS depressants; MAO inhibitors may prolong and intensify anticholinergic and sedative effects
Documented hypersensitivity; peripheral vascular disease; severe arteriosclerosis; severe hypertension; coronary artery disease; phlebitis or cellulitis of lower extremities; pulmonary disease; collagen disease or fibrotic processes; impaired renal or hepatic function; valvular heart disease
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Continuous administration should not exceed 6 mo; retroperitoneal fibrosis and 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 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.
Adult
2 mg PO initial dose; increase every third day until beneficial effect demonstrated or until adverse effects occur
Usual maintenance dose: 8-32 mg in 3-4 divided doses
Pediatric
<2 years: Not established
2-6 years: 2 mg PO q8-12h; not to exceed 12 mg/d
6-14 years: 2-4 mg q8-12h; not to exceed 16 mg/d
>14 years: Administer as in adults
Potentiates effects of CNS depressants; MAO inhibitors may prolong and intensify anticholinergic and sedative effects of antihistamines
Documented hypersensitivity; glaucoma; acute asthmatic attack
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Common adverse effects include drowsiness, dizziness, blurred vision, dry mouth, increased appetite, and weight gain
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References
Perciaccante A. Migraine is characterized by a cardiac autonomic dysfunction. Headache. Jun 2008;48(6):973. [Medline].
Harling DW, Peatfield RC, Van Hille PT. Thunderclap headache: is it migraine?. Cephalalgia. Jun 1989;9(2):87-90. [Medline].
Forsyth PA, Posner JB. Headaches in patients with brain tumors: a study of 111 patients. Neurology. Sep 1993;43(9):1678-83. [Medline].
Agarwal S, Magu S, Kamal K. Reversible white matter abnormalities in a patient with migraine. Neurol India. Apr-Jun 2008;56(2):182-5. [Medline].
Guyuron B, Kriegler JS, Davis J. Comprehensive surgical treatment of migraine headaches. Plast Reconstr Surg. Jan 2005;115(1):1-9. [Medline].
Dirnberger F, Becker K. Surgical treatment of migraine headaches by corrugator muscle resection. Plast Reconstr Surg. Sep 1 2004;114(3):652-7; discussion 658-9. [Medline].
Conway S, Delplanche C, Crowder J. Botox therapy for refractory chronic migraine. Headache. Apr 2005;45(4):355-7. [Medline].
Schulte-Mattler WJ, Martinez-Castrillo JC. Botulinum toxin therapy of migraine and tension-type headache: comparing different botulinum toxin preparations. Eur J Neurol. Feb 2006;13 Suppl 1:51-4. [Medline].
[Best Evidence] Brandes JL, Kudrow D, Stark SR, O'Carroll CP, Adelman JU, O'Donnell FJ, et al. Sumatriptan-naproxen for acute treatment of migraine: a randomized trial. JAMA. Apr 4 2007;297(13):1443-54. [Medline].
Anand KS, Prasad A, Singh MM. Botulinum toxin type a in prophylactic treatment of migraine. Am J Ther. May-Jun 2006;13(3):183-7. [Medline].
Aurora S. Botulinum toxin type A for the treatment of migraine. Expert Opin Pharmacother. Jun 2006;7(8):1085-95. [Medline].
Biousse V, D'Anglejan-Chatillon J, Massiou H, Bousser MG. Head pain in non-traumatic carotid artery dissection: a series of 65 patients. Cephalalgia. Feb 1994;14(1):33-6. [Medline].
Busch V, Gaul C. Exercise in migraine therapy--is there any evidence for efficacy? A critical review. Headache. Jun 2008;48(6):890-9. [Medline].
Cutrer FM, Moskowitz MA. Wolff Award 1996. The actions of valproate and neurosteroids in a model of trigeminal pain. Headache. Nov-Dec 1996;36(10):579-85. [Medline].
Dennis M, Warlow C. Migraine aura without headache: transient ischaemic attack or not?. J Neurol Neurosurg Psychiatry. Jun 1992;55(6):437-40. [Medline].
Evans RW, Rosen N. Expert opinion: migraine, psychiatric comorbidities, and treatment. Headache. Jun 2008;48(6):952-8. [Medline].
Fisher CM. Late-life migraine accompaniments--further experience. Stroke. Sep-Oct 1986;DA - 19861119(5):1033-42. [Medline].
[Best Evidence] Freitag F, Diamond M, Diamond S, Janssen I, Rodgers A, Skobieranda F. Efficacy and tolerability of coadministration of rizatriptan and acetaminophen vs rizatriptan or acetaminophen alone for acute migraine treatment. Headache. Jun 2008;48(6):921-30. [Medline].
Hazard E, Munakata J, Bigal ME, Rupnow MF, Lipton RB. The Burden of Migraine in the United States: Current and Emerging Perspectives on Disease Management and Economic Analysis. Value Health. Jul 30 2008;[Medline].
Ingvardsen BK, Laursen H, Olsen UB, Hansen AJ. Possible mechanism of c-fos expression in trigeminal nucleus caudalis following cortical spreading depression. Pain. Sep 1997;72(3):407-15. [Medline].
Kawabe K, Ikeda K, Igarashi O, Iwasaki Y. Vertigo, dizziness, and syncope in migraine. Headache. Jun 2008;48(6):973-4. [Medline].
Lauritzen M. Pathophysiology of the migraine aura. The spreading depression theory. Brain. Feb 1994;117 (Pt 1):199-210. [Medline].
Lipton RB, Stewart WF. Migraine headaches: epidemiology and comorbidity. Clin Neurosci. 1998;5(1):2-9. [Medline].
Mathew NT, Kurman R, Perez F. Drug induced refractory headache--clinical features and management. Headache. Oct 1990;30(10):634-8. [Medline].
Moskowitz MA, Nozaki K, Kraig RP. Neocortical spreading depression provokes the expression of c-fos protein-like immunoreactivity within trigeminal nucleus caudalis via trigeminovascular mechanisms. J Neurosci. Mar 1993;13(3):1167-77. [Medline].
Olesen J. Synthesis of migraine mechanisms. In: Olesen J, Tfelt-Hansen P, Welch KMA, eds. The Headaches. New York: Raven; 1993:247-54.
Olesen J, Friberg L, Olsen TS. Timing and topography of cerebral blood flow, aura, and headache during migraine attacks. Ann Neurol. Dec 1990;28(6):791-8. [Medline].
Ramadan NM, Schultz LL, Gilkey SJ. Migraine prophylactic drugs: proof of efficacy, utilization and cost. Cephalalgia. Apr 1997;17(2):73-80. [Medline].
Rapoport AM. Pharmacological prevention of migraine. Clin Neurosci. 1998;5(1):55-9. [Medline].
Raps EC, Rogers JD, Galetta SL. The clinical spectrum of unruptured intracranial aneurysms. Arch Neurol. Mar 1993;50(3):265-8. [Medline].
Raskin NH, Hosobuchi Y, Lamb S. Headache may arise from perturbation of brain. Headache. Sep 1987;27(8):416-20. [Medline].
Rothrock JF, Reed RC. Preventive Migraine Therapy. Abcomm, Inc.; 1998:1-16.
Silberstein S, Diener HC, Lipton R, Goadsby P, Dodick D, Bussone G, et al. Epidemiology, risk factors, and treatment of chronic migraine: a focus on topiramate. Headache. Jul 2008;48(7):1087-95. [Medline].
Silberstein SD. Agents for migraine and other headaches. In: Rowland LP, ed. Current Neurologic Drugs. Philadelphia: William & Wilkins; 1998:24-81.
Silberstein SD. Evaluation and emergency treatment of headache. Headache. Sep 1992;32(8):396-407. [Medline].
Silberstein SD. Preventive treatment of migraine: an overview. Cephalalgia. Apr 1997;17(2):67-72. [Medline].
Silberstein SD, Lipton RB. Overview of diagnosis and treatment of migraine. Neurology. Oct 1994;44(10 Suppl 7):S6-16. [Medline].
Silberstein SD, Lipton RB, Goadsby PJ. Headache in Clinical Practice. Oxford: Isis Medical Media Ltd; 1998:31-40, 41-60, 61-90.
Stewart WF, Shechter A, Lipton RB. Migraine heterogeneity. Disability, pain intensity, and attack frequency and duration. Neurology. Jun 1994;44(6 Suppl 4):S24-39. [Medline].
Termine C, Ferri M, Balottin U. Acute treatment of migraine in children and adolescents. Funct Neurol. Apr-Jun 2008;23(2):63-9. [Medline].
Tfelt-Hansen P, Lipton RB. Prioritizing acute pharmacotherapy. In: Olesen J, Tfelt-Hansen P, Welch KMA, eds. The Headaches. New York: Raven; 1993:359-62.
Tfelt-Hansen P, Stewrt Johnson E. Nonsteroidal antiinflammatory drugs in the treatment of the acute migraine attack. In: Olesen J, Tfelt-Hansen P, Welch KMA, eds. The Headaches. New York: Raven; 1993:305-12.
Tfelt-Hansen P, Welch KMA. Prioritizing prophylactic treatment. In: Olesen J, Tfelt-Hansen P, Welch KMA, eds. The Headaches. New York: Raven; 1993:403-4.
Vermeulen M, van Gijn J. The diagnosis of subarachnoid haemorrhage. J Neurol Neurosurg Psychiatry. May 1990;53(5):365-72. [Medline].
Ward TN. Management of an acute primary headache. Clin Neurosci. 1998;5(1):50-4. [Medline].
Weiller C, May A, Limmroth V. Brain stem activation in spontaneous human migraine attacks. Nat Med. Jul 1995;1(7):658-60. [Medline].
Wijdicks EF, Kerkhoff H, van Gijn J. Long-term follow-up of 71 patients with thunderclap headache mimicking subarachnoid haemorrhage. Lancet. Jul 9 1988;2(8602):68-70. [Medline].
Woods RP, Iacoboni M, Mazziotta JC. Brief report: bilateral spreading cerebral hypoperfusion during spontaneous migraine headache. N Engl J Med. Dec 22 1994;331(25):1689-92. [Medline].
Further Reading
Keywords
complex migraine, migraine equivalent, migraine variant, classic migraine, cluster headache, aura
