MIGRAINE-ETIOPATHOGENESIS AND MANAGEMENT

By-Dr Sadaf SiddiquiJNMCH,Aligarh

Headache is the most common complaint for which people see neurologists and the seventh most common reason they visit their primary care doctors.

Headache is the third most common cause of missed work and it affects every area of a person’s life.

Hippocrates believed that headache could be triggered by exercise or intercourse and migraine resulted from vapors rising from the stomach to the head and that vomiting could partially relieve the pain of headache.

The term migraine itself is derived from the Greek word ‘hemicrania’, introduced by Galen in approximately AD 200.

Clearly, migraine was well known in the ancient world.

Migraine was distinguished from common headache by Tissot in 1783.

Headache classification

The most widely used headache classification system was developed in 1988 by the International Headache Society (IHS), and revised in 2004.

With the IHS system, Part 1 of the system classifies the primary headaches, Part 2 classifies the secondary headaches, and Part 3 of the system classifies the cranial neuralgias, central and primary facial pains, and other headaches.

The primary headache disorders are those in which the headache condition itself is the problem, and no underlying or dangerous cause for it can be identified.

Secondary headaches are those due to an underlying condition such as a tumor, infection or hemorrhage. The secondary headaches are classified according to their causes (e.g. vascular, psychiatric,etc.)

The ‘big three’ primary headache disorders,

• Migraine is the most common headache problem that causes patients to seek medical help.

• Tension-type headache is the most common headache disorder, but it is usually mild and self-limiting. It generally prompts medical consultation only when chronic.

• Cluster headache is the most severe of the three conditions, but it is uncommon

Migraine - Definition

“Migraine is a familial disorder characterized by recurrent attacks of headache widely variable in intensity, frequency and duration. Attacks are commonly unilateral and are usually associated with anorexia, nausea and vomiting”

World Federation of Neurology

INTERNATIONAL HEADACHE SOCIETY (IHS)CLASSIFICATION (IHC-2)

Migraine without aura Migraine with aura Childhood periodic syndromes that are commonly

precursors of migraine Retinal migraine Complications of migraine Probable migraine

THE EPIDEMIOLOGY,BURDEN, ANDCOMORBIDITIESOF MIGRAINE

Migraine is one of the most burdensome of the primary headache disorders.

Epidemiologic data can be used to describe this burden as well as its scope and distribution Understanding sociodemographic, genetic, and environmental risk factors for migraine helps identify groups at highest risk for migraine and may provide clues to treatment strategies or disease mechanisms.

THE EPIDEMIOLOGY OF MIGRAINE

The Incidence of Migraine

It is found that in females, the incidence of migraine with aura peaked between ages 12 and 13 and migraine without aura peaked between ages 14 and 17.

In males, migraine with aura peaked in incidence several years earlier, around 5 years of age and the peak for migraine without aura was between 10 and 11 years.

THE PREVALENCE OF MIGRAINE

Before puberty, migraine prevalence is higher in boys than in girls.

Adolescence- incidence and prevalence increase more rapidly in girls than in boys.

The American Migraine Prevention and Prevalence study (AMPP) showed the prevalence of migraine was about 18% in women and 6% in men.

overall prevalence of headache increases from preschool age children to mid adolescence.

One year period prevalence of migraine by age and sex adjusted for demographics

THE BURDENS OF MIGRAINE

The Burden of Migraine to the Individual

Migraine is a public health problem of enormous scope that has an impact on both the individual sufferer and on society.

The AMPP, conducted in 2005, estimated that in migraine attacks, most migraineurs reported severe impairment or the need for bed rest (53.7%).

Over a 3-month period, 35.1% of the migraineurs had at least 1 day of activity restriction related to headache.

NEJM 2002; 346(4): 257-269; XI Congress of the IHS, 2004

The Burden of Migraine to the Family

A Canadian study reported that 90% of people with migraine reported postponing their household work because of headaches, 30% had canceled family and social activities during their last migraine attack, and two-thirds feared letting others down because of their headaches.

One half believed that, because of their migraine, they were more likely to argue with their partners (50%) and children (52%).

The Comorbidities of Migraine

Both epilepsy and migraine can cause headache and transient alterations of consciousness.

Prodromal migraine symptoms, such as fatigue and irritability, may be part of comorbid depression.

The presence of comorbidity may provide clues to the pathophysiology of migraine, Independent genetic or environmental risk factors may produce a brain state that gives rise to both migraine and a comorbid condition.

Migraine triggers

Diet Hormonal changes Head trauma Stress and anxiety Sleep deprivation or excess Environmental factors

Phases of Acute Migraine

Prodrome

Aura

Headache

Postdrome

Prodrome

Vague premonitory symptoms that begin from 12 to 36 hours before the aura and headache

Symptoms include Yawning Excitation Depression Lethargy Craving or distaste for various foods

Duration – 15 to 20 min

Aura

Aura is a warning or signal before onset of headache.

Symptoms

Flashing of lights

Zig-zag lines

Difficulty in focussing

Duration : 15-30 min

Headache

Headache is generally unilateral and is associated with symptoms like: Nausea Anorexia Vomiting Photophobia Phonophobia Tinnitus

Duration is 4-72 hrs

Postdrome

Following headache, patient complains of Fatigue Depression Severe exhaustion Some patients feel unusually fresh

Duration: Few hours or up to 2 days

Migraine-diagnostic criteria

PATHOPHYSIOLOGY

Genetic basis

Migraine has a strong genetic component. Approximately 70% of migraine patients have a first-

degree relative with a history of migraine. The risk of migraine is increased 4-fold in relatives of

people who have migraine with aura.

Kors EE, Haan J, Ferrari MD. Genetics of primary headaches. Curr Opin Neurol

The Hyperexcitable Brain

Migraine patients have a brain that is too excitable, a so-called “hyperexcitable.

Specific neurons in the brain—or nuclei—discharge too easily, activating pathways that initiate the mechanism of pain and associated symptoms, and resulting in the migraine syndrome. The tendency to fire is what is inherited.

Nitric Oxide

There are many hypotheses about what it is in neurons that makes them hyperexcitable.

One possibility is that migraine nerve cells are too sensitive to nitric oxide, a chemical messenger released by some nerve cells to activate certain others

Magnesium

Another theory is that some patients with migraine have too little magnesium in the brain.

Low magnesium may lead to nerves becoming hyperexcitable. Low magnesium destabilizes nerves by altering the ability to control the influx and efflux of charged ions, resulting in nerve cells firing too easily

Calcium Channels and Familial Hemiplegic Migraine

The genetic basis for some patients with this very rare form of migraine, familial hemiplegic migraine (FHM), has been identified.

The mutant calcium channel does not open and close properly and cannot regulate the amount of calcium coming into the cell, so calcium influx and efflux regulation goes awry. This in turn leads to neurons firing too easily. Because abnormal calcium channels are a cause of FHM, blocking them with a calcium channel blocker specifically treats this form of migraine

Migraine aura

In 1944, Leao proposed the theory of cortical spreading depression (CSD) to explain the mechanism of migraine with aura.

CSD is a well-defined wave of neuronal excitation in the cortical gray matter that spreads from its site of origin at the rate of 2-6 mm/min.

This cellular depolarization causes the primary cortical phenomenon or aura phase; in turn, it activates trigeminal fibers, causing the headache phase

The neurochemical basis of the CSD is the release of potassium or the excitatory amino acid glutamate from neural tissue.

This release depolarizes the adjacent tissue, which, in turn, releases more neurotransmitters, propagating the spreading depression.

Functional MRI and other physiological studies of humans with aura suggest that this is the cause aura is therefore be neurological, not vascular..

The Migraine Generator This is the area in the lower part of the brain (brain-

stem) in which nerve cells turned on at the beginning of the migraine, remained on for the length of the migraine and clicked off at the end of the migraine.

This center is known as the migraine generator. The exact location for the generator may be the dorsal

raphe nucleus of the brainstem.

The migraine generator connects to nerve pathways that lead to the meninges, coverings around the brain between brain and skull.

These pathways lead to other nerves that encircle and serve blood vessels of the meninges.

When this occurs, blood vessels in the meninges dilate and the neurons release inflammatory chemicals around the vessels. The combination of meningeal blood vessel dilation and inflammation is believed to be the cause of migraine pain.

Migraine headache-how it is generated?Vascular theory It was believed that ischemia induced by intracranial

vasoconstriction is responsible for the aura of migraine and that the subsequent rebound vasodilation and activation of perivascular nociceptive nerves resulted in headache.

This theory was based on the following 3 observations: Extracranial vessels become distended and pulsatile during a

migraine attack

Stimulation of intracranial vessels in an awake person induces headache

Vasoconstrictors (eg, ergots) improve the headache, whereas vasodilators (eg, nitroglycerin) provoke an attack.

Neurovascular theory Complex series of neural and vascular events initiates migraine migraine is primarily a neurogenic process with secondary

changes in cerebral perfusion. Involves abnormal activation of trigeminocervical afferents

Cutrer FM, Charles A. The neurogenic basis of migraine. Headache

The Trigeminovascular System The connection between the migraine generator and the

nerves and blood vessels of the meninges is called the trigeminovascular system.

To simplify: the migraine central generator clicks on the switch, the trigeminovascular system is activated, the blood vessels of the coverings of the brain dilate, and the meninges become inflamed.

The central generator is in the brain and the peripheral pain mechanism in the meninges.

A primary dysfunction of brain stem pain and vascular control centers elicits a cascade of secondary changes in vascular regulation within pain-producing intracranial structures that ultimately manifests in headache pain and associated symptoms.

A synthesis of these views and observations forms the neurovascular hypothesis of migraine.

This suggest that there are several key steps in the generation of migraine pain:

(1)-Intracranial meningeal blood vessel dilation which activates perivascular sensory trigeminal nerves (2) Vasoactive neuropeptide release from activated trigeminal sensory nerves. These peptides can worsen and perpetuate any existing

vasodilation, setting up a vicious cycle that increases sensory nerve activation and intensifies headache pain.

The peptides include substance P (increased vascular permeability), neurokinin A (dilation and permeability changes) and calcitonin gene-related peptide (CGRP; long-lasting vasodilation

(3) Pain impulses from activated peripheral sensory nerves are relayed to second-order sensory neurons within the trigeminal nucleus caudalis in the brain stem and upper cervical spinal cord (C1 and C2, trigeminocervical complex). (4) Headache pain signals ascend to the thalamus, via the quintothalamic tract which decussates in the brain stem, and on to higher cortical centers where migraine pain is registered and perceived.

Serotonin and migraine The serotonin receptor (5-hydroxytryptamine [5-HT]) is

believed to be the most important receptor in the headache pathway

Serotonin is a neurotransmitter that can both excite and inhibit— and therein lies the story of how it controls migraine.

5-HT1 receptors are negative or inhibitory receptors; 5-HT2

receptors are positive or excitatory receptors.

When serotonin binds to the excitatory 5HT2 receptors near the migraine central generator, it turns on the migraine.

Serotonin, activating the 5-HT1D receptor, may help get rid of migraine pain by inhibiting CGRP release.

Therefore, when the serotonin binds to both 5-HT1B and 5-HT1D receptors, both mechanisms of migraine, blood vessel dilation and inflammation, are turned off.

Cutaneous allodynia Burstein et al described the phenomenon of cutaneous

allodynia, in which secondary pain pathways of the trigeminothalamic system become sensitized during a migrainous episode.(1)

This observation demonstrates that, along with the previously described neurovascular events, sensitization of central pathways in the brain mediates the pain of migraine.

1.Burstein R, Yarnitsky D, Goor-Aryeh I, Ransil BJ, Bajwa ZH. An association between migraine and cutaneous allodynia. Ann Neurol

Dopamine pathway Some authors have proposed a dopaminergic basis for migraine.[1]

dopaminergic hypersensitivity is present in patients with migraine. Few symptoms of migraine headaches, such as nausea, vomiting,

yawning, irritability, hypotension, and hyperactivity, can be attributed to relative dopaminergic stimulation.

Dopamine antagonists (eg, prochlorperazine) completely relieve almost 75% of acute migraine attacks

1. Peroutka SJ. Dopamine and migraine. Neurology

Menstrual and Hormonal Aspects of Migraine

Migraine often begins—or increases dramatically—when a woman enters puberty and generally improves after menopause.

This is due to the fact that the sex hormones estrogen and progesterone have an effect on migraine.

The most distinctive form of menstrual migraine occurs just after the onset of flow and appears to be due to the sudden drop in estrogen that occurs around the menses.

Replacing estrogen reduces the occurrence of these migraine.

MANAGEMENT

Management

Establish a partnership with the patient Promote patient education Establish a treatment plan• Nature and mechanism of the disorder• Strategies for identifying and avoiding triggers

• Behavioral management strategies− Regular sleep, exercise, meals− Stress management, biofeedback− Cognitive behavioral therapy Develop pharmacologic management plan• Acute treatment• Preventive strategies

STRATEGIES FOR MIGRAINETREATMENT

Acute migraine medication

Nonspecific NSAIDs Combination analgesics Opioids Neuroleptics / antiemetics CorticosteroidsSpecific Ergotamine / DHE Triptans

Acute treatment principle

Treat early in attack Use correct dose and formulation Use for a maximum of 2 to 3 days per week Stratify treatment Treat at least two different attacks with same medication

before determining efficacy.

If treatment ineffective Reconsider diagnosis Treat early Use optimal dose Change formulation/route of administration Change drug Be sure there are no interfering medications or overuse Add adjunct

There are two strategies for initial therapy: step care and stratified care.

Step care use of medications in a sequential order, based on a

predetermined plan. Therapy starts with the lowest level of treatment,

independent of the characteristics of the attack. This approach to treatment is not necessarily based on the

individual needs of the patient.

Stratified care treatment based on attack characteristics, including peak

intensity, time to peak intensity, associated symptoms, and disability.

It is also individually tailored to specific patient needs. Stratified care takes into account patient preferences for

treatment and allows the patient to select medications for each particular attack.

INCREASING EVIDENCE FOR TREATINGEARLY WHEN PAIN IS MILD

Retrospective studies (sumatriptan , zolmitriptan and almotriptan) support higher pain-free rates when treating while pain is mild

Retrospective analysis: triptans, ergotamine plus caffeine, and aspirin plus metoclopramide, all provided higher pain-free response. Triptans more effective and less recurrence

Prospective rizatriptan study: effective at all levels of pain but enhanced benefit if taken while pain is mild

Cady RK et al. Headache. 2000. Cady RK et al. Clin Ther. 2000.

Hu XH et al. Headache. 2002. Winner et al. Mayo Clin Proc. 2003

CONSIDERATIONS FOR TREATINGEARLY IN THE ATTACK

Advantages May prevent disability May reduce headache recurrence and decrease number of

tablets used per attack May prevent sensitization and allodyniaDisadvantages Treating early may lead to over treatment To avoid overuse: limit use of acute treatment to no more

than 3 days per week

Triptan (serotonin 1B/1Dreceptor agonists)

Effective and safe

acute management

Appropriate initial choice in patients with moderate to severe migraine

Routes-oral, subcutaneous and nasal

Drugs – sumatriptan-50-100mg tablet at onset , may repeat after 2hour (max 200mg/d)

Rizatriptan –most efficacious, early onset of action, 5-10 mg tablet at onset may repeat after 2hr max 30mg/d)

Naratriptan, almotriptan,frovatriptan, zolmitriptan

Triptans should not be used more than 3 days weekly to avoid transformed migraine and medication overuse headache

Caution-avoid in patients of CADAdverse effects Paresthesia, jaw or neck tightness, warm/cold sensation

etc.

Ergot alkaloids and derivatives-nonselective 5-HT1 agonists) Ergotamine PO/PR (and caffeine combination) may be

considered in the treatment of selected patients with moderate to severe migraine.

Dose 2mg PO, f/b 1-2mg every 30 min until attack is aborted, no more than 6mg/day

Adverse effects-vasospasm, angina, tachycardia, numbness of extremities, rebound headache, ergotism, gangrene etc

Dihydroergotamine- alpha adrenergic blocking agent with a direct stimulating effect on smooth muscle of peripheral and cranial blood vessels. It is a non selective 5-HT1 agonist

Route- iv or nasal Dose- 1mg iv/im repeated 1 hrly , no more than 3 mg for

im and 2mg for iv Nasal-1 spray 0.5mg in each nostril not more than 6

sprays/24hr

DHE nasal spray is effective for the treatment of acute migraine attacks and should be considered for use in patients with moderate to severe migraine

DHE IV plus antiemetics IV is an appropriate treatment choice for patients with severe migraine

Antiemetics -: Oral antiemetics are an adjunct to treat nausea associated

with migraine . Metoclopramide IM/IV is an adjunct and may be considered

as IV monotherapy for migraine pain relief Prochlorperazine IV, IM, and PR may be a therapeutic choice

in the appropriate setting Chlorpromazine IV 5-HT3 antagonists may be considered as adjunct therapy to

control nausea in selected patients with migraine attacks

NSAIDs, nonopiate analgesics, and combination analgesics. Acetaminophen, alone, is not recommended for

migraine . NSAIDs (oral) and combination analgesics containing

caffeine are a reasonable first-line treatment choice for mild to moderate migraine attacks or severe attacks that have been responsive in the past to similar NSAIDs or nonopiate analgesics

Opiate analgesics.

Butorphanol nasal spray is a treatment option for some patients with migraine.

Butorphanol may be considered when other medications cannot be used or as a rescue medication when significant sedation would not jeopardize the patient

Other medications. Isometheptene and isometheptene combination agents

may be a reasonable choice for patients with mild-to-moderate headache .

Corticosteroids (dexamethasone or hydrocortisone) are a treatment choice for rescue therapy for patients with status migrainosus

ACUTE MIGRAINE TREATMENTIN URGENT CARE SETTING

Status migrainosus Consider sumatriptan sc Start an IV and hydrate Start repetitive IV treatment• Antiemetics plus DHE• Neuroleptics• Ketorolac 30-60 mg IM• Opioids• Corticosteroids• Magnesium? Valproate?

WHEN IS PROPHYLAXIS INDICATED?

According to the US Headache Consortium Guidelines, indications for preventive treatment include:

Patients who have very frequent headaches (more than 2 per week)

Attack duration is > 48 hours

Headache severity is extreme

Migraine attacks are accompanied by prolonged aura

Unacceptable adverse effects occur with acute migraine treatment

Contraindication to acute treatment Migraine substantially interferes with the patient’s daily

routine, despite acute treatment Special circumstances such as hemiplegic migraine or

attacks with a risk of permanent neurologic injury Patient preference

5 principal classes of drugs are used -: Antiepileptics Antidepressants Antihypertenseives Serotonin antagonists NSAIDS

ANTIEPILEPTICS Well tolerated Divalproex and valproic acid are among the first-line

agents in migraine prevention The initial dose is usually from 250 mg daily, titrated up to

1,500 mg.

Ramadan NM, Silberstein SD, Freitag FG, Gilbert TT, Frishberg BM, for the US Headache Consortium. Evidence-based guidelines for migraine headache in the primary care setting: pharmacological management for prevention of migraine

Special indications• Prolonged or atypical migraine aura• Tension-type headache• Concurrent epilepsy, mania, trigeminal neuralgia, cluster

headache Carbamazepine Gabapentin topiramate

ANTIDEPRESSANTS

Tricyclic antidepressants Amitriptyline- 10-75mg at night Nortriptyline

Selective serotonin reuptake inhibitors Fluoxetine

Other antidepressants Bupropion, mirtazepine, trazodone, venlafaxine

Tricylic antidepressants are another class of medication considered as first-line treatment in migraine prophylaxis.

Response is usually more rapid (within 4 weeks) than with β-blockers.1

Tertiary amines, such as amitriptyline, are more effective than the secondary amines, such as nortriptyline.

Couch JR, Hassanein RS. Amitriptyline in migraine prophylaxis. Arch Neurol Evans RM. Managing migraine today (II): pharmacologic and nonpharmacologic treatment [JAMA Migraine

ANTIHYPERTENSIVESBeta-blockers The scientific and clinical evidence supports β-blockers

as the drugs of choice for the prevention of migraines. The most commonly used agent is propranolol

hydrochloride. Dose-40-320 mg

Noble SL, Moore KL. Drug treatment of migraine: part II. preventive therapy. Am Fam Physician 1997

Special indications Concurrent hypertension Tremor Anxiety or panic attacks (specifically propranolol) Calcium channel blockers Calcium channel blockers are effective second-line

agents. They are usually slower in onset than β-blockers, and an

initial increase in headache frequency may occur.

Daily dose range Verapamil hydrochloride: 120 to 480 mg Nifedipine: 30 to 90 mg Diltiazem: 120 to 360 mg Nimodipine: 60 to 120 mg

NSAIDS Aspirin ,Mefenamic acid,Ibuprofen,Naproxen/naproxen

sodium The NSAID naproxen sodium has also been used for

prophylaxis. In controlled clinical trials, naproxen sodium

demonstrated better efficacy than placebo and similar efficacy to propranolol.

However, this agent should be reserved for short-term use, such as for menstrual migraines

Third-line agents Two medications that have proved effective in

prophylaxis but are reserved for severe or refractory cases are methysergide and phenelzine sulfate.

Methysergide is the fourth agent indicated and approved for migraine prophylaxis by the FDA.

Phenelzine—a monoamine oxidase inhibitor should be considered only in severe refractory cases, specifically those that are compounded by tension headaches or atypical depression.

drugs with an uncertain or unproven role in migraine prophylaxis

The efficacy of fluoxetine hydrochloride has not been well established in prophylaxis, but some experts already consider it a viable alternative to tricyclic antidepressants.

Some evidence exists that riboflavin (vitamin B2) in high doses (400 mg daily) has some effect in migraine prophylaxis.

Similarly, magnesium at doses of 400 to 600 mg daily may also be of benefit, but there is less evidence for its efficacy than that for riboflavin.

Schoenen J, Jacquy J, Lenaerts M. Effectiveness of high-dose riboflavin in migraine prophylaxis: a randomized controlled trial. Neurology 1998

Nonpharmacological treatment

The United States Headache Consortium pointed out that nonpharmacologic treatments might be particularly well suited for patients who

1. Have a preference for nonpharmacologic interventions 2. Display a poor tolerance for specific pharmacologic

treatments 3. Exhibit medical contraindications for specific

pharmacologic treatments 4. Have insufficient or no response to pharmacologic

treatment

5. Are pregnant, are planning to become pregnant, or are nursing

6. Have a history of long-term, frequent, or excessive use of analgesic or acute medications that can aggravate headache problems (or lead to decreased responsiveness to other pharmacotherapies)

7. Exhibit significant stress or deficient stress-coping skills

Biofeedback Cognitive-behaviour therapy Relaxation therapy avoidance of migraine triggers

The FDA approved the Cerena Transcranial Magnetic Stimulator (Cerena TMS), the first device to relieve pain caused by migraine headache with aura.

Users hold the device with both hands to the back of the head and press a button to release a pulse of magnetic energy that stimulates the occipital cortex.

The recommended daily usage of the device is not to exceed one treatment in 24 hours.[1]

US Food and Drug Administration. FDA allows marketing of first device to relieve migraine headache pain December 13, 2013.

Complementary and Alternative Treatments

A variety of other CAM techniques may be perceived to be of benefit to patients.

Techniques that some patients use for headache relief include the following: Body work - Eg, chiropractic, massage, and craniosacral therapy. Nutritional/herbal supplements - Eg, vitamins and herbs Yoga Acupressure and acupuncture BiofeedbackLinde K, Vickers A, Hondras M, ter Riet G, Thormählen J, Berman B, et al. Systematic reviews of complementary therapies

Surgical care

Surgical therapy for migraine is highly controversial. In a study of 60 patients, Dirnberger and Becker reported that corrugator muscle resection produced total relief of migraine in 28.3% of patients, essential improvement in 40%, and minimal or no change in 31.7%. The more severe their migraine, however, the less likely patients were to experience improvement.

In addition, 11 patients who had a very favorable short-term response experienced a gradual return of their headaches to preoperative intensity within about 4 weeks postoperatively.[1]

Dirnberger F, Becker K. Surgical treatment of migraine headaches by corrugator muscle resection. Plast Reconstr Surg. 2004

Novel Treatments and Future Drugs

Tonabersat is a novel benzopyran compound that markedly reduces cortical spreading depression (CSD) and CSD-associated events by inhibiting gap-junction communication between neurons and satellite glial cells in the trigeminal ganglion.[1]

Durham PL, Garrett FG. Neurological mechanisms of migraine: potential of the gap-junction modulator tonabersat in prevention of migraine. Cephalalgia. 2009 

The pipeline of future compounds for the treatment of acute migraine headaches also includes the following medications: Transient receptor potential vanilloid type 1 antagonists Prostaglandin E receptor 4 receptor antagonists Serotonin 5HT1(F) receptor agonists Nitric oxide synthase inhibitors

references Blau jn. migraine: theories of pathogenesis. Lancet. 1992;339:1202-1207. Ramadan nm, silberstein sd, freitag fg, gilbert tt, frishberg bm, for the us

headache consortium. evidence-based guidelines for migraine headache in the primary care setting: pharmacological management for prevention of migraine [am acad neurol web site]. april 25, 2000.

Migraine prophylaxis in adult patients, west j med. 2000 nov; 173(5): 341–345.

Atlas of migraine and other headaches second edition Neurol clin 27 (2009),migraine and other primary headache Understanding migraine and other headaches,stewart j tepper,md

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