Migraine Headache – Update on Diagnosis & Treatment Herbert L. Muncie, Jr., M.D.

What is the diagnosis? Sarah, a previously very healthy 14 year old female complains of a severe headache & nausea. It is the start of the Thanksgiving holiday and all she wants to do is lay on the sofa. PMH H. flu meningitis age 7 months Car motion sickness as a child Family history positive for migraines – maternal grandmother & mother

Diagnosing Migraine Headache Any severe or recurrent headache most likely is a form of migraine Almost all patients will have family history of migraines or at least “sick” headaches Only 15% have preceded or accompanied focal neurologic symptoms Usually visual Vision loss or distortion in one eye – ‘ocular migraine’ “Classic migraine”

Sarah Spent most of Thanksgiving holiday resting on the sofa Diagnosed with onset of migraine headaches

Recurrent Headaches Primary Migraine Tension Cluster Other benign – cough, cold temperature, post coital, exertion

Recurrent Headaches Secondary (pain from complications) Intracranial tumor Intracranial aneurysm Intracranial A-V malformation Temporal arteritis 6

Migraine with aura – Criteria* At least 2 attacks with 3 of the following: Fully reversible aura symptoms At least 1 aura symptom develops gradually during more than 4 minutes or 2 symptoms occur in succession Any aura symptom lasts less than 60 minutes Headache follows the aura within 60 minutes *International Headache Society - 2004

Migraine with aura Visual aura common Slowly evolving scintillating scotoma that moves or passes through visual field Duration of aura – 22 minutes Should not be called ocular migraine if bilateral eye involvement Just call them migraine with aura

Visual aura rating scale (VARS) Visual Symptom Risk Score Duration 5 - 60 minutes 3 Develops gradually over 5 min 2 Scotoma Zigzag line (fortification) Unilateral (homonymous) 1 MIGRAINE with AURA DIAGNOSIS ≥ 5

Migraine with aura – vascular risk? Migraine with aura is associated with 2 fold risk of ischemic stroke & cardiovascular event Absolute risk is low (4 per 10000 women years) May be indication for aggressive treatment of other risk factors Unclear if more intense treatment & prevention of migraines will alter the risk

Migraine without aura – Criteria* At least 5 attacks (bunch of them) Lasting 4-72 hours untreated or unsuccessfully treated (didn’t just go away quickly) Must have one of these to be migraine: Nausea or vomiting Photophobia Phonophobia *International Headache Society - 2004

Migraine without aura – Criteria* Then usually have at least 2 of these: Unilateral pain Throbbing/pulsating Aggravation on movement Moderate or severe intensity And of course to be sure not something else: H & P does not suggest organic disorder H & P suggests an organic disorder which is then ruled out An organic disorder is present but attacks do not occur for the 1st time in close time to the disorder *International Headache Society - 2004

Diagnosing the acute headache The classification criteria are best suited for a between-attack assessment of their typical headache However, they are often used for the acute attack Once acute pain relieved, take time to make an accurate diagnosis Up to 1/3 of ED patients cannot be assigned a diagnosis Despite a through questionnaire-based assessment

ER Clinical Decision Rule “ID Migraine” – three features Sensitivity to light Nausea or vomiting Disabling intensity of headache 0 - 1 positive - low probability If 2 positive higher probability of migraine Criteria focus on typical attacks not the current acute attack

Epidemiology - Migraine Can start at any age, however, Peak incidence of onset is mid-adolescence (age 13-16) History of colic or motion sickness support Dx Median frequency - 1.5/month Greater increase in prevalence with aging in women Females - 6.4% age 12 - 17; 17.3% age 18 - 29 Males - 4.0% age 12 - 17; 5.0% age 18 – 29 Usually more severe in women

Pathophysiology Migraine is a primary neural event Something lowers threshold for a cortical spreading depression (CSD) Which causes regional hypoperfusion (aura) Release of proinflammatory neurochemicals Neural event results in vasodilation Which leads to pain & more nerve activation Migraine headache is not a primary vascular event

Why does it hurt? Substance of brain is largely insensate Pain could come from: Cranial blood vessels Trigeminal innervations of vessels Reflex connection of trigeminal system with cranial parasympathetic flow No clear explanation for why it hurts

Testing Indications* Laboratory tests not helpful or needed to make the diagnosis EEG not indicated as routine evaluation Neuroimaging guidelines Typical migraine with normal neurologic exam Neuroimaging not warranted (SOR-B) Insufficient evidence regarding imaging in presence of neurologic symptoms (SOR-C) *U.S. Headache Consortium (2000)

Neuroimaging - EBM For non-acute HA with unexplained abnormal finding on neurologic examination – obtain neuro image (SOR-B) If atypical features or headache does not fulfill definition of migraine – lower the threshold for obtaining imaging (SOR-C) CT vs. MRI? Insufficient data to recommend MRI compared to CT in evaluation of migraine or other nonacute headache (Grade C)

Red Flags! Strongly consider neuroimaging if New onset > age 50 Thunderclap onset Focal and nonfocal symptoms Abnormal signs Headache with change in posture Valsalva headache HIV or cancer diagnosis

Prodrome (before headache) Some patients experience symptoms hours to days before the headache (prodrome) Fatigue Inattentiveness/confusion Restlessness, elation, +/- irritability Insomnia +/- depression Joint pain Hunger or food craving Yawning

Treatment Goals of treatment Reduce frequency, severity, & duration of headaches Improve quality of life (QOL) Avoid acute medication escalation Treatment Guidelines are based upon having a specific diagnosis Often difficult initially to make specific Dx Therefore, significant uncertainty about ‘best’ initial treatment

Treatment - Migraine The brain of patients with migraines does not tolerate peaks or troughs of life Patients should get: Regular sleep Go to bed and awaken same time every day Regular meals Eat same time every day Never skip meals – fasting associated with precipitating headache Regular exercise Avoid peaks of stress, troughs of relaxation Avoid unique dietary triggers

Migraine & Diet - EBM Frequency, duration & severity are NOT increased by dietary choices (SOR-A) Cheese, alcohol, chocolate, citrus are not universal triggers Low-fat diet reduced frequency of migraines (SOR-B)

Migraine & Supplements - EBM Supplements reduced frequency & intensity Riboflavin – 400 mg qd Effect begins at 1 month, maximal @ 3 months Magnesium – 600 mg qd Diarrhea common - almost 20% 360 mg qd during luteal phase reduced menstrual migraine Others Butterbur 100-150 mg/d CoQ10 300 mg/d Feverfew 18.75 mg/d National Guideline Clearing House SOR – A http://www.guideline.gov/summary/summary.aspx?doc_id=6231&nbr=004002&string=migraine Answer to TQ#2

27 250 Question 22 yo female presents with throbbing headache, nausea, photophobia for 5 hours. BP 116/76, P 86. Which of these treatments would be appropriate for her? Ketorolac (Toradol®) 60 mg IM Metoclopramide (Reglan®) 20 mg IV Prochlorperazine (Compazine®) 10 mg IV D.H.E. 45 1 mg IV Sumatriptan (Imitrex®) 6 mg SQ

Treatment of Acute Pain NSAID (SOR-A) Ketorolac (Toradol®) – 10 mg oral, 60 mg IM, or 30 mg IV(SOR-C) Combinations Isometheptene mucate, dichloralphenazone and acetaminophen (Midrin®) Butalbital has not been effective in controlled trials (butalbital/acetaminophen/caffeine- 50/325/40 Fioricet®, butalbital/ASA/caffeine-50/325/40 Fiorinal®) Answer to TQ#1

Treatment of Acute Pain NSAIDs – more effective when: Taken early With adequate initial dose Combined with antiemetic ASA 1000 mg Combined with metoclopramide IM (Reglan®) reduces nausea/vomiting but not better pain control Answer to TQ#1

Treatment of Acute Pain IV fluids may benefit patients, although benefit is not well established Unlikely to be harmful especially in patients with persistent GI symptoms Parenteral therapy preferred due to gastric stasis & delayed absorption of oral medications Answer to TQ#1

Treatment of Acute Pain Droperidol (Inapsine®) probably most effective of dopamine agonists Pain relief at 2 hours approaching 100% Ideal dose – 2.5 mg IV FDA warning about QT prolongation

Treatment of Acute Pain Prochlorperazine (Compazine®) 10 mg IV Effective with diphenhydramine (Benadryl®) – 25 mg IV [Friedman 2008] Superior to SC sumatriptan in ED setting [Kostic 2010] Children 0.15 mg/kg IV over 15 minutes (max 10 mg) If EPS develop give diphenhydramine 1mg/kg (max 50 mg) Randomized blinded trial of IV Compazine (10 mg with 12.5 mg Benadryl IV) vs SC sumatriptan (6 mg) superior. Also probably less costly overall. [Kostic 2010] Although time for IV insertion and patient acceptance may alter the decision process.

Treatment of Acute Pain Metoclopramide* (Reglan®) IV – monotherapy 10 - 20 mg IV IM – 10 mg adjunct to other therapies (SOR-C) * FDA boxed warning 2/26/09 – Long-term or high-dose use of metoclopramide has been linked to tardive dyskinesia.

Treatment of Acute Pain Ergot alkaloids Dihydroergotamine (D.H.E. 45®) – 1 mg IM/IV/SC Since it may cause nausea, more effective with metoclopramide (Reglan®) to reduce nausea Nasal spray effective Ergotamine/caffeine (1/100) (Cafergot®) Little evidence effective alone High risk of overuse & rebound headache

Treatment of Acute Pain Sodium valproate (Depacon®) 500 – 1000 mg in 10 ml normal saline IV over 30 min May be effective but less than prochlorperazine (Compazine®)

Treatment of Acute Pain Complementary medicine Topical menthol 10% was more effective at complete pain relief than placebo at 2 hours (38.3% vs 12.1%) [Haghighi 2010] 10% solution of menthol crystals in ethanol Forehead and the temporal area most painful are washed with tap water After drying 1 ml is applied with sponge on a surface area of 5 x 5 cm Can be reapplied in 30 min

Treatment of Acute Pain - EBM Patients with substantial disability will benefit from serotonin 5-HT1B/1D agonists (‘triptans’) SOR – A Clinical Evidence http://www.clinicalevidence.com/ceweb/conditions/nud/1208/1208.jsp

Triptan Efficacy No one triptan is superior in all pain relief parameters Use one triptan for 2-3 attacks before abandoning that medication If one does not work try another one Answer to TQ#3

How is pain relief measured? Was pain better within 2 hours? Did the pain go away at 2 hours? Did the pain stay away for at least 24 hours? (No immediate recurrence) Did the patient consistently obtain pain relief from that medication?

Oral Triptan Efficacy Was pain better within 2 hours? 55-65% of patients experience improvement at 2 hours Can be repeated in 1 – 2 hours if partial response

Oral Triptan Efficacy Did pain go away within 2 hours? 25-35% of patients are pain free at 2 hours

Oral Triptan Efficacy Did pain stay away for 24 hours? Freedom from pain at 2 hours, no rescue medication, no recurrence of pain in 24 hours 20 - 25% of patients have sustained freedom from pain

Oral Triptan Efficacy Intra-patient Consistency? The same patient experiences pain relief with the same medication Rizatriptan (Maxalt®) has highest intra-patient consistency of the oral medications

Sumatriptan (Imitrex®) – Parenteral 6 mg SC Pain decreased within 2 hours - 76% Pain gone within 2 hours - 48% Consistent pain relief for that patient - 90% In ER best candidates are those with previous response to this treatment Adverse events more frequent than with oral medication And more intense

Sumatriptan (Imitrex®) – Parenteral Cutaneous allodynia - sensation of pain in response to normally non-toxic touch stimuli (e.g. brushing hair, taking shower, putting hair in ponytail) Presence of cutaneous allodynia associated with reduced response to SC sumatriptan Needle-free injection available (Sumavel® DosePro™) Causes as much pain as needle & more swelling, bruising & bleeding at site

Triptans (Medical Letter 2008) Onset of action Elimination half-life Almotriptan (Axert®) 30 - 60 min 3 - 4 hours Eletriptan (Relpax®) Frovatriptan (Frova®) ~ 2 hrs ~ 25 hrs Naratriptan (Amerge®) 1 - 3 hrs ~ 6 hrs Rizatriptan (Maxalt®) 2 - 3 hrs Sumatriptan (Imitrex®) tablets nasal spray 10 - 15 min SC injection ~ 10 min Zolmitriptan (Zomig®)

27 250 Question 22 yo female presents with throbbing headache, nausea, photophobia for 5 hours. BP 116/76, P 86. Which of these treatments would be appropriate for her? Ketorolac (Toradol®) 60 mg IM Metoclopramide (Reglan®) 20 mg IV Prochlorperazine (Compazine®) 10 mg IV D.H.E. 45 1 mg IV Sumatriptan (Imitrex®) 6 mg SQ 46

Triptans – Side Effects Tingling Paresthesias Warmth head, neck, chest & limbs Nasal spray associated with taste disturbance

Triptans – Cautions Contraindicated with CAD, uncontrolled hypertension or cerebrovascular disease, hemiplegic migraine Should not be taken within 24 hrs of another triptan or ergotamine-containing/ergot-type medication Taking them with an SSRI or SNRI can cause life-threatening serotonin syndrome

Combining Medications Sumatriptan 85 mg & Naproxen 500 mg (Treximet®) more effective than either alone for acute pain relief Unknown effect of taking 2 separate pills (not tested) The combination may have some increased benefit in mild/moderate pain but no evidence of need for fixed dose combination (Medical Letter 2008)

Early Recurrence Up to 75% of patients will experience a recurrence of pain within 48 hours Naproxen (500 mg) or sumatriptan (100 mg) equally effective treating the recurrence [Friedman 2010] Naproxen prophylactically can prevent recurrence (NNT – 3) Triptans should not be used prophylacticly

Preventing Early Recurrence Parenteral dexamethasone (10-25 mg IV) Produced 26% relative reduction in recurrence within 72 hours [Colman 2008] Modest benefit in the ED – prevented 1 in 10 patients from experiencing moderate or severe recurrence [Singh 2008] Later trials failed to find benefit with oral dexamethasone or prednisone

Acute Pain & Parenteral Opioids Should not be used as 1st line therapy International Headache Consortium Canadian Association of Emergency Physicians American Academy of Neurology Meperidine (Demerol®) less effective than DHE and there is an: Increased risk of sedation Toxic metabolite with repetitive use Friedman BW et al 2008;52:705-713. No trials have compared morphine or hydromorphone for the treatment of migraine nor has a trial compared sumatriptan to opioid.

New Treatments Acute Pain Diclofenac oral solution (Cambia®) – dissolve contents in water Sumatriptan patch (Zelrix™) – similar levels to SC Cambia was approved in June 2009 and is now being marketed. It has a faster tmax and onset of action compared to tablet. Levadex approval is anticipated in 2011.

New Treatments Acute Pain DHE inhaled (Levadex®) – patients not responding to triptans or more than 6 hours into headache? Calcitonin gene-related peptide (CGRP) antagonist (telcagepant) – as effective as zolmitriptan 5 mg oral Single-pulse transcranial magnetic stimulation (sTMS) More effective than placebo in pain-free at 2 hours (39% vs 22%)

After the Migraine - Postdrome Some patients may have: Mood changes “Hangover” Tired Weak Disoriented “Not right”

Chronic Migraine (CM) or Medication Overuse Headache (MOH) Chronic migraine previously called ‘transformed migraine’ Consider medication overuse if ≥ 2 days/week for > 3 months analgesic use Over period of time (months to years) can become almost daily headache Resembles mixture of tension & migraine Occasionally called ‘tension-vascular’ Hint – if awaken with headache consider medication overuse MOH is more prevalent during ages 40-50 and affects about 3 times more women than men. Diagnosis of MOH is based on history and clinical presentation. Prescriptions for acute migraine should be closely monitored to prevent overuse and to detect possible MOH earlier. Chronic migraine treatment requires a team based comprehensive strategy. Most patients will be candidates for referral to a center specializing in the treatment of headaches. For additional information refer to: Silberstein S et al. Epidemiology, risk factors, and treatment of chronic migraine: a focus on topiramate. Headache 2008;48:1087-1095. Walker BB et al. An evidence-based practice approach. J Clin Psychol 2006:62:1367-1378.

CM Modifiable Risk Factors Risk factor associated with increased risk of developing CM Stressful life events Sleep disturbance (i.e. Snoring/sleep apnea) Obesity Baseline headache frequency Medication overuse However, there is no evidence that treatment of these modifiable risk factors reduces the risk of CM. Their treatment with non-pharmacologic means would be appropriate but has not been proven in randomized trials.

CM & MOH Treatment Must stop acute medication to determine Headaches will go away in a few days if medication overuse is etiology No controlled trials of medication withdrawal May get severe withdrawal headache Severe withdrawal headache can be treated with short course of prednisone Randomized trial found no difference with steroid compared to placebo Duration of withdrawal headache varied by the previous treatments. It was 4.1 days for triptans, 6.7 days for ergots and 9.5 days for analgesics. Relapse is high especially during the first year. Expect almost 50% of patients to relapse.

Preventive Medication Candidates: Unresponsive to acute attack medication & disabling headache ≥ 2 attacks/month Increasing frequency of attacks Migraines with potential neurological sequelae Patient preference (just wants to use medication to prevent headaches)

29 250 Audience Question 23 y. o. female with recurrent migraine headaches. You advise starting preventive therapy. Which medication would be appropriate? Anticonvulsant medication Bipolar/anticonvulsant medication Beta-blocker medication Tricyclic medication 60

Prevention therapy - EBM First line treatment should be: Propranolol (Inderal®) 20 – 240 mg/day Timolol 10 – 30 mg/day Less evidence to support other beta-blockers Amitriptyline 10 – 150 mg/day

Prevention therapy - EBM First line treatment should be: Divalproex sodium (Depakote®) 125 – 500 mg BID Topiramate (Topamax®) 50 - 100 mg BID May be as good as propranolol Anti-epileptic drugs had greater suicidal ideation vs. placebo (0.43% vs 0.22%) Topiramate – start with 50 mg nightly for 1 week and increase increments of 25 mg every week. Goal dosage is 50 mg bid. May be considered in overweight patients, have epilepsy or β-blockers are contraindicated. European Federation of Neurological Societies recommends β -blockers, topiramate and valproic acid as 1st line therapies for prevention.

Prevention therapy Second line (SOR-B) Gabapentin - pregnancy category D Carbamazepine* - pregnancy category D * FDA Alert 12/12/07 – Dangerous or even fatal skin reactions can be caused by Carbamazepine therapy in patients with a particular HLA-B*1502 allele.

Prevention Therapies - EBM Relaxation training (SOR-A) Progressive muscular relaxation Breathing exercises Directed imagery Cognitive-behavioral (SOR-A) Combined with medication (SOR-B) Acupuncture appears to be effective (SOR-A) Sham acupuncture just as effective as real [Linde 2009] Thermal biofeedback with relaxation training For complete review of evidence-based treatments of migraine go to: Campbell JK et al. Evidence-based guidelines for migraine headache: behavioral and physical treatments. http://www.aan.com/professionals/practice/pdfs/g10089.pdf

29 250 Audience Question 23 y. o. female with recurrent migraine headaches. You advise starting preventive therapy. Which medication would be appropriate? Anticonvulsant medication Bipolar/anticonvulsant medication Beta-blocker medication Tricyclic medication 65

Menstrual Migraine – two classes Pure menstrual migraine without aura Migraine without aura on days -2 to +3 of cycle During at least 2 of 3 cycles Menstrual related migraine without aura Migraine without aura as above and At other times of the month

Menstrual Migraine Strongly associated with estrogen Steep drop in estrogen just prior to menses may trigger headache Peak incidence is 1st day and preceding day of cycle Other clinical features Greater severity of pain Increased risk of nausea & vomiting Less responsive to acute treatment

Menstrual Migraine Acute therapy the same as other migraines Short-term prevention NSAID on days -7 to +6 helped Naproxen sodium (Anaprox®) & mefenamic acid (Ponstel®) orally have been studied Triptans starting day -2 for 5-6 days helped Frovatriptan (Frova®), naratriptan (Amerge®) & sumatriptan (Imitrex®) orally have been studied

Prognosis of Migraines Study with 10 year follow-up of 11-14 year olds at onset of migraines 40% no longer had headache 20% had episodic tension headache 20% had migraine type that was different from the original diagnosed headache Frequency & intensity usually decreases after menopause Two fold increased risk of CVA [Spector 2010] May influence how aggressive to be with other therapies to reduce risk of CVA

Areas of Uncertainty Causal relationship between patent foramen ovale (PFO) & migraine postulated Closure of PFO suggested for treatment Relationship remains uncertain & treatment of unselected patients is questionable Intranasal lidocaine provided no relief of migraine pain in ED

Tension Type Headache (TTH) - Criteria First No vomiting – if vomiting probably a migraine Not worsened by routine physical activity But can have one of these clinical features Photophobia Phonophobia

TTH - Criteria If no vomiting & only 1 other symptom - then need 2 of the following: Pressing, tightening or non-pulsatile pain Mild to moderate intensity of pain Bilateral No aggravation with movement Diagnosis best made with use of headache diary for 4 weeks

TTH Underlying cause uncertain Muscle tenderness & psychological tension associated with aggravating them But are not clearly the cause Susceptibility influenced by genetic factors

TTH Gender ration female:male 5:4 Age of onset – 25-30 years old Peak prevalence – 30-39 years old Prevalence increases with higher educational level

TTH – Treatment OTC analgesic medications NSAID (prescription) May be augmented with: Promethazine (Phenergan®) Diphenhydramine (Benadryl®) Metoclopramide (Reglan®) Efficacy tends to decrease with increasing frequency of headaches

Chronic Tension Headache Tension headache that occurs 15 or more days a month For at least 6 months

Treatment of Chronic Tension Headache – EBM Beneficial (1st choice) Amitriptyline (Start 10 – 25/day; increase up to 150 mg daily) If no effect in 4 weeks, change therapy Other effective therapies (second choice) Mirtazapine (Remeron®) Venlafaxine (Effexor®) Likely to be beneficial Cognitive behavioral therapy

Treatment of Chronic Tension Headache – Clinical Evidence Unknown effectiveness Acupuncture Indian head massage Relaxation or EMG biofeedback SSRI Tricyclics other than amitriptyline Likely to be ineffective or harmful Benzodiazepines Regular acute pain medication Botulism toxin

Cluster Headaches - Criteria Severe unilateral, bilateral, supraorbital or temporal pain lasting 15-180 minutes (untreated) and one of following on same side Lacrimation Rhinorrhea Forehead or facial swelling Ptosis Miosis Eyelid edema

Cluster Headaches - Criteria Sense of restlessness (93% patients) or agitation Prefer to be erect & move about 5 attacks with frequency of 1-8 on any given day from no other cause 75% of attacks last < 60 minutes

Cluster Headaches Male : female – 2.1 : 1 Peak onset in 40’s 60% right sided Probably most severe pain known to humans Female patients describe attacks as worse than childbirth

Episodic cluster ≥ 2 cluster periods lasting 7-365 days & separated by pain-free remission ≥ 1 month Absence of aura, nausea, vomiting Distinguishes it from migraine

Cluster Headache Treatment Acute Sumatriptan 6 mg SC – relief in 15 min Intranasal spray sumatriptan or zolmitriptan – relief in 30 min Triptans limits on daily usage Limit to 2 SC or 3 nasal sprays per day to prevent tachyphylaxis or rebound High flow O2 effective & safe [Cohen 2009] O2 – 7 - 15 L/min with loose fitting nonrebreathing facial mask for 15 min

Cluster Headache Treatment Acute DHE 0.5 - 1 mg IM or IV useful as abortive agent Octreotide (Sandostatin®) 100 mcg SC can abort an attack NNT 5 for complete relief in 30 min Prednisone 50-80 mg – short course

Cluster Headache Treatment Prophylactic Verapamil 240-960 mg/day

Daily Headache When chronic daily headache is strictly unilateral, same side, consider diagnosis to be: Hemicrania continua Ipsilateral side one or more autonomic symptoms (ptosis, lacrimation, etc.) Defined by absolute response to indomethacin (25 – 300 mg daily, must be continued indefinitely) If intolerant of indomethacin conside COX2 inhibitor

Key Points Diagnosis of migraine headache is clinical Almost always positive family history Triptans are preferred treatment for frequent migraines Discuss preventive therapy with all patients Provide treatment plan for breakthrough pain

What Questions do you have?

References Cohen AS et al. High-flow oxygen for treatment of cluster headache. JAMA 2009;302:2451-2457. Colman I et al. Parenteral dexamethasone for acute severe migraine headache: meat-analysis of randomized controlled trials for preventing recurrence. BMJ 2008;336:1359-1361. Friedman BW et al. The relative efficacy of meperidine for the treatment of acute migraine: a meta-analysis of randomized controlled trials. Ann Emerg Med 2008;52:705-713. Friedman BW et al. A randomized controlled trial of prochlorperazine versus metoclopramide for treatment of acute migraine. Ann Emerg Med 2008;52:399-406. Friedman BW et al. Treating headache recurrence after emergency department discharge: A randomized controlled trial of naproxen versus sumatriptan. Ann Emerg Med 2010;

References Haghighi AB et al. Cutaneous application of menthol 10% solution as an abortive treatment of migraine without aura: a randomised, double-blind, placebo-controlled, crossed-over study. Int J Clin Pract 2010;64:451-456. Kostic MA et al. A prospective, randomized trial of intravenous prochlorperazine versus subcutaneous sumatriptan in acute migraine therapy in the Emergency Department. Ann Emerg Med 2010;56:1-6. Linde K et al. Acupuncture for migraine prophylaxis. Cochrane Database Syst Rev 2009;(1):CD001218 Schurks M et al. Migraine and cardiovascular disease: systematic review and meta-analysis. BMJ 2009;339:b3914.

References Singh A et al. Does the addition of dexamethasone to standard therapy for acute migraine headache decrease the incidence of recurrent headache for patient treated in the emergency department. Acad Emerg Med 2008;15:1223-1233. Spector JT et al. Migraine headache and ischemic stroke risk: an updated meta-analysis. Am J Med 2010;123:612-624.