new york headache center magnesium, migralex and migraine alexander mauskop, md

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New York Headache Center Magnesium, Migralex and Migraine Alexander Mauskop, MD

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Page 1: New York Headache Center Magnesium, Migralex and Migraine Alexander Mauskop, MD

New York Headache Center

Magnesium, Migralex and Migraine

Alexander Mauskop, MD

Page 2: New York Headache Center Magnesium, Migralex and Migraine Alexander Mauskop, MD

Lecture outlineLecture outline

Migraine diagnosis

Migraine pathogenesis – research update

Current and future abortive therapies

Role of magnesium

Migralex

[email protected]

Page 3: New York Headache Center Magnesium, Migralex and Migraine Alexander Mauskop, MD

Number of Migraine Sufferers in the U.S.

1989 (Million)

1999 (Million)

Overall 23.6 27.9

Female 18.0 20.9

Male 5.6 6.9

Lipton et al. 2001.American Migraine Study II.

Page 4: New York Headache Center Magnesium, Migralex and Migraine Alexander Mauskop, MD

Hu et al. Arch Intern Med.1999.

Economic Impact of MigraineEconomic Impact of Migraine

Migraine costs employers $13 billion annually

—Missed work and reduced productivity

Migraine produces 112 million bedridden days per year

Most of the burden takes the form of reduced productivity

Page 5: New York Headache Center Magnesium, Migralex and Migraine Alexander Mauskop, MD

Impact of Migraine onQuality of LifeImpact of Migraine onQuality of Life

Adapted from Solomon GD et al. Headache 1994;34(3):143-147

Physicalfunctioning

Rolefunctioning

Socialfunctioning

Mentalhealth

Healthperceptions

Pain

-1.2

-1

-0.8

-0.6

-0.4

-0.2

0.2

0.4

0

No chronic conditionsDiabetesMigraine

HypertensionAngina

Qu

alit

y o

f L

ife

Mea

sure

Page 6: New York Headache Center Magnesium, Migralex and Migraine Alexander Mauskop, MD
Page 7: New York Headache Center Magnesium, Migralex and Migraine Alexander Mauskop, MD
Page 8: New York Headache Center Magnesium, Migralex and Migraine Alexander Mauskop, MD
Page 9: New York Headache Center Magnesium, Migralex and Migraine Alexander Mauskop, MD

Migraine DiagnosisMigraine Diagnosis

Migraine is under-diagnosed

94% of patients presenting to a PCP with recurrent

headache met IHS criteria for migraine or probable

migraine

Nearly 90% of “sinus headache” patients met IHS criteria

for migraine or probable migraine

Nearly 90% of “tension/stress” headache patients met

IHS criteria for migraine or probable migraine

Page 10: New York Headache Center Magnesium, Migralex and Migraine Alexander Mauskop, MD

1.1 Migraine Without Aura Diagnostic Criteria1.1 Migraine Without Aura Diagnostic Criteria

At least five attacks fulfilling the following criteria:

Headache lasts 4 to 72 hours (untreated or unsuccessfully treated)

Headache has at least 2 of the following characteristics:• Unilateral location• Pulsating quality• Moderate or severe intensity (inhibits or prohibits daily

activities)• Aggravation by walking stairs or similar routine physical

activity

During headache at least 1 of the following occurs:• Nausea and/or vomiting• Photophobia and phonophobia

Page 11: New York Headache Center Magnesium, Migralex and Migraine Alexander Mauskop, MD

Migraine Diagnostic QuestionnaireMigraine Diagnostic Questionnaire

Has a headache limited your activities for a day or more in the last three months?

Are you nauseated or sick to your stomach when you have a headache?

Does light bother you when you have a headache?

Sensitivity - 0.81 (95% CI, 0.77 to 0.85) Specificity - 0.75 (95% CI, 0.64 to 0.84) Positive predictive value - 0.93 (95% CI, 89.9 to 95.8). Test-retest reliability was good - kappa of 0.68 (95% CI, 0.54 to 0.82).

R. Lipton et al. Neurology 2003;61:375-382

Page 12: New York Headache Center Magnesium, Migralex and Migraine Alexander Mauskop, MD

Hemiplegic migraine isoverdiagnosedHemiplegic migraine isoverdiagnosed

The International Classification of Headache Disorders 2nd Edition

  "distinction between migraine with aura and hemiparesthetic

migraine is probably artificial and therefore not recognized

in this classification"

  "Common mistakes (in diagnosing typical aura with migraine

headache) are...mistaking sensory loss for weakness"

Page 13: New York Headache Center Magnesium, Migralex and Migraine Alexander Mauskop, MD

The myth of basilar migraineThe myth of basilar migraine

M. Kirchmann, L.L. Thomsen, J. Olesen. Basilar-type migraine: Clinical, epidemiologic, and genetic features. Neurology 2006; 66(6):880-886.

Conclusions:

Basilar-type aura seemingly may occur at times in any

patient with migraine with typical aura. There is no firm

clinical, epidemiologic, or genetic evidence that basilar

migraine is an independent disease entity different from

migraine with typical aura.

Page 14: New York Headache Center Magnesium, Migralex and Migraine Alexander Mauskop, MD

Causes of MigrainesCauses of Migraines

A single gene is responsible for familial hemiplegic

migraine

Common migraine is polygenetic, which accounts

for its variable expression

Multiple triggers modify the frequency and the

severity of attacks

Page 15: New York Headache Center Magnesium, Migralex and Migraine Alexander Mauskop, MD

0

0.2

0.4

0.6

0.8

1

0 20 40 60 80 100

Migrainewith aura

Migrainewithout aura

Controls

Hyperexcitability of Visual Cortex in Patients with MigraineHyperexcitability of Visual Cortex in Patients with Migraine

Aurora SK et al. Cephalalgia. 2003;23:258–263.

Pro

babi

lity

of P

hosp

hene

Magnetic Stimulus Intensity (%)

P=0.0001 (Logrank test) for difference in threshold levels.

Page 16: New York Headache Center Magnesium, Migralex and Migraine Alexander Mauskop, MD

Dysfunction of brain stem pain and vascular control centers

Dysfunction of brain stem pain and vascular control centers

Weiller C et al. Nat Med. 1995;1:658–660Weiller C et al. Nat Med. 1995;1:658–660

–16 mm–16 mm –18 mm–18 mm

CNS Activation During MigraineCNS Activation During Migraine

Pain Perception*

Anterior cingulate cortex

Migraine Generator*

Raphe nucleiLocus coeruleusPeriaqueductal gray

*Areas of red indicate cerebral blood flow increases (P<0.001).

Page 17: New York Headache Center Magnesium, Migralex and Migraine Alexander Mauskop, MD

Trigeminovascular Migraine Pain PathwaysTrigeminovascular Migraine Pain Pathways

Adapted with permission from Hargreaves RJ et al. Adapted with permission from Hargreaves RJ et al. Can J Neurol SciCan J Neurol Sci. 1999;26(suppl 3):S12. 1999;26(suppl 3):S12––S19.S19.

Trigeminal Activation Leading to Sterile Inflammation

Pain Signal Transmission

Trigeminal Nucleus Caudalis

Trigeminal Ganglion

Cranial Parasympathetic Activation Leading to Dural Vasodilation

Page 18: New York Headache Center Magnesium, Migralex and Migraine Alexander Mauskop, MD

5-HT1DCGRP 5-HT1D /CGRP

Human Trigeminal Tract: CGRP Fibers Co-express 5-HT1D ReceptorsHuman Trigeminal Tract: CGRP Fibers Co-express 5-HT1D Receptors

Page 19: New York Headache Center Magnesium, Migralex and Migraine Alexander Mauskop, MD

Calcitonin Gene-Related PeptideCalcitonin Gene-Related Peptide

Released from sensory nervesPotent vasodilatordirect effects on smooth muscle vs nitric oxide mediatedIn migraineurs:• CGRP levels are elevated in cranial venous

effluent during an attack• CGRP infusion can produce migraine-like

symptoms

Hargreaves RJ. Semin Headache Manag. 1999;4:10–15.

Page 20: New York Headache Center Magnesium, Migralex and Migraine Alexander Mauskop, MD

CGRP antagonists in migraineCGRP antagonists in migraine

Olesen, Diener, Husstedt et al.

Calcitonin gene-related peptide receptor antagonist

BIBN 4096 BS for the acute treatment of

migraine.N Engl J Med. 2004;350(11):1104-10.

Response rate:

2.5-mg - 66%

placebo - 27%

(P=0.001).

Page 21: New York Headache Center Magnesium, Migralex and Migraine Alexander Mauskop, MD

CGRP antagonists in migraineCGRP antagonists in migraine

MK-0974

Pain relief at 2 hours Pain free

300 mg n=38 68.1% 45.2%

400 mg n=45 48.2%

24.3% 600 mg n=40

67.5% 32.1% rizatriptan n=34

69.5% 33.4% placebo n=115.

46.3% 14.3%

Page 22: New York Headache Center Magnesium, Migralex and Migraine Alexander Mauskop, MD

CGRP and Botulinum ToxinCGRP and Botulinum Toxin

Meng J, Wang J, Lawrence G, Dolly JO

Synaptobrevin I mediates exocytosis of CGRP from

sensory neurons and inhibition by botulinum toxins

reflects their anti-nociceptive potential.

J Cell Sci. 2007;120(16):2864-74

Page 23: New York Headache Center Magnesium, Migralex and Migraine Alexander Mauskop, MD

Acute Treatment Goals Acute Treatment Goals

Rapidly relieve attack

Consistently relieve attack

No recurrence

Restore ability to function

Minimize need for backup medications

Optimize self-care (prevent ER/physician visits)

Cost-effective

Minimize or avoid adverse eventsUS Headache Consortium: 2000

Page 24: New York Headache Center Magnesium, Migralex and Migraine Alexander Mauskop, MD

Prescription DrugsPrescription Drugs

Cafergot, Wigraine

Migranol

Midrin

Fioricet, Fiorinal, Esgic

NSAIDs, COX-2

codeine, hydrocodone

Stadol NS

Non-triptans

Page 25: New York Headache Center Magnesium, Migralex and Migraine Alexander Mauskop, MD

Prescription DrugsPrescription Drugs

Imitrex - sumatriptan

Zomig - zolmitriptan

Maxalt - rizatriptan

Amerge - naratriptan

Axert - almotriptan

Frova - frovatriptan

Relpax - eletriptan

TriptansTriptans

Page 26: New York Headache Center Magnesium, Migralex and Migraine Alexander Mauskop, MD

TriptansTriptans

Partial or no response

Recurrence

Risk of CV side effects

Risk of other side effects

Very high cost

Restrictions by HMOs

Limited frequency of use

Limitations

Page 27: New York Headache Center Magnesium, Migralex and Migraine Alexander Mauskop, MD

Triptans Triptans

Ischemic heart disease

Coronary vasospasm

Multiple risk factors for CAD

Hemiplegic or basilar migraine

Uncontrolled hypertension

Use within 24 hours of ergot or another triptan

Pregnancy: Category C

Contraindications

Page 28: New York Headache Center Magnesium, Migralex and Migraine Alexander Mauskop, MD

OTC DrugsOTC Drugs

Excedrin Migraine

Advil Migraine

Motrin Migraine

Bayer Aspirin

Anacin

Tylenol

Page 29: New York Headache Center Magnesium, Migralex and Migraine Alexander Mauskop, MD

OTC DrugsOTC Drugs

Gastro-intestinal side effects, liver and kidney toxicity

Presence of caffeine can cause rebound headaches, insomnia, anxiety

Lack of efficacy for a large percentage of sufferers

Limitations

Page 30: New York Headache Center Magnesium, Migralex and Migraine Alexander Mauskop, MD

MigralexMigralex

A new paradigm inthe treatment of migraines

Aspirin – 500 mg

Magnesium oxide – 75 mg

A new paradigm inthe treatment of migraines

Aspirin – 500 mg

Magnesium oxide – 75 mg

Page 31: New York Headache Center Magnesium, Migralex and Migraine Alexander Mauskop, MD

Low-dose aspirin for migraine prophylaxis.Buring JE, Peto R, Hennekens CH, JAMA1990;264(13).

Physicians’ Health Study (n=22,071)

Aspirin, 325 mg every other day migraines 661 (6.0%)

Placebo 818 (7.4%)

20% reduction (statistically significant)

Aspirin in Migraine

Page 32: New York Headache Center Magnesium, Migralex and Migraine Alexander Mauskop, MD

Effervescent metoclopramide and aspirin (Migravess) versus effervescent aspirin or placebo for migraine attacks: a double-blind studyPeer Tfelt-Hansen, Jes Olesen, Cephalalgia1984(4):107.

Aspirin, 650 mg with metoclopramide 10 mg vs

Aspirin 650 mg vs Placebo (n=118 patients)

Both active groups were statistically better (p<0.01) than placebo for pain with no difference between the two active groups

Aspirin in Migraine

Page 33: New York Headache Center Magnesium, Migralex and Migraine Alexander Mauskop, MD

Acetylsalicylic acid effervescent 1000 mg (Aspirin) in acute migraine attacks; a multicentre randomized, double-blind, single-dose, placebo-controlled parallel group study.Lange R, Schwartz J, Hohn M. Cephalalgia, 2000;20(7):663-667

Aspirin in Migraine

Relief at 2 hours (n=343 patients):

Aspirin 55%

Placebo 36%

P<0.001

Page 34: New York Headache Center Magnesium, Migralex and Migraine Alexander Mauskop, MD

Mouth-dispersible aspirin in the treatment of migraine: A placebo-controlled study.MacGregor EA, Dowson A, Davies TG. Headache2002;42(4)249-255

Aspirin in Migraine

Relief at 2 hours (n=71 patients):

Aspirin (900 mg) 48%

Placebo 19%

P=0.0005

Page 35: New York Headache Center Magnesium, Migralex and Migraine Alexander Mauskop, MD

Aspirin is efficacious for the treatment of acute migraine.Lipton RB, Goldstein J, Baggish JS et al. Headache 2005;45(4):283-92

Aspirin in Migraine

Relief at 2 hours (n=401 patients):

Aspirin (1000 mg) 52%

Placebo 34%

P<0.001

Page 36: New York Headache Center Magnesium, Migralex and Migraine Alexander Mauskop, MD

Aspirin in MigraineAspirin in Migraine

Efficacy of 1,000 mg Effervescent Acetylsalicylic Acid and Sumatriptan in Treating Associated Migraine Symptoms H.C. Diener et al. European Neurology 2004;52:50-56

433 patients Relief Pain-free

1,000 mg effervescent ASA 49.3% 25.3% 50 mg sumatriptan 48.8% 24.4% placebo 32.9% 14.5%

All active treatments were superior to placebo (p < 0.05).

Page 37: New York Headache Center Magnesium, Migralex and Migraine Alexander Mauskop, MD

CaffeineCaffeine

CNS side effects: anxiety, jitteriness, tremor, insomnia

Other side effects: palpitations, stomach pain/GERD

Potential for causing rebound headaches

The case against caffeine as an ingredientin a migraine product

Page 38: New York Headache Center Magnesium, Migralex and Migraine Alexander Mauskop, MD

CaffeineCaffeine

52% moderate or severe headache

11% depression

11% low vigor

8% anxiety

8% fatigue

235 mg (2.5 cups) a day235 mg (2.5 cups) a day

“Withdrawal syndrome after the double-blind cessation of caffeine consumption.”

(Silverman et al. NEJM 1992)

Page 39: New York Headache Center Magnesium, Migralex and Migraine Alexander Mauskop, MD

Low brain magnesium in migraine

N.M. Ramadan, H. Halvorson, A. Vande-Linde et al.Headache 1989;29:590-593.

Magnesium and Migraine

Page 40: New York Headache Center Magnesium, Migralex and Migraine Alexander Mauskop, MD

Magnesium and MigraineMagnesium and Migraine

Trauninger et al. Headache 42:114-119;2002

Oral magnesium load test in patients with migraineOral magnesium load test in patients with migraine

Conclusions:

Magnesium retention occurs in patients with migraine

after oral loading, suggesting a systemic magnesium

deficiency

Page 41: New York Headache Center Magnesium, Migralex and Migraine Alexander Mauskop, MD

Magnesium and MigraineMagnesium and Migraine

glutamate

angiotensin II

potassium

serotonin

G proteins

Known effects of IMg2+Known effects of IMg2+

acetylcholine

nitric oxide

norepinephrine

calcium

enzyme complexes (325)

Page 42: New York Headache Center Magnesium, Migralex and Migraine Alexander Mauskop, MD

NMDA (N-Methyl-D-Aspartate)Receptor ComplexNMDA (N-Methyl-D-Aspartate)Receptor Complex

Ca2+

Zn GLY

PCP MK801

Mg2+

TCA

NMDACaCa2+2+

MgMg2+2+

Page 43: New York Headache Center Magnesium, Migralex and Migraine Alexander Mauskop, MD

IV MgSO4 for Acute MigraineIV MgSO4 for Acute Migraine

IMg2+

mmol/LIMg2+

mmol/L

0.58

0.56

0.54

0.52

0.50

0.48

0.46

0.44

0.42

0.58

0.56

0.54

0.52

0.50

0.48

0.46

0.44

0.42

xxxxxx oo

oooo

oo

xxxxxx

xxxxxxxx

xxxxxxxxxxxxxxxx

oooo

oooooooooooooooo

oooooooo

oooooo

x = non-respondersx = non-responders

o = responderso = responders

A. Mauskop et al, ClinScience 1995;89:633-6

Page 44: New York Headache Center Magnesium, Migralex and Migraine Alexander Mauskop, MD

IV MgSO4 forCluster Headaches

IV MgSO4 forCluster Headaches

IMg2+

mmol/LIMg2+

mmol/L

0.60

0.58

0.56

0.54

0.52

0.50

0.48

0.46

0.44

0.60

0.58

0.56

0.54

0.52

0.50

0.48

0.46

0.44

0.760.76

oo

oooooo

oooooooooooooo

oooo

oooooooooo

oooooooo

xx

xx

xxxx

xxxxxxxxxxxxxxxxxx

xxxx

x = non-respondersx = non-responders

o = responderso = responders

Mauskop et al,

Headache 1995;35:597-600.

Page 45: New York Headache Center Magnesium, Migralex and Migraine Alexander Mauskop, MD

Efficacy of intravenous magnesium sulfate in the treatment of acute migraine attacks.

Demirkaya S, Vural O, Dora B, et al. Headache 2001;41:171-177

Randomized, single-blind, placebo controlled trial

15 patients – 1 g of MgSO4; 13 complete relief, 2 - partial

15 patients – placebo, followed by 1 g MgSO4 ; 4 – partial

relief, 11 – none; after 1 g MgSO4 14 – complete relief.

Magnesium and Migraine

Page 46: New York Headache Center Magnesium, Migralex and Migraine Alexander Mauskop, MD

Parenteral treatment of acute migrainesParenteral treatment of acute migraines

magnesium sulfate – 1 gram IV

sumatriptan – 4-6 mg SC

ketorolac – 60 mg IV

dexamethasone – 8 mg IV

metoclopramide – 10 mg IV

dihydroergotamine – 1 mg IV

valproate sodium – 500 mg IV

droperidol – 2.5-5 mg IV

Goal: Keep patients out of the ER

Page 47: New York Headache Center Magnesium, Migralex and Migraine Alexander Mauskop, MD

Magnesium prophylaxis of menstrual migraine:Effects on intracellular magnesium.

F. Facchinetti, G. Sances, A.R. Genazzani, G. Nappi.Cephalagia 1996; 16:257-263.

Magnesium pyrrolidone carboxylic acid – 360 mg

Days with migraine reduced 4.7 to 2.4 (p<0.01)

Significant reduction in MDQ scores (p<0.05)

Magnesium and Migraine

Page 48: New York Headache Center Magnesium, Migralex and Migraine Alexander Mauskop, MD

Magnesium in the prophylaxis of migraine:A double-blind, placebo-controlled study.

Pfaffenrath V, Wessely P, Meyer C, et al.Cephalagia 1996; 16:436-440.

Magnesium-u-aspartate-hydrochloride-trihydrate – 20 mmol

No relief of headaches – interim analysis of 69 patients.

Diarrhea: 45.7% on magnesium, 23.5 on placebo

Magnesium and Migraine

Page 49: New York Headache Center Magnesium, Migralex and Migraine Alexander Mauskop, MD

Prophylaxis of migraine with oral magnesium: results from a prospective, multicenter, placebo-controlled and double-blind randomized study.

A. Peikert, C. Wilimzig, R. Kohne-Volland, Cephalagia1996; 16:257-263.

Trimagnesium dicitrate – 600 mg

Attack frequency reduced 41.6% vs 15.8% (p<0.05)

Days with migraine reduced 52.3% vs 19.5% (p<0.05)

Magnesium and Migraine

Page 50: New York Headache Center Magnesium, Migralex and Migraine Alexander Mauskop, MD

Oral magnesium oxide prophylaxis of frequent migrainous headache in children: A randomized, double-blind, placebo-controlled trial.

Wang F, Van Den Eeden S, Ackerson L, et al.Headache 2003;43:601-610.

Magnesium oxide 9 mg/kg

86 of 118 completed;

“statistically significant downward trend in HA frequency over time in MgO but not placebo group”

Magnesium and Migraine

Page 51: New York Headache Center Magnesium, Migralex and Migraine Alexander Mauskop, MD

Magnesium and MigraineMagnesium and Migraine

Stress

Alcohol

Genetics

Low dietary intake

Gastro-intestinal disorders

Chronic illness

Potential causes of magnesium deficiencyPotential causes of magnesium deficiency

Page 52: New York Headache Center Magnesium, Migralex and Migraine Alexander Mauskop, MD

MigralexMigralex

A new paradigm inthe treatment of migraines

Aspirin – 500 mg

Magnesium oxide – 75 mg

A new paradigm inthe treatment of migraines

Aspirin – 500 mg

Magnesium oxide – 75 mg

Page 53: New York Headache Center Magnesium, Migralex and Migraine Alexander Mauskop, MD

MigralexMigralex

Both ingredients relieve all migraine symptoms, but through different mechanisms, which may result in superior efficacy due to synergistic effect

Low recurrence rate due to the sustained effect of magnesium and antiplatelet effect of aspirin

Magnesium facilitates absorption and reduces potential GI side effects of aspirin

Rapidly absorbed

AdvantagesAdvantages

Page 54: New York Headache Center Magnesium, Migralex and Migraine Alexander Mauskop, MD

MigralexMigralex

Can be effective for “overindulgence headaches”

Effective for “sinus” and tension headaches

May have lasting preventive effect

Caffeine-free

Magnesium is potentially beneficial in asthma, stroke, neonates, cardiac arrhythmias, PMS, etc.

Aspirin has many other potential benefits and lacks the stigma of other NSAIDs (cardiovascular risks)

AdvantagesAdvantages

Page 55: New York Headache Center Magnesium, Migralex and Migraine Alexander Mauskop, MD

Migralex andAcute Treatment Goals Migralex andAcute Treatment Goals

Rapidly relieve attack

Consistently relieve attack

No recurrence

Restore ability to function

Minimize need for backup medications

Optimize self-care/prevent ER/MD visits

Cost-effective

Minimize or avoid adverse eventsUS Headache Consortium: 2000

Page 56: New York Headache Center Magnesium, Migralex and Migraine Alexander Mauskop, MD

New York Headache Center

Magnesium, Migralex and Migraine

Alexander Mauskop, MD