Advances in MigraineAdvances in Migraine

Alexander Mauskop, MDAlexander Mauskop, MD

New York Headache CenterNew York Headache Center

Potential Conflict of Interest DisclosurePotential Conflict of Interest Disclosure

Allergan Pozen

AstraZeneca Procter & Gamble

Bristol-Myers Squibb PR Osteo

Elan Royal Numico/GNC

GlaxoSmithKline UCB Pharma

Merck Weber & Weber

Novartis Winston Laboratories

Ortho-McNeil Wyeth

Pfizer

News in Migraine

Pathophysiology

CGRP antagonists

PFO

Classification

Basilar migraine

Chronic migraine

Magnesium

Botulinum toxin

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

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-0.6

-0.4

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0

No chronic conditionsDiabetesMigraine

HypertensionAngina

Qu

alit

y o

f L

ife

Mea

sure

Migraine Is a NeurovascularDisorder

The genesis of migraine is neurologic

Likely that hyperexcitability of CNS confers susceptibility to migraine attacks

Migraine associated with regional reduction in cerebral blood flow and cortical spreading depression (CSD)

Trigeminovascular system involved in production of migraine pain

Aurora SK, Welch KMA. Curr Opin Neurol. 1998;11:205-209; Aurora SK, Welch KMA. Curr Opin Neurol. 2000;13:273-276.

Cause of MigrainesCause 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

Neuronal Hyperexcitabilityin MigraineNeuronal Hyperexcitabilityin Migraine

Neuronal hyperexcitability predisposes individuals to migraine— Migraine patients visualized phosphenes following transcranial

magnetic stimulation

Increased neuronal hyperexcitability may be multifactorial— Abnormal calcium channels that influence presynaptic

neurotransmitter release

— Abnormal glutamate metabolism

— Deficiency of systemic and brain magnesium

Migraine may be prevented by reducing neuronal hyperexcitability— Inhibition of excitatory neurotransmission (eg, Na+ channel)

— Enhancement of inhibitory neurotransmission (eg, GABA)

Welch, et al. Neurol Clin. 1990;8:817-828; Aurora SK, Welch KMA. Curr Opin Neurol. 1998;11:205-209; Cutrer, et al. Cephalalgia. 1997;17:93-100.

Early Intervention May PreventCentral SensitizationEarly Intervention May PreventCentral Sensitization

Clinical experience suggest that migraineurs are most-responsive to medications within the initial 30-60 minutes of an attack.

The development of central hypersensitivity points to the need for the early use of anti-migraine drugs.

Benefits of Early TreatmentBenefits of Early Treatment

Early pain-free response

Less recurrence

Prevents progression of attack

Less disability

Less need for multiple doses and rescue meds

Effective early treatment may prevent chronic migraine

Sinus headache is the most common misdiagnosis

Symptoms include:

• Dull ache located near the nose

• Pressure in the sinus cavities

• Thick, colored nasal discharge

• OTCs can sometimes relieve the pain

Migraine Is Often Overlooked

Caffeine-containing DrugsCaffeine-containing Drugs

Cafergot

Wigraine

Esgic

Fiorinal

Fioricet

Norgesic

Synalgos DC

RxRx

Caffeine-Containing DrugsCaffeine-Containing Drugs

Anacin

Anacin Maximum Strength

Aspirin Free Excedrin

Excedrin Extra Strength

Excedrin Migraine

Maximum Strength Midol

OTCOTC

CaffeineCaffeine

“The analgesic effects of caffeine in headache”(Ward et al., Pain 1990)

Caffeine (65 mg and 130 mg) equals to 650 mgof acetaminophen

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)

Low brain magnesium in migraine

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

Magnesium and Migraine

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

MagnesiumMagnesium

glutamate

angiotensin II

potassium

serotonin

G proteins

Known effects of IMg2+Known effects of IMg2+

acetylcholine

nitric oxide

norepinephrine

calcium

enzyme complexes (325)

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

Ca2+

Zn GLY

PCP MK801

Mg2+

TCA

NMDACaCa2+2+

MgMg2+2+

Magnesium and MigraineMagnesium and Migraine

Stress

Alcohol and caffeine

Genetics

Low dietary intake

Gastro-intestinal disorders

Chronic illness

Potential causes of magnesium deficiencyPotential causes of magnesium deficiency

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

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x = non-respondersx = non-responders

o = responderso = responders

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

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

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x = non-respondersx = non-responders

o = responderso = responders

Mauskop et al,

Headache 1995;35:597-600.

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

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

Oral magnesium oxide prophylaxis of frequent childhood migraine

Wang F, Van Den Eeden S, Ackerson L, et al.Cephalagia 2000;20:424 (abstract).

Magnesium and Migraine

Effectiveness of High-dose Riboflavin in Migraine ProphylaxisEffectiveness of High-dose Riboflavin in Migraine Prophylaxis

J. Shoenen, J. Jacquy, M. Lenaerts. Neurology 1998; 50:466-440.

*

No. of Attacks per Month

Month

4

3

2

1

1 2 3 4

Placebo

Riboflavin

P=0.001*

Botanical RemediesBotanical Remedies

FeverfewFeverfew

Randomized double-blind placebo-controlled trialof feverfew in migraine prevention.

Murphy JJ, Heptinsall S, Mitchell JRA.The Lancet, 23 July 1988, pp 189-192.

FeverfewFeverfew

Reduction in mean number of attacks –3.6 vs 4.7 (p<0.005)

Global assessment of improvement on VAS –74 vs 60 (p<0.0001)

Reduced severity of nausea and vomiting (p<0.02)

Tendency toward milder intensity of pain

No effect on duration of attacks

ResultsResults

Natural RemediesNatural Remedies

Migraine is a multifactorial disease

Any single pharmacologic agent hasno more than 60% efficacy

Single nutraceutical therapies may haveno more than 50% efficacy

The Case for Multi-Agent TherapiesThe Case for Multi-Agent Therapies

Natural RemediesNatural Remedies

Migra-Lieve:

Possible CombinationsPossible Combinations

Riboflavin 400 mg

Magnesium 300 mg

Feverfew 100 mg

Petasites hybridusPetasites hybridus

Inhibits constriction of smooth muscle preparation induced by acetylcholine, histamine and potassium chloride

Inhibits leukotriene synthesis

Possible mechanisms of action:Possible mechanisms of action:

What to recommend?What to recommend?

Natural RemediesNatural Remedies

Aerobic exercise, neck exercise

Biofeedback / relaxation

Magnesium, riboflavin, feverfew

Acupuncture

Massage, shiatsu, reflexology

Dietary approaches

Candidates for Preventive TherapyCandidates for Preventive Therapy

Disabling primary headachesChronic migraine

Frequent migraine

Chronic tension-type headache

Medication overuse (“drug-induced headache”)

Headaches refractory to routine treatment

Contraindication to acute therapy

Currently Used Preventive TherapiesCurrently Used Preventive Therapies

Migraine Tension-type

Beta-blockers X

Antidepressants X X

Anticonvulsants X

Calcium channel blockers X

Methysergide X

NSAIDs X X

Muscle relaxants X

Potential Side Effects of Prophylactic DrugsPotential Side Effects of Prophylactic Drugs

Beta-blockers fatigue, dizziness, depression

Antidepressants dry mouth, drowsiness, weight gain, constipation, sexual dysfunction

Anticonvulsants weight gain, cognitive dysfunction, drowsiness, fatigue, constipation

Calcium channel blockers constipation, edema

Methysergide fibrosis, water retention, leg cramps

NSAIDs dyspepsia, peptic ulcers, renal disease

Muscle relaxants sedation, dizziness

Prophylactic Drugs:Additional Drawbacks Prophylactic Drugs:Additional Drawbacks

Work in minority of patients

Compliance

Fear of adverse events

Drug-drug interactions

History of BTX-A Usein MigraineHistory of BTX-A Usein Migraine

Anecdotal reports of reduced migraines from patients receiving BTX-A treatment for other indications

A retrospective review of patient charts suggested migraine relief was associated with certain injection sites

This information was used in designing early clinical studies

The Neuromuscular JunctionThe Neuromuscular Junction

Botulinum Toxin Type A Mechanism of Action: Current HypothesisBotulinum Toxin Type A Mechanism of Action: Current Hypothesis

Botulinum Toxin Type A: Migraine Headache StudyBotulinum Toxin Type A: Migraine Headache Study

Binder WJ, et al. Otolaryngol Head Neck Surg 2000;123:669-676

Open-label study

Dx: Migraine

N=77

Variable dose

Outcome measure:—Complete response—Partial response—No response

Botulinum Toxin Type A for Migraine HeadacheBotulinum Toxin Type A for Migraine Headache

Silberstein S, et al. Headache. 2000;40:445-450.

Double-blind, vehicle-controlled study

Dx: Migraine (N=123)—Placebo (n=41)—25 U botulinum toxin type A (n=42)—75 U botulinum toxin type A (n=40)

3-month duration

Outcome measure:—Reduction in migraine severity

Frontalis & Glabellar

BTX-A Injection Sites: Fixed Sites, Fixed Dose

BTX-A Injection Sites: Fixed Sites, Fixed Dose

Temporalis

(Bilateral)

Proof-of-Concept Studies Proof-of-Concept Studies

Two double-blind, vehicle-controlled studies— 1-month baseline period, treatment, 3-4 month follow-up

Study 1 (N=123)

— 2-8 moderate to severe migraines/month at baseline

— Vehicle (n = 41); 25 U BTX-A (BOTOX®; n = 42); 75 U BTX-A (n = 40)

Study 2 (N=418)

— 4-8 moderate to severe migraines/month at baseline

— Vehicle (n = 106); 7.5 U BTX-A (n = 105); 25 U BTX-A (n = 101); 50 U BTX-A (n = 106)

*

*

-2.4

-2

-1.6

-1.2

-0.8

-0.4

0

0 1 2 3

Months Postinjection

Mea

nC

hang

e fr

om B

asel

ine

75U BTX-A

25U BTX-A

Vehicle

Botulinum Toxin Type Afor Migraine Silberstein S, et al.

Botulinum Toxin Type Afor Migraine Silberstein S, et al.

*P <.042 vs vehicle

Study 2Study 2

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-2

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-0.8

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0

0 1 2 3 4

Months Postinjection

Mea

n C

hang

e Fr

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asel

ine

50U BTX-A

25U BTX-A

7.5U BTX-A

Vehicle

Safety Summary Safety Summary

BTX-A was well tolerated

All treatment-related adverse events were local and transient

Most common were

—Blepharoptosis

—Injection site weakness

—Skin tightness

There were no serious treatment-related adverse events

Summary of Development StudiesSummary of Development Studies

Results of initial studies using frontal injections are not definitive

—Improvement from baseline in migraine frequency and acute medication use in one study

—Patients perceived significant global improvement in both studies

—Safe and well tolerated in both studies

Future studies should employ alternative treatment approaches

Injection Sites: Glabellar andFrontal RegionsInjection Sites: Glabellar andFrontal Regions

XX X

XX

X

X

XX

Injection Site:Temporalis MuscleInjection Site:Temporalis Muscle

X

XXX

Injection Site:Suboccipital RegionInjection Site:Suboccipital Region

Trapeziusmuscle

Adapted with permission from: Netter FH. Atlas of Human Anatomy. Icon Learning Systems; Teterboro, NJ. 1997.

X

X

Splenius capitismuscle

X

Injection Site:Occipitalis MuscleInjection Site:Occipitalis Muscle

XX

Botulinum Toxin Type A: Cost in MigrainesBotulinum Toxin Type A: Cost in Migraines

A. M. Blumenfeld, Impact of Botulinum Toxin Type-A Treatemnt on Medication Costs and Usage in Difficult-to-Treat Chronic Headache: Case Studies.

Headache Quarterly 2002;13(1):241-244.

BTX-A-induced decreases in the frequency and/pr severity of chronic headaches led to decreased headache medication costs. A reduction in ED and office visits may provide further savings.