Advances in Migraine

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Advances in Migraine
New York Headache Center

• Alexander Mauskop, MD

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Potential 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

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News in Migraine

• Pathophysiology
• CGRP antagonists
• PFO
• Classification
• Basilar migraine
• Chronic migraine
• Magnesium
• Botulinum toxin

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Impact of Migraine onQuality of Life
Adapted from Solomon GD et al. Headache
199434(3)143-147
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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.
199811205-209 Aurora SK, Welch KMA. Curr Opin
Neurol. 200013273-276.
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Cause 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

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Neuronal 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. 19908817-828 Aurora
SK, Welch KMA. Curr Opin Neurol. 199811205-209
Cutrer, et al. Cephalalgia. 19971793-100.
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Early 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.

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Benefits 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

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Migraine Is Often Overlooked

• 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

Cady et al. Headache Free. 199336-38.
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Migraine Is Often Overlooked

• 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

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Caffeine-containing Drugs
Rx

• Cafergot
• Wigraine
• Esgic
• Fiorinal
• Fioricet
• Norgesic
• Synalgos DC

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Caffeine-Containing Drugs
OTC

• Anacin
• Anacin Maximum Strength
• Aspirin Free Excedrin
• Excedrin Extra Strength
• Excedrin Migraine
• Maximum Strength Midol

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Caffeine
The analgesic effects of caffeine in
headache (Ward et al., Pain 1990)
Caffeine (65 mg and 130 mg) equals to 650 mgof
acetaminophen
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Caffeine
235 mg (2.5 cups) a day

• 52 moderate or severe headache
• 11 depression
• 11 low vigor
• 8 anxiety
• 8 fatigue

Withdrawal syndrome after the double-blind
cessation of caffeine consumption.
(Silverman et al. NEJM 1992)
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Magnesium and Migraine
Low brain magnesium in migraine N.M. Ramadan, H.
Halvorson, A. Vande-Linde et al. Headache
198929590-593.
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Magnesium and Migraine
Oral magnesium load test in patients with
migraine

• Trauninger et al. Headache 42114-1192002

• Conclusions
• Magnesium retention occurs in patients with
  migraine
• after oral loading, suggesting a systemic
  magnesium
• deficiency

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Magnesium
Known effects of IMg2

• glutamate
• angiotensin II
• potassium
• serotonin
• G proteins

acetylcholine nitric oxide norepinephrine calcium
enzyme complexes (325)
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NMDA (N-Methyl-D-Aspartate)Receptor Complex
Ca2
Mg2
Zn GLY
Ca2
PCP MK801
NMDA
Mg2
TCA
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Magnesium and Migraine
Potential causes of magnesium deficiency

• Stress
• Alcohol and caffeine
• Genetics
• Low dietary intake
• Gastro-intestinal disorders
• Chronic illness

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IV MgSO4 for Acute Migraine
A. Mauskop et al, Clin Science 199589633-6
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IV MgSO4 forCluster Headaches
x
0.76
x
0.60 0.58 0.56 0.54 0.52 0.50 0.48 0.46 0.44
o
x
x
o
x non-responders
o
xxx
o
xxx
o responders
ooo
xxx
IMg2 mmol/L
oooo
o
x
o
x
ooo
o
o
oo
Mauskop et al, Headache 199535597-600.
o
o
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Magnesium and Migraine
Magnesium prophylaxis of menstrual
migraine Effects on intracellular magnesium.
F. Facchinetti, G. Sances, A.R. Genazzani, G.
Nappi. Cephalagia 1996 16257-263.
Magnesium pyrrolidone carboxylic acid 360 mg
Days with migraine reduced 4.7 to 2.4
(plt0.01) Significant reduction in MDQ scores
(plt0.05)
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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 16257-263.
Trimagnesium dicitrate 600 mg
Attack frequency reduced 41.6 vs
15.8 (plt0.05) Days with migraine reduced 52.3
vs 19.5 (plt0.05)
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Magnesium and Migraine
Oral magnesium oxide prophylaxis of frequent
childhood migraine
Wang F, Van Den Eeden S, Ackerson L, et
al.Cephalagia 200020424 (abstract).
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Magnesium and Migraine
Magnesium in the prophylaxis of migraine A
double-blind, placebo-controlled study.
Pfaffenrath V, Wessely P, Meyer C, et
al.Cephalagia 1996 16436-440.
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Effectiveness of High-dose Riboflavin in Migraine
Prophylaxis
4
No. of Attacks per Month
3
Placebo Riboflavin P0.001
2


1
1
2
3
4
Month
J. Shoenen, J. Jacquy, M. Lenaerts. Neurology
1998 50466-440.
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Botanical Remedies
Feverfew
Randomized double-blind placebo-controlled
trialof feverfew in migraine prevention.
Murphy JJ, Heptinsall S, Mitchell JRA. The
Lancet, 23 July 1988, pp 189-192.
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Feverfew
Results

• Reduction in mean number of attacks 3.6 vs 4.7
  (plt0.005)
• Global assessment of improvement on VAS 74 vs
  60 (plt0.0001)
• Reduced severity of nausea and vomiting (plt0.02)
• Tendency toward milder intensity of pain
• No effect on duration of attacks

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Natural Remedies
The Case for Multi-Agent Therapies

• Migraine is a multifactorial disease
• Any single pharmacologic agent hasno more than
  60 efficacy
• Single nutraceutical therapies may haveno more
  than 50 efficacy

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Natural Remedies
Possible Combinations

• Migra-Lieve

Riboflavin 400 mg Magnesium 300 mg Feverfew 100 mg
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Petasites hybridus
Possible mechanisms of action

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

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Botanical Remedies

• Aromatherapy
• Topical preparations
• Oral preparations

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Botanical remedies
Effect of Peppermint andEucalyptus Oil

• Double-blind, placebo-controlled,
  randomizedcross-over design
• 32 healthy subjects
• Parameters tested
• EMG activity
• Exteroceptive suppression periods
• Contingent negative variation
• Sensitivity to experimental pain
• Current mood states

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Results

Combination of Peppermint Oiland Ethanol

• Analgesic effect
• Muscle relaxing effect
• Mentally relaxing effect

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Natural Remedies
What to recommend?

• Aerobic exercise, neck exercise
• Biofeedback / relaxation
• Magnesium, riboflavin, feverfew
• Acupuncture
• Massage, shiatsu, reflexology
• Dietary approaches

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Candidates for Preventive Therapy

• Disabling primary headaches
• Chronic migraine
• Frequent migraine
• Chronic tension-type headache
• Medication overuse (drug-induced headache)
• Headaches refractory to routine treatment
• Contraindication to acute therapy

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Currently 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

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Potential 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

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Prophylactic DrugsAdditional Drawbacks

• Work in minority of patients
• Compliance
• Fear of adverse events
• Drug-drug interactions

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History 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

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The Neuromuscular Junction
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Botulinum Toxin Type A Mechanism of Action
Current Hypothesis
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Botulinum Toxin Type A Migraine Headache Study

• Binder WJ, et al. Otolaryngol
• Head Neck Surg 2000123669-676
• Open-label study
• Dx Migraine
• N77
• Variable dose
• Outcome measure
• Complete response
• Partial response
• No response

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Botulinum Toxin Type A for Migraine Headache

• Silberstein S, et al. Headache. 200040445-450.
• Double-blind, vehicle-controlled study
• Dx Migraine (N123)
• Placebo (n41)
• 25 U botulinum toxin type A (n42)
• 75 U botulinum toxin type A (n40)
• 3-month duration
• Outcome measure
• Reduction in migraine severity

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BTX-A Injection Sites Fixed Sites, Fixed Dose
(Bilateral)

• Frontalis Glabellar

Temporalis
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Proof-of-Concept Studies

• Two double-blind, vehicle-controlled studies
• 1-month baseline period, treatment, 3-4 month
  follow-up
• Study 1 (N123)
• 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 (N418)
• 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)

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Botulinum Toxin Type Afor Migraine Silberstein
S, et al.
P lt.042 vs vehicle
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Study 2
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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

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Summary 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

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Injection Sites Glabellar andFrontal Regions
X
X
X
X
X
X
X
X
X
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Injection SiteTemporalis Muscle
X
X
X
X
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Injection SiteSuboccipital Region
Trapezius muscle
Splenius capitismuscle
X
X
X
Adapted with permission from Netter FH. Atlas of
Human Anatomy. Icon Learning Systems Teterboro,
NJ. 1997.
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Injection SiteOccipitalis Muscle
X
X
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Botulinum Toxin Type A Cost in Migraines

• M. Blumenfeld, Impact of Botulinum Toxin Type-A
  Treatemnt on Medication Costs and Usage in
  Difficult-to-Treat Chronic Headache Case
  Studies.
• Headache Quarterly 200213(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.