advances in migraine alexander mauskop, md new york headache center
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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
-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
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
xxxxxx oo
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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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xx
xx
xxxx
xxxxxxxxxxxxxxxxxx
xxxx
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
-2.4
-2
-1.6
-1.2
-0.8
-0.4
0
0 1 2 3 4
Months Postinjection
Mea
n C
hang
e Fr
om B
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.