Transcript Botulinum Toxin in the Treatment of Chronic Pain and Headaches

New York Headache Center
Advances in Migraine
Alexander Mauskop, MD
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
News in Migraine
Pathophysiology
CGRP antagonists
PFO
Classification
Basilar migraine
Chronic migraine
Magnesium
Botulinum toxin
Impact of Migraine on
Quality of Life
No chronic conditions
Diabetes
Migraine
0.4
Hypertension
Angina
Quality of Life Measure
0.2
0
-0.2
-0.4
-0.6
-0.8
-1
-1.2
Physical
functioning
Role
functioning
Social
functioning
Mental
health
Health
perceptions
Adapted from Solomon GD et al. Headache 1994;34(3):143-147
Pain
Migraine Is a Neurovascular
Disorder
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 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 Hyperexcitability
in 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 Prevent
Central 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 antimigraine drugs.
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
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
Caffeine-containing Drugs
Rx
Cafergot
Wigraine
Esgic
Fiorinal
Fioricet
Norgesic
Synalgos DC
Caffeine-Containing Drugs
OTC
Anacin
Anacin Maximum Strength
Aspirin Free Excedrin
Excedrin Extra Strength
Excedrin Migraine
Maximum Strength Midol
Caffeine
“The analgesic effects of caffeine in headache”
(Ward et al., Pain 1990)
Caffeine (65 mg and 130 mg) equals to 650 mg
of acetaminophen
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)
Magnesium and Migraine
Low brain magnesium in migraine
N.M. Ramadan, H. Halvorson, A. Vande-Linde et al.
Headache 1989;29:590-593.
Magnesium and Migraine
Oral magnesium load test in
patients with migraine
Trauninger et al. Headache 42:114-119;2002
Conclusions:
Magnesium retention occurs in patients with migraine
after oral loading, suggesting a systemic magnesium
deficiency
Magnesium
Known effects of IMg2+
glutamate
acetylcholine
angiotensin II
nitric oxide
potassium
norepinephrine
serotonin
calcium
G proteins
enzyme complexes (325)
NMDA (N-Methyl-D-Aspartate)
Receptor Complex
Ca2+
Mg2+
Zn
GLY
Ca2+
NMDA
PCP MK801
Mg2+
TCA
Magnesium and Migraine
Potential causes of
magnesium deficiency
Stress
Alcohol and caffeine
Genetics
Low dietary intake
Gastro-intestinal disorders
Chronic illness
IV MgSO4 for Acute Migraine
0.58
0.56
0.54
xxx
x
xx
x
xx
xxxxxx
0.52
IMg2+
mmol/L
0.50
0.48
x
xx
o
oo
oo
ooooo
ooo
oooo
x = non-responders
o = responders
oo
o
0.46
0.44
0.42
o
A. Mauskop et al, Clin
Science 1995;89:633-6
IV MgSO4 for
Cluster Headaches
0.76
x
x
o
0.60
0.58
x
x
0.56
0.54
IMg2+
mmol/L
xxx
xxx
xxx
0.52
0.50
0.48
0.46
0.44
x
x
o
o
o
ooo
oooo
o
o
ooo
o
o
oo
o
o
x = non-responders
o = responders
Mauskop et al,
Headache 1995;35:597-600
Magnesium and Migraine
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 doubleblind randomized study.
A. Peikert, C. Wilimzig, R. Kohne-Volland, Cephalagia
1996; 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).
Effectiveness of High-dose Riboflavin
in Migraine Prophylaxis
4
No. of
Attacks
per
Month
3
Placebo
Riboflavin
2
*
*
1
1
2
3
4
Month
J. Shoenen, J. Jacquy, M. Lenaerts. Neurology 1998; 50:466-440.
P=0.001
Botanical Remedies
Feverfew
Randomized double-blind placebo-controlled trial
of feverfew in migraine prevention.
Murphy JJ, Heptinsall S, Mitchell JRA.
The Lancet, 23 July 1988, pp 189-192.
Feverfew
Results
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
Natural Remedies
The Case for Multi-Agent Therapies
Migraine is a multifactorial disease
Any single pharmacologic agent has
no more than 60% efficacy
Single nutraceutical therapies may have
no more than 50% efficacy
Natural Remedies
Possible Combinations
Migra-Lieve:
Riboflavin
400 mg
Magnesium
300 mg
Feverfew
100 mg
Petasites hybridus
Possible mechanisms of action:
Inhibits constriction of smooth muscle
preparation induced by acetylcholine,
histamine and potassium chloride
Inhibits leukotriene synthesis
Natural Remedies
What to recommend?
Aerobic exercise, neck exercise
Biofeedback / relaxation
Magnesium, riboflavin, feverfew
Acupuncture
Massage, shiatsu, reflexology
Dietary approaches
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
Currently Used
Preventive Therapies
Migraine
Beta-blockers
X
Antidepressants
X
Anticonvulsants
X
Calcium channel blockers
X
Methysergide
X
NSAIDs
X
Muscle relaxants
Tension-type
X
X
X
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
Prophylactic Drugs:
Additional Drawbacks
Work in minority of patients
Compliance
Fear of adverse events
Drug-drug interactions
History of BTX-A Use
in 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 Junction
Botulinum Toxin Type A Mechanism of
Action: Current Hypothesis
Botulinum 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 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
BTX-A Injection Sites:
Fixed Sites, Fixed Dose
(Bilateral)
Frontalis & Glabellar
Temporalis
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)
Botulinum Toxin Type A
for Migraine Silberstein S, et al.
Months Postinjection
0
1
2
3
Mean
Change from Baseline
0
-0.4
-0.8
-1.2
*
-1.6
-2
-2.4
75U BTX-A
25U BTX-A
Vehicle
*
*P <.042 vs vehicle
Study 2
Months Postinjection
0
1
2
3
4
Mean
Change From Baseline
0
50U BTX-A
-0.4
-0.8
-1.2
-1.6
-2
-2.4
25U BTX-A
7.5U BTX-A
Vehicle
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
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 and
Frontal Regions
X
X
X
X X
X
X
XX
Injection Site:
Temporalis Muscle
X
X
X
X
Injection Site:
Suboccipital Region
Trapezius
muscle
X
X
Splenius capitis
muscle
X
Adapted with permission from: Netter FH. Atlas of Human Anatomy. Icon Learning Systems; Teterboro, NJ
Injection Site:
Occipitalis Muscle
X
X
Botulinum 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.