Using BOTOX ® as an adjunct
in the treatment for MIGRAINE
by Dr. Patrick Treacy
Medical Director
Ailesbury Clinics
Ireland
Migraine Association of Ireland
Lecture will cover
1. The history of the development of Botox ®
2. What exactly is Botox ® and how does it work?
3. What are the current uses of Botox in medicine?
4. How exactly does Botox works for migraine?
5. What is the evidence for the use of Botox ®?
6. What are the possible side effects of Botox ®?
WHAT EXACTLY IS BOTOX ®?
History of Botox starts
in the new century 1900
German chemical warfare brought new means of killing people
Ypres April 22nd 1915
Non specific method. 5,000 British troops died on the
first day and 5,000 Germans on the second
Next year Ireland strikes for freedom.
Dublin 1916
1916 British built a new chemical
warfare complex
7000 acres of scrubland in Porton Down Wiltshire
Porton Down Research Centre
Research experiments on Botulinum by scientist
Dr. Paul Fides gave rise to DysPORT
Clostridium botulinum
 Anaerobic, Gram-positive,
rod-shaped, sporeforming organism
 Found in soil samples
and aquatic sediments
 Produces the neurotoxin
botulin
 Recognized in 1896 by
Emile van Ermengen
10
Porton Down is still active today
First victim of experiments
Aircraftman Ronald Madison died in May 1953
Reinhard Heydrich
Assassinated by Czech agents in Prague on
27th May 1942 by use of Botulinum toxin
1953 US built chemical
warfare plant at Fort Detrick
American experiments by Edward Schantz gave rise to Botox
Botox Research
 Edward J. Schantz purified toxins
from C. botulinum, S. aureus, B.
cereus, and shellfish
 Dr. Alan Scott, was specializing in
strabismus (cross-eye) looking to
weaken overactive eye muscles
 Schantz gave Scott preparations
of the botulinum toxin (BTX-A)
Edward J. Schantz
1908-2005
15
Strabismus
The various muscles of the eye that might
be affected by strabismus.
Demonstration of the various inflictions of
strabismus
16
How did Botox reach such popularity?
The use of BOTOX cosmetically
Pictures courtesy of
Ailesbury Clinics
Same patient 5 days later
When did Botox become so popular?
1987 Canadian ophthalmologist Jean Carruthers
noted that frown lines disappeared following the
use of Botox to treat patients for blepharospasm.
She told her dermatologist husband
Dr. Alastair Carruthers
1990, The Carruthers published their findings
“The treatment of glabellar furrows with
Botulinum-A exotoxin”
Carruthers JDA, Carruthers JA. J Dermatol Surg Oncol. 1990;
Botox and Cosmetic Medicine
1991 Carruthers presented their
findings at the American Society for
Dermatologic Surgery, Florida
1992 Carruthers article in J Dermatol Surg
Oncol.1992;18:17-21 made the FDA approve
Botox for use in cosmetic medicine.
Botox and Headaches
1992 The headache and Botox connection
began emerging in 1992 when a California
physician noted his patients who got Botox
injections said they were having fewer
headaches.
Where does Botox come from?
Botulinum toxin (BTX) is produced by a bacterium
called Clostridium botulinum,
The clinical syndrome of botulism can occur following
ingestion of contaminated food from this bacterium
Botulinum toxin is broken into 7 neurotoxins
(types A, B, C [C1, C2], D, E, F, and G),
which are distinct but structurally similar.
Human botulism is mainly due to types A, B, E,
and, rarely, F,G.
Types C and D cause toxicity only in animals.
What does the Botox look like?
Botox is a single chain that
can split to form a dichain
molecule with a disulfide
bridge.
The light chain is similar to
tetanus toxin
The heavy chain can bind the
toxin to nerve receptors
Scientific History of Botox
1822 German doctor Justinus Kerner published
symptoms of "sausage poison" in 200 cases of
gastroenteritis in Stuttgart in medical journal . He
suggested the idea of a possible therapeutic use of
“sausage poison“ in St. Vitus dance
1870, German doctor Muller coined the name botulism
for the symptoms. Botulus is Latin for sausage.
1895, Microbiologist Prof. Emile Van Ermengem
checked 3 deaths from food poisoning outbreak in
Ellezelles and isolated the bacterium
Clostridium botulinum.
20th century History of BTX-A toxin
•1944, Edward Schantz cultured Clostridium
botulinum and isolated the toxin (BTX-A) .
•1949, Burgen et al discovered that botulinum
toxin blocks neuromuscular transmission.
.
FDA approval for Botox
•1973, Alan B Scott, MD, of Smith-Kettlewell Eye
Research Institute used (BTX-A) in monkey
experiments
•1980, Scott suggested and used BTX-A for the first
time in humans to treat strabismus.
•I989, BTX-A approved by the FDA for treatment of
strabismus, blepharospasm, and hemifacial spasm in
patients aged younger than 12 years.
FDA approved uses of BTX-A
1. Cervical dystonia
2. Blepharospasm
3. Cranial nerve 11 disorders
4. Facial spasm
5. Glabellar frown lines
‘Extralabel’ use of BTX-A
•Spasticity
•Stroke
•Traumatic brain injury
•Cerebral palsy
•Multiple sclerosis
•Spinal cord injury

Achalasia (oesophageal)
Chronic anal fissures
Migraine and tension headaches
Hyperhidrosis
Cerebral Palsy
Low back pain
Myofascial pain syndrome
Tics
Spastic bladder and urinary sphincters
‘Extralabel’ use of BTX-A
•Focal dystonias - Involuntary, sustained, or spasmodic
patterned muscle activity
•Cervical dystonia (spasmodic torticollis)
•Blepharospasm (eyelid closure)
•Laryngeal dystonia (spasmodic dysphonia)
•Limb dystonia (writer's cramp)
•Oromandibular dystonia
•Orolingual dystonia
•Truncal dystonia

•Sweating disorders
•Axillary and palmar hyperhidrosis
•Frey syndrome, also known as
auriculotemporal syndrome
‘Extralabel’ use of BTX-A
•Disorders of localized muscle spasms and pain
•Chronic low back pain
•Myofascial pain syndrome
•Temporomandibular joint disorders
•Tension headache
•Migraine headache
•Cervicogenic headache

Smooth muscle hyperactive disorders
• Detrusor-sphincter dyssynergia
• Achalasia cardia
• Hirschsprung disease
• Sphincter of Oddi dysfunctions
• Chronic anal fissures
How does Botox work?
At a normal neuromuscular
junction, a nerve impulse
triggers the release of
acetylcholine, which
causes the muscles to
contract.
How does Botox work?
Botox acts by binding to
receptor sites on the nerve
terminals blocking the release
of ACETYLCHOLINE
This mechanism laid the
foundation for the development
of the toxin as a therapeutic
tool.
Mechanism of BLOCKING of BTX-A
The Botox light chain stops
ACETYLCHOLINE release by
cleaving a protein called
SNAP-2
SNAP-2 is required for the
docking of acetylcholine
vesicles on the inner side of
the nerve terminal plasma
membrane.
Where does BOTOX® Block Ach?
 Skeletal Muscle
Motor Nerve
Alpha/Gamma




Arms
Legs
Face
Neck
This use in stroke and cerebral palsy
Where else does BOTOX® block Ach release?
Hyperhidrosis
Sialorrhea
 Autonomic Nerves
 Secretory glands
Autonomic Nerves
 Sweat glands
 Salivary glands
 Smooth muscle
Smooth Muscle
Bladder
 Bladder
 Diaphragm
This use in sweating and incontinence
Why does Botox stop working?
Clinical effect lasts about
2-6 months and then
resolve
Recovery occurs through
formation of new nerve
terminals
Study by De Paiva
suggests that regeneration
of the original
neuromuscular junction
can take place.
The Migraine Story
Triggers and Risk Factors
Migraine headaches are often
triggered by specific things
Triggers: Changes in Daily Cycles
Triggers: Environment or Diet
Triggers: Mental
Migraine Takes Time Out From Your Life
In the past 3 months in the US alone...
9 million
14 million
Missed Work or School
Functioned less than half as well at
work/school
21 million
Were unable to do chores/household work
18 million
Functioned less than half as well at
household chores
16 million
Missed family or leisure activity
How Migraine Stacks Up Against
Other Common Diseases
12%
Affected Patients
7%
5%
6%
1%
Rheumatoid
arthritis
Asthma
Diabetes
Osteoarthritis
Migraine
From the Centers for Disease Control and Prevention, the US Census Bureau,
and the Arthritis Foundation.
The Stages of a Migraine Attack
Migraine Unnecessary Suffering
 More than 50% of people with migraine
suffer for at least a year before they are
properly diagnosed
 About 38% of people with migraine suffer
for about 3 or more years before they are
properly diagnosed
National Headache Foundation. American Migraine Study II: Migraine in the United States:
`Burden of Illness and Patterns of Treatment
How do Migraines happen?
3
4
Changes in nerve cell
activity and blood flow
may result in visual
disturbance,
numbness or tingling,
and dizziness.
Chemicals in the brain
cause blood vessel
dilation and inflammation
of the surrounding tissue
5
The inflammation
irritates the trigeminal
nerve, resulting in
severe or throbbing pain
2
Electrical impulses
spread to other
regions of the brain.
1
Migraine originates deep
within the brain
Chemicals irritate Trigeminal Nerve
This triggers other nerves
How does Botox help?
Arterial Activation
Release of
Neurotransmitter
Worsening of Pain
Botox blocks these neurotransmitters
Glut
cGRP
Sub P
The blocking effects of BOTOX
Sensory Nerve
Type C, A-delta, ABeta
Motor Nerve
Alpha/Gamma
Autonomic
Cholinergic
Smooth Muscle
SP, cGRP, Glu
Ach
Ach
SNARE
SNARE complex
Single site of action = SNARE
protein via SNAP-25
BOTOX
* BTX/A→SNAP-25; BTX/B →VAMP
How Botox into Muscle stops Headache Pain
Proposed
Neurogenic
Antidromic
Central
Chronic
Peripheral
Response
Effects
ofto
Inflammation:
Stimulation:
Sensitization:
Inflammation
Sensitization:
Stimulus
Dilation
BTX
AP’s
travel of
both
An
increase
-Increase
inin
and
Pain:
arterioles,
centrally,
and
Direct inhibition
VESICULAR
responsiveness
leakage
of
Wind-upof
peripherally,
ofexcitability
inflammatory
of
neurons
release
of
plasma
from
Feedback
loop
invading
peripheral
mediators`
within
CNS
mediators
venules
(edema)
branches
of the
nociceptors
stimulate
same
neuron
outside
the area
nociceptors
of injury
Bk
His
Central
Sensitization
Antidromic Stimulation
cGRP
Sub-P
Peripheral Sensitization
cGRP
Sub-P
Vesicle mediated release
K+
How does Botox stop Migraine?
 It is not really clear how Botox curbs
headache pain and stiffness. Researchers
think Botox blocks sensory nerves that
relay pain messages to the brain and
relaxes muscles, making them less
sensitive to pain.
How Botox injection blocks pain
BOTOX®
Brain
Blocks Sensory
Input to CNS
Spinal cord
Sensory
neuron
Reduces Input to
Muscle Spindle
Sensory ganglion
Sensory
Input
Nerves
Motor
Output
Motor Neuron
Interneuron
The Scientific Proof
Durham 2003: Inhibition of cGRP chemical
release from Trigeminal nerve cells
Without Botox
With Botox
KCl, IFC or Cap stimulus
4-5 fold increase in cGRP released
Inhibited cGRP KCl-stimulated
release
Stimulated changes in cGRP secretion in TG cells
Dose response of cGRP released from stimulated TG
cells

Mayo Clinic Study in Scottsdale, Arizona

David W. Dodick, M.D., April 14, 2005

Observations

More than half of the 48 patients said their migraine occurrences
dropped by 50 percent or more.

61 percent said they had headaches less frequently and almost 30
percent said the headaches were less severe.


Conclusion
“BTX-A significantly reduces frequency of headache attacks in
migraine patients suffering from chronic daily headaches (CHD).”
Dodick D.W J Neurol 2005; 9:188
Baylor College of Medicine Headache Clinic
 58 patients participated in a controlled trial.
 Some got Botox and others water injections.
 At 3 months, 55% of patients who received Botox
reported at least moderate improvement in their
headaches.
 2 of the 29 (7%) who got the placebo water injections
reported similar results.
Dr. William Ondo
Baylor College Trial
 "The biggest advantage to Botox is its lack
of side effects, especially compared to
other medications," Dr. William Ondo of
the Baylor College of Medicine said in an
AHS press release. "It really is extremely
safe and appears to be very effective for
some people."
Thomas Jefferson School of Medicine Study
 Compared with subjects who received placebo inj.
subjects in the Botox treatment group experienced:
 Significantly fewer migraine attacks per month
 Reduced severity of migraine attacks

 Fewer days using abortive/rescue medications
 Fewer episodes of vomiting
Silberstein, Mathew, Saper, and Jenkins. "Botulinum Toxin Type A as a Migraine Preventive Treatment.
" Headache: The Journal of Head and Face Pain 40 (6), 445-450 December 2003
Allergan FDA studies
 Allergan Inc completed several exploratory
Phase II clinical trials investigating the
potential use of BOTOX to treat various forms
of headache and levels of headache severity
in an effort to identify a responsive patient
population, dose and efficacy endpoints to
guide its Phase III program.
Allergan FDA results
 Significant differences in favour of BOTOX
were demonstrated on measures such as
decrease in the frequency of headache
episodes; decrease of at least 50% in
headache days; and decrease in acute
medication use.
FDA trials
 Based on the Phase II findings specific to
patients with CDH, Allergan reached an
agreement with the FDA to move forward with a
large Phase III clinical trial program
 No significant between-group differences were
observed on predetermined outcome measures
 BOTOX is not currently approved by the FDA for the treatment of
any headache disorder.
Migraine Injection Points
Any side effects of Botox?
Since the mechanism of action of BTX-A is so specific,
side effects are uncommon and systemic effects rare.
Flulike syndrome has been
reported, generally shortlived. Other s/e muscle
soreness, headaches, lightheadedness, fever, chills,
hypertension, weakness,
diarrhoea, and abdominal
pain are not necessarily a
result of BTX-A treatment.
They include .
What about the famous droopy eyelids?
Patient with eyelid ptosis
ANATOMY OF FOREHEAD MUSCLES
FRONTALIS
Action:
Elevates eyebrows and
the skin of the forehead
Action: Elevates eyebrows and
the skin of the forehead
ANATOMY OF FOREHEAD MUSCLES
CORRUGATOR
SUPERCILII
Action: Depresses eyebrows
and wrinkles forehead
ANATOMY OF FOREHEAD MUSCLES
ORBICULARIS
OCULI
Action:Depresses eyebrows
Closes the eyelids
Helps drainage of tears
REMEMBER final brow position is a balance
between DEPRESSORS and ELEVATOR
PROCERUS MUSCLE
CORRUGATOR MUSCLE
ORBICULARIS OCULI
FRONTALIS
FINAL BALANCE DEPENDS ON SKILL OF DOCTOR
Contraindications to Botox injections
Treat patients with
diseases of the
neuromuscular junction
(eg, myasthenia gravis)
cautiously because
underlying generalized
weakness can be
exacerbated, and local
weakness at injection sites
can occur more than
otherwise expected
IF YOU DO NOT KNOW WHAT YOU ARE DOING
YOU PAY THE PRICE
NOW! HOW DO I GET BACK UP?
THE MIGRAINE INJECTION POINTS
INJECT ONLY
CORRUGATOR,
PROCERUS AND
FRONTALIS
MUSCLES
DANGER: AVOID INJECTING 1CM ABOVE MID-PUPILLARY LINE
BOTULINUM-A TOXIN formulations
BOTOX ®
Botox® is an American form of
BTX-A produced from the Hall
strain of C botulinum
Botox ® is distributed by Allergan Inc.
Headquarters Irvine California
Manufactured Westport Co. Mayo
BOTULINUM-A TOXIN formulations
DYSPORT ®
Dysport ® is a British form of
BTX-A made in England and
mostly available in Europe.
Dysport ® is produced by Speywood Pharmaceuticals in
England (Dysport)
BOTULINUM-A TOXIN formulations
MYOBLOC ®
Myobloc™ is BTX-B (botulinum
toxin type B) is also used to treat
facial wrinkles. FDA approved for
the use of cervical dystonia in
Dec 2000
Myobloc™ is distributed by Elan
Pharmaceuticals in Athlone, Ireland
Peripheral Sensitization Leads to
Central Sensitization
Peripheral
Stimulation
Release of Glutamate
and Peptides in CNS
CNS
Antidromic Activation
Release of Neuropeptides
Decreased Inhibition
at the dorsal horn
Additional Activation
Peripheral Sensitization
Increased afferent signals
Lack of sensitivity of nerve endings
Central
Sensitization
Botulinum Toxin May Prevent Peripheral
Sensitization and Central Sensitization
Peripheral
Stimulation
Release of Glutamate
and Peptides in CNS
Botulinum Toxin
CNS
Antidromic Activation
No peripheral release
Prevents Peripheral Sensitization:
May Indirectly
Prevent:
•Central Sensitization
•Inhibits release of neuropeptides
Clinical relevance of these preclinical results remain to be established
Translating these Mechanisms to Humans
Peripheral Sensitization
PNS
Glu, Sp, cGRP, NA, NGF
BK, PGs, HA, 5-HT, H+
Adenosine, NO
CNS
Central Sensitization
Glu
Sp
C-fos
C-fiber/ A delta
Impulses
Increase
WDR
A fiber
Spinal Cord or
Nucleus Trigeminal Caudalis
DRG or TGG
Peripheral Sensitization, leading to Central Sensitization
Blocking Headaches with Botox
PNS
Peripheral Sensitization
Glu, Sp, cGRP, NA, NGF
BK, PGs, HA, 5-HT, H+
Adenosine, NO
CNS
Central Sensitization
Glu
Sp
C-fiber/A delta
Impulses
Increase
WDR
BTX/A
A fiber
DRG or TGG
Spinal Cord or
Nucleus Trigeminal Caudalis
BTX/A inhibits release of mediators at the peripheral pain
fibres, resulting in an indirect effect on the CNS