The Action of Botox on Migraine

Using BOTOX ® as an adjunct in the treatment for MIGRAINE

by Dr. Patrick Treacy

Medical DirectorAilesbury Clinics

Ireland

Migraine Association of Ireland

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 ®?

Lecture will cover

WHAT EXACTLY IS BOTOX ®?

History of Botox starts in the new century 1900

History of Botox starts in the new century 1900

German chemical warfare brought new means of killing people

Ypres April 22nd 1915 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

Next year Ireland strikes for freedom. Dublin 1916

1916 British built a new chemical warfare complex

1916 British built a new chemical warfare complex

7000 acres of scrubland in Porton Down Wiltshire

Porton Down Research Centre

Porton Down Research Centre

Research experiments on Botulinum by scientist Dr. Paul Fides gave rise to DysPORT

Clostridium botulinumClostridium botulinum

Anaerobic, Gram-positive, rod-shaped, spore-forming organism

Found in soil samples and aquatic sediments

Produces the neurotoxin botulin

Recognized in 1896 by Emile van Ermengen

Anaerobic, Gram-positive, rod-shaped, spore-forming 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

Porton Down is still active today

First victim of experimentsFirst victim of experiments

Aircraftman Ronald Madison died in May 1953

Reinhard Heydrich 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

1953 US built chemical warfare plant at Fort Detrick

American experiments by Edward Schantz gave rise to Botox

Botox ResearchBotox 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 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) 15

Edward J. Schantz 1908-2005

StrabismusStrabismus

16

The various muscles of the eye that might be affected by strabismus.

Demonstration of the various inflictions of strabismus

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 dystonia2. Blepharospasm

3. Cranial nerve 11 disorders4. 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


•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


•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?Where does BOTOX® Block Ach?

Skeletal Muscle

Arms Legs Face Neck

Skeletal Muscle

Arms Legs Face Neck

Motor NerveAlpha/Gamma

This use in stroke and cerebral palsy

Where else does BOTOX® block Ach release?Where else does BOTOX® block Ach release?

Autonomic Nerves

Secretory glands Sweat glands Salivary glands

Smooth muscle Bladder Diaphragm

Autonomic Nerves

Secretory glands Sweat glands Salivary glands

Smooth muscle Bladder Diaphragm

Hyperhidrosis Sialorrhea

Autonomic Nerves

Smooth MuscleBladder

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 FactorsTriggers and Risk Factors

Migraine headaches are often triggered by specific things

Migraine headaches are often triggered by specific things

Triggers: Changes in Daily CyclesTriggers: Changes in Daily Cycles

Triggers: Environment or DietTriggers: Environment or Diet

Triggers: MentalTriggers: Mental

In the past 3 months in the US alone...

9 million

14 million

21 million

18 million

16 million Missed family or leisure activity

Functioned less than half as well at household chores

Were unable to do chores/household work

Functioned less than half as well at work/school

Missed Work or School

Migraine Takes Time Out From Your Life

Migraine Takes Time Out From Your Life

How Migraine Stacks Up Against Other Common

Diseases

How Migraine Stacks Up Against Other Common

Diseases

From the Centers for Disease Control and Prevention, the US Census Bureau, and the Arthritis Foundation.

1%

5%6%

7%

12%

Rheumatoid arthritis

Asthma Diabetes Osteoarthritis Migraine

Affected Patients

The Stages of a Migraine AttackThe Stages of a Migraine Attack

Migraine Unnecessary SufferingMigraine 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

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

1Migraine originates deep

within the brain

2Electrical impulses

spread to other regions of the brain.

3Changes in nerve cell activity and blood flow

may result in visual disturbance,

numbness or tingling, and dizziness.

4Chemicals in the brain cause blood vessel

dilation and inflammation of the surrounding tissue

5The inflammation irritates

the trigeminal nerve, resulting in severe or

throbbing pain

How do Migraines happen?How do Migraines happen?

Chemicals irritate Trigeminal Nerve Chemicals irritate Trigeminal Nerve

This triggers other nervesThis triggers other nerves

Arterial Activation

Release of Neurotransmitter

Worsening of Pain

How does Botox help?

Botox blocks these neurotransmittersBotox blocks these neurotransmitters

cGRP

Sub P

Glut

Motor NerveAlpha/Gamma

Sensory NerveType C, A-delta, A-

Beta

SP, cGRP, Glu

Autonomic Cholinergic

Smooth Muscle

SNARE

BOTOX

AchAch

The blocking effects of BOTOXThe blocking effects of BOTOX

* BTX/A→SNAP-25; BTX/B →VAMP

SNARE complexSingle site of action = SNARE

protein via SNAP-25

Sub-PcGRP

BkK+

His

Sub-PcGRP

How Botox into Muscle stops Headache Pain How Botox into Muscle stops Headache Pain

BTX

Central Sensitization

Central Sensitization: An increase in responsiveness

of neurons within CNS

Peripheral Sensitization:

-Increase in excitability of

peripheral nociceptors

Response to Stimulus

VESICULAR release of mediators stimulate

nociceptors

Antidromic Stimulation

Neurogenic Inflammation:

Dilation of arterioles, leakage of

plasma from venules (edema)

Chronic Inflammation

and Pain:Wind-up

Feedback loop

Proposed Effects of BTXDirect inhibition of inflammatory

mediators`

Peripheral Sensitization

Antidromic Stimulation:

AP’s travel both centrally, and peripherally,

invading branches of the same neuron

outside the area of injury

Vesicle mediated release

How does Botox stop Migraine?

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.

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.

Sensory ganglion

Motor Neuron

Nerves

Spinal cordSensory neuron

Interneuron

Brain

Sensory Input

Motor Output

Sensory ganglion

Motor Neuron

Nerves


Interneuron

Brain

Sensory Input

Motor Output

Sensory ganglion

Motor Neuron

Nerves


Interneuron

Brain

Sensory Input

Motor Output

Sensory ganglion

Motor Neuron

Nerves


Interneuron

Brain

Sensory Input

Motor Output

Sensory ganglion

Motor Neuron

Nerves


Interneuron

Brain

Sensory Input

Motor Output

Sensory ganglion

Motor Neuron

Nerves


Interneuron

Brain

Sensory Input

Motor Output

Sensory ganglion

Motor Neuron

Nerves


Interneuron

Brain

Sensory Input

Motor Output

Sensory ganglion

Motor Neuron

Nerves


Interneuron

Brain

Sensory Input

Motor Output

How Botox injection blocks painHow Botox injection blocks pain

BoNT

BOTOX®

Blocks Sensory Input to CNS

Reduces Input to Muscle Spindle

The Scientific Proof

Dose response of cGRP released from stimulated TG cellsStimulated changes in cGRP secretion in TG cells

Without Botox KCl, IFC or Cap stimulus 4-5 fold increase in cGRP

released

Without Botox KCl, IFC or Cap stimulus 4-5 fold increase in cGRP

released

With Botox Inhibited cGRP KCl-

stimulated release

With Botox Inhibited cGRP KCl-

stimulated release

Durham 2003: Inhibition of cGRP chemical

release from Trigeminal nerve cells

Mayo Clinic Study in Scottsdale, Arizona 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).”

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

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.

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 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."

"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

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

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 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 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 resultsAllergan 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.

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 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.

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 PointsMigraine Injection Points

Any side effects of Botox?

Flulike syndrome has been reported, generally short-lived. Other s/e muscle soreness, headaches, light-headedness, fever, chills, hypertension, weakness, diarrhoea, and abdominal pain are not necessarily a result of BTX-A treatment. They include .

Since the mechanism of action of BTX-A is so specific, side effects are uncommon and systemic effects rare.

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


CORRUGATOR SUPERCILII

Action: Depresses eyebrows and wrinkles forehead


ORBICULARIS OCULI

Action:Depresses eyebrows Closes the eyelidsHelps drainage of tears

REMEMBER final brow position is a balance between DEPRESSORS and ELEVATOR

PROCERUS MUSCLECORRUGATOR MUSCLEORBICULARIS 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® 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

BOTOX ®


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)

DYSPORT ®


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

MYOBLOC ®

Peripheral Sensitization Leads to Central Sensitization

Peripheral Sensitization Leads to Central Sensitization

Peripheral Stimulation

Release of Glutamate and Peptides in CNS

Release of Neuropeptides

Peripheral SensitizationIncreased afferent signals

Lack of sensitivity of nerve endings

Antidromic Activation

CNS



Additional Activation

Decreased Inhibition at the dorsal horn

Botulinum Toxin May Prevent Peripheral Sensitization and Central Sensitization

Botulinum Toxin May Prevent Peripheral Sensitization and Central Sensitization

Peripheral Stimulation

Release of Glutamate and Peptides in CNS

No peripheral release

Prevents Peripheral Sensitization:

•Inhibits release of neuropeptides

Antidromic Activation

CNSBotulinum Toxin

May Indirectly Prevent:

•Central Sensitization

Clinical relevance of these preclinical results remain to be established

PNS CNSPeripheral SensitizationGlu, Sp, cGRP, NA, NGF

BK, PGs, HA, 5-HT, H+

Adenosine, NO


GluSp

C-fiber/ A delta

A fiber Spinal Cord or Nucleus Trigeminal Caudalis

DRG or TGG

Impulses

IncreaseWDR

Peripheral Sensitization, leading to Central Sensitization

C-fos

Translating these Mechanisms to Humans

Peripheral Sensitization

Glu, Sp, cGRP, NA, NGFBK, PGs, HA, 5-HT, H+

Adenosine, NO


GluSp

C-fiber/A delta

A fiber

Impulses

BTX/A

PNS CNS

IncreaseWDR

Spinal Cord or Nucleus Trigeminal CaudalisDRG or TGG

BTX/A inhibits release of mediators at the peripheral pain fibres, resulting in an indirect effect on the CNS

Blocking Headaches with Botox

Health & Medicine

The Action of Botox on Migraine