2. Using BOTOX ® as an adjunct in the treatment for MIGRAINE by Dr. Patrick Treacy Medical Director Ailesbury Clinics Ireland

4. 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

5. WHAT EXACTLY IS BOTOX ®?

6. History of Botox starts in the new century 1900 German chemical warfare brought new means of killing people

7. Ypres April 22 nd 1915 Non specific method. 5,000 British troops died on the first day and 5,000 Germans on the second

8. Next year Ireland strikes for freedom. Dublin 1916

9. 1916 British built a new chemical warfare complex 7000 acres of scrubland in Porton Down Wiltshire

10. Porton Down Research Centre Research experiments on Botulinum by scientist Dr. Paul Fides gave rise to DysPORT

11. Clostridium 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

12. Porton Down is still active today

13. First victim of experiments Aircraftman Ronald Madison died in May 1953

14. Reinhard Heydrich Assassinated by Czech agents in Prague on 27 th May 1942 by use of Botulinum toxin

15. 1953 US built chemical warfare plant at Fort Detrick American experiments by Edward Schantz gave rise to Botox

16. 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 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

17. Strabismus 16 The various muscles of the eye that might be affected by strabismus. Demonstration of the various inflictions of strabismus

18. How did Botox reach such popularity?

19. The use of BOTOX cosmetically Pictures courtesy of Ailesbury Clinics

20. Same patient 5 days later

21. 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;

22. 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.

23. 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.

24. 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.

25. 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

26. 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.

27. 20 th 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..

28. 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.

29. FDA approved uses of BTX-A 1. Cervical dystonia 2. Blepharospasm 3. Cranial nerve 11 disorders 4. Facial spasm 5. Glabellar frown lines

30. ‘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

31. ‘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

32. ‘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

33. How does Botox work? At a normal neuromuscular junction, a nerve impulse triggers the release of acetylcholine, which causes the muscles to contract.

34. 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.

35. 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.

36. Where does BOTOX® Block Ach?  Skeletal Muscle  Arms  Legs  Face  Neck Motor Nerve Alpha/Gamma This use in stroke and cerebral palsy

37. Where else does BOTOX® block Ach release?  Autonomic Nerves  Secretory glands  Sweat glands  Salivary glands  Smooth muscle  Bladder  Diaphragm Hyperhidrosis Sialorrhea Autonomic Nerves Smooth Muscle Bladder This use in sweating and incontinence

38. 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.

39. The Migraine Story

40. Triggers and Risk Factors Migraine headaches are often triggered by specific things Migraine headaches are often triggered by specific things

41. Triggers: Changes in Daily Cycles

42. Triggers: Environment or Diet

43. Triggers: Mental

44. 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

45. 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 AsthmaDiabetesOsteoarthritisMigraine Affected Patients

46. The Stages of a Migraine Attack

47. 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  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

48. 1 Migraine originates deep within the brain 2 Electrical impulses spread to other regions of the brain. 3 Changes in nerve cell activity and blood flow may result in visual disturbance, numbness or tingling, and dizziness. 4 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 How do Migraines happen?

49. Chemicals irritate Trigeminal Nerve

50. This triggers other nerves

51. Arterial Activation Release of Neurotransmitter Worsening of Pain How does Botox help?

52. Botox blocks these neurotransmitters cGRP Sub P Glut

53. Motor Nerve Alpha/Gamma Sensory Nerve Type C, A-delta, A- Beta SP, cGRP, Glu Autonomic Cholinergic Smooth Muscle SNARE BOTOX Ach The blocking effects of BOTOX * BTX/A→SNAP-25; BTX/B → VAMP SNARE complex Single site of action = SNARE protein via SNAP-25

54. Sub-P cGRP Bk K+ His Sub-P cGRP 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 BTX Direct 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

55. 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.

56. How Botox injection blocks pain BoNT  BOTOX®  Blocks Sensory Input to CNS  Reduces Input to Muscle Spindle

57. The Scientific Proof

58. Dose response of cGRP released from stimulated TG cells Stimulated 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 Durham 2003: Inhibition of cGRP chemical release from Trigeminal nerve cells

59. 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

60. 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

61. 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."

62. 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

63. 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.

64. 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.

65. 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.

66. Migraine Injection Points

67. 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.

68. What about the famous droopy eyelids? Patient with eyelid ptosis

69. ANATOMY OF FOREHEAD MUSCLES FRONTALIS Action: Elevates eyebrows and the skin of the forehead Action: Elevates eyebrows and the skin of the forehead

70. ANATOMY OF FOREHEAD MUSCLES CORRUGATOR SUPERCILII Action: Depresses eyebrows and wrinkles forehead

71. ANATOMY OF FOREHEAD MUSCLES ORBICULARIS OCULI Action:Depresses eyebrows Closes the eyelids Helps drainage of tears

72. 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

73. 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

74. IF YOU DO NOT KNOW WHAT YOU ARE DOING YOU PAY THE PRICE NOW! HOW DO I GET BACK UP?

77. THE MIGRAINE INJECTION POINTS INJECT ONLY CORRUGATOR, PROCERUS AND FRONTALIS MUSCLES DANGER: AVOID INJECTING 1CM ABOVE MID-PUPILLARY LINE

78. 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 ®

79. BOTULINUM-A TOXIN formulations 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 ®

80. BOTULINUM-A TOXIN formulations 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 ®

81. Peripheral Sensitization Leads to Central Sensitization Peripheral Stimulation Release of Glutamate and Peptides in CNS Release of Neuropeptides Peripheral Sensitization Increased afferent signals Lack of sensitivity of nerve endings Antidromic Activation CNS Central Sensitization Additional Activation Decreased Inhibition at the dorsal horn

82. 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 CNS Botulinum Toxin May Indirectly Prevent: Central Sensitization Clinical relevance of these preclinical results remain to be established

83. PNSCNS Peripheral Sensitization Glu, Sp, cGRP, NA, NGF BK, PGs, HA, 5-HT, H + Adenosine, NO Central Sensitization Glu Sp C-fiber/ A delta A  fiber Spinal Cord or Nucleus Trigeminal Caudalis DRG or TGG Impulses Increase WDR Peripheral Sensitization, leading to Central Sensitization C-fos Translating these Mechanisms to Humans

84. Peripheral Sensitization Glu, Sp, cGRP, NA, NGF BK, PGs, HA, 5-HT, H + Adenosine, NO Central Sensitization Glu Sp C-fiber/A delta A  fiber Impulses BTX/A PNSCNS Increase WDR Spinal Cord or Nucleus Trigeminal Caudalis DRG 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