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Botox: To Inject or Not Inject? For Chronic Migraine Prophylaxis

https://i2.wp.com/bioislifemedia.com/wp-content/uploads/2017/04/migraine.jpg?resize=397%2C328

Jennifer Shin, PharmD

PGY2 Ambulatory Care Resident CommUnityCare Clinic

October 20, 2017

Learning Objectives:

1. State the definition, background, and pathophysiology of chronic migraines (CM) 2. Identify the current guideline recommendations for standard treatment 3. Discuss outcomes from literature about botox and its place in therapy for CM prophylaxis

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I. Introduction

A. Epidemiology1,2,3

1. 1 in every 10 people suffers from migraine

2. Ranked by the World Health Organization (WHO) as 19th among causes for

years lived with disability

3. Migraine most often begins at puberty and most affects those aged between

35 and 45 years

4. More common in women, usually by a factor of about 2:1, because of

hormonal influences

II. Migraines2,3

A. Pathophysiology

1. Migraine appears to begin when a nerve cluster deep in the brain called the

trigeminal nucleus caudalis (TNC) system becomes overactive. This activates

the trigeminal nerve that carries sensory information in the face

2. Activation of the trigeminal nerve causes blood vessels to dilate

3. This appear to prompt the release of irritants that stimulate nerves near the

vessels and cause pain

Figure 2. Pathophysiology of migraines

B. Background2,4,5

Figure 1. Migraine Clinical Presentation

https://www.epainassist.com/headache/diagnosis-of-headach

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1. Common and debilitating condition

2. Divided into two groups based on headache days per month

3. Caused by the activation of a mechanism deep in the brain that leads to

release of pain-producing inflammatory substances around the nerves and

blood vessels of the head

4. Can present with or without aura

5. Migraine aura symptoms include: Visual, sensory, speech/and/or language,

motor, brainstem, and retinal

6. Migraine is recurrent, often life-long

7. Headache attacks typically include:

a. Moderate or severe intensity

b. one-sided

c. pulsating in quality

d. aggravated by routine physical activity

e. with duration of hours to 2-3 days

f. nausea (the most characteristic associated feature);

g. attack frequency between once a year and once a week

8. Clinical presentation6

a. Throbbing headache

b. Nausea and vomiting

c. Diarrhea

d. Lightheadedness

e. Dizziness

f. Tinnitus

C. Chronic Migraines4,5:

1. Definition

a. A headache occurring on > 15 days per month

b. For more than 3 months

c. With typical features of migraine at least 8 days per month

D. Risk factors7

Table 1. Risk Factors Associated with Migraines

Modifiable Non-modifiable

Obesity

Depression

Medication overuse

Sleep related problems

Caffeine overuse

Age

Female sex

Caucasian race

Low educational level/socioeconomic status

Head injury

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E. Diagnosis: International Classification of Headache Disorders (ICHD)10

1. At least five attacks fulfilling criteria (2)–(4)

2. Headache attacks lasting 4–72 h (untreated or unsuccessfully treated)

a. Headache has at least two of the following four characteristics:

b. unilateral location

c. pulsating quality

d. moderate or severe pain intensity

e. aggravation by or causing avoidance of routine physical activity (e.g.

walking or climbing stairs)

3. During headache at least one of the following:

a. nausea and/or vomiting

b. photophobia and phonophobia

4. Not better accounted for by another ICHD-3 diagnosis

F. Goals of therapy2

1. Reduce attack frequency, severity, and disability

2. Reduce reliance on poorly tolerated, ineffective, or unwanted acute

pharmacotherapies

3. Improve quality of life

4. Avoid acute headache medication escalation

5. Educate and enable patients to manage their disease to enhance personal

control of their migraine

6. Reduce headache-related distress and psychological symptoms

G. Guidelines

1. The 2015 NICE Diagnosis and management of headaches8

2. The 2012 AHS/AAN guidelines for prevention of migraine9

H. Management12,13,14

1. Prophylaxis initiation

a. Prevention should be initiated

1. At least six headache days per month

2. At least four headache days with at least some impairment

3. At least three headache days with severe impairment or

requiring bed rest

b. Prevention should be considered with:

1. Four to five migraine days per month with normal functioning

2. Two to three migraine days per month with some impairment

3. Two migraine days with severe impairment

c. Prevention is not indicated with

1. Less than four headache days per month and no impairment

2. Zero or one headache day per month regardless of impairment

2. Optimizing therapy

a. Start at a low dose

b. Give each preventive medication an adequate trial, >2 months

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c. Avoid interfering, contraindicated, or overused medications

d. Reevaluate therapy; follow-up is important

e. Discuss contraception with women in childbearing age and the potential

risk of medication with pregnancy

f. Involve patients in their care to improve adherence

g. Consider comorbid problems, and choose one medication to treat

multiple comorbid disorders where possible

h. Choose a drug based on efficacy, patient’s preferences, headache

profile, the drug’s side effects, and the presence or absence of

coexisting or comorbid conditions

I. Guideline recommendations: Prophylaxis management9

1. Initiate therapy with medications that have the highest level of evidence-

based efficacy

2. Initiate therapy with the lowest effective dose of the drug

3. Give each drug an adequate trial

4. Avoid interfering medications (e.g., overuse of acute medications)

5. Use of a long-acting formulation may improve compliance

J. Pharmacologic therapies9

1. See appendix A for descriptions of management approach levels

2. See Appendix B for Medication recommended dosing

3. See Appendix C for Drug classes mechanism, contraindications, and adverse

drug reactions

4. Appendix D for complete list of migraine preventative therapies in the U.S.

III. Botox® (OnabotulinumtoxinA)16,17

A. Approved October 2010 for prophylaxis in adult patients with CM

B. Has been included in the AHS/AAN guidelines for chronic migraine prophylaxis as a

statement after the most recent guidelines

C. Dosing: 155 units once every 12 weeks

1. Equally divided and administered bilaterally, into 31 total sites

Figure 3. Injection sites for botox in chronic migraines

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D. Suspected mechanism

Figure 4. Botox mechanism in chronic migraines

1. Affects the nervous system within the neuromuscular junctions by means of a

specific cleavage of the soluble N-ethylmaleimide-sensitive factor (NSF)-

attachment protein receptor complex (SNARE)-like synaptosomal-associated

protein of 25 kDa (SNAP-25)

2. Result is the disruption of pain neurotransmission, including the inhibition of

the release of CGRP, SP and glutamate

E. Safety18

1. PREEMPT I (n=679)

a. Primary endpoint: reduction of migraine episodes (non-significant)

b. Significant differences in reduction of headache and migraine days

2. PREEMPT II (n=705)

a. Primary endpoint: confirmed efficacy of botox in reduction of headache

days

3. Identical study design, slightly different end points

a. Commonly reported adverse events: neck pain, injection site pain, and

eyelid ptosis

b. Led to the approval of botox in prophylaxis of chronic migraine

F. Guideline recommendations8,9

1. Guidelines of the American Academy of Neurology state that botox is effective

and should be offered to patients with CM

2. NICE guidelines recommend botox as a prophylaxis medication treatment for

CM in patients who did not respond to at least 3 prior prophylaxis therapies

G. Clinical question: Botox for chronic migraine:

Safe and effective? When should we use it?

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IV. Literature review:

Aurora SK, Dodick DW, Diener HC, et al. OnabotulinumtoxinA for chronic migraine: efficacy, safety, and tolerability in patients who received all five treatment cycles in the PREEMPT clinical program. Acta Neurol Scand. 2014;129(1):61-70. Purpose Assess efficacy, safety and tolerability of botox as headache prophylaxis in adults with chronic migraine

from PREEMPT1 and PREEMPT2 trials who completed all five treatments

Study Design 24 week, double-blind, parallel-group, placebo controlled phase followed by a 32-week open-label phase

Inclusion criteria Patients that completed all five cycles 18-65 years with a history of migraine defined by International classification of headache disorders Had to have headache occurring on ≥15 days/4 weeks, with each day consisting of ≥4 h of

continuous headache, and ≥50% of headache days being migraine or probable migraine days Experience ≥4 distinct headache episodes, each lasting ≥4 h during this period

Exclusion criteria Headache prophylactic medication within 4 weeks prior to start date of baseline Naïve to OnabotulinumtoxinA prior to trial

Outcomes Primary Frequency of headache days at 24 weeks

Secondary Frequency of migraine days Moderate/severe headache days Headache episodes Migraine episodes Acute headache medication intake

Methods Patients were randomized (1:1) to onabotulinumtoxinA (155 U) or placebo Study medications were administered as 31 fixed-site, fixed-dose, intramuscular injections

across seven specific head/neck muscle areas every 12 weeks for 24 weeks Study medications were administered as 31 fixed-site, fixed-dose, intramuscular injections

across seven specific head/neck muscle areas every 12 weeks for 24 weeks

Statistics Primary analysis – covariate analysis of variance (ANCOVA)

Responder incidences and other binomial responses were compared using Pearson’s chi-squared tests

o Logistic regression with baseline covariate was used for variables that had an imbalance at baseline

Results Mean change from baseline in headache days

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All patients who completed the double-blind phase were eligible to receive onabotulinumtoxinA treatment at Weeks 24, 36, and 48

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Percent of patients who completed all give treatment cycles and were classified as 50% responders

at week 56

Author’s conclusions

Patients treated earlier with botox had better outcomes at week 56 There is a continued need and cumulative benefit over time with continued prophylaxis Botox is a safe and effective option for use in CM

Critical appraisal Strengths: Well designed and largest trial thus far investigating use of botox in CM Resulted in FDA approval for botox use in CM Revealed earlier treatment with botox had better outcomes Looked at patients that completed all 5 cycles

Weaknesses: Placebo response noted in both studies Lacking report on differences between those with or without medication use headaches

Matharu M, Pascual J, Nilsson remahl I, et al. Utilization and safety of onabotulinumtoxinA for the prophylactic treatment of chronic migraine from an observational study in Europe. Cephalalgia. 2017;:333102417724150.

Purpose Examine utilization patterns and safety of botox for prophylactic treatment of chronic migraine in routine clinical practice

Study Design Prospective, observational post-authorization study

Inclusion criteria Botox treated and Botox naïve patients recruited by their physicians 18 years or older with a new or established physician diagnosis of CM Decision to initiate or continue treatment was independent of patient’s enrollment in the study. Completed at least one botox treatment session

Methods Patients were followed up for up to 64 weeks after the baseline treatment, with the last follow-up visit scheduled for approximately 12 weeks after the final study treatment session at 48 to 52 weeks.

Data were collected at the first study injection and approximately every three months for: o <52 weeks for utilization o <64 weeks for safety data, and summarized using descriptive statistics.

Statistics Descriptive statistics

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Results

Number of patients in each treatment session

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Author’s conclusions

Adverse event findings are similar to the PREEMPT studies Adverse event incidence rate decreased with each treatment session Data adds onto support the favorable safety profile of botox for CM prophylaxis

Critical appraisal Strengths: Observe and assess patient with CM in a real world setting Large observational study in multiple settings

Weaknesses: Observational study: increases generalizability

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Cady RK, Schreiber CP, Porter JA, Blumenfeld AM, Farmer KU. A multi-center double-blind pilot comparison of onabotulinumtoxinA and topiramate for the prophylactic treatment of chronic migraine. Headache. 2011;51(1):21-32.

Purpose Compare efficacy of onabotulinumtoxinA with topiramate in individuals with chronic migraine

Study Design 3-center,double-blind randomized pilot study

Inclusion criteria Outpatients, male or female, of any race, between18 and 65 years of age Female subjects of child-bearing potential with a negative urine pregnancy test who practiced

reliable contraception throughout the study period

Subjects met criteria for CM as defined by Second Edition of the International Classification for Headache Disorders

Exclusion criteria Female subjects who were pregnant,breast feeding, or planning to become pregnant during the time frame of the study

Individuals with headache disorders other than CM Subjects with medical disorders that increase the risk with exposure to onabotulinumtoxinA Subjects who had previously used botulinum toxin of any type or topiramate regardless of indication Subjects with recent evidence of alcohol/drug abuse or overuse of acute medication

Outcomes Primary Physician global assessment: treatment responder rate Indicated improvement in both groups over 12 weeks Secondary Measured at weeks 4 and 12

Headache days per month, migraine days, headache free-days, days on acute medication, and severity of headache episodes

Methods CM defined as 3-8 attacks of migraine per month with on average 21 days of headache per month. Subjects were randomized to receive injections of onabotulinumtoxinA plus daily placebo tablets or

topiramate and placebo injections. The investigators and study coordinators were blinded to study conditions

Up to 200 units of onabotulinumtoxinA or placebo were injected with 100 units into fixed locations and up to an additional 100 units in a “follow the pain” scheme determined at the investigators discretion

Topiramate dosing was initiated at 25 mg daily and escalated to 100mg in weekly incremental changes of 25mg.

The Physician Global Assessment was calculated for each subject at weeks 4 and 12

Statistics Demographic data – two-sided chi-square test or Fisher exact test Physician Global Assessment and MIQ – Wilcoxan signed rank test Baseline changes in headache diaries or MIQ scores – ANCOVA/rank

Results

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Author’s conclusions

Topiramate and botox demonstrated efficacy in treating subjects with CM Improvements were noted from both medications Support the use of botox for patients with frequent migraine

Critical appraisal Strengths: Completed a direct comparison between the two drugs Subjects were asked to pursue an open label

Weaknesses: Small sample size Questionable blinding due to injection reactions Lack a placebo arm

4.4 3

8.1 8

0

2

4

6

8

10

Group 1Topiramate

Group 2Botox

Group 1Topiramate

Group 2Botox

Headache free days/month

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V. Conclusion

A. Summary

1. Diagnosis and treatment for chronic migraines is complex and clinicians should

be mindful refractory to treatment is common

2. Botox has proven efficacy in primary endpoints for reducing migraine days

3. Guidelines of the American Academy of Neurology and NICE both recommend

botox in CM

4. Would recommend for patients that have failed two previous agents level A

and/or B medications

a. Botox will likely become a level A or B medication in the next updated

guidelines for use in CM

b. Trials comparing botox to treatment arms other than placebo are

lacking

c. Botox while safe and efficacious has not proven superiority over other

agents

B. Future topics for research

1. Studies comparing efficacy outcomes of botox to other approved agents for

chronic migraine are needed

2. Studies to determine if botox reaches a plateau effect.

3. Studies in patients with comorbidities in addition to CM

4. Studies to determine impact of botox on indirect and direct costs of CM

compared to the agents well studied in CM

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References

1. Katsarava, Z., Buse, D. C., Manack, A. N., & Lipton, R. B. (2012). Defining the Differences Between

Episodic Migraine and Chronic Migraine. Current Pain and Headache Reports, 16(1), 86–92.

http://doi.org/10.1007/s11916-011-0233-z

2. Practice parameter: Evidence-based guidelines for migraine headache (an evidence-based review)

Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology.

2000;55(6):754.

3. Migraine Research Foundation. Available at https://migraineresearchfoundation.org/

4. Adams AM, Serrano D, Buse DC, et al. The impact of chronic migraine: The Chronic Migraine

Epidemiology and Outcomes (CaMEO) Study methods and baseline results. Cephalalgia.

2015;35(7):563-78.

5. Goadsby PJ. Pathophysiology of migraine. Ann Indian Acad Neurol. 2012;15(Suppl 1):S15-22.

6. Adapted from Paulino J, Griffith, CJ. Headache Sourcebook : The Complete Guide to Managing

Tension, Migraine, Cluster, and Other Recurrent Headaches in Adults, Adolescents, and Children.

New York, NY: Contemporary Books; 2001

7. Katsarava, Z., Buse, D. C., Manack, A. N., & Lipton, R. B. (2012). Defining the Differences Between

Episodic Migraine and Chronic Migraine. Current Pain and Headache Reports, 16(1), 86–92.

http://doi.org/10.1007/s11916-011-0233-z

8. National Institute for Health and Care Excellence. Headaches in over 12s: diagnosis and

management. Available at https://www.nice.org.uk/guidance/cg150/chapter/Key-priorities-for-

implementation

9. Silberstein SD, Holland S, Freitag F, et al. Evidence-based guideline update: pharmacologic treatment

for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the

American Academy of Neurology and the American Headache Society. Neurology. 2012;78(17):1337-

45.

10. Weatherall MW. The diagnosis and treatment of chronic migraine. Ther Adv Chronic Dis.

2015;6(3):115-23.

11. Lexicomp Online® , Lexi-Drugs Online® , Hudson, Ohio: Lexi-Comp, Inc.; July 25, 2017.

12. Silberstein SD, Goadsby PJ. Migraine: preventive treatment. Cephalalgia. 2002;22(7):491–512.

13. Silberstein SD, Lipton RB, Goadsby PJ. Headache in Clinical Practice, 2nd ed. London: Informa

Healthcare; 2002. Chapter 16, page 92.

14. Estemalik E, Tepper S. Preventive treatment in migraine and the new US guidelines. Neuropsychiatr

Dis Treat. 2013;9:709-20.

15. Pringsheim T, Davenport W, Mackie G, Worthington I, Aubé M, Christie SN, Gladstone J, Becker WJ;

Canadian Headache Society Prophylactic Guidelines Development Group. Can J Neurol Sci. 2012

Mar;39(2 Suppl 2):S1-59.

16. Lexicomp Online® , Pediatric & Neonatal Lexi-Drugs® , Hudson, Ohio: Lexi-Comp, Inc.; August 21

2017.

17. Szok D, Csáti A, Vécsei L, Tajti J. Treatment of Chronic Migraine with OnabotulinumtoxinA: Mode of

Action, Efficacy and Safety. Toxins (Basel). 2015;7(7):2659-73.

18. Escher CM, Paracka L, Dressler D, Kollewe K. Botulinum toxin in the management of chronic

migraine: clinical evidence and experience. Ther Adv Neurol Disord. 2017;10(2):127-135.

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Appendix A: Descriptions of management approach levels

Level A: Medications with established efficacy

Level B: Medications are probably effective

Level C: Medications are possibly effective

Level U: Inadequate or conflicting data to support or refute medication use

Other: Medications that are established as possibly or probably ineffective

Appendix B: Level A and B medications with recommended dosing

Level A Medications

Starting dose Target dose

Antiepileptic drugs

Divalproex sodium 250mg twice daily 500-1000mg daily

Topiramate 12.5 mg daily 50–100 mg twice daily

β blockers

Propranolol 10 mg three times daily 40–80 mg three times daily

Metoprolol 25 mg twice daily 100 mg twice daily

Triptans

Frovatriptan 2.5mg as needed 7.5mg (max)

Herbal preparations

Petasites 75 mg twice daily

Level B Medications

β blockers

Atenolol 25 mg once daily 100 mg once daily

Tricyclics

Amitriptyline 10 mg daily 75–100 mg daily

Triptans

Naratriptan 1-2.5mg as needed 5mg daily (max)

Zolmitriptan 1.25-2.5mg as needed 5mg (max dose)

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Appendix C: Level A and B medications mechanism, contraindications, and adverse drug reactions

Anti-epileptics11

MOA Contraindications/ Warnings Adverse drug reactions

Divalproex sodium

Increased GABA availability Severe hepatic impairment; Hepatic failure, pancreatitis, CNS depression

Headache, drowsiness, dizziness, insomnia, nervousness

Topiramate Increases GABA(A) activity, antagonizes AMPA/kainate glutamate receptors

CNS, hyperammonemia, metabolic acidosis, oligohydrosis, ophthalmic effects, renal calculus, visual field defects

Paresthesia, drowsiness, dizziness, insomnia, memory impairment, nervousness, nausea,

Beta blockers

11 MOA Contraindications/ Warnings Adverse drug reactions

Propranolol Nonselective beta-adrenergic blocker

Uncompensated CHF, cardiogenic shock, severe braydcardia, heart block

> 1st

degree

Bradycardia, fatigue, dizziness

Metoprolol Selective B1-adrenergic blocker

AV block, bradycardia, CNS depression, hypotension

Hypotension, dizziness, fatigue

Atenolol Selective B1-adrenergic blocker, Beta2 blockade at

high doses

Uncompensated CHF, cardiogenic shock, severe braydcardia, heart block

> 1st

degree

Bradycardia, fatigue, dizziness

Tricyclics

11 MOA Contraindications/ Warnings Adverse drug reactions

Amitriptyline Inhibit reuptake of

serotonin and

norepinephrine in CNS

Suicide ideation, anticholinergic

effects, CNS depression, hematologic

effects

Blurred vision, constipation,

drowsiness, memory

impairment, orthostatic

hypotension

Triptans

11 MOA Contraindications/ Warnings Adverse drug reactions

Zolmitriptan Selective serotonin agonist

(1B and 1D) of trigeminal

system

Uncontrolled HTN, cerebrovascular

syn, MAOi, severe hepatic

impairment

Unpleasant taste (nasal) ,

dizziness, drowsiness, chest

pressure,

Frovatriptan Selective serotonin agonist

(1B and 1D) of trigeminal

system

Uncontrolled HTN, cerebrovascular

syn, MAOi, severe hepatic

impairment

Dizziness, flushing, fatgiue, chest

pain

Naratriptan Selective serotonin agonist

(1B and 1D) of in cranial

arteries

Uncontrolled HTN, cerebrovascular

syn, MAOi, severe hepatic

impairment

Nausea, dizziness, pain,

drowsiness

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Appendix D Classification of migraine preventive therapies in the U.S. Level A Level B Level C Level U Other

Antiepileptic drugs Antidepressants/ SSRI/SNRI/TCA

ACE inhibitors Lisinopril Carbonic anhydrase inhibitor

Established as note effective

Divalproex sodium Amitriptyline Angiotensin receptor blockers

Acetazolamide Antiepileptic drugs

Sodium valproate Venlafaxine Candesartan Antithrombotics Lamotrigine

Topiramate Beta blockers Anlpha-agonists Acenocoumarol Probably not effective

Beta blockers Atenolol Clonidine Coumadin Clomipramine

Metoprolol Propranolol

Timolol Nadalol Guanfacine Pictomaide Possibly not effective

Triptans (MRM) Triptans (MRM) Antiepileptic drugs Antidepressants SSRI/SNRI

Acebutolol

Frovatriptan Naratriptan Fluvoxamine Clonazepam

Zolmitriptan Carbamazepine Beta Blockers Nebivolol Pindolol Antihistamines Cyproheptadine

Fluoxetine Antiepileptic drugs Gabapentin TCAss Protriptyline Beta blockers Bisoprolol Calcium blockers Nicardipine Nifedipine Nimodipine Verapamil Direct muscle relaxants Cyclandelate

Nabumetone Oxcarbazepine Telmisartan

MRM=Menstrually related migraine

Appendix E Classification of migraine preventative therapies in the U.S of herbal preparations, minerals, vitamins, and others

Level A Level B Level C Level U Other

Herbal preparations, vitamins, minerals, and other

NSAIDs NSAIDs NSAIDs Probably not effective

Petasites Fenoprofen Flubiprofen Aspirin Leukotriene receptor antagonist

Ibuprofen Mefenamic acid Indomethacin Montelukast

Ketoprofen Herbal preparations vitamins, minerals, and other

Herbal preparations vitamins, minerals, and other

Naproxen Naproxen Sodium

CoQ10 Estrogen

Omega-3 Other

Herbal preparations vitamins, minerals, and other

Antihistamine Hyperbaric oxygen

Magnesium Cyproheptadine

MIG-99 (feverfew) Riboflavin Histamines Histamine SC