Shin 1 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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Shin 1
Botox: To Inject or Not Inject? For Chronic Migraine Prophylaxis
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
Shin 2
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
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
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.