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8/11/2019 Role AEDs in Migraine prevention
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A Role of AEDs drugin migraine
Surat Tanprawate, MD, MSc(Lond.), FRCPTHeadache clinic, Chiangmai University
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PART 1. Principle ofmigraine prevention
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A young female student with episodic headache for1 years
Headache characters: throbbing, alternate side,temper, eye, occiput, lasting for 4-6 hours
Frequency: 3 attacks / week
Associated symptom: nausea, photophobia
Severity: 7/10
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Migraine is considered as a chronic
disorder with episodic attacks (CDEA)
Nomigraine
LFEM
0-9 days of
headache/month
HFEM
10-14 days of
headache/month
ChronicMigraine
Chronic migraine associated with
Conceptualized of clinical course of migraine
Poor quality of life
Highly associated with psychiatric disorderRisk of medication overused
Risk of stroke? (MwA)
Bigal and LiptonNeurology 2008;71;848-855
2.5%/yr EM to CM
6%/yr HFEM to CM
26% 2-yrs transition rate CM to EM
Rate of transition
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Migraine treatment
Give the information of migraine
Life style modification
Acute medication
Preventive medication
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Risk factor for migraine
progression
Bigal ME et al. Current Opinion in Neurology2009, 22:269276
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Issue on preventive
medication?
Start
When should we start?
What should we start?
Evaluation
When should we
evaluate?
What should we
evaluate?
Stop
When should we
stop?
How to stop?
Drug titration Duration
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When to use preventive
medication? Migraine significantly interfere with patients daily routine,
despite acute Rx
Acute medication contraindicated, ineffective, intolerableAEs, or overused
Frequency of acute medication use > 2 / week
How often of migraine attack should
we start preventive medication?
Dodick DW, Siberstein SD Pract Neurol 2007;7:383-393
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Estimated 1-year incidence rate of: (a) chronic daily headache (180+ HA day/
year); or (b) increased HA (105-179) in an episodic headache population
Headache frequency associated with onset of CDH:a study on episodic headache (2-104 day/year)
Scher A.I. et al. Pain106 (2003) 8189
4.33 / month
n=798
Frequency of migraine attacks > 1 / wk
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Migraine condition that
needs preventive med
Hemiplegic migraine
Basilar migraine
Migraine with prolonged, disabling or
frequent aura
Migrainous cerebral infarction
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The major group of
preventive medication Anticonvulsants
Antidepressants
B-adrenergic blockers
Calcium channel antagonists
NSAIDs
Serotonin antagonists
Other (including riboflavin, minerals, herbs, botulinum toxin)
Drug choice?1. Migraine condition
(EM, CM, RM, MOH)2. Efficacy3. Adverse events
4. Comorbidity5. Cost
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Titration regimen Start low, go slow: recommend every week titration
reach target dose within 1 month
Target dose
dose recommend in clinical trials
stop when reach efficacy / or side effects
Dodick DW, Siberstein SD Pract Neurol 2007;7:383-393
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Maintenance regime There have no evidence on the optimal length of prophylactic
treatment
Duration
6 weeks should appear clinical efficacy
3 months is usually considered sufficient to assess
prophylactic efficacy
6 months may be need to reach maximum effect
Treatment length may be continue to 3-6 months if there there
was some improvement during the first 3 months
Dodick DW, Siberstein SD Pract Neurol 2007;7:383-393
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Assessing improvements
with migraine prevention Common endpoints used in preventive studies
Reduction in attack frequency
Reduction in attack intensity/severity
Decrease in migraine induced disability
% of patients with > 50% reduction in attack
frequency
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Headachefollow up form
Headache day
Acute med used
HIT-6 scale
Treatment response
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Headache ImpactTest (HIT-6)
!"#(< 49)$%&'(%)(50-55)
*%'(56-59)*%'+,-(>60)
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Issue on preventive
medication?
Start
When should we start?
What should we start?
Evaluation
When should we
evaluate?
What should weevaluate?
Stop
When should we
stop?
How to stop?
Drug titration Duration
severity
frequency
acute med use
type of migraine
efficacy
comorbidity
1 month 3-6 months
6 wks-3 mo-6 mo
frequency
impact
3-6 months
slow tapering off with
maintain lowest dose if
headache occurs
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PART2. Role of AEDsin migraine
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Evidence of neuronal
excitability in migraine Co-morbid condition of migraine and epilepsy
Cortical spreading depression (CSD) in migrainewith aura
Mutation in Familial Hemiplegic Migraine (FHM)
Response of migraine with AEDs
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Discovery ofanti-epileptic drugs
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Old generation
1800s Bromide Solution
1912 Phenobarbital 1938 Phenytoin
1960 Ethosuximide
1973 Carbamazepine
1978 Valproate
New generation
1993 Felbamate
1993 Gabapentin
1994 Lamotrigine
1996 Fosphenytoin
1996 Topiramate 1997 Tiagabine
1999 Vigabatrin
2000 Oxcarbazepine
2000 Levetiracetam
2005 Pregabalin
Discovery ofanti-epileptic drugs
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Old generation
1800s Bromide Solution
1912 Phenobarbital 1938 Phenytoin
1960 Ethosuximide
1973 Carbamazepine
1978 Valproate
New generation
1993 Felbamate
1993 Gabapentin
1994 Lamotrigine
1996 Fosphenytoin
1996 Topiramate 1997 Tiagabine
1999 Vigabatrin
2000 Oxcarbazepine
2000 Levetiracetam
2005 Pregabalin
Discovery ofanti-epileptic drugs
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Old generation
1800s Bromide Solution
1912 Phenobarbital 1938 Phenytoin
1960 Ethosuximide
1973 Carbamazepine
1978 Valproate
New generation
1993 Felbamate
1993 Gabapentin
1994 Lamotrigine
1996 Fosphenytoin
1996 Topiramate 1997 Tiagabine
1999 Vigabatrin
2000 Oxcarbazepine
2000 Levetiracetam
2005 Pregabalin
Discovery ofanti-epileptic drugs
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Calabresi P et al. Trends in Pharm Sci2007; 28(4):188-195
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Calabresi P et al. Trends in Pharm Sci2007; 28(4):188-195
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AEDs in migraine treatment
Type of treatment
prophylaxis
acute treatment
Type of Migraine
episodic vs chronic migraine
with/without aura
refractory migraine
CM with MOH
Migraine variant
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Episodic vs Chronic vs Refractory
Episodic migraine
0-14 headache days per month
Chronic
15 or more headache days per month for 3 or more months
8 or more days meet criteria for migraine with our aura/or response to migrainespecific drug
Refractory (preventive medication)
Failed adequate trials of preventive med at least 2/4 drug classes (Beta-
blocker, Anti-convulsants, Tricyclic anti depressant, Calcium channel
blocker)
Medication overuse headache (MOH)
Overused acute medication > 10 / or 15 days per months more than 3 months
why 15 days cut-off point?
Schulman EA et al.Headache2008;48:778-782)
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AEDs used in
Episodic migraine
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S.D. Silberstein, et al.Neurology 2012;78;1337
AAN/AHS 2012
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Sodium valproate/Divalproex sodium
1975: Welch et al. reported change in CSF GABA levelsduring migraine episodes in humans
Valproate enhances GABAergic transmission (highlypleiotropic), blocks Na channels and
Early studies
1988; Sorensen et al. reported 11/22 pt. with migrainebecome headache free during 1200 mg valproate
1992; Hering & Kurtzky: the first D-B, P-C, valproate 800mg/d for migraine prophylaxis
Approved by FDA for the management of migraine
Cli i l di f AED f i i h l i
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Clinical studies of AEDs for migraine prophylaxis
Sodium valproate/valproic acid
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Divalproex sodium in migraine
prophylaxis
0
12.5
25
37.5
50
PlaceboDivalproex Na
Patients(%)
P
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Caution in VA used Child bearing age
Adverse events that can cause discontinuation from
long term safety study = 21%
alopecia (6%)
tremor (2%)
weight gain (2%)
vomiting (5%)
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Divalproate vs Amitriptyline: RCT trial
300 migraine DVA-ER vs AMT
Kalita J et al.Acta Neurol Scand2013: 128: 6572
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Divalproate vs Amitriptyline: RCT trial
Kalita J et al.Acta Neurol Scand2013: 128: 6572
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Topiramate
Acts on AMPA receptors, blocking the glutamate
binding site, but also blocks kainate receptors
and Na+ channels, and enhances GABAcurrents (highly pleiotropic*)
Studies of TPM in migraine
2001: double-blind placebo control trial
Storey JR et al. Headache2001 41, 968-975
Cli i l t di f AED f i i h l i
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Clinical studies of AEDs for migraine prophylaxis
Topiramate
T i t i i i ti
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Topiramate in migraine prevention(Large Controlled Trial)
26-weeks, double-blind, placebo controlled
487 EM patient, TPM 50, 100, 200 mg vs placebo
Silberstein SD.Arch Neurol.2004;61:490-495
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Topiramate in migraine prevention
(Large Controlled Trial)
Silberstein SD.Arch Neurol.2004;61:490-495
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331 subjects (172 TPM vs 159 AMT) dose titration25 to 100 mg/d
Primary outcome: change from baseline in themean monthly no. of migraine episode: NS
Secondary outcome: functional ability, QoL: NS
Outcome: NS
DW Docick et al. Clinical therapeutic2009;31(3):542-559
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Percent weight change from baseline between
TPM vs AMT
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Efficacy of Gabapentin in migraineprevention (EM): D-B, P-C study
0
12.5
25
37.5
50
Gabapentin (n=56) Placebo (n=31)
46%
16%
P 50% reduction
in attack frequency (4 weeks)
Mathew et al. Headache 2001
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Conclusion EM prevention
1. Evidence based: AAN/AHS guideline
2. All Level A recommendation has similar efficacy,but different side effect
3. Most DBPC studies evaluated efficacy 3-6 months
4. Long term used still save in some studies
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Preventive medication
in chronic migraine
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Brain change in chronicmigraine
Structural brain change
Periaqueductal greymatter change (PAG): irondeposition
Functional brain change
Central sensitisationCentral sensitization ofTrigeminal nucleus
caudalis(TNC)
Summary of evidence for prophylactic medications in
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Summary of evidence for prophylactic medications in
undifferentiated chronic daily headache and chronic migraine
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Randomized, placebo-controlled, parallel-group
16 weeks
Topiramate 100 mg/d vs placebo
306 pts included (153 topiramate vs 153 placebo)
SD SilbersteinHeadache 2007;47:170-180
Change from baseline in monthly (28 day) rate of
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17+/- 5.4 17+/- 5.0
Primary outcome
Topiramate Placebo
Migraine/Migraine days
Baseline+/- SD
-6.4+/- 5.8
-4.7+/- 6.1
P=0.01
-1
-2
-3
-4
-5
-6
-7
Change from baseline in monthly (28 day) rate ofmigraine/migraine days
SD SilbersteinHeadache 2007;47:170-180
Th ff t f di l t
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The effect of sodium valproate onCDH, and its subgroups
Yurekli VA.J Headache Pain2008; 9:3741
Double-blind, Placebo-controlled 70 CDH; 29 CM, and 41 CTTHSodium valproate 500 mg(1st wk) to 1000 mg ; 3 months f/u
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Medication overuse
headache
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(6) Topiramate 100 mg (up to 200 mg) per day is probably
effective in the treatment of MOH
(7) Corticosteroid (at least 60 mg prednisolone) and amitryptyline
(up to 50 mg) are possibly effective in treatment to withdrawal
symptoms
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Conclusion: CM +/- MOH
Few strong evidence of preventive medicationused in CM/MOH
TPM -> CM/MOH, BTx->CM
In clinical practice, may use medication based onEM evidence, comorbitity, cost, preference
Although widely use of combination therapy, thestrong evidence is still lacking
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Migraine variants
Fact
Most of studied migraine prevention was done in
MwoA/MwA
Few studies done in migraine variant: only caseseries/report
Recommended drug sometime can not be appliedin migraine variants prevent
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Evidence of preventive drugs for FHM/SHM
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Topiramate in HM
TPM in HM has not been described
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AEDs for acute migrainetherapy
600 - 1200 mg can be used if oral
acute medication failed
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Conclusion
Start Evaluation Stop
Migraine is a complex neurological disorder
Multimodality treatment is needed to prevent migraine
chronic transformationAEDs is one of the effective migraine prevention
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Thank you
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