A Role of AEDs drug

in migraine
Surat Tanprawate, MD, MSc(Lond.), FRCPT
Headache clinic, Chiangmai University

Principle of migraine prevention

Role of anti-epileptic drug for

migraine
Topic
PART 1. Principle of
migraine prevention

A young female student with episodic headache for

1 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
Migraine is considered as a chronic
disorder with episodic attacks (CDEA)
No
migraine
LFEM
0-9 days of
headache/month
HFEM
10-14 days of
headache/month
Chronic
Migraine
Chronic migraine associated with
Conceptualized of clinical course of migraine
Poor quality of life
Highly associated with psychiatric disorder
Risk of medication overused
Risk of stroke? (MwA)
Bigal and Lipton Neurology 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
Migraine treatment

Give the information of migraine

Life style modication

Acute medication

Preventive medication
Risk factor for migraine
progression
Bigal ME et al. Current Opinion in Neurology 2009, 22:269276
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
When to use preventive
medication?

Migraine signicantly interfere with patients daily routine,

despite acute Rx

Acute medication contraindicated, ineffective, intolerable

AEs, 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
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. Pain 106 (2003) 8189
4.33 / month
n=798
Frequency of migraine attacks > 1 / wk
Migraine condition that
needs preventive med

Hemiplegic migraine

Basilar migraine

Migraine with prolonged, disabling or

frequent aura

Migrainous cerebral infarction

The major group of
preventive medication

Anticonvulsants

Antidepressants

B-adrenergic blockers

Calcium channel antagonists

NSAIDs

Serotonin antagonists

Other (including riboavin, minerals, herbs, botulinum toxin)

Drug choice?
1. Migraine condition
(EM, CM, RM, MOH)
2. Efcacy
3. Adverse events
4. Comorbidity
5. Cost
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 efcacy / or side effects

Dodick DW, Siberstein SD Pract Neurol 2007;7:383-393
Maintenance regime

There have no evidence on the optimal length of prophylactic

treatment

Duration

6 weeks should appear clinical efcacy

3 months is usually considered sufcient to assess

prophylactic efcacy

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 rst 3 months
Dodick DW, Siberstein SD Pract Neurol 2007;7:383-393
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
Headache
follow up form
Headache day
Acute med used
HIT-6 scale
Treatment response
Headache Impact
Test (HIT-6)
!"# (< 49)
$%&'(%) (50-55)
*%' (56-59)
*%'+,- (>60)
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
severity
frequency
acute med use
type of migraine
efcacy
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
PART2. Role of AEDs
in migraine
Evidence of neuronal
excitability in migraine

Co-morbid condition of migraine and epilepsy

Cortical spreading depression (CSD) in migraine

with aura

Mutation in Familial Hemiplegic Migraine (FHM)

Response of migraine with AEDs

Discovery of
anti-epileptic drugs
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 of
anti-epileptic drugs
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 of
anti-epileptic drugs
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 of
anti-epileptic drugs
Calabresi P et al. Trends in Pharm Sci 2007; 28(4):188-195
Calabresi P et al. Trends in Pharm Sci 2007; 28(4):188-195
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
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 migraine
specic 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. Headache 2008;48:778-782)
AEDs used in
Episodic migraine
S.D. Silberstein, et al. Neurology 2012;78;1337
AAN/AHS 2012
Sodium valproate/Divalproex sodium

1975: Welch et al. reported change in CSF GABA levels

during migraine episodes in humans

Valproate enhances GABAergic transmission (highly

pleiotropic), blocks Na channels and

Early studies

1988; Sorensen et al. reported 11/22 pt. with migraine

become headache free during 1200 mg valproate

1992; Hering & Kurtzky: the rst D-B, P-C, valproate 800
mg/d for migraine prophylaxis

Approved by FDA for the management of migraine

Clinical studies of AEDs for migraine prophylaxis
Study design and
period of treatment
N
Headache
type
Results Results
D-B, P-C (8 weeks)
(1992)
32
MwoA and
MwA
400 mg
Reduction in migraine freq., intensity and
duration in 80% of the treated group
Multicenter,
randomised, D-B,
P-C (8 weeks)
(1995))
107
Migraine
not specic
Adjust to
serum level of
70-120 mg/l
>50% reduction in migraine freq. No SEs
on headache intensity/duration
Multicenter,
randomised, D-B,
P-C, (8 weeks)
(1997)
171
MwoA and
MwA
500 mg;1000
mg;1500 mg
Reduction in freq/ greater in 1000 mg
Randomised, D-B,
P-C (2002)
237
MwoA and
MwA
500-1000 mg
extended
release
Reduction in 4 week migraine rate
Sodium valproate/valproic acid
Divalproex sodium in migraine
prophylaxis
0
12.5
25
37.5
50
Placebo
Divalproex Na
P
a
t
i
e
n
t
s

(
%
)
P<0.001
P<0.05 (Dose 500
-1500 mg)
Methew NT et al. ARCH Neurol 1995 Klapper J Cephalalgia 1997
48%
14%
% pt. > 50% HA freq. reduction in 12 weeks
14%
44%
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%)
Divalproate vs Amitriptyline: RCT trial
300 migraine DVA-ER vs AMT
Kalita J et al. Acta Neurol Scand 2013: 128: 6572
Divalproate vs Amitriptyline: RCT trial
Kalita J et al. Acta Neurol Scand 2013: 128: 6572
Topiramate

Acts on AMPA receptors, blocking the glutamate

binding site, but also blocks kainate receptors
and Na+ channels, and enhances GABA
currents (highly pleiotropic*)

Studies of TPM in migraine

2001: double-blind placebo control trial

Storey JR et al. Headache 2001 41, 968-975
Clinical studies of AEDs for migraine prophylaxis
Study design and
period of treatment
N
Headache
type
Results Results
Single-center,
randomised, D-B,
P-C (8 weeks)
(2001)
35
MwoA and
MwA
100-200 mg
Reduction in mean 28 day HA freq. (36%
vs 14%)
Multicenter,
randomised, D-B,
P-C (18 weeks)
(2004)
483
MwoA and
MwA
50 mg;100 mg;
200 mg
Reduction in mean monthly migraine freq.
(TPM 100 and 200 mg)
Multicenter,
randomised, D-B,
P-C, parallel group
(18 weeks) (2004)
487
MwoA and
MwA
50 mg;100 mg;
200 mg
Reduction in mean monthly migraine freq.
(TPM 100 and 200 mg)
Multicenter,
randomised vs
propranolol or
placebo (18
weeks) (2004)
575
MwoA and
MwA
100 mg; 200
mg; vs
propranolol
Reduction freq., monthly migraine day
100 mg TPM vs PPN: similar efcacy

Topiramate
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
Topiramate in migraine prevention
(Large Controlled Trial)
Silberstein SD. Arch Neurol. 2004;61:490-495

331 subjects (172 TPM vs 159 AMT) dose titration

25 to 100 mg/d

Primary outcome: change from baseline in the

mean monthly no. of migraine episode: NS

Secondary outcome: functional ability, QoL: NS

Outcome: NS
DW Docick et al. Clinical therapeutic 2009;31(3):542-559
Percent weight change from baseline between
TPM vs AMT
Efcacy of Gabapentin in migraine
prevention (EM): D-B, P-C study
0
12.5
25
37.5
50
Gabapentin (n=56) Placebo (n=31)
46%
16%
P<0.05 ITT population
TID dosing
Gabapentin titrated to 2400 mg/d
% of patients with > 50% reduction
in attack frequency (4 weeks)
Mathew et al. Headache 2001
Conclusion EM prevention
1. Evidence based: AAN/AHS guideline
2. All Level A recommendation has similar efcacy,
but different side effect
3. Most DBPC studies evaluated efcacy 3-6 months
4. Long term used still save in some studies
Preventive medication
in chronic migraine
Brain change in chronic
migraine

Structural brain change

Periaqueductal grey
matter change (PAG): iron
deposition

Functional brain change

Central sensitisation
Central sensitization of
Trigeminal nucleus
caudalis(TNC)
Summary of evidence for prophylactic medications in
undifferentiated chronic daily headache and chronic migraine
Treatment Evidence for use in CDH/CM
Anticonvulsants
Topiramate Double-blind, placebo-controlled trial in CM
Gabapentin One double-blind, placebo-controlled trial in CDH
Valproate Double-blind, placebo-controlled in CDH including CM
Antidepressants
Amitriptyline Small open-labeled trial in TM
Fluoxetine Small double-blind, placebo-controlled trial in CDH
Tizanidine Small double-blind, placebo-controlled trial in CDH
Onabotulinumtoxin A Double-blind, placebo controlled trial in CM

Randomized, placebo-controlled, parallel-group

16 weeks

Topiramate 100 mg/d vs placebo

306 pts included (153 topiramate vs 153 placebo)

SD Silberstein Headache 2007;47:170-180
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 of
migraine/migraine days
SD Silberstein Headache 2007;47:170-180
The effect of sodium valproate on
CDH, and its subgroups
Yurekli VA. J Headache Pain 2008; 9:3741
Double-blind, Placebo-controlled 70 CDH; 29 CM, and 41 CTTH
Sodium valproate 500 mg(1st wk) to 1000 mg ; 3 months f/u
Medication overuse
headache
(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
Conclusion: CM +/- MOH

Few strong evidence of preventive medication

used in CM/MOH

TPM -> CM/MOH, BTx->CM

In clinical practice, may use medication based on

EM evidence, comorbitity, cost, preference

Although widely use of combination therapy, the

strong evidence is still lacking
Migraine variants
Fact

Most of studied migraine prevention was done in

MwoA/MwA

Few studies done in migraine variant: only case

series/report

Recommended drug sometime can not be applied

in migraine variants prevent
Evidence of preventive drugs for FHM/SHM
Drug Standard dosage Study group Outcome
Flunarizine 10 mg daily FHM/SHM
Reduce attack
freq 85 %
Verapamil 120-240 mg/d FHM/SHM
Pain free/reduce
freq and severity
Sodium valproate 500-2,000 mg/d HM with epilepsy
Reduce attacks
freq.
Lamotrigine 100-500 mg/d
Migraine with
disabling aura
(incl. HM)
Reduce freq. after
3-6 months
Acetazolamide 250-1,000 mg/d HM
Reduce attack
freq.
Topiramate in HM

TPM in HM has not been described

AEDs for acute migraine
therapy
600 - 1200 mg can be used if oral
acute medication failed
Conclusion
Start Evaluation Stop
Migraine is a complex neurological disorder
Multimodality treatment is needed to prevent migraine
chronic transformation
AEDs is one of the effective migraine prevention
Thank you
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