Role AEDs in Migraine prevention

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



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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



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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



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Old generation



1960 Ethosuximide

1973 Carbamazepine

1978 Valproate

New generation

1993 Felbamate

1993 Gabapentin

1994 Lamotrigine

1996 Fosphenytoin


1999 Vigabatrin

2000 Oxcarbazepine

2000 Levetiracetam

2005 Pregabalin



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Old generation



1960 Ethosuximide

1973 Carbamazepine

1978 Valproate

New generation

1993 Felbamate

1993 Gabapentin

1994 Lamotrigine

1996 Fosphenytoin


1999 Vigabatrin

2000 Oxcarbazepine

2000 Levetiracetam

2005 Pregabalin



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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

FB: openneurons

Role AEDs in Migraine prevention

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