Advances in Migraine

Prevention

Clinical Experience With Topiramate

Migraine Classification
and Overview of Therapy
 International Headache Society (IHS)
Classification System
Primary Headache Disorders
1. Migraine
1.1 Migraine without aura
1.2 Migraine with aura
1.3 Ophthalmoplegic migraine
1.4 Retinal migraine
1.5 Childhood periodic syndromes that may be precursors to
or associated with migraine
1.6 Complications of migraine
1.7 Migrainous disorder not fulfilling above criteria
2. Tension-type headache
3. Cluster headache and chronic paroxysmal hemicrania
4. Miscellaneous headaches unassociated with structural lesion

Headache Classification Committee of the IHS. Cephalalgia. 1988;8(suppl 7):1-96.

 1.1 Migraine Without Aura
Diagnostic Criteria
At least five attacks fulfilling the following criteria:
Headache lasts 4 to 72 hours (untreated or unsuccessfully treated)
Headache has at least 2 of the following characteristics:
Unilateral location
Pulsating quality
Moderate or severe intensity (inhibits or prohibits daily activities)
Aggravation by walking stairs or similar routine physical activity
During headache at least 1 of the following occurs:
Nausea and/or vomiting
Photophobia and phonophobia

Headache Classification Committee of the IHS. Cephalalgia. 1988;8(suppl 7):1-96;

Silberstein SD, et al. Headache in Clinical Practice. 1998;61-90.
 1.1 Migraine Without Aura
Diagnostic Criteria
At least 1 of the following:
History, physical and neurologic exams do not
suggest an organic disorder
History, and/or physical and/or neurologic exams
do suggest such a disorder but it is ruled out by
appropriate investigations
Such disorder is present, but migraine attacks do
not occur for the first time in close temporal relation
to the disorder
Headache Classification Committee of the IHS. Cephalalgia. 1988;8(suppl 7):1-96.
 1.2 Migraine With Aura
Diagnostic Criteria
At least 2 attacks fulfilling the following:
At least 3 of the following 4 characteristics:
One or more fully reversible aura symptoms occur,
indicating brain dysfunction
At least one aura symptom develops gradually over
more than 4 minutes, or 2 or more symptoms occur in
succession
No single aura symptom lasts more than 60 minutes
Headache follows aura with a free interval of less than
60 minutes (it may also begin before or simultaneously
with the aura)
Headache Classification Committee of the IHS. Cephalalgia. 1988;8(suppl 7):1-96.
 1.2 Migraine With Aura
Diagnostic Criteria
History, physical examination and, where appropriate,
diagnostic tests to exclude a secondary cause

Headache Classification Committee of the IHS. Cephalalgia. 1988;8(suppl 7):1-96.

 Acute vs Preventive Therapy
Acute therapy
Taken to relieve pain and disability and to stop
progression once attack has begun (eg, selective
serotonin receptor agonists [triptans], NSAIDs, aspirin,
or acetaminophen [alone or with butalbital, codeine, or
butorphanol])
Preventive therapy
Taken daily to reduce attack frequency, severity, and
duration
Patients taking preventive medication will likely also use
acute medication
Silberstein SD et al. Headache in Clinical Practice. 1998;61-90; Potter DL et al. Neurology.
2000;54(suppl 3):A15. Abstract.
 When to Consider Preventive Medication
Significant disability
2 attacks/month with disability that lasts 3 days
Infrequent attacks with profound disability
Acute medication
Ineffective, contraindicated, or troublesome
adverse events (AEs)
Overuse (>2/week)

Silberstein SD et al. Headache in Clinical Practice. 1998;61-90.

 Principles of Preventive
Drug Treatment
Start medication at low dose and increase slowly

Give medication adequate trial (2 or more months)

Avoid concomitant use of interfering, overused, and

contraindicated medications
Evaluate therapy
Use calendar
Stop treatment when headaches are well controlled
Avoid pregnancy
Ascertain birth control use
Silberstein SD et al. Headache in Clinical Practice. 1998;61-90.
 Preventive Drug Treatment: Dosing
Start medication at low dose
Migraineurs often respond to lower dose
Amitriptyline 10 to 20 mg vs 100 to 200 mg for depression
Divalproex 500 to 1000 mg vs higher doses for epilepsy and mania
Topiramate 50 to 200 mg vs higher doses for epilepsy
Migraineurs more sensitive to side effects
Increase dose slowly until
Therapeutic effects develop
Ceiling dose is reached
Side effects become intolerable
Ensure adequate trial on maximum tolerated dose before assuming drug ineffective

Silberstein SD et al. Headache in Clinical Practice. 1998;61-90; Potter DL et al. Neurology.

2000;54(suppl 3):A15. Abstract. Depakote Package Insert. 2000.
 Setting Treatment Priorities
Comorbid and Coexistent Disease
Therapeutic opportunities
Treat 2 disorders with single drug
Hypertension or angina and migraine:
beta-blocker or calcium channel blocker
Depression and migraine: TCA or SSRI
Epilepsy or mania and migraine: divalproex, topiramate
Therapeutic limitations
Avoid certain drugs
Depression: beta-blocker
Epilepsy: antidepressants, neuroleptics, or sumatriptan
Silberstein SD et al. Headache in Clinical Practice. 1998;61-90.
 Preventive Medication Classes
Anticonvulsants Calcium channel blockers

Valproate/divalproex, Verapamil, nimodipine

gabapentin, topiramate
Serotonin antagonists
Antidepressants
Methysergide
TCAs, SSRIs
Others
Beta-blockers
NSAIDs, neuroleptics
Propranolol, nadolol,
atenolol, timolol

Silberstein SD et al. Headache in Clinical Practice. 1998;61-90.

 Adverse Events and Contraindications
of Preventive Drug Classes
Adverse Events Contraindication
Beta-blockers Drowsiness, depression, decreased Asthma, diabetes
exercise tolerance, impotence in males
Antidepressants Sedation, dry mouth, weight gain Glaucoma, urinary retention,
(TCAs) caution with heart block
Calcium channel Constipation, Bradycardia/atrioventricular
blockers atrioventricular block conduction defect
Anticonvulsants Nausea, somnolence, platelet Liver disease (divalproex),
dysfunction, dizziness, ataxia, pregnancy*
tremor, hepatotoxicity,
weight gain, hair loss
*Use in pregnancy only when benefits deemed to outweigh risks

Silberstein SD et al. Headache in Clinical Practice. 1998;61-90; Tfelt-Hansen P, Welch KMA. In: Olesen J
et al, eds. The Headaches. 2nd ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2000:499-505.
 Migraine Mechanisms
and the Role of Antiepileptic
Drugs
 Migraine Is a Neurovascular Disorder
The genesis of migraine is neurologic

Likely that hyperexcitability of CNS confers

susceptibility to migraine attacks
Migraine associated with regional reduction in cerebral
blood flow and cortical spreading depression (CSD)
Trigeminovascular system involved in production of
migraine pain

Aurora SK, Welch KMA. Curr Opin Neurol. 1998;11:205-209; Aurora SK, Welch KMA. Curr Opin Neurol.
2000;13:273-276.
 Neuronal Hyperexcitability in Migraine
Neuronal hyperexcitability predisposes individuals to migraine
Migraine patients visualized phosphenes following transcranial
magnetic stimulation
Increased neuronal hyperexcitability may be multifactorial
Abnormal calcium channels that influence presynaptic
neurotransmitter release
Abnormal glutamate metabolism
Deficiency of systemic and brain magnesium
Migraine may be prevented by reducing neuronal hyperexcitability
Inhibition of excitatory neurotransmission (eg, Na+ channel)
Enhancement of inhibitory neurotransmission (eg, GABA)
Welch, et al. Neurol Clin. 1990;8:817-828; Aurora SK, Welch KMA. Curr Opin Neurol. 1998;11:205-209;
Cutrer, et al. Cephalalgia. 1997;17:93-100.
 Cortical Spreading Depression in Migraine
CSD starts at the occipital pole, spreads anteriorly
Increase in extracellular K+, H+, glutamate
Increase in intracellular Ca++, Na+
Following CSD, cortical cerebral blood flow decreases
by 20% to 30% for 2 to 6 hours
Ventral spread of CSD may cause neurogenic
inflammation and pain-sensitive fiber sensitization

Lauritzen M. In: Olesen et al, eds. The Headaches. 2nd ed. Philadelphia, Pa: Lippincott
Williams & Wilkins; 2000:189-194; Olesen J, Goadsby PJ. In: Olesen et al, eds. The Headaches. 2nd ed.
Philadelphia, Pa: Lippincott Williams & Wilkins; 2000:331-336.
 Trigeminovasular System in Migraine
Trigeminal nerve stimulation

Release of neuropeptides from sensory C-fibers

Neurogenic inflammation, plasma extravasation

Sensitization of nerve fibers

Transmission of nociceptive information

Moscowitz MA, McFarlane R. Cerebrovasc Brain Metab Rev. 1993;5:159-177; Strassman et al.
Nature. 1996;384:560-563; Silberstein et al. Headache in Clinical Practice. Oxford, UK:
ISIS Medical Media; 1998:41-58.
 Brainstem in Migraine
Brainstem relays nociceptive information

Brainstem activation may be in addition to nociception

Increased cerebral blood flow in the brain stem during
a migraine attack
Persistance after drug-induced relief from migraine
Other evidence for role of brainstem in migraine:
Contains antimigraine drug-binding sites
Stimulation causes migraine-like episodes

May A, Goadsby PJ. J Cereb Blood Flow Metab. 1999;19:115-127; Silberstein et al. Headache in Clinical
Practice. Oxford, UK: ISIS Medical Media; 1998:41-58.
 Mechanisms of Migraine:
Proposed Synthesis
Endogenous Exogenous

Environmental

Adapted from Olesen J and Goadsby PJ. In: Olesen J et al, eds. The Headaches. 2nd ed.
Philadelphia, Pa: Lippincott Williams & Wilkins; 2000:331-336.
 Comorbidity of Migraine and Epilepsy
Median prevalence of epilepsy in patients with migraine found to
be 5.9%, compared with 0.5% for epilepsy alone in the general
population
Risk of migraine >2x higher in persons with versus without epilepsy
Highest in those with epilepsy due to head trauma
Strong association independent of seizure type, age at onset,
etiology, or family history of epilepsy
For patients with comorbid epilepsy and migraine, agents potentially
useful for both should be considered

Andermann E, Andermann F. In: Andermann FA, Lugaresi E, eds. Migraine and Epilepsy. Boston:
Butterworths, 1987:281-291; Ottman R, Lipton RB. Neurology. 1994;44:2105-2110.
 Role of Glutamate, GABA, and Na+
Channels in CNS Disorders
Glutamate GABA Sodium Channels

Seizures Seizures Seizures

Neuropathic pain Neuropathic pain Neuropathic pain

Neurotoxicity Migraine Neurotoxicity

Neurodegenerative Manic-depressive Neurodegenerative

disorders disorder disorders
Migraine Essential tremor Manic-depressive
disorder
Welch KMA, et al. Neurol Clin. 1990;8:817-828; Ekbom K and Solomon S. The Headaches. 2000:731-740;
Sandkhler and Jensen. The Headaches. 2000:117-124. Heinemann U, Eder C. Epilepsy: A
Comprehensive Textbook. 1998;237-250
TopiramateBackground and
Data in Headache Therapy
 Topiramate:
Clinical Development Program

Topamax Package Insert. 2000; Data on file.

 Topiramate: Current Indications
Partial-onset seizures in adults
and children 2 years of age and older
(adjunctive therapy)
Primary generalized tonic-clonic seizures in
adults and children 2 years of age and older
(adjunctive therapy)

Topamax Package Insert. 2000.

Topiramate: Multiple Mechanisms of Action

Site Action

Voltage-activated Limits sustained repetitive firing via state-dependent

Na+ channels blockade of Na+ channels

GABAA receptor Potentiates GABA-mediated inhibition at GABAA

subtype(s) site not modulated by benzodiazepines or barbiturates

Glutamate Blocks glutamate-mediated neuroexcitation with

receptor subtype(s) no apparent effect on NMDA receptor activity
(AMPA/kainate)

Voltage-activated Mild reduction of amplitude of highvoltage activated

Ca++ channel subtypes Ca++ currents

Carbonic anhydrase Inhibits types II and IV carbonic anhydrase isoenzymes

Shank RP et al. Epilepsia. 2000;41(suppl 1):S3-S9.
 Topiramate Clinically Important
Pharmacokinetic Parameters
Rapid absorption (Tmax ~2 h)
Bioavailability (~80%) unaffected by food
Low level of plasma protein binding (9% to 17%)
Linear pharmacokinetics
Not extensively metabolized
Predominantly renal excretion
Half-life suitable for BID dosing
Limited pharmacokinetic drug interactions
Garnett WR. Epilepsia. 2000;41(suppl 1):S61-S65; Johannessen SI. Epilepsia.1997;38(suppl 1):S18-S23.
 Topiramate Pharmacokinetics
in Infants and Children
Infants 24 to 30 months
Clearance at least twice that in adults
Children 4 to 17 years
Clearance ~50% higher than in adults
Plasma concentration reduced
~33% lower than in adults for same mg/kg dose

Glauser TA et al. Epilepsia. 1999;40:788-791; Rosenfeld WE et al. Pediatr Neurol. 1999;20:339-344.

 Topiramate Administration
If CNS adverse events occur (depending on severity)
Do not increase dosage until adverse events
resolve (eg, 1 to 2 wk)
Reduce dosage of concomitant AED or reduce
topiramate dosage to previous dose level
Restart dose escalation as needed when adverse
events resolve

Sander JWAS. Epilepsia. 1997;38(suppl 1):S56-S58.

 Titration Strategy to Minimize
or Reduce Adverse Events
Previous Revised
Package Package
Insert1 Insert2
AM PM AM PM

Week 1 50 mg 25-50 mg

Week 2 50 mg 50 mg Titrate up by

Week 3 50 mg 100 mg 25-50 mg/wk increments

Week 4 100 mg 100 mg to optimal clinical response

1Topamax Package Insert. 1999; 2Topamax Package Insert. 2000.

 Topiramate: Weight Loss
Adults Children

Mean decreases (1.6-6.5 kg), Net decrease 10% in 95% of

depending on children
Baseline weight
Generally begins within 2 to 4
Topiramate dosage weeks, with <6 month duration;
Duration of therapy weight increased thereafter in
(stabilization after majority
12 to 18 mo)
Retrospective data: Topiramate
In add-on clinical trials, weight appears to slow weight gain but has
loss occurred in no effect on height
7% to 13% of patients
Also associated with reports
of anorexia
Reife R et al. Epilepsia. 2000;41(suppl 1):S66-S71; Data on file; Morita DA et al. Neurology. 2000:54(suppl
3):A193. Abstract.
 Topiramate: Summary
of Clinical Profile
Multiple mechanisms of action may contribute to broad-
spectrum clinical profile
Predictable pharmacokinetics; limited drug interactions
Effective as adjunctive therapy in adults and children with
partial-onset seizures, Lennox-Gastaut syndrome,
and primary generalized tonic-clonic seizures
Clinical data to support efficacy in monotherapy
No evidence of topiramate tolerance
Most common AEs CNS-related; usually mild to moderate
and transient
Shank RP et al. Epilepsia. 2000;41(suppl 1):S3-S9; Garnett WR. Epilepsia. 2000;41(suppl 1):
S61-S65; Gilliam FG et al. Neurology. 1999;52(suppl 2):A248. Abstract; Data on file.
 Topiramate in Migraine Prevention
Retrospective Chart Analysis
Chart review of 98 patients treated with topiramate for
prevention of migraine headaches
69 patients with IHS diagnosis of migraine and at least
1 follow-up visit after 4 weeks on topiramate were included
56 female, 13 male; mean age 43 years (range, 18 to 68)
Median dose of topiramate: 100 mg/day (range,
25-500 mg/day)
Patients divided into 2 groups for data analysis
Failed <9 preventive medications (n=31)
Failed 9 preventive medications (n=38)
Von Seggern RL et al. Neurology. 2000;54(suppl 3):A267-A268. Abstract.
 Topiramate in Migraine Prevention
Retrospective Chart Analysis: Results
Reduction in Mean 28-Day Moderate/Severe Headache Frequency
Baseline Topiramate P=.034
12 P=.0004
P=.0036
11.4
10 10.6
9.5
8 8.8
28-Day 7.4
Headache 6
Frequency 4 5.8

0
All patients Patients Failing Patients Failing
N=69 <9 Preventive 9 Preventive
Medications; n=31 Medications; n=38
Von Seggern RL et al. Neurology. 2000;54(suppl 3):A267-A268.
 Topiramate Migraine
Initial Open-Label Results
Krusz and Scott, 1999
28 patients with refractory migraine
Average migraine reduction of 72%
Average topiramate dose 325 mg/day
10 patients discontinued (AEs, noncompliance or lack of efficacy)
Storey et al, 1999
9 patients with refractory migraine
Average migraine reduction of 80.5% (8/9 patients)
Average topiramate dose 104 mg/day
2 patients discontinued due to adverse effects
Storey et al, 1999
5 patients with intractable daily headache
Average topiramate dose 310 mg/day
Improvement in all patients
Krusz JC, Scott V. Headache. 1999;39:S363; Storey JR, Calder CS, Potter DL. Ann Neurol. 1999;46:494;
Storey JR, Calder CS, Potter DL. Neurology. 1999;52(suppl 2)P03.055.
 Topiramate in Migraine Prevention
Open-Label Study
Good preventative efficacy in pilot study of 37 patients
with frequent refractory migraines
Dose: 25 to 100 mg/day
Duration of treatment: 2 to 9 months
11 patients had >60% reduction in headache
frequency
11 patients had 40% to 60% reduction in headache
frequency

Shuaib A et al. Cephalagia. 1999;19:379-380. Abstract.

 A Double-Blind, Randomized Trial of
Topiramate vs Placebo in the
Prophylactic Treatment of Migraine
Headache With and Without Aura

Edwards KR, Glantz MJ, Norton JA, Cross N

Western New England Headache Clinic and Neurological
Research Center
Bennington, Vermont

Edwards KR et al. Headache. 2000;40:407. Abstract.

 Protocol Design
Double-blind, placebo- Subjects and diagnosis
controlled, randomized Men and women aged
18 to 65 years
Migraine with or without aura
Study Design (IHS criteria)
4 Weeks 6 Weeks 12 Weeks

Baseline Titration Maintenance

phase phase (100 mg BID)

Double-blind phase

Edwards KR et al. Headache. 2000;40:407. Abstract.

 Protocol Design
Topiramate dosage
Initiated at 25 mg/day
Titrated in 25 mg increments to target dosage of 100 mg BID
Key inclusion criteria
Migraines present for >1 year, averaging: 2/month
Baseline
2-8 migraines per 4 weeks
With/without concomitant prophylactic therapy
Key exclusion criteria
Use of abortive therapy 3 days/week
Tension-type headaches >12 days/month
Edwards KR et al. Headache. 2000;40:407. Abstract.
 Patient Demographics
Topiramate Placebo
No. of patients 15 female 14 female
1 male
Age
Mean (y) 45.8 7.0 43.9 10.0
Range (y) 32-60 30-62

No. of patients on 4 3
concomitant prophylactic
medications

Mean dose of 173 mg/d*

topiramate
*11 of 15 patients achieved target dose of 200 mg.
Edwards KR et al. Headache. 2000;40:407. Abstract.
 Results
Mean 28-Day Migraine Frequency at Baseline and During Treatment
(Double-Blind Phase)
4.5
Baseline
4.2 4.1 Treatment
4.0 3.8
3.5
3.0
3.0
Mean 2.5
Migraine P=.09*
2.0
Frequency
1.5
1.0
0.5
0.0
TPM (n=15) Placebo (n=15)

*Analysis of covariance with baseline migraine frequency as covariate.

Edwards KR et al. Headache. 2000;40:407. Abstract.
 Results
Mean Reduction in 28-Day Migraine Frequency
(Entire Double-Blind Phase)
1.5
Topiramate (n=15)
1.2 Placebo (n=15)

1.0
Mean Reduction
in Migraine
Frequency P=.09*
0.5 0.4

0.0
*Analysis of covariance with baseline migraine frequency as covariate.
Edwards KR et al. Headache. 2000;40:407. Abstract.
 Results
Percentage of Patients Achieving 50% Reduction
in Migraine Frequency
50 46.7%
Topiramate (n=15)
40
Placebo (n=15)
% of Patients
With 50% 30
Reduction in
Migraine 20 P=.035*
Frequency
10 6.7%

*Fisher exact test.

Edwards KR et al. Headache. 2000;40:407. Abstract.
 Changes From Baseline in Migraine
Characteristics

Topiramate Placebo
(n=15) (n=15) P
Severity -0.38 0.03 .0296
Disability -0.38 0.05 .0120
Duration -1.91 0.13 .2162

Edwards KR et al. Headache. 2000;40:407. Abstract.

 Changes in Mean Body Weight

Topiramate Placebo
(n=15) (n=15) P

Weight at baseline 160.4 34.7 180.2 50.6

Weight at last visit 154.2 29.0 179.5 52.6

Mean weight change -6.20 -0.67 .0141*

from baseline

*Analysis of covariance with baseline body weight as covariate.

Edwards KR et al. Headache. 2000;40:407. Abstract.
 Adverse Events*
Topiramate Placebo
n % n %
Paresthesia 9 60 4 27
Diarrhea 4 27 1 7
Altered taste 3 20 1 7
Somnolence 3 20 1 7
Dry mouth 2 13 2 13
Memory impairment 2 13 2 13
*Occurring in 10% of patients on topiramate.
Edwards KR et al. Headache. 2000;40:407. Abstract.
 Study Discontinuations

Topiramate Placebo
Adverse events 4 0
Lack of efficacy 1 3
Noncompliance 1 0
Other 1 3
Total 7 6

Edwards KR et al. Headache. 2000;40:407. Abstract.

 Edwards et al: Summary

These encouraging results provide additional support

for the potential role of topiramate in the preventive
treatment of episodic migraine
Topiramate was well tolerated

These data support the evaluation of topiramate as a

migraine preventive in multicenter controlled trials

Edwards KR et al. Headache. 2000;40:407. Abstract.

 A Double-Blind, Randomized,
Placebo-Controlled Study of
Topiramate in the Prophylactic
Treatment of Migraine

Potter DL, Hart DE, Calder CS, Storey JR

Upsate Neurology Consultants, LLP
Albany, New York

Potter DL et al. Neurology. 2000;54(suppl 3):A15. Abstract.

 Protocol Design
Double-blind, placebo- Subjects and diagnosis
controlled, randomized, parallel Men and women aged
18 to 65 years
Migraine with or without aura
Study Design (IHS criteria)

4 Weeks 8 Weeks 8 Weeks

Baseline Titration Maintenance

phase phase phase
(100 mg BID)
Double-blind phase

Potter DL et al. Neurology. 2000;54(suppl 3):A15. Abstract.

 Protocol Design
Topiramate dosage
Initiated at 25 mg/day
Titrated in 25 mg increments to target dosage of 100 mg BID
Key inclusion criteria
Migraines present for >1 year and averaging 2/month
Baseline
2 migraines per 4 weeks
With/without concomitant prophylactic therapy
Key exclusion criteria
Use of abortive therapy >3 days/week
Frequent tension-type headaches >12 days/month
Potter DL et al. Neurology. 2000;54(suppl 3):A15. Abstract.
 Patient Demographics
Topiramate Placebo

No. of patients 19 female 20 female

1 male
Age - all patients
Mean (y) 38.3 38.1
Range (y) 19-62 24-56

Mean dose of topiramate 125 mg/d

Range 25-200 mg

Potter DL et al. Neurology 2000;54(suppl 3):A15. Abstract.

 Results
Mean 28-Day Migraine Frequency at Baseline and During Treatment
(Double-Blind Phase)
6
Baseline
5.1
5 Treatment
4.4

4 3.8
Mean 3.3
Migraine 3
Frequency
2 P=.0015*
1

0
TPM (n=19) Placebo (n=21)

*Analysis of covariance with baseline migraine frequency as covariate.

Potter DL et al. Neurology. 2000;54(suppl 3):A15. Abstract.
 Results
Mean Reduction in 28-Day Migraine Frequency
(Double-Blind Phase)

2.0 1.8 Topiramate (n=19)

Placebo (n=21)
1.5
Mean Reduction
in Migraine P=.0015*
1.0
Frequency
0.5
0.5

0.0
*Analysis of covariance with baseline migraine frequency as covariate.
Potter DL et al. Neurology. 2000;54(suppl 3):A15. Abstract.
 Results
Percentage of Patients Achieving 50% Reduction in Migraine Frequency

30 Topiramate (n=19)
26.3%
Placebo (n=21)

% of Patients 20
With 50%
Reduction in P=.226*
Migraine 9.5%
Frequency 10

*Fisher exact test.

Potter DL et al. Neurology. 2000;54(suppl 3):A15. Abstract.
 Results
Mean Reduction in 28-Day Migraine Frequency
With/Without Prevention (Double-Blind Phase)
2.5 Topiramate (n=19)
2.09
Placebo (n=21)
2.0
1.68
Mean Reduction 1.5
in Migraine
Frequency 1.0 0.9

0.5 0.28

0.0
n=7 n=12 n=12 n=9
No Prophylactic With Prophylactic
Medication Medication
P=.0006* P=.32*
*Analysis of covariance with baseline migraine frequency as covariate.
Potter DL et al. Neurology. 2000;54(suppl 3):A15. Abstract.
 Changes in Mean Body Weight

Topiramate Placebo
(n=19) (n=21) P

Weight at baseline 170.8 33.3 181.0 41.6

Weight at last visit 165.9 33.8 181.5 40.1

Mean weight change -4.9 +0.6 .015*

from baseline

*Analysis of covariance with baseline body weight as covariate.

Potter DL et al. Neurology. 2000;54(suppl 3):A15. Abstract.
 Adverse Events*
Topiramate Placebo
n % n %
Paresthesia 13 68 4 19
Weight loss 10 53 6 29
Altered taste 7 37 0 0
Anorexia 4 21 1 5
Memory impairment 4 21 1 5
Emotional lability 3 16 1 5
Dysarthria 3 16 0 0
Urinary frequency 3 16 1 5
Abnormal vision 3 16 0 0
Anxiety 2 10 0 0
*Difference between topiramate and placebo patients 10%.
Potter DL et al. Neurology. 2000;54(suppl 3):A15. Abstract.
 Study Discontinuations

Topiramate Placebo
Adverse events 2 0
Noncompliance 0 1
Withdrew consent 1 1
Total 3 2

Potter DL et al. Neurology. 2000;54(suppl 3):A15. Abstract.

 Potter et al: Summary
Study results suggest that topiramate may be effective
for the prevention of episodic migraine
Topiramate was well tolerated

These data support the evaluation of topiramate as a

migraine preventive in larger, multicenter, controlled
trials

Potter DL et al. Neurology. 2000;54(suppl 3):A15. Abstract.

 Open-Label Study of Topiramate
in Cluster Headache
19 consecutive cluster headache patients
(8 females, 11 males)
Mean age 46.3 years (range 15 to 72 years)

Mean age cluster onset 32.6 years (range 10 to 59 years)

Mean topiramate dose: 77 mg/d (range 25 to 200 mg/d)

Wheeler SD, Carrazana EJ. Cephalalgia. 2000;20:330. Abstract.

 Open-Label Study of Topiramate
in Cluster Headache
Usual cluster period duration: 2 weeks to 36 months
(mean range 6.1 to 7.8 months)
Cluster period duration at time of topiramate treatment:
1 day to 36 months (mean duration 6.2 months)
Topiramate induced cluster remission in 1 day to 3 weeks

Mean time to remission induction: 1.4 weeks

One patient able to taper steroids without recurrence

Wheeler SD, Carrazana EJ. Cephalalgia. 2000;20:330. Abstract.

 Conclusions
Pathophysiology of migraine
Neuronal hyperexcitability
Multiple mediators and modulators
Topiramate
Multiple mechanisms of action
Preliminary studies support utility in migraine
prevention
Additional studies needed to confirm findings