1. No category

PROCEEDINGS
A
AN UPDATE ON MIGRAINE TREATMENT*
—
Stephen D. Silberstein, MD†
ABSTRACT
Although some pharmacologic treatments are
used for both migraine and epilepsy, fundamental
differences in treatment approaches and treatment
goals exist. Migraine treatment requires acute
and/or preventive therapy, whereas most epilepsy
treatments are preventive (the exception being status
epilepticus treatment). Some of the most commonly
used preventive migraine therapies are antiepileptic
drugs (AEDs). The mechanism of migraine activation is not yet completely understood, but it is associated with central and peripheral sensitization.
Migraine-preventive drugs may raise the threshold
for migraine activation or stabilize the excitable/
sensitive nervous system. The biggest difference
between the goals of migraine treatment and the
goals of epilepsy treatment is the definition of treatment success—seizure free for epilepsy versus
reduction in attack frequency, severity, and duration
for migraine. This article discusses the principles of
migraine-preventive therapy and the factors that
affect drug choice, and compares them with the
principles of epilepsy treatment. Only 2 AEDs (divalproex and topiramate) are approved by the US
Food and Drug Administration for migraine prevention. The possibility of using a single drug to treat
both disorders is a “therapeutic opportunity.”
However, given the differing and sometimes conflicting treatment principles and treatment goals that
exist, the entire patient profile should be considered
in determining not only optimal drug choice but also
dosing and definition of treatment success.
(Adv Stud Med. 2005;5(6E):S666-S675)
*Based on a presentation given by Dr Silberstein at a
roundtable held in Philadelphia on February 5, 2005.
†Director, Jefferson Headache Center, Thomas Jefferson
University Hospital; Professor of Neurology, Thomas
Jefferson University, Philadelphia, Pennsylvania.
Address correspondence to: Stephen D. Silberstein, MD,
Thomas Jefferson University, 111 South 11th St, Ste 8130,
Philadelphia, PA 19107.
E-mail: [email protected].
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lthough there is some overlap in the
pharmacologic treatment of migraine
and epilepsy, fundamental differences
in treatment approaches and goals exist.
One distinction is that migraine management involves acute and preventive therapy, whereas most epilepsy treatments are preventive (with the
exception of status epilepticus, in which the individual
attack is treated). Acute migraine treatment is used
after the attack has begun, to relieve pain and disability and stop progression. Although many patients with
migraine require only acute treatment for effective
management, a subset of patients requires preventive
therapy, which is used primarily to reduce the frequency, severity, and duration of headache attacks.
Patients taking preventive medication still need acute
medication for breakthrough headaches. Some of the
most commonly used preventive migraine therapies
are antiepileptic drugs (AEDs).
MECHANISMS OF MIGRAINE PREVENTION
The drugs used for migraine prevention are listed
in Table 1. Of the drugs, only 4 (divalproex and topiramate, which are AEDs, and propranolol and timolol,
which are beta blockers) are approved by the US Food
and Drug Administration for migraine prevention. All
other preventive migraine drugs are used off-label.
MECHANISMS OF MIGRAINE
The mechanism of migraine activation is not yet
completely understood; whether it includes a
“migraine generator” in the midbrain is controversial.
[See a more extensive review on this topic in
Silberstein 2004].1 Migraine may begin with activation
of a sensitive (or hyperexcitable) nervous system by
either an environmental factor (eg, stress) or an
endogenous change in the body, such as declining
estrogen levels that occur with menstruation.
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Hyperexcitability may be due to decreased magnesium
levels or increased glutamate levels. If the activation
continues long enough, the threshold for migraine is
surpassed and a wave of neuronal activation is followed
by a wave of neuronal depression, which moves slowly
and steadily across the cortex (at about 3 mm/sec).
This accounts for the aura of migraine. The spreading
wave activates trigeminal afferents and the vascular
structures they innervate. Headache probably results
from the activation of meningeal and blood vessel
nociceptors combined with a change in central pain
modulation. Headache and its associated neurovascular changes are subserved by the trigeminal system.
Activation results in vasoactive intestinal polypeptide
release and vasodilation.
Trigeminal sensory neurons contain substance
P (SP), calcitonin gene-related peptide (CGRP), and
neurokinin A. Stimulation results in SP and CGRP
release from sensory C-fiber terminals and neurogenic
inflammation. The neuropeptides interact with the
blood vessel wall, producing dilation, plasma protein
extravasation, and platelet activation. Neurogenic
Table 1. Drug Therapies for Migraine Prevention and Their Proposed Mechanisms of Action in Migraine
Raise Threshold for Migraine Activation
Inhibit
Migraine
Generator
Enhance
Antinociception
Anticonvulsants
Divalproex*
Gabapentin
Topiramate*
?
X
Antidepressants
TCAs
SSRIs
MAOIs
?
Beta blockers
Propanolol*
Timolol*
?
Stabilize Reactive
Nervous System
Inhibit CSD
Inhibit
Sensitization
Block
Neurogenic
Inflammation
Modulate Sympathetic or
Serotonergic Tone
X
?
?
X
X
X
?
X
X
X
X
X
?
X
X
X
X
CA2+-channel blockers
Verapamil
?
NSAIDs
5-HT antagonists
Methysergide
X
X
X
X
Neurotoxins
Botulinum
X
Angiotensin system
ACE inhibitors
Antagonists
Acetylcholinesterase inhibitors
Other
Riboflavin
CoQ10
Feverfew
X
*FDA approved for migraine prevention.
CSD = cortical spreading depression; TCAs = tricyclic antidepressants; SSRIs = selective serotonin reuptake inhibitors; MAOIs = monoamine oxidase inhibitors; NSAIDs =
nonsteroidal anti-inflammatory drugs; ACE = angiotensin-converting enzyme.
Advanced Studies in Medicine
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PROCEEDINGS
inflammation sensitizes nerve fibers (peripheral sensitization). Now innocuous stimuli, such as blood vessel pulsations, are interpreted as painful, causing, in part, the
throbbing pain of migraine. Burstein et al have proposed
that sensitization of trigeminovascular neurons may
account for intracranial hypersensitivity, such as pain
worsening during coughing, bending over, or rapid head
movement, during migraine or the throbbing nature of
the headache.2 Nerve impulses are also transmitted back
into the trigeminal nucleus caudalis in the brain stem,
which projects to the thalamus and cerebral cortex.
Central sensitization (CS) can also occur. CS may
account for extracranial sensitivity, such as cutaneous
allodynia.1,2 As the migraine progresses, brain stem reflexes are thought to produce some of the migrainous symptoms, such as nausea, vomiting, photophobia, and
phonophobia. Autonomic activation via the facial nerve
causes nasal congestion, rhinorrhea, and lacrimation,
which are experienced by nearly half of all migraineurs.
Each migraine-preventive drug listed in Table 1
appears to affect migraine by either raising the threshold for migraine activation or stabilizing the
excitable/sensitive nervous system.3-6
APPROACHES TO MIGRAINE TREATMENT
In the presence of epilepsy, every patient is treated
with AEDs. In migraine, however, not all patients
require preventive medication. Acute migraine medication overuse is a common and important concern, and
its presence or absence helps to determine whether preventive medication will be used. Medication overuse
occurs when acute medications are used so frequently
that the migraine treatment itself increases migraine
attack frequency and the drugs have to be withdrawn.
Preventive migraine medication should be considered when specific circumstances exist. For example,
some patients receiving acute treatments may still
experience migraines that interfere with their daily
routine. When headache frequency is more than 2 per
week, medication overuse is a risk. Preventive medications are also warranted when acute medications are
ineffective, contraindicated, poorly tolerated, or
overused. Patients at times prefer preventive medication, because the risk of a migraine is too great.
Preventive medication is used in some less common
types of migraine, such as hemiplegic migraine, basilar
migraine, migraine with prolonged aura, or migrainous infarction.7 Lipton et al have shown that although
S668
58% of migraineurs meet disability and frequency criteria for preventive treatment (ie, 1-2 days of activity
restriction per episode), only 5% are currently using
preventive therapy, based on 2 large population-based
surveys.8,9 Migraine prevention is an unmet need.
Preventive migraine therapy employs certain principles, independent of drug choice. The philosophy of
“start low and go slow” is important, because migraine
patients often need a lower dose of these medications
than patients who take them for other indications. An
adequate drug trial (2-3 months) is also important,
because onset of action can take several weeks (as
opposed to treatment for epilepsy, which usually controls the attack quickly, suggesting a difference in underlying pathophysiology and mechanism of action). Drug
overuse with acute medications is a concern and should
be avoided. Efficacy can be monitored and evaluated by
having the patient keep a migraine diary or calendar,
and drugs can sometimes be tapered (or discontinued)
if the headaches are well controlled. Preventive medications often affect the cytochrome 450 enzyme system,
so potential drug-drug interactions should be considered and pregnancy should be avoided if possible, especially when patients are using AEDs.7
The goals of migraine-preventive treatment are 5fold: (1) to reduce attack frequency, severity, and duration; (2) to improve responsiveness to acute treatment;
(3) to improve function and reduce disability; (4) to
prevent disease progression; and (5) to reduce costs.7
The first goal (ie, to reduce frequency, severity, and
duration of headache) is an important departure from
epilepsy treatment, wherein seizure-free status is the
goal. Preventive migraine treatment can prevent disease progression wherein episodic migraine progresses
to chronic migraine, defined as migraine on 15 or
more days a month without medication overuse.10,11
The use of preventive migraine medication also
reduces overall treatment costs. We performed a retrospective evaluation of a large claims database to determine resource utilization over an 18-month period
among patients treated for migraine. Direct costs to
patients who used only acute treatment were compared
with direct costs to patients who added preventive treatments to their acute drug regimens. The results showed
substantial cost decreases across several measures of
resource utilization with concomitant preventive therapy: a 51% decrease in physician office visits, an 82%
decrease in emergency department visits, a 75% decrease
in computed tomography scans, an 88% decrease in
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PROCEEDINGS
magnetic resonance imaging scans, and a $48 to $138
reduction in monthly medication costs per patient.
Drug choice for preventive treatment depends on
several factors: headache type, efficacy and adverse
event profile of the drug, comorbid or coexisting conditions (ie, other present conditions that are not associated with headache), and patient preference. As
discussed by Dr Lipton in this monograph, comorbid
and/or coexisting conditions can present therapeutic
opportunities as well as therapeutic limitations,
depending on the preventive therapy and the patient’s
current medical status.
of 163 patients from 24 centers were followed to evaluate the long-term safety of divalproex. The most frequently used dose (ie, in 26% of patients) for headache
was 1000 mg/day, ranging from 500 to 2500 mg/day.
The efficacy results confirmed results from other studies of divalproex and showed that improvements are
maintained long-term (excluding those who dropped
out of the study), as shown in Figure 2. The other
main outcome measures were number and proportion
of patients reporting treatment-emergent adverse
AEDS FOR MIGRAINE PREVENTION
Figure 1. Responder Rates with Divalproex for
Migraine Prevention
48%
50
Placebo
44%
45
Divalproex
40
% of Patients
Several currently available AEDs have been studied
for migraine prevention, but the data to support their
use vary widely among individual drugs. Divalproex
and topiramate both have strong scientific evidence
(ie, placebo-controlled, double-blind trials) to support
their use as migraine-preventive therapy. The data for
gabapentin, carbamazepine, and zonisamide are limited and sometimes conflicting. Levetiracetam has not
been shown to be effective in migraine. Data for
phenytoin and pregabalin are not available.
35
30%
30
25
24%
24%
20
14%
15
10
5
0
Klapper et al
Advanced Studies in Medicine
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Matthew et al
Freitag et al
The study by Freitag et al was the only study shown here that used the
extended-release formulation of divalproex.
Data from Klapper21; Mathew et al22; Freitag et al.23
Figure 2. Sustained Efficacy of Divalproex in
Migraine Prevention for Up to 3 Years
6
5
Number of Attacks
DIVALPROEX
Divalproex sodium is an oligomeric complex of
sodium valproate and valproic acid in a 1:1 molar
ratio. Along with its indications for epilepsy and mania
in bipolar disorder, it was approved by the US Food
and Drug Administration for migraine treatment. A
total of 5 placebo-controlled, double-blind trials have
established the efficacy of divalproex in migraine prevention, and other groups have studied its use in cluster and chronic daily headache with mixed results.12-17
A brief review of the evidence is described here but is
discussed more extensively elsewhere.18-20
Two of the 3 US trials used the standard formulation of divalproex. The results (ie, responder rate, or
percentage of patients achieving at least 50% improvement in outcome) from these trials are shown in
Figure 1.21-23 Of note, results from the Freitag study are
not consistent with other studies. Overall, responder
rates were between 44% and 48%.21-23
We performed a long-term (up to 3 years) openlabel study of patients who completed 1 of 2 multicenter, double-blind, randomized, placebo-controlled
studies of divalproex for migraine prevention. A total
6.1
5.43
5.3
Baseline Period
4
Treatment Period
3
3.11
2.41
2.5
Month 0-3
Month 13-18
Month 31-36
(n=162)
(n=73)
(n=27)
2
1
0
Results shown here do not include patients who discontinued during the
open-label study period.
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PROCEEDINGS
MIGR-00126
MIGR-00227
PRI/TOP-INT-47
MIGR-00328
200
200
200
100
50
100
50
100
—
Comparator(s)
Placebo
Placebo
Placebo,
Propanolol (180
mg/day)
Location
United States
United States,
Canada
Europe (9),*
Asia (2),
Australia,
South Africa
Dose of
topiramate
(mg/day)
*Number of countries.
events, prevalence and incidence for each treatmentemergent adverse event, vital signs, and body weight.
Nausea (in 37%) occurred early in the treatment
course and declined 3% to 6% by 6 months. Tremor
(in 35%) and weight gain (in 24%) tended to occur
later, at 6 months. Alopecia declined after 12 months;
and discontinuations due to adverse events were primarily caused by these 4 adverse events (alopecia 6%,
nausea 4%, weight gain 2%, and tremor 2%).24 In
clinical practice, the most common adverse events
associated with divalproex use are gastrointestinal disturbance (anorexia, nausea, vomiting, dyspepsia, and
diarrhea), asymptomatic serum hepatic transaminase
elevations, tremor, sedation, increased appetite, weight
gain, and alopecia. Less common are rashes and hematologic dysfunction; ataxia is rare. Hepatitis and pancreatitis are rare; their incidence depends on the
number of concomitant medications, the patient’s age,
the presence of genetic metabolic disorders (although
migraine in mentally disabled persons is not common), and the patient’s general health.
The extended-release (ER) formulation of divalproex
minimizes adverse events. Starting doses are 250 mg
twice daily for the delayed-release (DR) version and 500
mg qhs for the ER version. Doses are started low and
titrated up to 500 mg/day to 1000 mg/day (DR, twice
daily, qhs). A dose-response curve has not been observed
in clinical studies. Unlike in epilepsy, rapid titration is
not necessary. However, higher doses are needed for
patients with comorbid epilepsy.
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TOPIRAMATE
Topiramate, an AED, was recently approved for
migraine prophylaxis. It is a sulfamate-substituted
monosaccharide (a fructose-1,6-diphosphate analog)
that inhibits carbonic anhydrase and modulates
kinase phosphorylation on neuronal ion channels.
Shank et al proposed that topiramate binds to presynaptic ion channel proteins and blocks their phosphorylation, thus allosterically modulating channel
conductance. It also blocks postsynaptic gammaaminobutyric acid and kainate receptors.25 The exact
mechanisms by which it prevents migraine are not yet
known, although blocking phosphorylation of protein kinase A on these various proteins appears to be
the common factor. Topiramate has been studied as
preventive treatment for migraine, cluster headache,
and chronic migraine.
Four phase 3 clinical trials have been completed in
the United States and their results are published.
Table 2 outlines the study doses and comparator
groups in the 3 published studies.26-28 MIGR-001,
-002, and -003 were large studies, and the primary
efficacy end point in all 3 studies was a reduction in
mean 28-day rate of migraine periods compared with
baseline rates. The migraine period was defined as the
length of time between onset and cessation of painful
migraine symptoms; it could last up to but not more
than 24 hours (eg, a headache lasting 25 hours would
extend into a second period).
Figure 3. Topiramate Responder Rate in US and
Canadian Trials
6
5
Number of Attacks
Table 2. Phase 3 Clinical Trials with Topiramate for
Migraine Prevention
6.1
5.43
5.3
Baseline Period
4
Treatment Period
3
3.11
2.41
2.5
Month 0-3
Month 13-18
Month 31-36
(n=162)
(n=73)
(n=27)
2
1
0
Data from Silberstein et al26; Brandes et al.27
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PROCEEDINGS
dose should be titrated more slowly or reduced.
Topiramate has a rapid onset of action (within the first
month of treatment) and a high responder rate.
Median (%) Reduction in
Monthly Migraine Frequency
Figure 4. Topiramate Responder Rate—Pooled
Data Analysis
60
*P = NS
= 0.002 vs placebo
†P
50
40
GABAPENTIN, CARBAMAZEPINE, AND LAMOTRIGINE
Two US studies have evaluated the use of
gabapentin as preventive therapy for migraine. A
50.7%†
34.7%*
30
20
20.7%
Figure 5. Response to Topiramate Therapy
10
0
Placebo
TPM 50 mg
TPM 100 mg
(n=229)
(n=233)
(n=244)
>95% Reduction
60
50%-74% Reduction
TPM = topiramate.
Data from data on file (TOPMIG 6000) Janssen-Cilag; Silberstein et al26;
Brandes et al.27
Advanced Studies in Medicine
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50
6
40
19
% of Patients
6
6
6
24
30
17
17
20
29
10
19
20
14
0
MIGR-001
MIGR-002
Propranolol
160 mg/d
MIGR-003
MIGR-003
Data from Silberstein et al26; Brandes et al27; Diener et al.28
Figure 6. Topiramate Migraine Prevention Trials:
Change in Body Weight
Placebo
Topiramate 100 mg/d
Topiramate 50 mg/d
Topiramate 200 mg/d
Propranolol 160 mg/d
3
2.3§
2
Change in Body Weight* (%)
Responder rates for the American and Canadian
studies (MIGR-001 and -002) showed a dose response
up to 100 mg, with the highest responder rates at about
50% (Figure 3). Pooled data from MIGR-001, -002,
and -003 also show a dose response up to 100 mg (Figure
4), with a maximum reduction in the primary end point
of 50.7% (an absolute reduction of 30%), and approximately half of the responders had at least a 75% decrease
in migraine frequency.26-29 Onset of action appears to be
early, significantly more than placebo at 4 weeks and
continuing up to 26 weeks.30 Approximately 6% of
patients have a greater than 95% reduction in mean
monthly migraine periods (Figure 5).26-28
Treatment-emergent side effects with topiramate
include weight loss, loss of appetite, nausea, taste
perversion, kidney stones, paresthesias, fatigue,
memory difficulty, and diarrhea.26 Those considered
to be most treatment-limiting are paresthesias,
fatigue, memory difficulty, and insomnia.31
Topiramate is a unique AED in that it is associated
with modest weight loss (up to 5% change in body
weight), which may be a benefit rather than an
adverse event for some patients. Pooled data from all
3 major studies show a dose response in weight loss
with topiramate (Figure 6).26-29
Overall, topiramate significantly reduces mean
monthly migraine periods at dosages of 100 mg and
200 mg/day (some patients may require doses as
high as 600 mg/day-800 mg/day). As with all
migraine-preventive treatment, it should be titrated
up slowly. If adverse events become intolerable, the
75%-94% Reduction
1
0.6
0.3
0.2
0
-1
-2
-3
-4
-2.2‡
-2.4†
-2.7‡
-3.3‡
-3.4‡
†
-3.9† -3.8
-4.5‡
-5
MIGR-001
MIGR-002
MIGR-003
*Least squares mean; = .004; ≤.001; = .025.
Data from Silberstein et al26; Brandes27; Diener28; Storey et al.29
†P
‡P
§P
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PROCEEDINGS
Table 3. AED Efficacy in Migraine: Responder Rate
AED
Responder Rate
Drug
Placebo
Divalproex
Klapper21
Mathew22
Freitag23
Jensen37
44%
48%
30%
50%
21%
14%
24%
16%
23%
34%
6%
34%
Topiramate
Silberstein26
Brandes27
54%
49%
23%
23%
31%
26%
Gabapentin32
36%
16%
20%
Difference
AED = antiepileptic drug.
small, double-blind, placebo-controlled study of 45
patients indicated that gabapentin had no effect on
migraine frequency.32 In a second double-blind, placebo-controlled study of 145 patients, the response rate
was 36% versus 16%, gabapentin versus placebo,
respectively, in the intent-to-treat population.33 The
most common drug-associated adverse events were
somnolence, dizziness, and asthenia; however only
somnolence occurred significantly more frequently
with gabapentin compared with placebo.33 Gabapentin
is dosed between 900 and 2400 mg 3 times daily with
a maximum dosage of 3600 mg/day.
The data for carbamazepine experience in migraine
are scarce and poorly described.34,35 Only 2 small double-blind, placebo-controlled studies with lamotrigine
have been published, and the results indicate that lamotrigine is ineffective in migraine prevention but may
have some benefit in treating aura symptoms.36,37 There
are no published data for the other AEDs (ie, zonisamide, levetiracetam, oxcarbazepine, vigabatrin, and
tiagabine).
Table 3 summarizes the responder rates in large clinical trials with the 3 main AEDs for migraine prophylaxis—divalproex, topiramate, and gabapentin.21-23,26,27,33,38
CONCLUSION
Managing patients with comorbid migraine and
epilepsy presents challenges—not only in diagnosis
but also in treatment options. The possibility of using
a single drug to treat both disorders is a “therapeutic
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opportunity.” However, given the differing and sometimes conflicting treatment principles and treatment
goals between migraine and epilepsy, the entire patient
profile should be considered in determining not only
optimal drug choice but also dosing and definition of
treatment success.
DISCUSSION
Dr Haut: I am always fascinated by the use of valproate and topiramate in migraine in contrast to
our experience in epilepsy. Many adult patients
with epilepsy have trouble tolerating topiramate,
and valproate has many troubling side effects. Is
there a difference in tolerance between migraine
and epilepsy patients?
Dr Silberstein: In my experience, migraine patients
respond differently than patients with epilepsy. Also, I
think the doses are different. What dose, for example, of
divalproex or topiramate would you give for epilepsy?
Dr Haut: The doses are higher, but with topiramate I often cannot get to the higher doses. I generally give 200 mg and above.
Dr Silberstein: For migraine, the general dose is
25 mg to 50 mg and we go very slow. If it takes us
8 weeks to titrate to 100 mg, we do not have to
worry about it. Since we know it takes a couple of
months to get the benefit, I am perfectly willing to
go up 15 mg or 25 mg every other week. Whereas
in epilepsy, you cannot wait 2 months to get a
patient with epilepsy under control. I think that is
the fundamental difference. With gabapentin, however, we need high doses, and we often have a lot
more side effects at higher doses, which we need for
migraine. With lamotrigine, if we go slow, we do
not seem to have a problem with rash, but it seems
to only be effective for migraine with aura, less
effective for patients with migraine without aura.
Most of the other AEDs do not seem to be effective.
Zonisamide may be, but the side-effect profile is
very similar to topiramate. Phenytoin and phenobarbital do not seem to have a benefit.
Oxcarbazepine does not seem to have a benefit
proven in placebo-controlled trials. We use that
more often for trigeminal neuralgia.
Dr Gidal: I have had similar experience with topiramate. I think it is a wonderful drug for headache in
our population, but like epilepsy, and presumably with
migraine, you get patients who are refractory.
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Dr Silberstein: We use lots of combination therapy.
We learned about combination therapy by accident.
If you had somebody on valproate who had a lot of
side effects, you decreased their dose and started
him/her, for example, on topiramate and his/her
headaches got better; on combination therapy the
patient did better than on monotherapy. I think that
the combination of topiramate and valproate is reasonable, as is the combination of AEDs with drugs of
an entirely different class. Nobody has thoroughly
studied these at all. In epilepsy, many of the new trials are using add-on therapy. So, you study a drug as
add-on first and then as monotherapy. In migraine it
is studied as monotherapy; nobody ever studies addon therapy. That is something that desperately needs
to be done in a refractory population to see if add-on
therapy makes a difference. We have never done it.
Juliet Pascual has open-label data for combination
therapy, but nobody has ever studied it scientifically.
Dr Lipton: It is considered unethical to treat a
migraine sufferer with placebo, so you cannot do
placebo-controlled trials.
Dr Gidal: To study topiramate as add-on therapy
in nonresponders might be interesting.
Dr Silberstein: It will take time to do that. There
are ongoing migraine trials now comparing topiramate
and amitriptyline. There are no good modern trials on
amitriptyline. The second ongoing trial is studying
chronic migraine. The ideal situation would be to
study add-on therapy in a patient who is not stable on
topiramate. It is going to be very difficult to get a
pharmaceutical company to do that, and it is difficult
so far to get federal funding to do what needs to be
done for headache studies.
Dr Lipton: When you do add-on therapy, would
you tend to do combinations within a class, such as 2
neuromodulators, or would you be more inclined to
do combinations across classes?
Dr Silberstein: Both. It depends on what they are.
For example, I would not combine zonisamide with
topiramate, or topiramate with gabapentin, but I
would combine topiramate with valproate simply
because I discovered that by accident. If I have somebody on monotherapy, I am more likely, in general, to
add drugs of another class, but occasionally I will use
topiramate. Patients often will do well on something
like valproate, but they cannot take the side-effect profile of weight gain or tremor. So, we often find that low
doses of 2 drugs work together just as for epilepsy. But
Advanced Studies in Medicine
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that is, I think, a refractory strategy. In less difficult
patients, I might simply add a small amount of an
antidepressant to a small amount of a neuromodulator,
taking cues from a large amount of experience from
psychiatry in treating bipolar disorder.
Dr Krumholz: In epilepsy treatment, we often look
at blood levels to guide therapy. Do you do that in
migraine patients?
Dr Silberstein: Blood levels are mainly a truth
detector. The major value is if I have a patient who is
on a lot of medicine, and he/she is not doing well, and
he/she has no side effects, you would be amazed that
when you get a level back he/she finally tells you the
truth—that he/she was not taking the drugs but did
not want to tell me because he/she did not want to
hurt my feelings. I have a few reliable patients who
have no benefit and no side effects. Most often, I just
follow the side-effect profile and the patient’s response.
Dr Lipton: The exception may be nortriptyline in
high doses.
Dr Silberstein: The exception to my rule is when
I start using drugs like nortriptyline and amitriptyline
at levels used to treat depression, because of the potential cardiac adverse events. But it is more a safety concern than a therapeutic concern.
Dr Lewis: One difference from the pediatric perspective is the use of another antiepileptic drug, levetiracetam. There is one retrospective report, which
included 19 children, mean age of 12, who were treated
with 125 to 250 mg twice daily for 4 months to reduce
the frequency of their migraines. The mean frequency of
headache attacks before treatment was 6.3/month and
after treatment, fell to 1.7/month (P <.0001). More than
half of them experienced “elimination” of migraine and
there were no side effects in the 80% of the children, but
10% discontinued the drug due to side effects.39
Dr Silberstein: It is hard to tell what mechanism of
an AED will work for both diseases. For example,
valproate and topiramate both work for migraine
and epilepsy. Why don’t some of the other medicines work? I understand that pregabalin has been
approved by the FDA [US Food and Drug
Administration], but is being held up by the DEA
[Drug Enforcement Administration]. Did you
know that?
Dr Gidal: There are 2 lines of evidence. One, there
is some preclinical evidence suggesting euphoria, and
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the agencies decided that could lead to some drugseeking behavior in patients. So, my guess is the DEA
is going to make it a schedule IV drug. I have looked
on the FDA’s Web site; I can only find the approvable
letters for the pain indication, and there are no action
items on epilepsy.
Dr Gidal: I want to turn the headache story
around, to ask about exacerbation of headaches. I
have had a reasonable amount of anecdotal experience with carbamazepine. It appears that it worsens
their complaints of headache. How about exacerbation with AEDs?
Dr Silberstein: I look at migraine like a roller coaster. Often patients will come to you when their headaches
are getting worse, and they get better, and they get worse
again, and it is difficult to tell whether it is the drug. It
could be just coincidental, or it could be an adverse event
from the drug. It can aggravate the migraine, so it is hard
to tell. Certain drugs, I am convinced, make people
worse, but I have not seen this with carbamazepine. I
think it is neutral, to be honest with you. But if you give
a patient a drug and he/she gets a constant side effect,
that can make people migrainous.
Dr Lewis: What is the usual duration of treatment
for prevention of migraine?
Dr Silberstein: We don’t know. That is the bottom
line, and you get a bunch of people in the room, you
force them to stay there, they all come up with
6 months. Nobody has yet done discontinuation trials.
Nobody has done well-controlled trials.
In the 001 and 002 topiramate trials, we have longterm data, but it is open-label. In the European 003
trial, it is placebo-controlled, so eventually we may
have some data on what happens to patients who have
been discontinued. We do not know the answer to that
question. It has not been done. Nobody has shown
whether, if a patient is on a drug for 6 months and well
controlled, he or she needs to continue on the drug.
Very practically, I say if the headache is controlled for
6 months, that is the magic number, and we try to
taper and discontinue the medication.
Dr Lewis: In kids, we use September until June,
during the school year.
Dr Silberstein: Everybody knows headaches get
better in the summertime.
Dr Kossoff: For some of the epilepsy drugs when
we are treating epilepsy, the half-life is important. So,
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twice-daily and 3-times-daily dosing for some of
these drugs matters, but it seems like in migraine it is
not as important.
Dr Silberstein: We are lucky because we give the
extended-release formulation of valproate at bedtime,
and topiramate has close to a 24-hour half-life. So, we
can if we need to give topiramate at bedtime. I start it
twice daily mainly because its Tmax is 1 hour, and when
you are titrating up the dose, I think there are fewer side
effects by splitting the dose to begin with. When you get
steady-state levels, you can go to once-a-day dosing.
Dr Lipton: Once-a-day dosing is certainly a huge
advantage.
Dr Haut: But for epilepsy, once-daily dosing for
valproate ER formulation is not recommended
because of the reliance on steady-state levels.
Dr Silberstein: Yes, but in migraine we do not
have to worry about that. It is very interesting. In
epilepsy, the drug level is associated with seizure control. It is not in migraine, and my guess is that epilepsy is probably a neuronal disease, migraine is a glial
disease, and there is increasing evidence now that a lot of
the problems in both migraine and chronic neuropathic
pain states are probably related to abnormalities in glia.
In familial hemiplegic migraine Type II, the ATPase fundamental abnormality is in the alpha 2 subunit of the
Na/K pump, involved in glia transport of glutamate. So
I think that is the fundamental difference. It may be the
way epilepsy produces migraine, with secondary changes
in the surrounding tissue.
Dr Lipton: Do you want to comment on whether
preventive therapy alters the efficacy of the key
treatment?
Dr Silberstein: There is a trial now being designed
to prove that. David Dodick did a subset analysis in
topiramate trials and showed it did. It is our experience over and over again that a patient will come in,
take an acute drug and it does not work, but they go
on a preventive drug and it works. There are a lot of
ideas about why that happens. Rami Burstein has
shown that in patients who develop central sensitization
(which is manifested as allodynia, in which unpainful
stimuli hurt), a lot of the acute drugs do not work or do
not work as well.40 We have some evidence in our laboratory that preventive drugs may inhibit central sensitization. If that is the case, it may explain the synergism
between acute and preventive medication. Our experience has been that acute drugs work better in the pres-
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PROCEEDINGS
ence of preventive medication. The mechanism may be
decreased central sensitization, but there still needs to be
a lot more work. A trial now going on will look at a triptan (almotriptan) alone and in conjunction with a preventive medication (topiramate) in unblinded
conditions, to see if that makes a difference. We believe
it, and finally somebody is testing it.
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