1. No category

PROCEEDINGS
PREVENTIVE THERAPY FOR MIGRAINE:
FOCUS ON 2 NEW TREATMENTS*
—
Based on a presentation by Stephen D. Silberstein, MD, FACP†
ABSTRACT
There are 7 classes of preventive migraine
drug therapy: antiepileptic drugs (AEDs), antidepressants, beta blocking agents, calcium channel
blocking agents, nonsteroidal anti-inflammatory
drugs, serotonin antagonists, and a general
eclectic group of “other” drugs. Most of these
drugs were originally designed or discovered to
treat other disorders. All 7 classes of migraine
preventive therapies are used off label on a regular basis, with varying levels of scientific evidence to support their use. AEDs are one of the
most common first-line agents used in migraine
prophylaxis. Good scientific evidence supports
the use of gabapentin, valproate, and carbamazepine for this indication based on recommendations from the US Headache Consortium.
Topiramate is the most recently developed AED
and, to date, shows positive results in migraine
prevention. Botulinum toxin A (Btx-A) is classified
under “other” and has shown benefit as both
acute and preventive migraine therapy. The most
recent safety and efficacy data for these 2 drugs
are discussed in this article. Topiramate appears
to be a safe and effective migraine preventive
treatment with relatively mild-to-moderate side
effects, and 2 more serious side effects (acute
myopia and secondary angle-closure glaucoma,
and treatment-emergent depression) appear to
*Based on a presentation by Dr Silberstein at the
American Headache Society Scottsdale Headache
Symposium.
†Director, Jefferson Headache Center, Professor of
Neurology, Thomas Jefferson University; Clinical Professor of
Neurology, Temple University, Philadelphia, Pennsylvania.
Advanced Studies in Medicine
■
be rare and apparently reversible with treatment
discontinuation. The efficacy of Btx-A in tensiontype headache is not yet unequivocal, but in
migraine prevention, it appears to offer some
benefit. Further work to identify appropriate
injection sites, doses, and treatment duration is
needed to optimize the potential for this therapy.
(Adv Stud Med. 2003;3(3B):S153-S158)
reventive medication for migraine is
designed to decrease frequency, severity,
and duration of migraine headaches. There
are 7 classes of preventive migraine drug
therapy: antiepileptic drugs (AEDs), antidepressants, beta blocking agents, calcium channel
blocking agents, nonsteroidal anti-inflammatory
drugs, serotonin antagonists, and a general eclectic
group of “other” drugs. Most of these drugs were
originally designed or discovered to treat other disorders. Methysergide, a serotonin antagonist, was
the only rationally developed migraine preventive
drug, based on the concept that migraine was caused
by excess serotonin. Antidepressants downregulate
serotonin and beta-adrenergic receptors; AEDs
decrease glutamate and enhance gamma amino
butyric acid (GABA).
All 7 classes of migraine preventive therapies are
used off label on a regular basis and have varying levels of scientific evidence to support their use.
Numerous classes of drugs are used to prevent
migraine, none of which is effective in every
P
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PROCEEDINGS
migraineur, strongly suggesting multiple mechanisms
are involved in the manifestation of a migraine
headache. As we have “the epilepsies,” we are most
likely also treating “the migraines.”
Migraine preventive therapies are thought to be
effective by one of several mechanisms that raises the
threshold to migraine activation (ie, inhibiting the
migraine generator, enhancing antinociception, or
inhibiting cortical spreading of depression)—they
appear to stabilize a more reactive nervous system.
Figure 1. Topiramate Responder Rate: MIGR-001*
PRINCIPLES OF PREVENTIVE MIGRAINE THERAPY
Before the availability of triptans, most treatment
recommendations (as a guideline for preventive therapy use) focused on the number of attacks occurring
each month to determine if preventive therapy was
warranted. Given the wide choices for therapy available, however, preventive treatment guidelines must
also consider patients’ response to acute medication,
patients’ needs or preferences, and characteristics of
migraine attacks. Patients’ needs and preferences
include the degree to which the migraine attacks interfere with daily routine despite appropriate acute therapy as well as any comorbid or coexisting conditions
or concomitant medications. Overall, the goals of preventive migraine therapy are to reduce attack frequency, severity, and duration; improve responsiveness to
acute treatment; and improve function and reduce
disability.
The US Headache Consortium has evaluated the
scientific evidence for all drugs in each class of preventive therapy. AEDs are one of the most common firstline agents used in migraine prophylaxis. Good
scientific evidence supports the use of gabapentin, valproate, and carbamazepine for this indication.
Topiramate is the most recently developed AED and,
to date, shows positive results in migraine prevention.
Botulinum toxin A (Btx-A) is classified under “other”
and has shown benefit as both acute and preventive
migraine therapy. The most recent safety and efficacy
data for these 2 drugs are discussed below.
TOPIRAMATE
Topiramate is a structurally unique AED—it is an
analog of a fructose-1-6-diphosphate but devoid of
hypoglycemic activity. Its resemblance to acetazolamide prompted its evaluation as an AED in epilepsy
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*Results as of November 2002.
†P = .039.
‡P < .001.
TPM = topiramate.
Table 1. AED Efficacy in Migraine Prevention
Responder Rate (%)
AED Type
Drug
Placebo
Difference
Gabapentin
Mathew12
36
16
20
Divalproex
Mathew13
Klapper14
48
44
14
21
34
23
Topiramate
Silberstein
54
23
31
AED = antiepileptic drug.
Data from Mathew et al12,13; and Klapper.14
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PROCEEDINGS
models. It is approved for the treatment of epilepsy as
adjunctive therapy in adults and children aged 2 to 16
years with partial onset seizures or generalized primary
clonic-tonic seizures, or seizures associated with LennoxGastaut syndrome (in patients older than 2 years).1
Topiramate affects several neurological pathways. Those
believed to be involved in migraine prevention include
blocking calcium channels, sodium channels,
AMPA/kainate receptors, and GABA channels, and
inhibiting carbonic anhydrase.2 Its broad activity among
cell membrane receptors is thought to be due to inhibition of protein kinase A phosphorylation.2
In small studies, topiramate has demonstrated
solid efficacy in migraine prophylaxis with relatively
minor side effects.3-7 It has also shown efficacy in cluster headache.7-10 Topiramate is under evaluation in 3
large, international clinical trials (MIGR-001, -002,
and -003) and a large US study (CAPSS-155).
MIGR-001 is a randomized, double-blind, placebo-controlled, parallel-group study comparing topiramate (50 mg, 100 mg, and 200 mg) vs placebo in 469
patients. After a 14-day washout period, a 28-day
baseline period, and an 8-week titration phase,
patients received their maintenance doses for 18
weeks. To date, results show the best response (defined
as at least 50% reduction in migraine periods) were
observed with the 100-mg and 200-mg doses (Figure
1), although the 50-mg dose also produced a significant response. The responder rate of topiramate is
comparable to that observed with the 2 other most
commonly used AEDs (Table 1).11-13
Topiramate is also known for its effect on weight loss,
and study results from MIGR-001 support this finding.
The higher doses of topiramate have produced almost
4% decreases in mean body weight (P < .004) after 18
weeks of treatment. The 50-mg dose was associated with
a 2.6% decrease in mean body weight (P < .004).
Investigators have also noted a correlation between body
weight at study onset and loss of body weight (ie, those
who are heavier tend to lose the most weight).
For any migraine preventive agent, treatmentemergent adverse events are important, especially if
the primary goal is to reduce disability and if
migraineurs are taking other medications. In MIGR001, the most common adverse events included paresthesias, taste change, loss of appetite, nausea, diarrhea,
memory difficulty, and dizziness (Table 2). Rates of
dizziness and nausea were not largely different from
placebo; diarrhea was predominantly seen with higher
Advanced Studies in Medicine
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Table 2. Treatment-Emergent Adverse Events:
MIGR-001*
Topiramate, n (%)
Event
Paresthesias
Placebo, n (%) 50 mg
(n = 116) (n = 118)
8 (7)
43(36)
100 mg
(n = 126)
200 mg
(n = 113)
59 (47)
53 (47)
Taste change
2 (2)
23 (19)
13 (10)
16 (14)
Loss of appetite
5 (4)
13 (11)
16 (13)
16 (14)
Nausea
14 (12)
8 (7)
20 (16)
16 (14)
Diarrhea
8 (7)
8 (7)
14 (11)
17 (15)
Memory difficulty
3 (3)
11 (9)
9 (7)
14 (12)
13 (11)
9 (8)
10 (8)
14 (12)
Dizziness
*Results as of November 2002.
Figure 2. Btx-A and Number of Moderate-to-Severe
Migraine Attacks per Month
*P<.042 vs the vehicle group.
Btx-A = botulinum toxin A.
Adapted with permission from Silberstein et al.22
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PROCEEDINGS
doses. Paresthesias were the most common adverse
event. It has been our clinical experience that potassium chloride (20-40 mEq per day) can alleviate paresthesias in most of these patients.14
RECOMMENDATIONS FOR USE
The best starting dose of topiramate for
migraine prevention is 25 mg, increasing by
15 to 25 mg each week. The “start low, go
slow” strategy is useful for topiramate as well
as other AEDs; benefit with topiramate can
be seen at doses as low as 50 mg. The optimal
dose appears to be 50 mg to 100 mg per day.
If treatment-emergent adverse events are
reported, 2 options are available: restart therapy at 7.5 to 15 mg daily; or decrease the dose
to a slightly lower dose, wait until the symptoms resolve, then increase slowly by smaller
amounts (eg, 7.5 mg per week).
Acute myopia and secondary angle-closure glaucoma have also been reported with
topiramate use.15-19 Typically, the myopia
and glaucoma are observed very early in
treatment (mean onset, 7 days; range, 1–49
days) with acute onset, do not resolve with
lowered doses, and are reversible with drug
discontinuation.19 In these rare cases (54
cases in 1.25 million treated as of March
2002), treatment with topiramate should be
discontinued. Anecdotally, depression, if it
occurs and is related to topiramate, also
appears early in treatment and does not
respond to lower doses. Treatment should
also be discontinued if this occurs.
BOTULINUM TOXIN A
Several studies have suggested the efficacy
of Btx-A in treating tension-type headache,
but the data are not conclusive.20-22 The rationale behind Btx-A therapy in tension-type
headache was based on its effect on muscle
pain and the hypothesis that increased muscle tension may contribute to tension-type
headaches. Btx-A reduces muscle tenderness
and pain in many diseases associated with
myofascial pain. The moderate or missed
effects of Btx-A in tension-type headache
may be due to incorrect or suboptimal choice
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of injection sites, dose of botulinum toxin, or duration
of treatment.22
Only 1 randomized, placebo-controlled study of
pericranial injection of Btx-A for migraine prevention
has been published.22 In this study, 123 subjects with a
history of 2 to 8 moderate-to-severe migraine attacks
per month, with or without aura, were randomized to
Table 3. US Headache Consortium: Migraine Prevention
Quality of
Evidence*
Scientific
Effect
Clinical
Impression
Adverse
Effects
Antiepileptic
Divalproex
Gabapentin
Topiramate
A
B
A
+++
++
+++
+++
++
+++
Occasional to frequent
Occasional to frequent
Occasional to frequent
Antidepressants
Amitriptyline
Nortriptyline
Fluoxetine
A
C
B
+++
?
+
+++
+++
+
Frequent
Frequent
Occasional
Beta blockers
Propranolol
Timolol
Atenolol
A
A
B
++
+++
++
+++
+++
++
Infrequent to occasional
Infrequent to occasional
Infrequent to occasional
Calcium channel blockers
Diltiazem
C
Verapamil
B
?
+
0
++
Infrequent to occasional
Infrequent to occasional
NSAIDs
Aspirin
Ibuprofen
Naproxen
B
C
B
+
?
+
+
+
+
Infrequent
Infrequent
Infrequent
Serotonin antagonists
Cyproheptadine
Methysergide
C
A
+
+++
+
+++
Frequent
Frequent
Other
Feverfew
Riboflavin
B
B
++
+++
+
++
Infrequent
Infrequent
Drug
*A = Multiple well-designed randomized clinical trials, directly relevant to the recommendation,
yielded a consistent pattern of findings; B = Some evidence from randomized clinical trials supported the recommendation, but scientific support was not optimal. Either few randomized trials existed, the trials that did exist were somewhat inconsistent, or the trials were not directly
relevant to the recommendation. An example of the last point would be the case where trials
were conducted using a study group that differed from the target group for the recommendation; C = The US Headache Consortium achieved consensus on the recommendation in the
absence of relevant randomized clinical trials.
NSAIDs = nonsteroidal anti-inflammatory drugs.
Adapted with permission from Silberstein et al.24
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PROCEEDINGS
receive single administrations of vehicle or Btx-A, 25 U or
ventive drugs based on their scientific efficacy.
75 U, injected into multiple sites of pericranial muscles at
Topiramate is considered a high-efficacy drug for
the same visit. Efficacy was based on patients’ daily
migraine prevention based on the quality of evidence,
diaries, in which they recorded migraine frequency,
scientific effect, and clinical impression (Table 3).
migraine severity, and occurrence of migraine-associated
Topiramate may also be used to treat epilepsy and possisymptoms. Results from 3-month follow-up postinjecbly mania as coexisting conditions with migraine, with
tion show 50% reduction in the number of moderate-torelatively few side effects (Table 4).24,25 Btx-A does not
appear to have any relative contraindications and may be
severe migraine attacks per month by the second month
preferred by some patients who want more “natural”
in patients receiving 25 U Btx-A (Figure 2). Unexpectedly, patients responded better to the 25-U
dose than to the 75-U dose. As with the tension-type headache studies, the cause of this
paradox may lie partly in the choice of injection sites. In this study, 6 sites were chosen
but were not necessarily related to location of
Table 4. Migraine Prevention and Coexisting Conditions
pain. Greater experience with optimal injection sites may improve the efficacy findings.22
An open-label study of 77 migraineurs
Comorbid Condition
also showed important positive responses to
Side
Relative
Relative
Btx-A for migraine prevention. With a
Drug
Efficacy Effects
Contraindication
Indication
mean 4.1 months’ duration of response,
51% (95% confidence interval, 39% to
Anticonvulsants
62%) reported complete response (sympDivalproex
4+
2+
Liver disease,
Mania, epilepsy,
tom elimination); 38% reported partial
bleeding disorders
anxiety disorders
Gabapentin
2+
2+
Epilepsy, mania?
response (≥50% reduction in headache freTopiramate
4+
2+
Kidney stones
Epilepsy, mania?
quency or severity), with a mean response
Antidepressants
duration of 2.7 months. Of 10 migraineurs
Tricyclics
4+
2+
Mania, urinary
Other pain disorders,
treated with Btx-A as acute treatment, 70%
retention, heart
depression, anxiety
reported complete response with improveblock
disorders, insomnia
ment 1 to 2 hours after treatment. No
SSRIs
2+
1+
Mania
Depression, OCD
adverse effects were reported.23
MAOIs
2+
4+
Unreliable patient
Refractory depression
As with other migraine preventive theraAntiserotonin
Methysergide 4+
4+
Angina, PVD
Orthostatic hypotension
pies, the exact mechanism of Btx-A in
Beta blockers
4+
2+
Asthma, depression,
Hypertension, angina
migraine—as acute or preventive therapy—is
CHF, Raynaud’s
not fully known. The prevailing hypothesis is
disease, diabetes
that Btx-A is an antinociceptive, with reducCalcium
channel
blockers
tion of muscle spasm related to pain, direct
Verapamil
2+
1+
Constipation,
Migraine with aura,
inhibition of nociceptive fibers with reduced
hypotension
hypertension, angina,
peripheral pain sensation, and indirect moduasthma
lation of the central nervous system. Further
NSAIDs
work is now being done to more precisely
Naproxen
2+
2+
Ulcer disease,
Arthritis, other
gastritis
pain disorders
characterize the mechanism of action of BtxOther
A in migraine prevention.
MIGRAINE PREVENTIVE DRUGS: SCIENTIFIC
EVIDENCE
The US Headache Consortium guidelines examined all 7 classes of migraine pre-
Advanced Studies in Medicine
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Riboflavin
Feverfew
Btx-A
2+
2+
2+
1+
2+
1+
Preference
for natural
products
SSRIs = selective serotonin reuptake inhibitors; OCD = obsessive-compulsive disorder; MAOIs =
monoamine oxidase inhibitors; PVD = peripheral vascular disease; CHF = congestive heart failure;
NSAIDs = nonsteroidal anti-inflammatory drugs; Btx-A = botulinum toxin A.
Adapted with permission from Silberstein et al.25
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PROCEEDINGS
treatments for their headaches (Table 4). Btx-A has not
yet been evaluated by the US Headache Consortium.
CONCLUSION
Topiramate appears to be a safe and effective
migraine preventive treatment with relatively mild-tomoderate side effects; 2 more serious side effects (acute
myopia and secondary angle-closure glaucoma, and
treatment-emergent depression) appear to be rare and
apparently reversible with treatment discontinuation.
The efficacy of Btx-A in tension-type headache is not
yet unequivocal, but it appears to offer some benefit in
migraine prevention. Further work to identify appropriate injection sites, doses, and duration of treatment
is needed to optimize the potential for this therapy.
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