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Publication Date: January 2007
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MIGRAINE PROPHYLAXIS

Julie Cromer, Pharm.D. Candidate


Migraine is a chronic, debilitating neurologi-
cal disorder with major implications on patient qual-
ity of life. As estimated in 2001, migraine affects
approximately 12% of Americans.1 Migraine occurs
more frequently in women (18%) than in men (6%),
and prevalence peaks around middle age, although it
occurs at all ages. The cost associated with migraine
and the undertreatment of migraine is significant.
Direct costs include the cost of medications and
health care expenses. Headache treatment accounts
for approximately one third of total OTC sales in the
US. The cost of prescription medications to treat
migraine is estimated to be at least $2 billion.2 The
indirect cost of migraine due to lost productivity is
between $5.6 and $17.2 billion.3 Acute treatment
with agents such as analgesics, anti-emetics and trip-
tans is often necessary in migraine sufferers, but
some patients require preventive treatment as well.
The goals of prophylactic treatment are to reduce
duration and severity of migraines, decrease fre-
quency (successful prophylaxis is considered a 50%
reduction in frequency within 3 months), improve
quality of life and minimize patient disability. Mi-
graine prevention may also decrease the rate of mi-
graine transformation to chronic daily headache.2
This article will focus on the current guidelines for
the use of migraine prophylaxis, as well as the role of
various agents in preventing migraine.


Pathophysiology
Migraine headaches have a multifactorial eti-
ology in which genetic and environmental factors
have a strong role. Migraine was initially believed to
be due to a progression of vascular events, beginning
with a period of vasoconstriction followed by vasodi-
lation and inflammation. This theory has evolved
into the belief that neurovascular instability is the
source of migraine, where vasoconstriction is the
cause of aura associated with migraine, and vasodila-
tion is the cause of throbbing pain.

Indications for Prophylaxis
Identification of patients needing migraine
prevention is imperative, as migraine is largely under
treated in the US.4 Many migraine sufferers (49%)
only use over-the-counter (OTC) drugs to treat acute
migraine, while even fewer (20%) use prescription
medications and approximately 29% of sufferers use
both. Approximately 12% of migraine sufferers util-
ize a daily prophylactic drug.5 Based on the 2006
European Federation of Neurological Sciences
(EFNS) Task Force guidelines, preventive treatment
for migraine should be considered when there is se-
vere impairment of quality of life, business duties, or
riL. .,^l


mm
PharmaNote Volume 22, Issue 4 January 2007


SPharmaNote


VOLUME 22, ISSUE 4 JANUARY 2007


INSIDE THIS ISSUE:

MIGRAINE PROPHYLAXIS


Volume 22, Issue 4 January 2007


PharmaNote







school attendance; frequency of attacks is two or
more per month; migraine attacks are unresponsive
to acute drug treatment; and attacks are accompanied
by frequent, very long, or uncomfortable auras.6
The 2000 US Headache Consortium Guideli-
nes7 offered more definitive standards for prophy-
laxis consideration as:

A. Recurring migraine that significantly in-
terferes with the patient's daily routine
despite acute treatment, for example:
1. Two or more attacks a month that
produce disability that lasts >3 days
2. Attacks that are infrequent but pro
duce profound disability
B. Failure, contraindications to, or trouble-
some side effects from acute medications
C. Overuse of acute medications


D. Special circumstances, such as hemiple-
gic or basilar migraine or attacks with a
risk of permanent neurologic injury
E. Very frequent headaches (more than 2 per
week) or a pattern of increasing attacks
over time, with the risk of developing
medication overuse
F. Patient preference

Choosing a prophylactic agent should be in-
dividualized to the patient with considerations for
efficacy, contraindications, precautions, side effects,
concurrent disease states, adherence and cost. Prior
to initiating and along with pharmacological preven-
tion of migraine, patients should be counseled on
nonpharmacological preventative measures. These
measures include maintaining regular sleep patterns,
eating regular meals, exercising and avoiding known


Table 1: Evidence supporting fi-blockers for migraine prophylaxis
Study (year) Design Outcome Discussion


Linde et al.10 (2i 14)


Holroyd et al.1 (1991)





Stellar et al.12 (1987)







Tfelt-Hansen et al.13
(1984)


Cochrane database review of 58
trials with 5,072 total partici-
pants comparing propanolol
(Inderal) to placebo or other
prophylactic medications




Meta-analysis of 2,403 patients
receiving propanolol for mi-
graine prevention



Comparison of timolol
(Blocadren) to placebo in 107
patients





Compared prophylactic effect of
timolol (10mg BID) and pro-
pranolol (80mg BID) to placebo
in 96 chronic migraine sufferers.


Calculated responder ratio
(comparable to relative risk) of
1.9 (95% confidence interval
[CI], 1.60 to 2.35)





Propanolol resulted in a 44%
average reduction of migraine
activity versus 14% with placebo



Patients receiving 20 to 30mg/
day of timolol showed signifi-
cantly reduced frequency and a
global response rate of 65% com-
pared to 40% on placebo.



The mean frequency of attacks
per 28 days was 3.35 on timolol,
3.69 on propranolol and 4.83 on
placebo. Mean severity of attacks
(0-3) was 1.75 on timolol, 1.83
on propranolol, and 1.93 on pla-
cebo. The difference between
propranolol and timolol was non-
significant: frequency of attacks
0.34 (95% CI, 0.26 to 0.89).


Many trials included had
methodological limitations.
Reviewers concluded that evi-
dence on long-term effects is
lacking, but propranolol seems
to be as effective and safe as
other drugs used for prophy-
laxis.

Modal treatment dose of
160mg daily supported propa-
nolol for short-term effective-
ness.


There was no change in sever-
ity or duration of migraines
which did occur. Timolol was
well tolerated.




Concluded that timolol and
propranolol are equally effec-
tive in doses for common mi-
graine prophylaxis.


Phrm~oe oum 2, sse4 anar 20


Volume 22, Issue 4 January 2007


PharmaNote







triggers such as specific food items (i.e. foods con-
taining nitrites and MSG), stress, bright lights and
strong odors. It is important for patients to maintain
a headache diary to allow prophylactic measures,
pharmacological and nonpharmacological, to be as-
sessed for efficacy and appropriateness.

Pharmacologic Options for Prophylaxis

f-blockers
Current clinical evidence suggests the use of
the P-blockers in migraine prophylaxis is appropri-
ate. Both propanolol (Inderal) and timolol
(Blocadren) are identified as first-line agents by the
2002 American Academy of Family Physicians and
American College of Physicians-American Society
of Internal Medicine guidelines.8 Migraine prophy-
laxis does not appear to be a class effect however.
Of the P-blockers, only timolol and propanolol are
identified as first line agents for migraine prophy-
laxis (Table 1). There is limited evidence supporting
the use of atenolol (Tenormin), the long-acting
preparation of metoprolol (Toprol XL), and
nadolol (Corgard).8 Silberstein et al. has proven
several P-blockers to be ineffective in the prevention
of migraine, including acebutolol (Sectral) and pin-
dolol (Visken).9 Common side effects of P-
blockers include drowsiness, fatigue, bradycardia
and decreased exercise tolerance. In patients with
comorbid chronic heart failure, asthma, Raynaud's
disease and insulin-dependent diabetes, alternative
first-line agents may be appropriate.

Tricyclic antidepressants
Amitriptyline (Elavil) is the only antide-
pressant with consistent evidence supporting its use
as a prophylactic agent. Couch et al.14 studied 162
persons with migraines compared amitriptyline ther-
apy (50 to 100 mg daily) with placebo over 4 weeks.
Results showed an odds ratio (OR) of 2.4 (95% CI,
1.1 to 5.4) for the number of patients reporting a
50% improvement in migraine index. Ziegler et al.15
compared amitriptyline with propranolol, suggesting
that propranolol is more effective in patients with a
single migraine type, whereas amitriptyline is more
beneficial for patients with mixed migraine and ten-
sion features. Amitriptyline significantly reduced
severity, frequency, and duration whereas propanolol
only reduced severity in this study. Amitriptyline is
also useful in patients with comorbid insomnia or,


when used at higher dosages, depression.

Divalproex sodium or valproic acid
The anticonvulsants divalproex sodium
(Depakote) and valproic acid are well supported by
evidence for use in migraine prevention. For a mi-
graine frequency reduction of 50% or more, authors
of a Cochrane Review of anticonvulsants for mi-
graine prophylaxis calculated a number needed to
treat (NNT) of 3.1 (95% CI, 1.9 to 8.9) for valproic
acid and 4.8 (95% CI, 3.5 to 7.4) for divalproex so-
dium.16 The Cochrane Review also showed that anti-
convulsants as a class have a low number needed to
harm (NNH).16

Topiramate
Several clinical trials, both open-label and
controlled, indicate that topiramate (Topamax) is
effective in migraine prophylaxis, and it is now con-
sidered a first-line agent (Table 2). In two concurrent
randomized, double-blind, placebo-controlled trials,
937 participants were randomized to receive topi-
ramate 50, 100, or 200 mg per day or placebo for 26
weeks. In both trials, more patients had at least a
50% reduction in monthly migraine frequency with
topiramate 50 to 200 mg per day (36 to 52%, respec-
tively) than with placebo (23%). The NNT for a dos-
age of 100 mg topiramate per day is 3.5 (95% CI, 2.8
to 4.9).16 Adverse events include weight loss, paras-
thesias and cognitive dysfunction, which can be re-
duced with slow dose titration. Comparative studies
with other prophylactic agents have yet to be con-
ducted.
Prophylaxis should be initiated with a first-
line agent, taking into consideration potential side
effects, special indications the patient may have,
cost, as well as efficacy based on current evidence.
Table 3 summarizes the drug classes currently con-
sidered as first-line migraine prevention options.

Second-line agents for migraine prevention

Gabapentin (Neurontin) has demonstrated
efficacy at dosages of 1,200 to 2,400 mg per day in
two clinical trials. At a dosage of 2,400 mg per day,
the NNT to reduce headache frequency by 50% or
more was 3.3 (95% CI, 2.1 to 8.4). 16,21 Further
evaluation for the use of gabapentin is warranted.
The most common adverse events associated with
gabapentin are dizziness and somnolence.


PharmaNote Volume 22, Issue 4 January 2007


Volume 22, Issue 4 January 2007


PharmaNote







Table 2: Evidence supporting topiramate for migraine prophylaxis


Study (year)
Silberstein et al.17 (21i"14






Brandes etal.18 (2"i14)







Peres et al.19 (2006)






Silvestrini et al.20 (2003)


Design
Randomized, double-blind,
placebo-controlled trial; 487
patients




Randomized, double-blind,
placebo-controlled trial; 483
patients





Open label study of 64 pa-
tients receiving topiramate 25-
500mg (median dose of
100mg)



Randomized, double-blind,
placebo-controlled trial of 28
patients with chronic migraine
with analgesic overuse re-
ceived 50mg or placebo


Nonsteroidal anti-inflammatory drugs
(NSAIDs) can be used daily or intermittently for mi-
graine prophylaxis. When migraine triggers are pre-
dictable, such as during menstruation, intermittent
therapy may be used. Migraines can be prevented
during menstruation when NSAIDs are used begin-
ning several days prior to start of menstruation and
continuing for the first few days of menses.22
Naproxen sodium (Naprosyn) is the most com-
monly used NSAID for migraine prophylaxis and the
dose is 1,100 mg daily. Adverse effects include dys-
pepsia, peptic ulceration and GI bleeding, but tend to
be infrequent with short-term therapy, increasing
with extended treatment. NSAIDs can be especially
helpful in patients with concurrent osteoarthritis or
dysmenorrhea.
Schrader et al.23 found the angiotensin-
converting enzyme inhibitor lisinopril (Zestril) to
be effective in the prevention of migraine. In a ran-
domized, double-blind, crossover trial with 55 pa-
tients, lisinopril 20 mg per day for 12 weeks reduced
the mean number of days with headache and the
mean number of days with migraine compared with


placebo. Thirty percent of patients receiving lisino-
pril experienced a 50% or greater reduction in the
number of days with migraine. Lisinopril was well
tolerated, although it was associated with a higher
incidence of cough than placebo.
The angiotensin receptor blocker candesartan
(Atacand) was evaluated in a prospective, random-
ized, double-blind, crossover study with 60 pa-
tients.24 As with lisinopril, candesartan 16 mg per
day reduced the mean number of days with headache
and with migraine compared with placebo. Candesar-
tan also appeared to significantly decrease headache
severity, level of disability, and days of sick leave
due to headache. The rate of response to candesartan,
based on a 50% or more reduction in the number of
days with migraine, was 40.4%, compared with 3.5%
for placebo (P < .001). Adverse effects with cande-
sartan were similar to those with placebo.
There is limited evidence for the use of cal-
cium channel blockers in migraine prophylaxis. Evi-
dence does not support the use of diltiazem
(Cardizem) in migraine prevention, and there is
only weak evidence in support of nifedipine


PharmaNote Volume 22, Issue 4 January 2007


Outcome
Reduction in migraine fre-
quency of 36% (50mg/day
dose), 54% (100mg/day), and
52% (200mg/day) compared
to 22% reduction on placebo.


Reduction in mean monthly
migraine frequency, migraine
days and rescue medication
use significant in both 100mg/
day and 200 mg/day groups
versus placebo.


>50% reduction in migraine
frequency achieved in 66% of
patients, with 28% having a
complete response (frequency
reduction > 95%)


Significant reduction in fre-
quency with topiramate use
(mean number of days with
headache 8.1 in topiramate
group vs 20.6 in placebo, P <
0.0007).


Discussion
No additional benefit was seen
in topiramate 200mg/day over
100mg/day.




Participants reported improve-
ment in migraine frequency
within the first month of treat-
ment, and effect continued for
duration of treatment.



Topiramate was well-
tolerated; only 6 patients
dropped out of study due to
adverse events. Target dose
appeared to be 100mg.


Topiramate reduced migraine
frequency in patients with
chronic migraine associated
with analgesic overuse.


Volume 22, Issue 4 January 2007


PharmaNote







Table 3: Overview of First-line Agents for Migraine Prophylaxis
Drug Class Dosages Side effects Special indications ARP Cost
P-Blockers Propranolol: 40 to 320 mg (kI '-241, Fatigue, Bradycardia, Concurrent hypertension, $13-39


TCAs


Divalproex/
Valproic acid







Topiramate


mg)
Timolol: 20 to 30 mg
Nadolol: 40 to 240 mg
Metoprolol: 50 to 300 mg (200 mg)
Atenolol: 50 to 200 mg
(100 mg)



Amitriptyline: 10 to 300 mg (30-
150 mg)
Doxepin: 10 to 200 mg (50-150
mg)
Imipramine: 10 to 200 mg (50-150
mg)
Nortriptyline: 10 to 150 mg (50-
150 mg)
Protriptyline: 15 to 40 mg


Divalproex: 250 to 500 mg twice
per day
Depakote ER: 500 to 1,000 mg per
day
Valproic acid: 250 to 500 mg twice
per day



50 mg twice per day titratee from
25 mg)


Dizziness, Depression,
Impotence, Broncho-
spasm, Nausea


Anticholinergic effects
(dry mouth, constipa-
tion, blurred vision),
sedation, postural hy-
potension, agitation,
tremor, seizures, sexual
dysfunction, weight
gain


Nausea, vomiting,
tremor, weight gain,
hair loss, drowsiness,
ataxia, hepatotoxicity





Paresthesia, fatigue,
nausea, weight loss


angina, post-MI, tremor,
anxiety or panic attacks
(specifically propranolol)


Tension-type headaches,
concurrent depression,
insomnia, and chronic pain


Concurrent seizure, or bi-
polar disorders







Concurrent seizure disor-
der


ARP: approximate retail price for typical dosage range


(Procardia) or verapamil (Calan). Of three small
trials comparing verapamil 240 or 320 mg per day
with placebo, two reported positive findings, with a
moderate calculated summary effect size of 0.78
(95% CI, 0.09 to 1.50).25,26 Two trials had high
27
dropout rates due to adverse events. Calcium chan-
nel blockers typically have a slower onset than 3-
blockers and may have an initial increase in head-
ache frequency. These agents may be an option for
patients who are unable to tolerate P-blockers.28

Miscellaneous Treatment Options

Oral magnesium (9 mg/kg per day divided
three times daily with food) reduced the number of
days with migraine in children.29 Another double-


blind randomized study demonstrated a 42% reduc-
tion in attack frequency in 81 adult patients taking
600 mg magnesium oxide daily.30 An open-label
study revealed efficacy of high-dose riboflavin (400
mg per day), significantly reducing headache fre-
quency and use of abortive medications. There was
no significant change in total headache hours or
headache intensity however.31
Hormonal prophylaxis may be indicated in
women suffering from menstrual migraine. Percuta-
neous estradiol at a dose of 1.5 mg four times daily
for 3 days prior to menses and continued for a total
of 6 days has demonstrated efficacy in two double-
blind studies.32'33 Hormonal prophylaxis can have
variable effects on menstrual migraine. Patients
should be monitored for development of aura or


Phara~oe Vlum 22 Isse 4Janary200


$32
$11-34
$14


$11

$8-16


$17-51

$10-26

$52-168


$78-124

$69-140

$14-28


$211-302


Volume 22, Issue 4 January 2007


PharmaNote







worsening of headaches. Estrogen therapy should
not be used in patients with a history of migraine
with aura, thromboembolism, or other contraindica-
tions to estrogen therapy. The migraine rescue medi-
cation frovatriptan (Frova) has shown benefit when
used prophylactically in women with menstrual mi-
graine. In women who are able to predict migraine
occurrence based on their menstrual cycle, use of
frovatriptan 2.5 mg twice daily for 6 days perimen-
strually reduces the frequency of menstrually associ-
ated migraine.34
Recent attention has turned to the use of mul-
tiple treatments with low doses of botulinum toxin
type A (Botox) for migraine prophylaxis. In un-
controlled studies, botulinum toxin type A decreased
migraine frequency. In Binder et al.35 complete re-
sponse was seen in 51% (95% confidence interval,
39% to 62%) of patients with a mean response dura-
tion of 4.1 months, and a partial response in 38% of
patients with a mean response duration of 2.7
months. As of yet, botulinum toxin type A has not
been proven more effective than placebo, though fu-
ture trials will assess higher doses, different injection
sites, and other migraine populations.36

Conclusion

Providers can decrease both indirect and di-
rect healthcare costs as well as improve patient qual-
ity of life with the proper recognition of patients in
need of migraine prevention. There are established
guidelines for the identification of patients that
would benefit from migraine prophylaxis. Propa-
nolol (Inderal), timolol, amitriptyline (Elavil),
divalproex (Depakote), valproic acid and topi-
ramate (Topamax) are first-line options. Choice of
prophylactic agent should take efficacy, contraindi-
cations, precautions, side effects, concurrent disease
states, compliance issues and cost into consideration
and should be individualized to the patient.

References

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miology and impact of migraine. In: Silberstein
SD, Lipton RB, Dalessio DJ, eds. Wolff's Head-
aches and Other Head Pain. New York: Oxford
University Press; 2001:85-107.
2. Bigal ME, Lipton RB. The preventive treatment
of migraine. The Neurologist 2006; 12:204-213.


PharmaNote


3. Matthew NT. Pathophysiology, epidemiology,
and impact of migraine. Clin Cornerstone 2001;4
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4. Goadsby PJ, Lipton RB, Ferrari MD. Migraine:
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Volume 22, Issue 4 January 2007







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