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Evidence-based medicine in migraine prevention

Article  in  Expert Review of Neurotherapeutics · June 2005

DOI: 10.1586/14737175.5.3.333 · Source: PubMed

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CONTENTS
Trial design in
migraine prevention
Classic drugs for the
prevention of migraine
Recent developments for
the prevention of
migraine: neuromodulators
Other potential
treatment options
Drug entities not effective in
migraine prevention
Expert opinion
ut
Five-year view
Key issues
References
A
Affiliations
† progress has been made for the treatment of acute
Author for correspondence
University Hospital Essen,
Department of Neurology,
Hufelandstrasse 55, 45122
Essen, Germany
Tel.: +49 201 723 2495
Fax: +49 201 723 5176
Volker.Limmroth@uni-essen.de
KEYWORDS:
evidence-based medicine,
migraine, migraine
prophylactic treatment
www.future-drugs.com
Review
Evidence-based medicine in
migraine prevention
Min-Suk Yoon, Irini Savidou, Hans-Christoph Diener
and Volker Limmroth†
Migraine headache is a chronic, painful, disabling and potentially progressive, condition
primarily occurring in early and middle adulthood. For many patients, daily activities are
of
impaired by the sudden and unpredictable occurrence of migraine attacks. In recent
years, significant progress has been made in the field of migraine treatment. For the acute
treatment of migraine attacks, 5-hydroxytryptophan1B/D agonists (so called triptans), were
ro
the most innovative development, successfully aborting attacks in less than 1 h. The search
for innovative drugs usable for migraine prevention, however, was less successful, mainly
due to the lack of reliable and predictive animal models. Recently, neuromodulators such
as valproic acid and topiramate, initially developed as anticonvulsants, have been shown
in large clinical trials to be effective in the prevention of migraine. As for the acute
rP
treatment of migraine attacks more than 10 years ago, large clinical trial programs are
now setting new standards for evidence-based medicine in migraine prevention. This
review summarizes the current options in migraine prevention with special emphasis on
clinical trial design and new developments such as topiramate.
ho
Expert Rev. Neurotherapeutics 5(3), 333–341 (2005)
The International Classification of Headache • Migraine attack frequency exceeds three or
Disorders II, edited by the International Head- more migraine attacks per month and/or
ache Society (IHS), defines migraine as a disor- when the patient suffers from an insufficient
der characterized by intermittent attacks of response to acute treatment
headache combined with nausea, photophobia • The existence of one or more migraine
and/or phonophobia [1]. Some rare forms of attacks per month lasting more than 48 h
migraine have been associated with specific
• One or more attacks with disabling or
alterations of genes encoding P/Q calcium
significant complications (e.g., extensive auras)
channels on chromosome 19 and a
sodium–potassium pump encoded on chromo- • There are significant socioeconomic aspects
some 1 [2,3]. The more common forms of due to migraine (e.g., significant loss of
migraine are those with or without aura. Spe- working days)
cific genes have not yet been described for these Unlike drugs for the acute treatment of
forms. Within the last 10 years, significant migraine attacks, almost all drugs that are
currently used for the prevention of migraine
migraine attacks as result of focused research, the were discovered by chance and initially devel-
development of animal models and drug devel- oped for other indications. These difficulties
opment plans according to arising pathophysio- to develop specific drugs for migraine preven-
logic concepts [4]. Patients with a high attack fre- tion are mainly due to the lack of reliable ani-
quency, however, require preventive medication mal models. Therefore, identification of ade-
to avoid uncontrolled use of antiheadache medi- quate prophylactic treatment relies entirely
cation and the risk of subsequent medication on clinical studies. The nature of migraine,
overuse headache [5]. According to recent consen- however, mandates specific considerations in
sus guidelines [101], preventive medication should the design of clinical studies. This review will
be considered when: therefore initially discuss the criteria for valid
10.1586/14737175.5.3.333 © 2005 Future Drugs Ltd ISSN 1473-7175 333
Yoon, Savidou, Diener & Limmroth
studies on preventative treatment in migraine based on the
recommendations of the IHS. Thereafter, the established and
most recent developments for the prevention of migraine will
be summarized.
Trial design in migraine prevention
As with many neurologic disorders, clinical trial design has
evolved significantly with the introduction of new generations
of drugs and has subsequently improved over the last decades.
In order to generate reliable data, it is now generally agreed that
trials in migraine prevention should meet the criteria described
below [6].
Clear diagnosis, exclusion of patients with medication
overuse headache
Several studies, particularly from older literature, have not con-
sistently differentiated between migraine and other headache
forms. The interpretation of their results may be confounded by
patient heterogeneity. Most of the drugs used in migraine pre-
vention, such as β-blockers, have not been proven to be effective
in the prophylaxis of nonmigraine primary headaches. There-
fore, a clear definition of the headache type is a conditio sine qua
non for clinical trials in migraine prevention [6]. In many
rP
patients, including those with migraine, chronic headache
and/or an increase in migraine frequency can also occur second-
ary to inappropriate use of headache medication such as analge-
sics, ergot alkaloids and 5-hydroxytryptophan (5-HT)1B/D
receptor agonists. Several studies indicate that migraine patients
who develop medication overuse headache do not respond to
ho
prophylactic treatment but rather require complete withdrawal
from their headache medication [5]. Therefore, strict exclusion
of patients with drug-induced headache or medication overuse
is a key aspect in producing reliable studies on prophylactic
migraine treatment, but is one that has not routinely been
ut
incorporated in earlier studies.
Basic trial design: randomized, double-blind,
parallel, multicenter
A
It almost goes without saying that trials in migraine prevention
must be randomized and double-blind in order to guarantee well-
balanced treatment arms with a (more or less) homogenous study
population [7]. Double-blinding is necessary in order to avoid any
influences on the results due to expectations or specific interests. In
migraine prevention, parallel design has clear advantages compared
with crossover designs since the effect of drugs may last longer than
predicted and subsequently cause significant carryover effects. Fur-
thermore, both the patient and evaluating physician may become
unblinded in the second part of the crossover study due to differ-
ences in adverse events which can then be compared between the
two parts of the study. Single-center studies may be used in proof-
of-concept studies or early Phase II studies. Patient populations
vary with regard to their headache history, duration of the head-
ache disorder or experience with different drugs between general
practitioners and specialized headache centers. Hence, multicenter
studies are the only way to minimize bias in the study population.
334
Primary & secondary outcome criteria
Many primary outcome criteria (POC) have previously been
used but only a few have proven to realistically reflect the
potential efficacy of a drug in migraine prevention. The Euro-
pean Medicines Agency suggests the reduction of migraine
attacks during 28 days as POC [8]. Another POC that has been
proven to be reliable is the percentage of patients achieving a
reduction of 50% or more of headache days per month com-
pared with baseline. The percentage of patients with a mean
reduction of 75 or 100% of monthly headache days can be used
as a secondary end point. Another secondary end point can be
the mean reduction of attack frequency per month compared
with baseline. In general, headache days per month appear to
be the more reliable parameter than the number of attacks,
since the attack can be short or long, and the differentiation
of
between a new attack closely following a successfully treated
attack and a recurrent attack (e.g., since acute treatment was
not sufficient) can be difficult or even impossible.
ro
Washout phases: discontinuation of possibly interfering drugs
A high frequency of migraine attacks is the most common rea-
son to initiate prophylactic treatment. Without a sufficiently
long washout period, however, it is impossible to precisely
determine prophylactic effects. The most reliable data concern-
ing attack frequency are generated by the use of headache dia-
ries with prospectively documented attacks. Based on the possi-
ble fluctuation of attack frequency, reliable studies require a
washout period of at least 4 weeks following the discontinua-
tion of all drugs which may influence the frequency of migraine
attacks. Furthermore, if trials are conducted using a crossover
design, a washout period of at least 4 weeks is required in order
to avoid carryover effects. Even longer washout periods may be
necessary if flunarzine is involved, since this drug has a very
long half-life [9]. Unfortunately, several studies appearing prior
to 1995 have not routinely included sufficiently long
washout periods.
Sufficient duration of the trial
The necessary duration of a reliable study on prophylactic
migraine treatment is determined by three factors: the minimal
frequency of attacks justifying prophylactic treatment
(i.e., three per month) and their possible fluctuation; the
required time for titration to effective dosages (see below); and
the time required to reach full prophylactic efficacy
(4–8 weeks). Based on these considerations, the study duration
for drugs in the prevention of migraine should be at least
3 months. Shorter studies may over emphasize placebo effects,
as indicated by a relatively high placebo responder rate in short
studies [6]. Due to these considerations, shorter studies are
likely to yield falsely negative results. The ideal trial will there-
fore last 6 months, enabling these potential effects to be
observed. In placebo-controlled trials this may cause ethical
problems which have to be addressed [10]. However, until now
very few trials have been conducted for 6 months. The vast
majority of all trials cover periods of 2 or 3 months.
Expert Rev. Neurotherapeutics 5(3), (2005)

Sufficient statistical power
The number of patients in several studies has apparently not
been based upon correct power calculations, which further com-
plicates appreciation of their value. Experience of former clinical
trials and power calculations based on a statistical power of 90%
to detect a difference between groups of 20–40% suggest to
include at least 70–80 patients per arm in a two-arm trial, and at
least 100 patients per arm in three- and four-arm trials.
Data-analysis: use of intention-to-treat analysis
Following the initiation of prophylactic treatment, many
patients experience adverse events during the first days of treat-
ment but the desired prophylactic effects require several weeks
to develop. This dissociation may impair patient compliance
and favor high drop-out rates, subsequently favoring the non-
placebo group or active treatment arm because patients who
experience already clinical efficacy from early on are more likely
to stay in the trial. Therefore, intention-to-treat analysis should
be conducted in order to exclude this potential selection bias.
Unfortunately, only a minority of trials on migraine pre-
vention have met all the criteria discussed above. The failure
to apply these aspects may lead to questionable results. This
has frequently been demonstrated. For example, some small
rP
studies have been unable to demonstrate the superiority of
propanolol or metoprolol when compared with placebo,
although after dozens of studies for propanolol only there is
no doubt that propanolol is effective in migraine
prevention [11–13].
ho
Classic drugs for the prevention of migraine
Drugs of first choice
β-adrenoreceptor blockers
The impact of β-adrenoreceptor blockers for migraine preven-
tion was accidentally discovered when patients with migraine
ut
received these drugs for the treatment of hypertension or
other cardiac disorders [14]. Among the available migraine pre-
ventive drugs, β-adrenoreceptor blockers have been studied
most intensively. They are considered the first choice for
A
migraine prevention and are being used most frequently [15,16].
Still, it is not known why β-adrenoreceptor blockers work in
migraine prevention. While the receptor selectivity does not
appear to be important for migraine prevention, it has been
suggested that interactions with 5-HT receptors may play a
crucial role [17–19]. However, looking at many clinical trials
that have been conducted with β-blockers for the prevention
of migraine, only those β-blockers with an intrinsic activity
(e.g., pindolol, acebutolol, alprenolol and oxprenolol) do not
appear to be clinically effective (TABLE 1) [20].
The first member of the now over 30 constituents of the β-
blocker family, propranolol, has been tested extensively. Follow-
ing more than 50 trials for the prevention of migraine there is
no doubt concerning propranolol’s efficacy in migraine preven-
tion [16,21–23], even when most of the studies do not meet mod-
ern standards of clinical trial design. The dose can be titrated
up to 160 mg/day but lower dosages are also often effective.
www.future-drugs.com
Evidence-based medicine in migraine prevention
Metoprolol, a β-1-selective β-adrenoreceptor blocker, exten-
sively tested in over 40 trials, can be considered as effective as
propranolol and possesses a superior pharmacokinetic
profile [24–26]. Clinical effects can be observed at dosages
between 50 and 200 mg/day.
Bisoprolol has also been tested in several trials. This drug can
be considered effective and now stands in line with propranolol
and metoprolol in dosages between 5 and 10 mg. Other β-
blockers may be as effective as the three discussed above but
have only been tested in a few trials and, as a result, these drugs
are rarely recommended [20].
β-adrenoreceptors can cause gastrointestinal complaints,
reduction in exercise tolerance, exazerbation of known depres-
sion, hypotension, bradycardia, nightmares, impotence and
may worsen pre-existing psoriasis. Of these, gastrointestinal
of
and decreased exercise tolerance are the most common.
Calcium channel antagonists
Basically, two types of calcium channels exist. The calcium
ro
entry channels include voltage-gated channels opened by cell
depolarization, ligand-gated channels opened by chemical mes-
sengers, and capacitative activated calcium channels, opened by
depletion of calcium out of the intracellular storage. The major
classes of L-type calcium channel blockers are dihydropyrind-
ines (e.g., nifedipine), benzothazepines (e.g., diltiazem) and
phenylalkylamines (e.g., verapamil).
Although, as in the β-blocker family, a large variety of calcium
channel antagonists (CCAs) have been introduced within the last
30 years, only two substances are used in the prevention of
migraine. The mechanism of drug action in migraine prevention
remains unclear. Flunarizine is the only CCA that has been studied
extensively in over 50 trials and can be considered effective in
migraine prevention using dosages between 5 and 10 mg
daily [27–31]. As with the β-blockers, most of these trials do not
meet the modern criteria of clinical trial design. In several trials, flu-
narizine was compared with β-adrenoreceptor blockers without
revealing any significant differences between these two treatment
options. The only other CCA that is considered to be useful in
migraine prevention is verapamil. Clinical efficacy, however, is sug-
gested by two older trials only, which again do not meet the criteria
discussed above [32,33]. The potential efficacy of verapamil in
migraine prevention is therefore not evidence based. Subsequently,
in European countries, where flunarizine is available, verapamil is
not used for this indication. In countries such as the USA where
flunarizine is not available, verapamil is used as a drug of second
choice. In several trials, other CCAs such as nimodipine, nifedipine
or cyclandelate have not been shown to be effective in migraine
prevention [18]. Known side effects of CCA are dizziness, hypo-
tension, edema and, for flunarizine, extrapyramidal syndromes
(rare cases), weight gain and exacerbation of known depression.
Drugs not of first choice
Serotonin antagonists
Methysergide is an ergotamine derivative, a 5-HT2 antagonist
and 5-HT1B/D agonist, whereas pizotifen is a 5-HT2 antagonist.
335
Yoon, Savidou, Diener & Limmroth
Methysergide was probably the first drug that was specifically
developed for migraine prophylaxis. In placebo-controlled tri-
als, methysegide revealed its efficacy against placebo in reduc-
ing migraine frequency [31,34]. Significant differences between
propranolol and methysergide in migraine prevention were not
observed [35]. Methysergide is an effective migraine prophylac-
tic agent in migraineurs with resistant headache and a high
migraine frequency. The doses range from 2 to 8 mg with a ini-
tial dose of 1 mg/day and gradually titrating 1 mg every
2–3 days. Pizotifen was tested in clinical trials against placebo
[34,36], and other agents which were known to be effective in
migraine prevention [26,37,38].
Compared with agents which are evidence based in migraine
there were no significant difference in efficacy between pizo-
tifen and flunarizine [38], and metoprolol [26]. The recom-
mended dose is 0.5 mg three-times daily or 1.5 mg once-daily
in the evening. After being widely used and considered drugs of
first choice from the late 1960s into the early 1990s, the clinical
significance has dropped sharply after both drugs have been
taken off the market in many European countries.
Both drugs (but pizotifen to a lesser extent) cause side effects
in most patients. These include abdominal complaints, weight
gain, drowsiness, hair loss, muscle aching and hallucinations.
rP
Methysergide is associated with retroperitoneal, pulmonary or
endocardial fibrosis and is therefore not suitable for long-lasting
therapy. After a time slot of 6 months, the therapy should be
discontinued for at least 1 month and can then be restarted. To
avoid a rebound effect after stopping methysergide, patients
should be weaned off the agent over 7–10 days. If a long-lasting
ho
treatment is necessary, physicans should attent to carefully
monitor cardiac function by echocardiography and check the
chest and abdomen by chest x-ray and magnetic resonance
imaging scan, respectively.
ut
Nonsteroidal antirheumatics & antiplatelet drugs
In clinical trials, aspirin has shown its efficacy in migraine pre-
ventive treatment. In a prospective trial in 1978, O’Neil and
Mann demonstrated a reduction of more than 50% in headache
A
frequency in 9 out of 12 migraineurs [39]. The subanalysis of the
Physician Health study, a double-blind, placebo-controlled trial
in 22,071 USA male physicians investigating the risk of vascular
events such as myocardial infarction or stroke, suggested a 20%
reduction in headache frequency in subjects with migraine
when treated with low-dose aspirin [40]. A double-blind, cross-
over study comparing aspirin 500 mg/day and metoprolol
20 mg/day showed a higher efficacy in migraine prevention by
metoprolol [41]. Naproxen, as well as aspirin, appears to be
effective in migraine prevention. Several studies have shown its
efficacy in migraine prophylaxis in the past [42–44].
As for other drugs that are used as acute treatment,
frequent use of aspirin and other nonsteroidal anti-inflam-
matory drugs may be overused and subsequently cause a
medication-overuse headache. Furthermore, their side
effects on gastrointestinal and renal function has to be kept
in mind and observed. Low-dose aspirin (100 mg) is
336
indicated for the prophylaxis of cardiovascular conditions,
and may, therefore, be a reasonable alternative for
migraineurs with vascular risk factors.
Antidepressives: tricyclics, monoamine reuptake inhibitors &
selective serotonin reuptake inhibitors
Much has been written about the use of antidepressants in the
treatment of headache. There is no doubt that tricyclics are the
drugs of first choice for the treatment of chronic tension-type
headache. For the prevention of migraine, however, there is hardly
any scientific evidence that tricyclics possess any clinical efficacy.
Older studies either did not meet modern standards of clinical
trial design [45,46] or failed to show convincing results [47,48]. Inter-
estingly, despite this lack of scientific evidence, tricyclics are con-
sidered drugs of first choice and are widely used in several coun-
of
tries such as the USA [49]. In most European countries, tricyclics
are considered as drugs of third choice or not indicated for the
prevention of migraine. The same accounts for other drug entities
used for the treatment of depression, such as monoamine
ro
reuptake inhibitors [48] or selective serotonin reuptake inhibitors
(SSRIs) [50]. To date, no recent clinical trial with an appropriate
design has been conducted to convincingly show any efficacy of
these entities in migraine prevention. Taken together, the use of
monoamine reuptake inhibitors or SSRIs in migraine prevention
is not evidence based and the use of tricyclics does not meet the
criteria of evidence-based medicine.
Recent developments for the prevention of
migraine: neuromodulators
Whereas the family of β-blockers or CCA was initially devel-
oped for non-neurologic indications, drugs initially developed
for the treatment of epilepsy have recently been shown to be
quite effective in migraine prevention. Unlike β-blockers and
CCAs, the idea for the development of these drugs was the
reduction of neuronal excitability. Pathophysiologic concepts in
migraine suggest that temporary states of hyperexcitability in
certain brain areas such as the occipital lobe or periaquaeductal
gray as a key mechanism in migraine. In other words, for these
drugs the clinician had, for the first time, a reasonable concept
as to why these drugs may work in migraine prevention.
Valproic acid
Valproic acid (2-propylpentanoic acid) is a branched-chain fatty
acid that was firstly used in the treatment of generalized seizures.
The best known pharmacologic action is its enhancement of γ-
aminobutyric acid (GABA)-ergic neurotransmission. It has been
suggested that, during migraine headache, GABA metabolism
is, to some extent, deranged [51]. The facilitation of GABAergic
neurotransmission may be a possible mechanism in migraine
prophylaxis [52]. Inhibiting GABA degradation, stimulating its
synthesis and release, and enhancing its postsynaptic effects
results in amplifying GABA activity. Furthermore, valproic acid
may have modulating influence on the central 5-HT system in
the mid brain [53]. Valproic acid shows a high degree of protein
binding. Its elimination half-life is up to 17 h.
Expert Rev. Neurotherapeutics 5(3), (2005)

Within the last 15 years, several studies have convincingly
demonstrated the efficacy of valproic acid in migraine preven-
tion [54–56]. However, the difference in efficacy compared with
β-adrenoreceptor blockers is not significant [57]. Since most of
these trials meet the modern criteria for clinical trial design, the
use of valproic acid in migraine prevention can be considered
evidence based. Subsequently, valproic acid should be
considered the drug of first choice in this indication.
Recommended dosages are between 300 and 900 mg [58–60].
Silberstein and colleagues evaluated the long-term safety of
divalproex sodium in an open-label study in which
163 migraineurs enrolled, 117 of whom were treated with
divalproex [61]. Frequently reported adverse events were nausea
(42%), infection (39%), alopecia (31%), tremor (28%), dys-
pepsia (25%) and somnolence (25%). The risk of hepatopathy
among migraineurs from valproic acid is low. Due to the tera-
togenic potential of valproic acid, it is strictly contraindicated
in pregnant woman. Furthermore, migraineurs with a history
of pancreatitis, hepatic disorder or hematologic disorder should
not be treated with valproic acid.
Topiramate
The anticonvulsant topiramate was discovered by accident while
rP
researching for structural analogues of fructose-1,6-diphospate to
block gluconeogenesis. The hypogylcemic effect in clinical evi-
dence is still not proven. Topiramate is a derivative of naturally
monosaccharide D-fructose. It has GABA-agonist, glutamate-
antagonist effects and also interacts with voltage-gated Na+ and
Ca2+ channels. Topiramate additionally has an influence on car-
ho
bonic anhydrase [62]. The evaluation of topiramate set a new
standard for clinical trials in the indication of migraine preven-
tion. In an comprehensive evaluation program, three large clini-
cal trials with over 1500 patients investigated the efficacy of
topiramate in migraine prevention in comparison with placebo
ut
and propranolol [63–65]. In two of these trials, migraineurs with a
migraine frequency between 3 and 12 migraine attacks were
enrolled during a 28-day baseline period [63,64]. Concomitant
preventive therapy was tapered off. The patients were then rand-
A
omized to either placebo or topiramate at doses of 50, 100 and
200 mg/day. The starting dose was 25 mg/day, increasing weekly
by 25 mg until the target dose was reached or side effects became
intolerable. The results in both studies were quite similar and
revealed that topiramate has a high efficacy in migraine preven-
tion at a daily dose of 100 or 200 mg/day. A dosage of 200 mg,
however, does not appear to be more effective but causes more
adverse events, so that 100 mg appears to reflect the best effi-
cacy–adverse event balance. Topiramate 100 mg/day compared
with β-adrenoreceptor blocker propranolol 160 mg/day
exhibited similar efficacy profiles [65].
Frequent side effects leading to discontinuation of topiramate
are paresthesia, difficulty in concentration, cognitive dysfunc-
tion and word-finding difficulties, nausea and fatigue. Patients
with a past history of kidney stones should be treated with
topiramate if the benefit justifies the potential risks. They
should attempt to maintain an adequate daily liquid intake. In
www.future-drugs.com
Evidence-based medicine in migraine prevention
very few cases, nongapped metabolic acidosis was reported as a
nondose-related complication. As topiramate is usually associ-
ated with weight loss, obese migraineurs or patients worried
about gaining weight may have benefits by pharmacologic
treatment with topiramate. Based on these trials, topiramate
should become a drug of first choice in the near future.
Other potential treatment options
Several other drug entities have been reported in case reports or
small single center studies to exhibit clinical effects in migraine
prevention. For some of these drugs larger clinical trials appear
to be warranted.
Lisinopril
Lisinopril, an angiotensin-converting enzyme inhibitor, is
of
indicated for cardiac failure and hypertension but appears to
have migraine-preventive properties. It has been tested in a
small double-blind, placebo-controlled crossover trial in
60 migraineurs [66]. Its efficacy in migraine prophylaxis may
ro
be due to the angiotensin converting enzyme (ACE) DD
gene that codes for a higher ACE activity in migraineurs [67].
The daily dose was 20 mg/day distributed in two single
doses. Common adverse effects were hypotension, cough
and fatigue.
Candesartan
An angiotensin II receptor blocker, candesartan was tested
in 60 migraineurs in a randomized, double-blind, placebo-
controlled crossover study in Norway [68]. The primary end
point was the mean number of days with headache. Com-
pared with placebo (18.5 days) treatment, candesartan
showed a statistically significant reduction in mean number
of days with headache to 13.6 days (p = 0.001). The daily
dose was 16 mg/day. Furthermore, a case report in eight
migraineurs with known hypertension showed an improve-
ment in Migraine Disability Assessment score from 29.4 to
9 points [69].
Petasites (petadolex)
Petasites is an extract from the plant Petasites hybridus found in
Europe and parts of Asia. In a randomized, double-blind, pla-
cebo-controlled trial, migraine patients were treated either with
50 mg petadolex or placebo [70]. Results showed a significant
reduction of migraine attacks and migraine days per month.
Potential side effects are liver damage and carcinogenesis in ani-
mals. These side effects are thought to be associated with pyr-
rolizidine alkaloids, which are removed in commercially availa-
ble presentations. Further trials are needed in order to confirm
these preliminary results. In another trial, 75 but not 50 mg
were superior to placebo [71].
Feverfew (tanacetum parthenium)
Previous studies have not shown any clear evidence that
feverfew is effective in migraine prevention. In a recently
conducted trial, 72 patients were randomized to receive
337
Yoon, Savidou, Diener & Limmroth

either feverfew or placebo for 4 months and then transferred
to the other treatment arm [72]. The results showed small
differences between both treatment arms, which were statis-
tically significant in favor of feverfew. Another trial has
shown no significance between placebo and feverfew in
reducing migraine frequency [73]. Adverse events were no
more common with feverfew than with placebo. Observed
side effects were mouth ulceration and oral inflammation
associated with loss of taste. Large-scale trials will have to
clarify the potential efficacy of feverfew in the future.
Other drugs
In the group of anticonvulsants, several drugs such as leveti-
ractam or zonisamide are currently under evaluation for the
prevention of migraine. These results will be available within
the next 12–24 months.

Table 1. Drugs for migraine prevention.

Drug Data Side effects Contraindications
Classic drugs in migraine prevention: first choice
β-adrenorecptor blocker ⇑⇑⇑ Fatigue, hypotension, insomnia, Asthma, atrioventricular block,

of
Metoprolol 50–200 mg dizziness, bronchial spasm, bradycardia diabetes, orthostatic dysregulation
Propranolol 80–240 mg
Bisoprolol 5–10 mg
Flunarizine ⇑⇑⇑ Fatigue, weight gain, depression Dystonia, pregnancy, depression

ro
5–10 mg

New drugs, potentially of first choice : neuromodulators

Valproic acid ⇑⇑⇑ Fatigue, dizziness, alopecia, weight gain, Hepatic disorders, pregnancy
500–900 mg hepatic disorder
rP
Topiramate ⇑⇑⇑ Paraesthesia, difficulty concentrating, Lactation, hepatic and renal disorder,
50–200 mg nausea, fatigue, weight loss nephrolithiasis

Classic drugs in migraine prevention: second choice

Methysergide ⇑ Fatigue, weight gain, hypertonus Hypertension, coronary
2–8 mg heart disease, pregnancy
ho

Pizotifen ⇑ Fatigue, weight gain, hunger, Glaucoma, prostatic hyperplasia,

0.5–1 mg xerostomia, obstipation coronary heart disease, pregnancy
Aspirin ⇑⇑ Stomach pain Ulcer, hemorrhage, asthma
300 mg
⇑⇑
ut

Naproxen Stomach pain Ulcer, hemorrhage, asthma

2 x 250 mg

Drugs used in migraine prevention: not evidence based

Amitriptylin ←→ Dry mouth, dizziness, cardiac disorder, Cardiac failure, prostatic hyperplasia
A

weight gain, urinary retention with urinary retention, pregnancy

MAO inhibitors ←→ Orthostatic hypotension, weight gain, Hypertension, combination with
insomnia, nauseas, headache pethidine, clomipramine
SSRIs ←→ Insomnia, drowsiness, fatigue, dizziness, Cardiac disorder, seizure, hepatic
nervousness and renal disorder

Potential developments
ACE inhibitors (⇑) Hypotension, fatigue, cough Renal disorder, renal artery stenosis
Sartans (⇑) Hypotension, dizziness Renal disorder, renal artery stenosis
Feverfew ⇑ Mouth ulceration, oral inflammation,
loss of taste
Petasitex ⇑ In animals: hepatic disorder, Lactation
carcinogenesis
⇑: Studies available; ←→: No evidence available; Studies negative or not reliable.
ACE: Angiotensin converting enzyme; MAO: Monoamine oxidase; SSRI: Selective serotonin uptake inhibitor.

338 Expert Rev. Neurotherapeutics 5(3), (2005)

 Evidence-based medicine in migraine prevention

Drug entities not effective in migraine prevention
Looking at the long list of publications on migraine prevention,
it remains surprising how many drugs have been reported to be
effective in this indication, although most were not evaluated
according to modern standards of clinical trial design. Some
drug entities, such as the sodium channel blockers phenytoin,
carbamazepine or lamotrigine [74,75], have been shown to lack
any clinical effect in migraine prevention. As for lamotrigine,
however, there seems to be some benefit for patients with
migraine with aura [76]. Several larger studies appear to confirm
these preliminary results [77,78].
Expert opinion
Great progress has been made in the acute treatment of migraine.
Although many drug entities have been, and are, used for the
and North America – other drugs such as flunarizine
(Europe) or tricyclics (North America). Treatment recom-
mendation and guidelines will, in the future, address the
need to examine the individual situation of each patient and
make accompanying aspects such as body weight, sleeping
habits and comorbidities key criteria for the selection of the
specific preventative medication more strongly than before.
However, new potential drugs for the prevention of migraine
are on the horizon. Especially among the group of anticon-
vulsive agents, drugs such as levetiracetam, pregabaline,
remacemide or zonisamide are about to, or will, be evaluated
in clinical trials for this indication. Hence, it is not unlikely
that in 5 years from now one or two additional drugs will be
available for the prevention of migraine.

of
prevention of migraine, just a few of these drugs can be consid-
ered drugs of first choice based on scientific evidence. Recent Key issues
developments and large development programs now set new
standards for clinical trial design and drug evaluation in migraine • Migraine headache is a chronic, painful, disabling and

ro
prevention. With the introduction of modern neuromodulators,
the pharmacologic repertoire for the preventative treatment of
patients with migraine will significantly improve and hopefully
fuel the further development of potent antimigraine drugs with
rP
low adverse event profiles.
Five-year view
Within the next 5 years, the triptan family will be the most
important group of agents for the acute treatment of
migraine. However, new drug entities such as the calcitonin
ho
potentially progressive condition requiring preventative
medication in up to 50% of the cases.
• β-adrenoreceptor blockers and specific calcium channel
antagonists such as flunarizine are still drugs of first choice
for the prevention of migraine.
• Neuromodulators, such as valproic acid and topiramate, have
been shown in large clinical trials to be effective in the
prevention of migraine and should therefore, also be
considered as drugs of first choice.
• Clinical trials to evaluate drugs potentially effective in the

gene-related peptide antagonists are coming closer and may
challenge the triptans at the end of the upcoming 5-year
bracket. As for the prevention of migraine, neuromodulators
are highly likely to establish themselves as drugs of first
choice together with β-blockers and – differently in Europe
ut
prevention of migraine should be conducted as randomized,
parallel, double-blind, placebo-controlled trials of 6-months
duration with 50% (or more) reduction of headache days per
month as primary outcome criterion.

References 4 Humphrey PP. How it started. Cephalalgia evaluation of clinical trials in

Papers of special note have been highlighted as: 21(Suppl. 1), 2–5 (2001). migraine therapy.
A

• of interest
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www.neurology.org
(Accessed April 2005)
Affiliations
• Min-Suk Yoon, MD
University Hospital Essen, Department of
Neurology, Hufelandstrasse 55,
45122 Essen, Germany
• Irini Savidou, MD
University Hospital Essen, Department of
Neurology, Hufelandstrasse 55,
45122 Essen, Germany
• Hans-Christoph Diener, MD, PhD
University Hospital Essen, Department of
Neurology, Hufelandstrasse 55,
45122 Essen, Germany
• Volker Limmroth, MD, PhD
University Hospital Essen, Department of
Neurology, Hufelandstrasse 55,
45122 Essen, Germany
Tel.: +49 201 723 2495
Fax: +49 201 723 5176
Volker.Limmroth@uni-essen.de
341