REVIEW

Migraine: preventive treatment

SD Silberstein & PJ Goadsby1
Jefferson Headache Center, and Thomas Jefferson University Hospital, Philadelphia, PA, USA, and 1Institute of Neurology, The National Hospital for
Neurology and Neurosurgery, London, UK

Silberstein SD & Goadsby PJ. Migraine: preventive treatment. Cephalalgia 2002;

22:491–512. London. ISSN 033-1024
Migraine is a common episodic headache disorder. A comprehensive headache
treatment plan includes acute attack treatment to relieve pain and impairment and
long-term preventive therapy to reduce attack frequency, severity, and duration.
Circumstances that might warrant preventive treatment include: (i) migraine that
significantly interferes with the patient’s daily routine despite acute treatment;
(ii) failure, contraindication to, or troublesome side-effects from acute medications;
(iii) overuse of acute medications; (iv) special circumstances, such as hemiplegic
migraine; (v) very frequent headaches (more than two a week); or (vi) patient preference.
Start the drug at a low dose. Give each treatment an adequate trial. Avoid interfering,
overused, and contraindicated drugs. Re-evaluate therapy. Be sure that a woman of
childbearing potential is aware of any potential risks. Involve patients in their care
to maximize compliance. Consider co-morbidity. Choose a drug based on its proven
efficacy, the patient’s preferences and headache profile, the drug’s side-effects, and the
presence or absence of coexisting or co-morbid disease. Drugs that have documented
high efficacy and mild to moderate adverse events (AEs) include b-blockers, amitripty-
line, and divalproex. Drugs that have lower documented efficacy and mild to moderate
AEs include selective serotonin reuptake inhibitors (SSRIs), calcium channel
antagonists, gabapentin, topiramate, riboflavin, and non-steroidal anti-inflammatory
drugs. u Migraine, prevention, treatment, prophylaxis
Stephen D. Silberstein MD, FACP, Thomas Jefferson University Hospital, Jefferson Headache
Center, Gibbon Building, Suite #8130, 111 South 11th Street, Philadelphia, PA 19107, USA.
Tel.+1 215 955-2243, fax +1 215 955-6682, e-mail Stephen.Silberstein@mail.tju.ed
Received 17 November 2000, accepted 9 April 2002

and certainly includes addressing the headache’s impact

Introduction
Migraine is a common episodic headache disorder
with a 1-year prevalence of approximately 18% in
women, 6% in men, and 4% in children (1). It is
characterized by attacks that consist of various com-
binations of headache and neurological, gastrointestinal,
and autonomic symptoms. The International Headache
Society (IHS) calls common migraine ‘migraine without
aura’ (1.1) and classic migraine ‘migraine with aura’
(1.2), the aura being the complex of focal neurological
symptoms that most often precedes or accompanies
an attack (2). Effective migraine treatment begins with
making an accurate diagnosis that may include ruling
out alternate causes and ordering appropriate studies,
on the patient. Migraine varies widely in its frequency,
severity, and impact on the patient’s quality of life. A
treatment plan should consider not only the patient’s
diagnosis, symptoms, and any coexistent or co-morbid
conditions, but also the patient’s expectations, needs,
and goals (3). Patients need to be informed of the goals
of treatment, the purpose of the various components
of their treatment plan, the need for follow-up care,
and the adverse effects of medications. Patient educa-
tion and commitment improve compliance and foster
the patient–physician relationship.
A comprehensive headache treatment plan includes
a combination of: (i) education and reassurance; (ii)
preventing attacks by avoiding triggers; (iii) the use of

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492 SD Silberstein & PJ Goadsby
non-pharmacological treatments such as relaxation,
biofeedback, and life style regulation, such as maintain-
ing a regular schedule, getting adequate sleep and
exercise; (iv) acute attack treatment to relieve pain and
impairment and stop progression; (v) long-term pre-
ventive therapy to reduce attack frequency, severity,
and duration; (vi) the use of physical and alternative
medicine when appropriate; and (vii) periodic
reassessment and reconsideration of the treatment plan.
The pharmacological treatment of migraine may be
acute (abortive) or preventive (prophylactic), and
patients with frequent severe headaches often require
both approaches. Acute treatment attempts to relieve
or stop the progression of an attack, or the pain and
impairment once an attack has begun. Acute treatment
is appropriate for most attacks and should be used a
maximum of 2–3 days a week. Preventive therapy is
given, even in the absence of a headache, in an attempt
to reduce the frequency and severity of anticipated
attacks.
Preventive treatment
Preventive medications are usually taken, whether or
not headache is present, to reduce the frequency,
duration, or severity of attacks. The United States
Evidenced Based Guidelines for Migraine (4) has
suggested that circumstances that might warrant pre-
ventive treatment include: (i) recurring migraine that
significantly interferes with the patient’s daily routine
despite acute treatment. (e.g. two or more attacks a
month that produce disability that lasts i3 days or
headache attacks that are infrequent but produce
profound disability); (ii) failure, contraindication to, or
troublesome side-effects from acute medications; (iii)
overuse of acute medications; (iv) special circumstances,
such as hemiplegic migraine or attacks with a risk
of permanent neurological injury; (v) very frequent
headaches (more than two a week), or a pattern of
increasing attacks over time, with the risk of developing
rebound headache with acute attack medicines; or (vi)
patient preference, i.e. the desire to have as few acute
attacks as possible. These rules are stricter during
pregnancy: severe disabling attacks accompanied by
nausea, vomiting, and possibly dehydration are
required for preventive treatment to be prescribed (5).
The major medication groups for preventive
migraine treatment (Table 1) include b-adrenergic
blockers, anti-depressants, calcium channel antagonists,
serotonin antagonists, anti-convulsants, non-steroidal
anti-inflammatory drugs (NSAIDs), and others (includ-
ing riboflavin, minerals, and herbs). If preventive
medication is indicated, the agent should be preferen-
tially chosen from one of the first-line categories, based
Table 1 Preventive prescription drugs
Anti-convulsants
Valproate, gabapentin, topiramate*
Anti-depressants
TCAs, SSRIs, MAOIs
b-adrenergic blockers
Propranolol/nadolol/metoprolol/atenolol/timolol
Calcium channel antagonists
Verapamil/flunarizine
Serotonin antagonists
Methysergide/methergine
Others
NSAIDs, riboflavin, magnesium, feverfew, Botox
*Very suggestive early clinical data require confirmation.
on the drug’s side-effect profile and the patient’s
coexistent and co-morbid conditions (6).
Principles of preventive therapy
Start the drug at a low dose and increase it slowly
until therapeutic effects develop, the ceiling dose for
the chosen drug is reached, or side-effects become
intolerable.
Give each treatment an adequate trial. A full
therapeutic trial may take 2– 6 months. In controlled
clinical trials, efficacy is often first noted at 4 weeks and
continues to increase for 3 months.
Avoid interfering, overused, and contraindicated
drugs. To obtain maximal benefit from preventive
medication, the patient should not overuse analgesics,
opioids, triptans, or ergot derivatives. Re-evaluate
therapy: migraine headaches may improve inde-
pendent of treatment; if the headaches are well
controlled, slowly taper and, if possible, discontinue
the drug. Many patients experience continued relief
with a lower dose of the medication and others may not
require it at all.
Be sure that a woman of childbearing potential is
aware of any potential risks and pick the medication that
will have the least adverse effect on the fetus (5). Women
taking valproate can easily add folic acid.
Involve patients in their care to maximize compliance.
Take patient preferences into account when deciding
between drugs of relatively equivalent efficacy. Discuss
the rationale for a particular treatment, when and how
to use it, and what side-effects are likely. Address
patient expectations. Discuss with the patient the
expected benefits of therapy and how long it will take
to achieve them.
Consider co-morbidity, which is the presence of two
or more disorders whose association is more likely
# Blackwell Science Ltd Cephalalgia, 2002, 22, 491–512

than chance. Conditions that are co-morbid with
migraine include stroke, epilepsy, mitral valve prolapse,
Raynaud’s syndrome, and certain psychological dis-
orders, including depression, mania, anxiety, and panic
(Table 2).
b-adrenergic blockers
b-blockers, the most widely used class of drugs in
prophylactic migraine treatment, are 60– 80% effective
in producing a >50% reduction in attack frequency.
Rabkin et al. (7 ) serendipitously discovered pro-
pranolol’s effectiveness in headache treatment in
patients who were being treated for angina (8, 9).
The Agency for Healthcare Policy and Research
(AHCPR) Technical Report (10) and the United States
Headache Consortium (11) analysed 74 controlled
trials of b-blockers for migraine prevention. Propranolol
was consistently effective for migraine prevention in
a daily dose of 120–240 mg. No absolute correlation
has been found between propranolol’s dose and its
clinical efficacy (12). One meta-analysis revealed that,
on average, propranolol yielded a 44% reduction in
migraine activity compared with a 14% reduction with
placebo. Overall, one of six patients discontinued
propranolol treatment (13).
The relative efficacy of the different b-blockers has not
been clearly established, and most studies show no
significant difference between drugs. One trial com-
paring propranolol and amitriptyline suggested that
propranolol is more efficacious in patients with migraine
alone and amitriptyline is superior for patients
Table 2 Migraine co-morbid disease
Cardiovascular
Hyper- or hypotension
Raynaud’s
Mitral valve prolapse
Angina/myocardial infarction
Stroke
Psychiatric
Depression
Mania
Panic disorder
Anxiety disorder
Neurological
Epilepsy
Positional vertigo
Gastrointestinal
Functional bowel disorders
Other
Asthma
Allergies
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Migraine: preventive treatment 493
with the phenotypes of migraine and tension-type
headache (14).
Four trials comparing metoprolol with placebo had
mixed results (15–18). Metoprolol was similar to pro-
pranolol (16, 19–21), flunarizine (22, 23), and pizotifen
(24). Timolol (25–27), atenolol (28–30), and nadolol
(31–36) are also likely to be beneficial based on
comparisons with placebo or with propranolol.
b-blockers with intrinsic sympathomimetic activity
(acebutolol, alprenolol, oxprenolol, pindolol) have not
been found to be effective for migraine prevention
(37– 42). The only factor that correlates with the efficacy
of b-blockers is the absence of partial agonist activity
(16, 19, 43– 46).
Mechanism of action
The mechanism of action of b-blockers is not certain, but
it appears that their anti-migraine effect is due to
inhibition of b1-mediated mechanisms (47 ). b blockade
results in inhibition of norepinephrine release by
blocking prejunctional b receptors. In addition, it results
in a delayed reduction in tyrosine hydroxylase activity,
the rate-limiting step in norepinephrine synthesis, in the
superior cervical ganglia. In the rat brainstem, a delayed
reduction of the locus ceruleus neurone firing rate has
been demonstrated after propranolol administration
(47 ). This could explain the delay in the prophylactic
effect of the b-blocker.
The action of b-blockers is probably central and
could be mediated by: (i) inhibiting central b receptors
interfering with the vigilance-enhancing adrenergic
pathway, (ii) interaction with 5-HT receptors (but
not all b-blockers bind to the 5-HT receptors), and (iii)
cross-modulation of the serotonin system (48, 49).
Schoenen et al. (50) have shown that contingent
negative variation (CNV), an event-related slow negative
scalp potential, is significantly increased and its habitua-
tion reduced in patients with untreated migraine
without aura. CNV normalizes after treatment with
b-blockers, consistent with central adrenergic hyper-
activity in migraine. Migraineurs who have elevated
CNV scores have a much better response to b-blocker
therapy (80% effective) than migraineurs who have a
low or normal score (22% effective), suggesting that
the CNV may predict the response to b-blocker treat-
ment (50). Migraineurs exhibit an enhanced centrally
mediated secretion of epinephrine after exposure to
light (51); this returns to normal after treatment with
propranolol.
All b-blockers can produce behavioural side-effects,
such as drowsiness, fatigue, lethargy, sleep disorders,
nightmares, depression, memory disturbance, and
hallucinations, indicating that they all affect the CNS.
Adverse events most commonly reported in clinical
494 SD Silberstein & PJ Goadsby
trials with b-blockers were fatigue, depression, nausea,
dizziness, and insomnia. These symptoms appear to
be fairly well tolerated and were seldom the cause of
premature withdrawal from trials (10). Common
side-effects include gastrointestinal complaints and
decreased exercise tolerance. Less common are ortho-
static hypotension, significant bradycardia, impotence,
and aggravation of intrinsic muscle disease. Propranolol
has been reported to have an adverse effect on the fetus
(52). Congestive heart failure, asthma, and insulin-
dependent diabetes are contraindications to the use of
non-selective b-blockers. At this time it appears that
b-blockers are not absolutely contraindicated in
migraine with aura unless a clear stroke risk is present.
Whether this includes prolonged aura is uncertain. The
reported adverse reactions to propranolol may be either
coincidental or idiosyncratic, but the actual risk is
uncertain.
Some authors have commented on continued
improvement (53) and lack of rebound (54) after
discontinuing propranolol. Others have found no
carry-over effects (55). However, it seems more
reasonable to slowly taper b-blockers, since stopping
them abruptly can cause increased headache (17)
and the withdrawal symptoms of tachycardia and
tremulousness (56).
Propranolol is a non-selective b-blocker with a half-life
of 4 – 6 h. It is also available in an effective long-acting
formulation (57, 58). The therapeutically effective dose
of propranolol ranges from 40 to 400 mg a day, with
no correlation between propranolol and 4-hydroxy-
propranolol plasma levels and headache relief (59).
The short-acting form can be given three to four times
a day, although we recommend twice a day, and the
long-acting form once or twice a day. Propranolol
should be started at a dose of 40 mg a day in divided
doses and slowly increased to tolerance. An advantage
of the regular propranolol is its greater dosing flexibility.
The dose in children is 1–2 mg/kg a day.
Nadolol is a non-selective b-blocker with a long
half-life. It is less lipid-soluble than propranolol and
has fewer CNS side-effects. The dose ranges from 20 to
160 mg a day given once daily or in split doses. Some
authorities prefer it to propranolol since it has fewer
side-effects (60).
Timolol is a non-selective b-blocker with a short half-
life. The dose ranges from 20 to 60 mg a day in divided
doses.
Atenolol is a selective b1-blocker with fewer side-
effects than propranolol. The dose ranges from 50 to
200 mg a day once daily.
Metoprolol is a selective b1-blocker with a short
half-life. The dose ranges from 100 to 200 mg a day in
divided doses. The long-acting preparation may be
given once a day.
Anti-depressants
Anti-depressants consist of a number of different
classes of drugs with different mechanisms of action.
Only tricyclic anti-depressants (TCAs) have proven
efficacy in migraine; we cover the newer components
for completeness and reader interest.
Clinical trials and use
A total of 16 controlled trials have investigated the
efficacy of the TCAs amitriptyline and clomipramine,
and the selective serotonin reuptake inhibitors (SSRIs)
fluoxetine and fluvoxamine (14, 15, 61–75). Amitriptyline
has been more frequently studied than the other agents,
and is the only anti-depressant with fairly consistent
support for efficacy in migraine prevention. Three
placebo-controlled trials found amitriptyline signifi-
cantly better than placebo at reducing headache index
or frequency (64 – 66, 73). One of these trials, conducted
in patients whose headaches were frequently severe or
disabling in intensity, found no significant difference
between amitriptyline and propranolol (73). Another
trial reported that amitriptyline was significantly more
efficacious than propranolol for patients with mixed
migraine and tension-type headache, while propranolol
was significantly better for patients with migraine alone
(14). Similarly, a trial conducted in a group of patients
with mixed migraine and tension-type headache found
that amitriptyline was significantly better than timed-
released dihydroergotamine (TR-DHE) at reducing
headache index (63). However, an analysis of the data
on headache duration, stratified by severity, showed that
amitriptyline was significantly better than TR-DHE at
reducing the number of hours of moderate and mild
tension-type headache-like pain. In contrast, TR-DHE
was significantly better than amitriptyline at reducing
the number of hours of extremely severe and severe
migraine-like pain. The evidence was insufficient to
support the efficacy of clomipramine (15, 70) and
fluvoxamine (75) for migraine prevention. Fluoxetine
was significantly better than placebo in one (61) but not
a second (71) migraine prevention trial.
Mechanism of action
TCAs, SSRIs, and serotonin norepinephrine reuptake
inhibitors (SNRIs) increase synaptic norepinephrine
(NE) or serotonin (5-HT) by inhibiting high-affinity
re-uptake. Some are more potent inhibitors of NE, others
of 5-HT re-uptake. Monoamine oxidase inhibitors
(MAOIs) block the degradation of catecholamines.
The most consistent neurochemical finding with
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anti-depressant treatment (including the TCAs, SSRIs,
MAOIs, and electroconvulsive therapy) is a decrease
in b-adrenergic receptor density and NE-stimulated
cyclic AMP response. Increased a1 receptor system
sensitivity is not seen as consistently with anti-
depressant treatment. Long-term anti-depressant treat-
ment decreases 5-HT2 receptor-binding and imipramine-
binding sites (related to the 5-HT uptake system)
but does not change 5-HT1 receptor binding. A strong
interaction exists between the NE and 5-HT systems.
Anti-depressant treatment b-receptor down-regulation
is dependent on an intact 5-HT system, while lesions
of the NE system block the decrease in 5-HT2
receptor binding (76). The decrease in 5-HT2 receptor
binding sites does not correlate with a decrease in
function; in fact, there may be enhanced physiological
responsiveness.
TCAs up-regulate the GABA-B receptor, down-
regulate the histamine receptor, and enhance the
neuronal sensitivity to substance P. Some TCAs are
5-HT2 receptor antagonists. TCAs also interact with
endogenous adenosine systems at central and peripheral
sites. They inhibit neurogenic uptake of adenosine
and augment the electrophysiological actions of
adenosine. The enhanced availability of adenosine
and activation of adenosine receptors contributes to
antinociception. Adenosine A1 receptor activation
results in antinociception mediated by inhibition of
adenylate cyclase, while adenosine A2 receptor activa-
tion is pronociceptive due to stimulation of adenylate
cyclase within the sensory nerve terminal (77).
Adenosine A3 receptors facilitate pain due to release of
histamine and 5-hydroxytryptamine from mast cells
(78, 79).
The mechanism by which anti-depressants effect
headache prophylaxis is uncertain, but does not result
from treating masked depression. Anti-depressants are
useful in treating many chronic pain states, including
headache, independent of the presence of depres-
sion, and the response occurs sooner than the expected
anti-depressant effect (80– 82). In animal pain models,
anti-depressants potentiate the effects of co-adminis-
tered opioids (83). The anti-depressants that are clini-
cally effective in headache prophylaxis either inhibit
noradrenaline and 5-HT re-uptake or are antagonists at
the 5-HT2 receptors (84).
Pharmacology of the TCAs
There is wide individual variation in the absorption,
distribution, and excretion of the TCAs, with a
10–30-fold variation in individuals’ drug metabolism.
A therapeutic window may exist above which the
TCAs are ineffective, but this has been evaluated only
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Migraine: preventive treatment 495
for nortriptyline for treatment of depression. TCAs
are lipid-soluble, have a high volume of distribu-
tion, and avidly bind to plasma proteins. The anti-
histamine and anti-muscarinic activity of the TCAs
account for many of their side-effects (85).
The TCAs most commonly used for headache
prophylaxis include amitriptyline, nortriptyline, doxe-
pin, and protriptyline. Imipramine and desipramine
have been used at times. With the exception of
amitriptyline, the TCAs have not been vigorously
evaluated; their use is based on anecdotal or uncon-
trolled reports.
Principles of tricyclic anti-depressant use
The TCA dose range is wide and must be individualized.
With the exception of protriptyline, TCAs are sedating.
Start with a low dose of the chosen TCA at bedtime,
except when using protriptyline, which should be
administered in the morning. If the TCA is too sedating,
switch from a tertiary TCA (amitriptyline, doxepin)
to a secondary TCA (nortriptyline, protriptyline). If a
patient develops insomnia or nightmares, give the TCA
in the morning. SSRIs can be given as a single dose in the
morning, although rigorous evidence for activity in
migraine is lacking. They are less sedating than the
TCAs and some patients may require a hypnotic for
sleep induction. Bipolar patients can become manic on
anti-depressants.
Side-effects are common with TCA use. Their adverse
effects are due to their interaction with multiple
neurotransmitters and their receptors. The anti-
muscarinic adverse effects are most common; however,
adverse effects related to anti-histaminic activity and
a-adrenergic mediation were from cerebral intoxication,
but cardiac toxicity and orthostatic hypotension can
occur. Anti-muscarinic side-effects include dry mouth,
a metallic taste, epigastric distress, constipation, dizzi-
ness, mental confusion, tachycardia, palpitations,
blurred vision, and urinary retention. Anti-histaminic
activity may be responsible for carbohydrate cravings,
which contributes to weight gain. Adrenergic activity
is responsible for the orthostatic hypotension, reflex
tachycardia, and palpitations that patients may experi-
ence. Amitriptyline and other TCAs rarely will cause
inappropriate secretion of ADH. Any anti-depressant
treatment may change depression to hypomania or
frank mania (particularly in bipolar patients). Ten
percent of patients may develop tremors, and confusion
or delirium may occur, particularly in older patients
who are more vulnerable to the muscarinic side-effects.
Anti-depressant treatments may also reduce the seizure
threshold (86), although this is not generally a problem
in anti-migraine treatment.
496 SD Silberstein & PJ Goadsby
Tertiary amines
Amitriptyline is a tertiary amine tricyclic that is
sedating and has anti-muscarinic activity. Patients
with coexistent depression are more tolerant and
require higher doses of amitriptyline. Start at a dose
of 10–25 mg at bedtime. The dose ranges from 10 to
400 mg a day.
Doxepin is a sedating tertiary amine TCA. Start at a
dose of 10 mg at bedtime. The dose ranges from 10 to
300 mg a day.
Secondary amines
Nortriptyline is a secondary amine that is less sedating
than amitriptyline. Nortriptyline is a major metabolite
of amitriptyline. If insomnia develops, give the drug
earlier in the day or in divided doses. Start at a dose
of 10–25 mg at bedtime. The dose ranges from 10 to
150 mg a day.
Protriptyline is a secondary amine similar to nor-
triptyline. Start at a dose of 5 mg a day. The dose ranges
from 5 to 60 mg a day.
Monoamine re-uptake inhibitors
Selective serotonin re-uptake inhibitors
Evidence for the use of SSRIs is poor. They may be
helpful in patients with co-morbid depression because
their tolerability profile is superior to tricyclics.
Fluoxetine, fluvoxamine, paroxetine, sertraline, and
citalopram are specific SSRIs that have minimal anti-
histaminic and anti-muscarinic activity. These drugs
produce less weight gain (and in some cases weight
loss) and have fewer cardiovascular side-effects than
the TCAs (87). The most common side-effects include
anxiety, nervousness, insomnia, drowsiness, fatigue,
tremor, sweating, anorexia, nausea, vomiting, and
dizziness or light-headedness. Headache was noted in
20.3% of patients on fluoxetine; however, it was also
noted in 19.9% of patients on placebo (88). The
combination of an SSRI and a TCA can be beneficial in
treating refractory depression (89) and, in our experi-
ence, resistant cases of migraine. The combination may
require dose adjustment of the TCA because levels may
significantly increase.
The efficacy analysis summarized in the AHCPR
Evidence Report did not indicate a clear benefit of the
racemic mixture of fluoxetine over placebo. In contrast, a
recent randomized controlled trial of S-fluoxetine
indicated a possible clinical benefit in migraine pre-
vention, as measured by a reduction in migraine
frequency, as early as 1 month after initiation of therapy
(90). Anecdotal reports (91) and our experience seem
to indicate its benefit in migraine prophylaxis where
coexistent depression is a prominent issue. Some
researchers have reported that fluoxetine does not
improve or may worsen headache (92). A recent
single-centre, randomized, double-blind, parallel study
of fluoxetine for the prophylactic control of migraine
consisted of two phases: 30 days of pharmacological
washout and 6 months of therapy and monthly follow-
up (93). A comparison of the total pain index between
basal values (calculated during the period of washout)
and monthly follow-up (calculated monthly during the
period of 6 months of the therapy) showed a significant
reduction (P<0.05) beginning from the third month of
treatment in the fluoxetine group and no significant
reduction in the placebo group.
Fluoxetine: start at a dose of 10 mg in the morning.
The dose ranges from 10 to 80 mg a day.
Monoamine oxidase inhibitors
MAOIs exists in two subtypes: MAO-A, which prefer-
entially deaminates NE and 5-HT, and MAO-B, which
preferentially deaminates dopamine. Phenelzine is a
non-selective inhibitor of MAO-A and MAO-B.
L-Deprenyl is a selective MAO-B inhibitor that may be
effective in the treatment of Parkinson’s disease.
The MAOI phenelzine at a dose of 15 mg TID was
shown to be effective (in an open study) (94), but no
placebo-controlled, double-blind trials exist. The dose
of phenelzine ranges from 30 mg to 90 mg a day in
divided doses. All patients on MAOI-A must be on a
restricted diet and avoid certain medications to pre-
vent hypertensive crisis. Meperidine, sympathomimetics
(including Midrin), alcohol, and foods with a high
tyramine content (cheddar cheese, fava beans, banana
peel, tap beers, Marmite and Veggie-Mite concentrated,
yeast extract, sauerkraut, soy sauce, and other soybean
condiments) must be avoided (95–100). Assistance from
a pharmacist when using MAOIs may be desirable to
avoid drug interaction.
The most common side-effects of MAOIs include
insomnia, orthostatic hypotension, constipation,
increased perspiration, weight gain, peripheral
oedema, and, less commonly, inhibition of ejaculation
or reduced libido. Insomnia can be reduced by giving
most of the medication early in the day. The risk of
hypertensive crisis may be reduced by having the
patient take the MAOI 3– 4 h before or after eating or
taking the entire dose at bedtime, as gut MAO activity
rapidly returns to normal (95). Sublingual nifedipine has
been used to treat hypertensive crisis when it occurs
in MAOI users (101).
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Calcium channel antagonists
Calcium, in combination with a calcium-binding protein
such as calmodulin or troponin, regulates many func-
tions, including muscle contraction, neurotransmitter
and hormone release, and enzyme activity. Its extra-
cellular concentration is high; its intracellular free
concentration is 10 000-fold smaller. The concentration
gradient is established by membrane pumps and the
intracellular sequestering of free calcium. When stimu-
lated, the cell can open calcium channels in the plasma
membrane or release intracellular stores of calcium (102).
Channel types and classes
Two types of calcium channels exist: calcium entry
channels, which allow extracellular calcium to enter
the cell, and calcium release channels, which allow intra-
cellular calcium (in storage sites in organelles) to enter
the cytoplasm. They include ryanodine and inositol
1,4,5-triphosphate receptors (103). Calcium entry chan-
nel subtypes include voltage-gated opened by depolar-
ization, ligand-gated opened by chemical messengers,
such as glutamate, and capacitative activated by deple-
tion of intracellular calcium stores.
There are six functional subclasses of voltage gated
calcium (Ca2+) channels that are named T, L, N, P, Q,
and R. They fall into two major categories: high-voltage
activated channels and the unique low-voltage activated
T-type, which is activated at negative potentials (104).
Voltage-gated calcium channels are heteromers con-
taining protein subunits of about 30–230 kDa that form
calcium-selective pores across the cell membrane. These
subunits have different functions, and subunit isoforms
give rise to distinct channel subtypes. The a1 subunit,
which consists of four homologous domains of six
transmembrane segments each, forms the trans-
membrane pore and contains most of the channel’s
known drug-binding sites. Molecular cloning has
revealed at least six a1 genes, which are associated
with auxiliary subunits, including a membrane-
spanning a2-d complex that increases the amplitude of
calcium currents and binds the anti-convulsant gaba-
pentin, and a cytoplasmic b subunit that modifies the
channel’s current amplitude, voltage dependence, and
activation and inactivation properties (103).
The three major classes of L-type Ca2+ channel
blockers are the dihydropyridines (e.g. nifedipine),
benzothiazepines (e.g. diltiazem), and phenylalkyl-
amines (e.g. verapamil). Regions of the a1 subunit
contain the binding sites for all these drugs (104).
Mechanism of action in migraine
The mechanism of action of the calcium channel
antagonists in migraine prevention is uncertain. They
# Blackwell Science Ltd Cephalalgia, 2002, 22, 491–512
Migraine: preventive treatment 497
were introduced into the treatment of migraine on the
assumption that they prevent hypoxia of cerebral
neurones, contraction of vascular smooth muscles, and
inhibition of the Ca2+-dependent enzymes involved
in prostaglandin formation. Perhaps it is their ability
to block 5-HT release, interfere with neurovascular
inflammation, or interfere with the initiation and
propagation of spreading depression that is critical
(105). The discovery that an abnormality in an a1a
subunit (P/Q channel) can produce familial hemiplegic
migraine (106) has led to a search for more fundamental
associations.
Clinical trials
The AHCPR Technical Report identified 45 controlled
trials of calcium antagonists, including flunarizine
(25 trials), nimodipine (11 trials), nifedipine (five trials),
verapamil (three trials), cyclandelate (three trials),
and nicardipine (one trial) (10). Flunarizine was com-
pared with placebo in eight migraine prevention trials
and effect sizes could be calculated for seven studies
(107–113) but not the eighth study (114). A meta-
analysis of these seven heterogeneous trials was
statistically significant in favour of flunarizine. Five
comparisons of flunarizine with propranolol (115, 116),
and two with metoprolol (23, 117), showed no significant
differences between flunarizine and these b-blocking
agents. There were no significant differences between
flunarizine and pizotifen (118–120), or between
flunarizine and methysergide (121). One trial compar-
ing flunarizine and dihydroergokryptine (122) (DEK)
reported mixed results, but suggested that differences
in the effects of the two treatments were small.
Nimodipine had mixed results in placebo-controlled
trials. Three placebo-controlled studies suggested no
significant differences (123, 124), while two reported
relatively large and statistically significant differences
in favour of nimodipine (123, 125). Nimodipine was
not different from flunarizine (126), pizotifen (118–120)
or propranolol (127). Our interpretation and our
clinical experience is that nimodipine is ineffective in
migraine prevention.
The evidence for nifedipine was difficult to interpret.
Two comparisons with placebo yielded similar effect
sizes that were statistically insignificant, but the 95%
confidence intervals associated with these estimates
were large and did not exclude either a clinically
important benefit or harm associated with nifedipine
(128, 129). Similarly ambiguous results were reported in
one comparison with flunarizine (130) and two com-
parisons with propranolol (20, 131). One trial found
that metoprolol was significantly better than nifedipine
498 SD Silberstein & PJ Goadsby
at reducing headache frequency (20). Our conclusion is
that nifedipine is ineffective as a migraine preventive.
Verapamil was more effective than placebo in two of
three trials, but both positive trials had high dropout
rates, rendering the findings uncertain (46, 132).
The single negative placebo-controlled trial included
a propranolol treatment arm. This trial reported no
significant difference between verapamil, propranolol,
and placebo (46, 133). Our conclusion is that there is
no rigorous, randomized, controlled trial evidence to
support the use of verapamil in migraine.
Diltiazem (60–90 mg QID) was effective in two small
open studies (134, 135). These studies are insufficient to
recommend the use of diltiazem.
Side-effects of the Ca2+ antagonists are dependent on
the drug, and include dizziness and headache (particu-
larly with nifedipine), depression, vasomotor changes,
tremor, gastrointestinal complaints (including constipa-
tion), peripheral oedema, orthostatic hypotension, and
bradycardia. Patients frequently report an initial
increase in headache. Headache improvement fre-
quently requires weeks of treatment. Adverse events
most commonly associated with flunarizine were seda-
tion, weight gain, and abdominal pain. Symptoms
reported with other calcium channel antagonists
included dizziness, oedema, flushing, and constipation.
Two trials of verapamil and one of nifedipine reported
high dropout rates due to adverse events (10). Side-
effects with nifedipine were frequent (54%) and included
dizziness, oedema, flushing, headache, and mental
symptoms (128).
Verapamil is available as a 40, 80, or 120-mg tablet or
as a 120, 180, or 240-mg sustained-release preparation.
Start at a dose of 80 mg two to three times a day, with
a maximum of 640 mg a day in divided doses. The
sustained-release preparation of verapamil can be given
once or twice a day, but unreliable absorption reduces
reliability. The most common side-effect is constipation;
dizziness, nausea, hypotension, headache, and oedema
are less common. Bioavailability is 20%. The absorbed
drug is tightly protein bound. Peak plasma levels occur
in 5 h; the half-life ranges from 2.5 h to 7.5 h.
Flunarizine is not available in the USA. The dose is
5–10 mg a day. The most prominent side-effects
include weight gain, somnolence, dry mouth, dizziness,
hypotension, occasional extrapyramidal reactions, and
exacerbation of depression. The elimination half-life of
flunarizine is 19 days.
Anti-convulsants
Anti-convulsant medication is increasingly recom-
mended for migraine prevention because of placebo-
controlled, double-blind trials that prove it to be
effective. With the exception of valproic acid and
phenobarbital, many anti-convulsants interfere with
the efficacy of contraceptives (136, 137).
Nine controlled trials of five different anti-convulsants
were included in the AHCPR Technical Report
(138–144).
Valproic acid possesses anti-convulsant activity in a
wide variety of experimental epilepsy models. Valproate
at high concentrations increases GABA levels in
synaptosomes, perhaps by inhibiting its degradation;
it enhances the post-synaptic response to GABA; and,
at lower concentrations, it increases potassium con-
ductance, producing neuronal hyperpolarization.
Valproate turns off the firing of the 5-HT neurones of
the dorsal raphe, which are implicated in controlling
head pain.
Disordered GABA metabolism during migraine has
been reported (145). Imbalance in the plasma concentra-
tions of GABA, an inhibitory amino acid, and glutamic
acid, an excitatory amino acid, has also been observed
(140–144, 146 –148).
The mechanism of action of valproate in migraine
prophylaxis may be related to facilitation of GABAergic
neurotransmission (149–151). Valproate enhances
GABA activity within the brain by inhibiting its
degradation, stimulating its synthesis and release, and
directly enhancing its post-synaptic effects. The con-
centration of valproate required to inhibit GABA
transaminase is greater than that which occurs during
therapy. However, active metabolites, one of which
(2-en-valproic acid) accumulates in the brain, have an
anti-convulsant effect and cause GABA accumulation
in vivo (149). Other potential mechanisms of action
include direct effects on neuronal membranes (it
suppresses induced and spontaneous epileptiform
activity), inhibition of kindling, and reduction of
excitatory neurotransmission by the amino acid aspar-
tate by blocking its release (150, 151). Valproate also
attenuates plasma extravasation in the Moskowitz
model of neurogenic inflammation (NI) by interacting
with the GABAA receptor. The relevant receptor may be
on the parasympathetic nerve fibres projecting from
the sphenopalatine ganglia; in so doing, it attenuates
nociceptive neurotransmission (149). In addition,
valproate-induced increased central enhancement of
GABAA activity may enhance central antinociception
(152). Valproate also interacts with the central 5-HT
system and it reduces the firing rate of midbrain
serotonergic neurones (152).
Five studies provided strong and consistent support
for the efficacy of divalproex sodium (140, 141, 153) and
sodium valproate (138, 147). Two controlled trials of
each of these agents showed them to be significantly
better than placebo at reducing headache frequency
# Blackwell Science Ltd Cephalalgia, 2002, 22, 491–512

(138, 141, 142, 147). A single study, reported in abstract
form only, compared divalproex sodium with pro-
pranolol and found differences favouring divalproex
sodium; however, the statistical significance of these
results could not be determined (open-label study
with high dropout rates) (140). A more recent study
(published after December 1996 and therefore not
included in the AHCPR Technical Report) found
divalproex sodium more effective compared with
placebo, but not significantly different compared with
propranolol, for prevention of migraine in patients
without aura (148). An extended release form of
divalproex sodium demonstrated comparable efficacy
to the tablet formulation (154).
Valproic acid is a simple 8 carbon, 2 chain fatty acid
with 80% bioavailability after oral administration. It
is highly protein-bound, with an elimination half-life
between 8 h and 17 h.
Nausea, vomiting and gastrointestinal distress are
the most common side-effects of valproate therapy.
These are generally self-limited and are slightly less
common with divalproex sodium than with sodium
valproate. When the therapy is continued, the incidence
of gastrointestinal symptoms decreases, particularly after
6 months. The fourth trial found significantly higher rates
of nausea, asthenia, somnolence, vomiting, tremor, and
alopecia when patients used divalproex sodium.
In an open-label study, Silberstein et al. (155)
evaluated the long-term safety of divalproex sodium
in patients who had completed one of two previous
double-blind, placebo-controlled studies evaluating the
safety and efficacy of divalproex in migraine prophy-
laxis. Of 163 patients enrolled, 46 had been treated with
placebo and 117 had been treated with divalproex. The
results, including data from the double-blind study,
represented 198 patient-years of divalproex exposure.
The average dose was 974 mg/day. Reasons for
premature discontinuation (67%) included administra-
tive problems (31%), drug intolerance (21%), and
treatment ineffectiveness (15%). The most frequently
reported adverse events were nausea (42%), infection
(39%), alopecia (31%), tremor (28%), asthenia (25%),
dyspepsia (25%), and somnolence (25%). Divalproex was
found to be safe and initial improvements were
maintained for periods of >1080 days. No unexpected
adverse events or safety concerns unique to the use of
divalproex in the prophylactic treatment of migraine
were found.
Valproate has little effect on cognitive functions
and it rarely causes sedation. On rare occasions,
valproate administration is associated with severe
adverse reactions, such as hepatitis or pancreatitis. The
frequency varies with the number of concomitant
medications used, the patient’s age, the presence of
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Migraine: preventive treatment 499
genetic and metabolic disorders, and the patient’s
general state of health. These idiosyncratic reactions
are unpredictable (156).
The risk of valproate hepatotoxicity is highest in
children under the age of 2 years, especially those treated
with multiple anti-epileptic drugs, those with metabolic
disorders, and those with severe epilepsy accompanied
by mental retardation and organic brain disease (157).
The relative risk of hepatotoxicity from valproate is low
in migraineurs. Valproate is potentially teratogenic and
should not be used in pregnant women or women
considering pregnancy (158). Hyperandrogenism,
resulting from elevated testosterone levels, ovarian
cysts, and obesity, is of particular concern in young
women with epilepsy who use valproate (159). It is
uncertain if valproate can cause these symptoms in
young women with migraine or mania.
Because of valproate’s potential idiosyncratic inter-
actions with barbiturates (severe sedation, coma),
migraine patients who are on valproate should not be
given barbiturate-containing combination analgesics for
symptomatic headache relief. If these drugs are used,
they should be given with caution and at a low dose.
Absolute contraindications to valproate are pregnancy
and a history of pancreatitis or a hepatic disorder such
as chronic hepatitis or cirrhosis of the liver. Other
important contraindications are haematological dis-
orders, including thrombocytopenia, pancytopenia and
bleeding disorders.
Valproic acid is available as 250-mg capsules and as
a syrup (250 mg/5 ml). Divalproex sodium is a stable
co-ordination complex comprised of sodium valproate
and valproic acid in a 1 : 1 molar ratio. An enteric-coated
form of divalproex sodium is available as 125, 250, and
500-mg capsules and a sprinkle formulation. Start with
250–500 mg a day in divided doses and slowly increase
the dose. Monitor serum levels if there is a question of
toxicity or compliance. (The usual therapeutic level is
from 50 to 100 mg/ml.) The maximum recommended
dose is 60 mg/kg per day. An extended release form of
divalproex sodium demonstrated comparable efficacy
to the tablet formulation. The adverse effect profile in
the clinical trial, however, showed almost identical
adverse effect rates for the placebo and active treatment
arms (160).
Gabapentin (600–1800 mg) was effective in episodic
migraine and chronic migraine in a 12-week open-label
study (161). Gabapentin was not effective in one
placebo-controlled, double-blind study (162), but a
more recent trial reported clinical efficacy for gabapentin
in migraine prevention (163). Gabapentin 1800–2400 mg
was superior to placebo in reducing the frequency of
migraine attacks. The responder rate (50% decrease in
attack frequency) was 36% for gabapentin and 14% for
500 SD Silberstein & PJ Goadsby
placebo (P=0.02). The two treatment groups were
comparable with respect to treatment-limiting adverse
events.
The most common adverse events reported in
association with the gabapentin were dizziness or
giddiness and drowsiness. Relatively high patient
withdrawal rates due to adverse events were reported
in some trials (10).
Topiramate is a structurally unique anti-convulsant
that was discovered serendipitously. It was originally
synthesized as part of a research project to discover
structural analogues of fructose-1,6-diphosphate capable
of inhibiting the enzyme fructose 1,6-bisphosphatase,
thereby blocking gluconeogenesis, but it has not to
date demonstrated clinical evidence of hypoglycaemic
activity. Topiramate is a derivative of the naturally
occurring monosaccharide D-fructose and contains a
sulfamate moiety. Topiramate is rapidly and almost
completely absorbed. In humans, the blood plasma
concentration increases linearly as a function of dose
over the pharmacologically relevant range (164, 165). It
is not extensively metabolized and is eliminated
predominantly unchanged in the urine. The average
elimination half-life is approximately 21 h (165).
The anti-convulsant activity of most anti-epileptic
drugs is thought to be due to a state-dependent
blockade of voltage-dependent Na+ or Ca2+ channels,
or an ability to enhance the activity of c-aminobutyrate
(GABA) at GABAA receptors (166, 167). Topiramate can
influence the activity of some types of voltage-activated
Na+ and Ca2+ channels, GABAA receptors, and the
a-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid
(AMPA)/kainate subtype of glutamate receptors.
Topiramate also inhibits some isozymes of carbonic
anhydrase (CA) and exhibits selectivity for CA II and CA
IV (168, 169).
Topiramate has been associated with weight loss,
not weight gain (a common reason to discontinue
preventive medication) with chronic use. Edwards et al.
(170) enrolled 30 migraineurs in a placebo-controlled,
double-blind prevention trial of topiramate. There was a
4-week baseline screening phase followed by a 6-week
titration of 200 mg qd of topiramate in divided doses or
placebo. This was followed by a one-half week steady
state. Percent responders (patients with i50% reduction
in 28-day migraine headache frequency) during the
18-week double-blind phase were topiramate 46.7% and
placebo 6.7% (P=0.035).
Potter et al. (171) evaluated the efficacy and safety of
topiramate in migraine prophylaxis. Forty patients who
were 18– 65 years of age and had migraine with or
without aura were randomized to topiramate or placebo
(1 : 1 ratio). The study duration was 20 weeks (baseline,
titration, and maintenance phase of 4, 8, and 8 weeks).
Nineteen patients were randomized to topiramate and
21 to placebo. Thirty-five patients completed the
study. The mean topiramate dose was 125 mg (range
25–200 mg). The baseline 28-day headache frequency
was 5.14 in topiramate patients and 4.37 in placebo
patients. The mean 28-day headache rate over the entire
double-blind phase was 3.31 (topiramate) vs. 3.83
(placebo; P=0.0025). The mean reduction in
headache rate was 1.83 (topiramate) vs. 0.55 (placebo;
P=0.0025). The median percent reduction in monthly
headache rate was 33% (topiramate) vs. 8% (placebo;
P=0.0061). Large-scale placebo-controlled studies are
underway.
Serotonin antagonists
The anti-serotonin migraine-preventive drugs are
potent 5-HT2B and 5-HT2C receptor antagonists, while
mCPP, a 5-HT2B and 5-HT2C receptor agonist, induces
migraine in susceptible individuals (172–175).
Methysergide, cyproheptadine, and pizotifen, effective
migraine prophylactic drugs, are 5-HT2B and 5-HT2C
receptor antagonists, while ketanserin, a selective
5-HT2A and a poor 5-HT2B and 5-HT2C receptor
antagonist, is not (176 –178).
mCPP, a major metabolite of the anti-depressants
trazadone and nefazodone, induces migraine hours after
the immediate pharmacological response to the drug
(monitored by elevation of plasma cortisol and prolactin)
is over. Gordon et al. (173) found that mCPP induced
headache in both migraineurs (five of eight) and in
non-migraine controls (four of 10). No significant
differences were found between the migraineurs and
normal subjects in terms of their neuroendocrine or
headache responses to mCPP, but there were highly
significant associations between the cortisol responses
and headache severity and duration.
Pizotifen and methylergometrine are potent rabbit
jugular vein endothelial cell 5-HT2 receptor antagonists.
5-HT2B or 5-HT2C receptor activation by mCPP or endo-
genously released 5-HT could dilate cerebral vessels.
Vasodilation, however, is neither necessary nor suffi-
cient to cause headache (179, 180), but endothelium-
derived nitric oxide (NO) can activate sensory tri-
geminovascular fibres resulting in calcitonin gene-
related peptide (CGRP) release, which mediates pial
artery vasodilation (181) and neurogenic inflammation
(178, 180, 182). mCPP itself can produce extravasation
in the dural membrane, which can be blocked by
selective 5-HT2B antagonists (183).
Methysergide is also a 5-HT1 receptor agonist (184),
but has lower affinity for the 5-HT1 than for the 5-HT2
binding site (185). Methysergide-induced contraction of
dog isolated saphenous vein is also mediated by 5-HT1B
# Blackwell Science Ltd Cephalalgia, 2002, 22, 491–512

receptors (186 –188). Chronic, but not acute, treatment
with methysergide attenuates dural plasma extra-
vasation following electric stimulation of the rat
trigeminal ganglion in the Moskowitz model (189). The
difference between acute and chronic drug administra-
tion could be due to the accumulation of the active
metabolite, methylergometrine. Methysergide (or
methylergometrine) presynaptically could inhibit the
release of CGRP from perivascular sensory nerves.
Methysergide
Methysergide is a semisynthetic ergot alkaloid that
is structurally related to methylergonovine. It is a
5-HT2 receptor antagonist and 5-HT1B/D agonist. It
was probably the first drug developed for migraine
prevention (190), but its usefulness is limited by
reports of retroperitoneal and retropleural fibrosis
associated with long-term, mostly uninterrupted,
administration (191).
The AHCPR Technical Report identified 17 controlled
trials of methysergide for migraine prevention (19, 121,
192–203). Four placebo-controlled trials suggested that
methysergide was significantly better than placebo at
reducing headache frequency (198, 199, 201, 202).
Four comparison trials showed no statistically sig-
nificant differences between methysergide and pizotifen
(194, 196, 200, 201). Two trials that directly compared
methysergide and propranolol failed to demonstrate
any statistically significant differences between these
treatments (19, 192). The only trial that compared
methysergide with metoprolol reported an unusually
low response to metoprolol (6%) and thus a misleading
relative increase in methysergide efficacy (192).
Methysergide was associated with a higher incidence
of adverse events than was placebo. Gastrointestinal
complaints were most common and included nausea,
vomiting, abdominal pain, and diarrhoea. Also fre-
quently reported were leg symptoms (restlessness or
pain), dizziness, giddiness, drowsiness, lassitude, and
paraesthesia. Adverse events were no more common
with methysergide than with pizotifen. The duration
of the trials reviewed here was too short to detect
the fibrotic complications sometimes observed with
long-term methysergide use.
Side-effects of methysergide noted in clinical practice
include transient muscle aching, claudication, abdom-
inal distress, leg cramps, hair loss, nausea, weight gain,
and hallucinations. Frightening hallucinatory experi-
ences after the first dose are not uncommon (204).
Curran and Lance (205) have treated leg claudica-
tion with vasodilators with some enhancement of
methysergide’s effectiveness, suggesting that its action
on headache is not a result of vasoconstriction. The
major complication of methysergide is the rare (1/5000)
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Migraine: preventive treatment 501
development of retroperitoneal, pulmonary, or
endocardial fibrosis (206, 207).
Methysergide is indicated for the treatment of
migraine. The dose ranges from 2 to 8 mg a day, with
the higher doses being given two or three times a day.
Many clinicians use higher doses, up to 14 mg a day,
without adverse events and with higher efficacy (208).
To minimize early adverse events, patients can start
with a dose of 1 mg a day and increase the dose
gradually by 1 mg every 2–3 days. (This can be
accomplished by breaking the 2-mg tablets if 1-mg
tablets are not available.) A trial of at least 2 months
should be given, with doses up to at least 8 mg a day.
Methysergide, in general, should not be taken con-
tinuously for long periods, since doing so may
produce retroperitoneal fibrosis (191, 206, 209). Instead,
the drug should be given for 6 months, stopped for 1
month, and then restarted. To avoid an increase in
headache when methysergide is stopped, the patient
should be weaned off the drug over a 1-week period.
Some authorities use methysergide on a continuous
basis with careful monitoring (208), which includes
auscultation of the heart and yearly echocardiography,
chest X-ray, and abdominal magnetic resonance imag-
ing. The drug should be discontinued immediately on
suspicion of pulmonary, cardiac, or retroperitoneal
fibrosis (208).
Contraindications to methysergide use include preg-
nancy, peripheral vascular disorders, severe arterio-
sclerosis, coronary artery disease, severe hypertension,
thrombophlebitis or cellulitis of the legs, peptic ulcer
disease, fibrotic disorders, lung diseases, collagen
disease, liver or renal function impairment, valvular
heart disease, debilitation, or serious infection. Patients
who receive methysergide should remain under the
supervision of the treating physician and be examined
regularly for development of the rare pulmonary/
cardiac or retroperitoneal fibrosis or the development
of vascular complications.
Methysergide is an effective migraine preventive
medication that is an appropriate consideration in
resistant headaches with a high attack frequency. All
of the open and controlled studies attest to its efficacy. In
addition to being effective in reducing attack frequency,
it often acts synergistically with ergotamine for break-
through attacks. Due to its side-effect profile, it should
be reserved for severe cases in which other migraine-
preventive drugs are not effective.
Cyproheptadine, an antagonist at the 5-HT2, histamine
H1, and muscarinic cholinergic receptors, is widely used
in the prophylactic treatment of migraine in children (95,
210, 211). Curran and Lance (205) found cyproheptadine
more effective than placebo but less effective than
methysergide. Cyproheptadine is available as 4-mg
502 SD Silberstein & PJ Goadsby
tablets. The total dose ranges from 12 to 36 mg a day
(given two to three times a day or at bedtime). Common
side-effects are sedation and weight gain; dry mouth,
nausea, light-headedness, ankle oedema, aching legs,
and diarrhoea are less common. Cyproheptadine may
inhibit growth in children (212) and reverse the effects
of SSRIs.
Pizotifen, a 5-HT2 receptor antagonist structurally
similar to cyproheptadine, is not available in the USA.
The United States Headache Consortium guidelines (11)
found that evidence was inconsistent for the efficacy of
pizotifen from 11 placebo-controlled trials (201, 222) and
19 comparisons with other agents (24, 118–120, 153, 194,
196, 200, 201, 213, 220, 223–230). Analysis of the placebo-
controlled trials suggested a large clinical effect that
was statistically significant. In direct comparisons with
other agents known to be efficacious for migraine
prevention, no significant differences were demon-
strated between pizotifen and flunarizine (118–120),
methysergide (194, 196, 200, 201), naproxen sodium
(213), or metoprolol (24). However, in the 26 trials
reviewed, pizotifen was generally poorly tolerated (10).
Substantial weight gain, tiredness, and/or drowsiness
were frequently reported. Pizotifen was associated with
a high rate of withdrawals due to adverse events.
Controlled and uncontrolled studies in Europe (231)
have shown this drug to be of benefit in 40–79% of
patients. The dose recommendation is 0.5–1 mg, one to
three times daily by titration. Side-effects include
drowsiness and weight gain (232).
Other drugs
Feverfew (Tanacetum parthenium)
Feverfew is a medicinal herb used in self-treatment of
migraine. Four trials were conducted: two that were
reported in the AHCPR and two that were conducted
after the report was published. The AHCPR Technical
Report listed two trials, distinctly different in design,
that compared feverfew with placebo and no treat-
ment. One trial was conducted in a self-selected group
of feverfew users and showed that withdrawing
feverfew led to a statistically significant increase in
headache frequency (233). A pilot study of 17 migrain-
eurs who ate fresh feverfew leaves daily was under-
taken at the City of London Migraine Clinic. Patients
were given capsules of freeze-dried feverfew or placebo.
Those receiving placebo had a tripling in the frequency
of migraine attacks. Patients on placebo reported
increased nervousness, tension headaches, insomnia,
or joint stiffness constituting a ‘post feverfew syndrome’
(perhaps another example of rebound).
The other, more conventional, trial was conducted in
a larger group of migraineurs, most of whom (71%)
had never used feverfew (234). This trial reported a
smaller difference between feverfew and the control
treatment than did the other trial, but still found the
difference to be statistically significant in favour of
feverfew (P<0.005). Two trials were not included in the
AHCPR report. One was a double-blind, randomized,
crossover trial that tested the efficacy of feverfew
compared with placebo, and reported that treatment
with feverfew was associated with a significant reduc-
tion in pain intensity and non-headache symptoms
(nausea, vomiting, photophobia, and phonophobia)
(235). The other trial reported no significant differences
between feverfew given as an alcoholic extract and
placebo for reducing migraine frequency (236).
Limited information indicates that adverse events
were no more common with feverfew than with
the control treatment (10). Feverfew’s side-effects
include mouth ulceration and a more widespread oral
inflammation associated with loss of taste. Feverfew’s
mechanism of action is uncertain. It is rich in sesqui-
terpene lactones, especially parthenolide, which may be
a non-specific NE, 5-HT, bradykinin, prostaglandin, and
acetylcholine antagonist. The biological variation in
the sesquiterpene lactone content and the long-term
safety and effectiveness of feverfew are of concern (233).
Until recently it was generally assumed that parthe-
nolides represent the active principle of feverfew. This
hypothesis was supported by in vitro experiments that
emphasized its biological activity. These studies have
demonstrated that the plant has inhibitory effects on
platelet aggregation and release of serotonin from blood
platelets and leucocytes (237, 238). One trial that used
feverfew extract with a standardized and constant
concentration of parthenolides to treat migraine did
not show any beneficial effect (236). Thus, the clinical
effectiveness of feverfew for migraine prevention has
not been established beyond reasonable doubt. More
clinical trials are needed, both on a larger scale and with
various feverfew extracts, including parthenolide-free
sesquiterpene lactone chemotypes (239).
Riboflavin
A mitochondrial dysfunction resulting in impaired
oxygen metabolism may play a role in migraine
pathogenesis (240–243). Riboflavin (vitamin B2) is the
precursor of flavin mononucleotide and flavin
adenine dinucleotide, which are required for the activity
of flavoenzymes involved in the electron transport
chain. Given to patients with mitochondrial encephalo-
pathy lactic acidosis and stroke (MELAS) or mito-
chondrial myopathies on the assumption that large
doses might augment activity of mitochondrial com-
plexes I and II, riboflavin improved clinical as well as
biochemical parameters (244 –247).
# Blackwell Science Ltd Cephalalgia, 2002, 22, 491–512

Based on the results of an open trial in migraine, a
placebo-controlled, double-blind trial of high dose of
vitamin B2 (400 mg) was performed and showed
significant benefit (248). Schoenen et al. (248) compared
riboflavin (400 mg) with placebo in migraineurs in a
randomized trial of 3 months duration. Riboflavin was
significantly superior to placebo in reducing the attack
frequency (P=0.005), headache days (P=0.012), and
migraine index (0.012). The proportion of patients who
improved by at least 50% in headache days, i.e.
‘responders’, was 15% for placebo and 59% for riboflavin
(P=0.002), and the number-needed-to-treat for effec-
tiveness was 2.3. Only three adverse events occurred:
two in the riboflavin group (diarrhoea and polyuria) and
one in the placebo group (abdominal cramps). None was
serious.
Magnesium supplementation was effective in one of
two trials. One study enrolled 81 patients who had IHS
migraine. Patients received 600 mg (24 mmol) of oral
magnesium (trimagnesium dicitrate) or placebo daily for
12 weeks. In weeks 9–12 the attack frequency was
reduced by 41.6% in the magnesium group and by
15.8% in the placebo group compared with the
baseline (P<0.05). The number of days with migraine
and symptomatic drug consumption also decreased
significantly in the magnesium group. Adverse
events were diarrhoea (18.6%) and gastric irritation
(4.7%) (249).
In another multicentre, prospective, randomized,
double-blind, placebo-controlled study, 20 mmol mag-
nesium-L-aspartate-hydrochloride trihydrate given in
divided doses was evaluated. An interim analysis was
performed with 69 patients (64 women, five men). Of
these, 35 had received magnesium and 34 placebo. There
were 10 responders in each group (28.6% magnesium
and 29.4% placebo). There was no benefit from
magnesium compared with placebo in the number of
migraine days or migraine attacks (250).
The studies differed in the amount of magnesium
(24 mmol vs. 20 mmol) and in the salt (dicitrate vs.
aspartate). Those differences may produce differences in
bioavailability and efficacy and account for the reported
difference.
Aspirin
O’Neill and Mann (251) and Masel et al. (252) found that
aspirin (ASA) (650 mg a day) decreased headache
frequency. Two major multicentre trials, however,
clearly proved the efficacy of ASA in the prophylaxis
of migraine: in 1988 ‘The British Physician Trial’ showed
that a daily dose of 500 mg ASA reduced the frequency
of migraine by an average of 30% (253). In a double-blind
trial of low-dose ASA (325 mg every other day) in 22 071
# Blackwell Science Ltd Cephalalgia, 2002, 22, 491–512
Migraine: preventive treatment 503
United States male physicians (Physician Health Study),
Buring et al. (254) found a 20% reduction in headache
frequency. Although this is statistically significant, it
may not be clinically significant. In a small open trial,
Baldratti et al. (255) compared the efficacy of ASA
(13.5 mg/kg) with propranolol (1.8 mg/kg). In this trial,
both drugs were equally effective and reduced the
frequency, duration, and intensity of attacks to the same
extent. In a double-blind crossover trial, ASA (500 mg
daily) was statistically less effective than 200 mg
propranolol daily (22). High-dose ASA use may lead
to overuse and the development of rebound headaches,
although, in practice, ASA is usually implicated with
other compounds in combination analgesics. Aspirin
in low doses is indicated for the prophylaxis of
myocardial infarction and transient ischaemic attacks.
We would use aspirin only in patients with prolonged or
non-visual aura.
Non-steroidal anti-inflammatory drugs
Some NSAIDs may be effective in migraine prophyl-
axis. These include sodium naproxen, fenoprofen,
ketoprofen, and tolfenamic acid (256). Some headache
disorders (paroxysmal hemicrania and hemicrania
continua) are defined by their responsiveness to
indomethacin (257–259). Although NSAIDs are
effective, they must be used with caution because of
their adverse effects on gastrointestinal and renal
function (260).
a Agonists
The United States Headache Consortium guidelines
and the AHCPR Technical Review included 17 con-
trolled trials of a2 agonists for the prevention of
migraine: 16 of clonidine (153, 261–275), and one of
guanfacine (272). The evidence from these trials
suggests that a2 agonists are minimally, and not
conclusively, efficacious. Three of 11 placebo-controlled
trials of clonidine found a significant difference in
favour of the active agent, but the magnitude of the effect
was small (265, 269, 270). Two comparative trials
comparing clonidine with the b-blockers metoprolol
(273) and propranolol yielded mixed results (274). Two
comparative trials showed no significant differences
among clonidine, practolol (265) and pindolol (275).
One trial each found no significant differences between
clonidine and pizotifen (153), or between clonidine and
carbamazepine (275).
Clonidine’s most commonly reported adverse events
were drowsiness and tiredness. In studies comparing
clonidine with b-blockers, adverse events occurred at
similar rates for both interventions.
504 SD Silberstein & PJ Goadsby

Botulinum toxin type A showed significantly more

Newer treatments
Botulinum toxin type A (BotoxR)
Silberstein et al. (276) evaluated the safety and efficacy
of pericranial Botulinum toxin type A injections as
prophylactic treatment of chronic moderate-to-severe
migraine. One hundred and twenty-three patients who
had chronic IHS-defined migraine and a history of two
to eight moderate-to-severe migraine attacks during a
1-month baseline were randomized to treatment with
either 0, 25, or 75 U of Botulinum toxin type A injected
symmetrically into glabellar, frontalis, and temporalis
muscles. Diaries were kept for three months post-
injection. At 12 centres, 41, 42, and 40 patients were
randomized to 0, 25, and 75 U Botulinum toxin type A
treatment groups and had baseline frequencies of
migraine of 4.41, 4.45, and 3.95 attacks per month,
respectively. The 25 U Botulinum toxin type A treatment
group fared significantly better than the placebo group
by the following measures: reduction in mean frequency
of moderate-to-severe migraines during days 31– 60;
incidence of 50% reduction and incidence of two
headache decrease in mild-to-severe migraines at days
61–90; and improvement by patient global assessment
for days 31– 60 post-injection. The 75 U Botulinum
toxin type A treatment group was significantly better
than the placebo group on patient global assessment for
days 31– 60, but not other parameters. Botulinum toxin
type A treatment was well tolerated, but high-dose
treatment-related adverse events than placebo. No
serious treatment-related adverse events were reported.
Pericranial injection of Botulinum toxin type A (25 U)
showed significant differences compared with vehicle
in reducing migraine frequency and associated symp-
toms during the 90 days following injection. Further
studies are currently underway. Their results will
allow us to ascertain the place of Botox in migraine
prevention.
Setting treatment priorities (Table 3)
The goals of treatment are to relieve or prevent the
pain and associated symptoms of migraine and to
optimize the patient’s ability to function normally. The
medications used to treat migraine can be divided into
four major categories: (i) drugs that have documented
high efficacy and mild to moderate adverse events (AEs),
which include b-blockers, amitriptyline, and divalproex;
(ii) drugs that have lower documented efficacy and
mild to moderate AEs, which include SSRIs, calcium
channel antagonists, gabapentin, topiramate, riboflavin,
and NSAIDs; (iii) drugs used based on opinion (a) mild
to moderate Aes, (b) major AEs or complex manage-
ment; (iv) drugs that have documented high efficacy
but significant AEs or are difficult to use, which
include methysergide and MAOIs; and (v) drugs that
have proven limited or no efficacy, which include

Table 3 Preventive drugs

High efficacy
Medications with proven high efficacy and mild-to-moderate adverse events
Propranolol, timolol, amitriptyline, valproate
Low efficacy
Medications with lower efficacy (i.e. limited number of studies, studies reporting conflicting results, efficacy suggesting
only ‘modest’ improvement) and mild-to-moderate adverse events
NSAIDs—aspirin, flurbiprofen, ketoprofen, naproxen sodium
b-blockers—atenolol, metoprolol, nadolol
Calcium channel blockers—Verapamil
Anti-convulsants—gabapentin, topiramate
Other—fenoprofen, feverfew, vitamin B2
Pizotifen
Unproven efficacy
Medication use based on opinion, not randomized controlled trials
Anti-depressants—doxepin, nortriptyline, imipramine, protriptyline, venlafaxine, fluvoxamine, mirtazepine, paroxetine,
protriptyline, sertraline, trazodone
Major AEs or complex management (Medication with proven efficacy but with frequent or severe adverse events (or safety
concerns), or complex management issues (special diets, high potential for severe adverse drug interactions, or drug holidays))
Methergine, MAOIs
Proven not effective
Medication proven to have limited or no efficacy
Acebutolol, carbamazepine, clomipramine, clonazepam, indomethacin, lamotrigine, nabumetone, nicardipine, nifedipine, pindolol

# Blackwell Science Ltd Cephalalgia, 2002, 22, 491–512


cyproheptadine, lithium, nifedipine, nimodipine, and
phenytoin. Choose a drug based on its proven efficacy,
the patient’s preferences and headache profile, the
drug’s side-effects, and the presence or absence of
coexisting or co-morbid disease (Table 2). Use the drug
with the best risk-to-benefit ratio for the individual
patient and take advantage of the drug’s side-effect
profile (277, 278). An underweight patient would be a
candidate for one of the medications that commonly
produce weight gain, such as a TCA; in contrast, one
would try to avoid these drugs in the overweight patient
and could consider the use of topiramate. Tertiary TCAs
that have a sedating effect would be useful at bedtime for
patients with insomnia. The older patient with cardiac
disease or patients with significant hypotension may not
be able to use TCAs or calcium channel or b-blockers, but
could easily use divalproex, topiramate, or gabapentin.
In the athletic patient, b-blockers should be used with
caution. Medication that can impair cognitive function-
ing should be avoided in patients who are dependent on
their wits (277, 278).
Co-morbid and coexistent diseases have important
implications for treatment. The presence of a second
illness provides therapeutic opportunities but also
imposes certain therapeutic limitations. In some
instances, two or more conditions may be treated with
a single drug. When migraine and hypertension and/or
angina occur together, b-blockers or calcium channel
blockers may be effective for all conditions (279). For
the patient with migraine and depression, TCAs or
SSRIs may be especially useful (280). For the patient
with migraine and epilepsy (281) or migraine and
bipolar illness (158, 282) divalproex and topiramate are
the drugs of choice. The pregnant migraineur who has
a co-morbid condition that needs treatment should be
given a medication that is effective for both conditions
and has the lowest potential for adverse effects on the
fetus. In individuals with more than one disease, certain
categories of treatment may be relatively contra-
indicated. For example, b-blockers should be used
with caution in the depressed migraineur, while TCAs,
neuroleptics, or sumatriptan may lower the seizure
threshold and should be used with caution in the
epileptic migraineur.
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