Migraine : Prophylactic Treatment

Rakesh Shukla*, Manish Sinha**

Abstract
Prophylactic treatment constitutes an important aspect of migraine management and includes avoidance of trigger factors
and life style advice followed by consideration of medications. The drugs of first choice are beta-blockers, flunarizine,
topiramate, valproate and amitriptyline. Drugs of second choice with less efficacy and evidence are venlafaxine,
gabapentin, naproxen, butterbur root, riboflavin and magnesium. Botulinum toxin type A has not yet been shown to
be effective. The choice of prophylactic drugs would depend on efficacy, co-morbidity, side effects, availability and
cost. Non-pharmacological treatments such as relaxation techniques, bio-feedback, cognitive behavioral therapy and
acupuncture are supported by some evidence but require far more specialist time or technical devices. All the drugs
used in migraine prophylaxis have been detected by serendipity. Drugs developed, in the future, on the basis of the
current knowledge of pathophysiology will hopefully be more effective.

Introduction

igraine is the most common headache diagnosis in

neurological services in Asia and is among the top 10
most disabling disorders worldwide.1 However, it still remains
under diagnosed and undertreated. Many patients require
management of individual migraine episodes as well as
prophylactic treatment to prevent future episodes. Migraine
prophylaxis involves avoidance of trigger factors, lifestyle advice
followed by consideration of medications. Adequate prophylaxis
is necessary to reduce the frequency and severity of migraine
attacks and thereby improve the quality of life and prevent
medication overuse headache.

Reduce the attack frequency, severity, and disability.

Avoid acute headache medication overuse.

Improve the quality of life.

Reduce headache-related distress and psychological

symptoms.

A. Medication use

Indications for Prophylaxis

Preventive treatment can be either preemptive, short term or
chronic. Preemptive treatment is used when there is a known
headache trigger, such as exercise or high altitude excursion or
sexual intercourse. Patients can be advised to pre-treat before
the activity. A single dose of indomethacin may abort exerciseinduced migraine. Short term prevention is used when the
patient is likely to have exposure for a certain period of time,
e.g. menstrual migraine. These patients can be treated with
daily medication just before and during exposure. Chronic
prophylaxis is used for patients with migraine frequency and
severity significant enough to interfere with their daily activities.

Recurring migraines that, in the patients opinion,significantly

interfere with their daily routines, despite acutetreatment

Contraindication to or failure or overuse of acute therapies

Therapy should be initiated with medications that have

the highest level of evidence-basedefficacy.

The lowest effective dose of the drug should be used

and increased slowly until clinical benefits are achieved
without any adverseevents.

An adequate trial of two to three months should be

given to each drug.

Use of a long-acting formulation may improve

compliance.

If sequential monotherapies are ineffective, combination

of first line drugs should be tried before advancing to
drugs of second choice.

Medication overuse should be suspected if there is a

lack of response to several prophylactic drugs.

The patients headache frequency and severity should

be monitored througha headache diary.

Therapy should be re-evaluated after 3 to 6 months,

and tapered or discontinued, if headaches are
wellcontrolled.

C. Coexisting conditions

Co-morbidity should be taken into account and a drug that

willtreat both should be selected.

D. Pregnancy

*
Professor, **Senior Resident, Department of Neurology, CSM Medical
University, Lucknow-226003, Uttar Pradesh

26

B. Evaluation

Recommendations for migraine prevention have in the past

focused on patients who had two or more attacks per month.
These recommendations did not account for the need of the
individual patient or other migraine characteristics. Recent
recommendations for starting preventive therapy are:2

Uncommon migraine conditions, such as

hemiplegic migraine, basilar migraine, migraine with
prolonged aura, ormigrainous infarction.

Principles of Prophylaxis

The goals of long-termmigraine treatment would be to:

Overwhelming costs of repetitive acute therapy

Patients should be advised to maintain a regular lifestyle,

with adequate sleep, meals, exercise, and manage stress. Any
identifiable trigger should be avoided. If this regimen does not
adequately control their migraine attacks, prophylactic drug
treatment is indicated. Adherence to the following principles
will enhance the successof therapy:2

Goals of prophylaxis

Most medications with proven benefit in migraine

prophylaxis are not safe in pregnancy. The severity of
the migraine episodes, frequency, response to acute
medications, patient preferences and the stage of pregnancy
should be considered while choosing a drug. If treatment is
absolutely necessary, a drug with the lowest risk of adverse
SUPPLEMENT OF JAPI april 2010 VOL. 58

(Level A). Divalproex and sodium valproate are comparable in

efficacy to propranolol, flunarizine and topiramate.5

effects on the foetus should be tried first.

E. Withdrawal

Other antiepileptic drugs

After 6 to 12 months of effective prophylaxis, gradual

withdrawal should be considered.

Gabapentin, levetericetam and zonisamide are less effective

than topiramate and valproate for migraine prophylaxis.
Lamotrigine is not efficacious in the treatment of migraine.5

Drugs for Migraine Prophylaxis

Antidepressants

Drugs used for migraine prophylaxis act in two ways:3

1.

By inhibition of cortical spreading depression (CSD) - The

antiepileptic drugs (topiramate, valproate, gabapentin),
calcium channel blockers (flunarizine, verapamil),
propranolol, amitriptyline, and tonabersat are some
examples of drugs that reduce neuronal hyperexcitability
and inhibit CSD.

2.

By restoration of nociceptive dysmodulation - Modulators

of serotonergic and adrenergic systems and cholinergic
enhancing drugs may restore descending nociceptive
inhibition and play a role in migraine prevention.

Amitriptyline is the only antidepressant with fairly

consistent support for efficacy in migraine prevention. It
downregulates serotonin receptors, increases the levels of
synaptic norepinephrine and enhances endogenous opioid
receptor actions. Amitriptyline is effective in the prophylaxis
of migraine at a dose of 10-75 mg per day (Level A). It is more
efficacious than propranolol for patients with mixed migraine
and tension-type headache. 6 Selective serotonin reuptake
inhibitors (SSRIs) have not shown significant benefits in migraine
prophylaxis.
Calcium channel antagonists

Beta blockers

The mechanism of action of the calcium channel antagonists

in migraine prophylaxis is uncertain. They prevent contraction
of vascular smooth muscles and inhibition of Ca++ dependent
enzymes involved in prostaglandin formation. Flunarizine in
doses of 5-10 mg per day has been found to be comparable
to propranolol, topiramate, and valproic acid for migraine
prophylaxis.11 Nimodipine, verapamil and nicardipine have been
less thoroughly studied than flunarizine.

Propranolol 40-160 mg per day is effective in reducing the

frequency of migraine and in providing moderate reduction in
headache intensity and/or duration (Level A).2,3 Propranolol is
comparable in efficacy to flunarizine, amitriptyline, naproxen
sodium, divalproex sodium, and methysergide.2
Other beta blockers such as metoprolol, atenolol, timolol,
and nadolol are likely to have similar benefits. Beta-blockers
with intrinsic sympathomimetic activity (acebutolol, alprenolol,
oxprenolol, pindolol) are ineffective for migraine prophylaxis. 2
When propranolol is prescribed to a patient using rizatriptan, the
patient should be advised to reduce the dose of rizatriptan by half
and to maintain a gap of two hours between intake of rizatriptan
and propranolol. Adverse events most commonly reported with
beta-blockers are fatigue, depression, nausea, dizziness, and
insomnia. These symptoms are fairly well tolerated and are
seldom the cause of premature withdrawal.

Alpha-2 agonists
Clonidine and guanfacine have been shown to be better
than placebo but inferior to beta blockers at reducing headache
frequency. 4 Most commonly reported adverse events with
clonidine are drowsiness and tiredness.
Nonsteroidal anti-inflammatory drugs (NSAIDs)
Many NSAIDs have been tried over the years for migraine
prophylaxis. Naproxen (750 to 1500 mg) has been extensively
investigated so far. It is especially useful in menstrual migraine. 2
Recent interest has been focused on aspirin (75 to 150 mg)
particularly in patients who need platelet inhibitors for other
medical conditions.

Antiepileptics
Topiramate
Topiramate blocks voltage-sensitive sodium channels and
voltage-activated calcium channels, inhibits glutamate release,
and increases GABA levels. It significantly reduces the mean
monthly frequency of migraine in patients receiving 50-100 mg
per day. Patients receiving 200 mg per day of topiramate tend to
have frequent adverse effects.4 The most common adverse effect
with topiramate is paresthesia, followed by fatigue, weight loss,
somnolence, psychomotor slowing, language problems, renal
calculi, and rarely secondary angle closure glaucoma. Topiramate
is started at a dose of 25 mg at bedtime. The dose is increased
by 12.5-25 mg per week to reach a target of 50 mg given twice a
day. Usually these paresthesias are transient and if the patient
is explained about it prior to starting the drug, they are able to
tolerate it and drug withdrawal is seldom required. If paresthesia
develops, the dose should be decreased to the least tolerable
dose and then increased to a lower target dose more slowly.
Topiramate is similar in efficacy to propranolol and valproate.

Other agents
Pizotifen, buspirone, acetazolamide, montelukast, and
methysergide are of limited value in prophylaxis of migraine.
Methysergide is associated with retroperitoneal and retropleural
fibrosis after prolonged use. Feverfew (Tanacetum parthenium),
butterbur extract (Petasites hybridus), magnesium, riboflavin
and coenzyme Q 10 have not been proven to be conclusively
effective. Lisinopril and candesartan have been shown to be
effective in isolated trials and are to be preferred in patients
with hypertension.3
Botulinum toxin A
Botulinum toxin type A (BoNT-A) is a focally acting protein
that inhibits the release of acetylcholine from presynaptic
nerve endings and blocks the release of pain mediators,
such as substance P, glutamate, and calcitonin gene related
peptide. The biologic effects of BoNT-A are reversible and
last for approximately 3 to 6 months. A meta-analysis of eight
randomized, double-blind, placebo-controlled trials concluded
that BoNT-A was not significantly different from placebo, both
from a clinical and statistical perspective. 7 Therefore, Botulinum
toxin A is not recommended for the prophylactic treatment of
migraine.

Divalproex/ sodium valproate

Valproate at high concentrations increases GABA levels
in synaptosomes, perhaps by inhibiting its degradation, by
facilitating the postsynaptic responses to GABA, by increasing
potassium conductance at lower concentrations and by
producing membrane hyperpolarization. In patients with
episodic migraine, divalproex 250-750 mg/day is recommended
SUPPLEMENT OF JAPI april 2010 VOL. 58

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Table 1 : Classification of prophylactic drugs according to efficacy and safety4

Group 1
Topiramate
Divalproex / valproic acid
Propranolol, metoprolol,
timolol
Amitriptyline
Flunarizine
Methysergide (severe
adverse events)

Group 2
Gabapentin
Fluoxetine, venlafaxine
Atenolol, nadolol
NSAIDS (aspirin,
indomethacin, naproxen
sodium)
Cyproheptadine
Riboflavin, magnesium
Lisinopril,
candesartan

Group 3
Clonidine, guanfancine
Carbamazepine
Verapamil, nicardipine,
nimodipine

Table 2 : Drugs of choice for comorbid conditions

Comorbid condition
Depression
Insomnia
Bipolar mood disorder
Neuralgic pain
Hypertension, angina
Hypotension
Epilepsy
Asthma
Diabetes mellitus
Obesity
Anorexia

Group 5
Clonazepam, oxcarbazepine
Acetazolamide
Montelukast

II or two Class III studies. Drugs in this group may be considered

for the migraine prophylaxis (Level C).

Drugs of choice
Amitriptyline, SSRI; avoid beta blockers and
flunarizine
Amitriptyline
Divalproex, topiramate
Amitriptyline
Beta blocker
Divalproex, topiramate
Divalproex, topiramate; avoid amitriptyline
Beta blockers contraindicated
Beta blockers contraindicated
Topiramate
Amitriptyline, flunarizine

Group 4. Medications with inadequate or conflicting evidence

to support their use for migraine prevention. Drugs in this group
have no recommendation (Level U).
Group 5. Medications proven to have limited or no efficacy.
Drugs in this group should not be considered for the migraine
prophylaxis (Level B).
The drugs in various groups are enumerated in Table 1.

NonpharmacologicalInterventions
Nonpharmacological interventions such as relaxation
training, biofeedback and cognitive-behavioral therapy may
be considered as treatment options for prevention of migraine
(Level A).16 Aerobic exercise has been tried, however its efficacy
is uncertain. Hyperbaric oxygen may be an effective, but rarely
practical prophylactic measure. These interventions are indicated
in patients who show insufficient or no response to drugs, have
contraindications or poor tolerance to drug treatment, pregnancy
and significant stress. Acupuncture has been shown to be at least
as effective as or possibly more effective than prophylactic drug
treatment in a recent Cochrane review and has fewer side effects.
Thus acupuncture should be considered a treatment option for
patients willing to undergo this treatment.17

Indian Literature on Migraine

Prophylaxis
There are several small, single center, open label and
double blind published Indian studies on drugs for migraine
prophylaxis. Clonidine did not show a statistically significant
difference as compared to placebo.8 Propranolol and flunarizine
were superior to placebo in reducing the frequency of migraine
attacks. 9,10 Nifedipine significantly reduced the frequency
and severity of pain in migraine.4 Low dose topiramate was
efficacious in migraine prophylaxis as compared to both placebo
and lamotrigine. 12 A combination of cyproheptadine and
propranolol provided significantly greater relief as compared
to individual drug treated groups and placebo. 13 Acupuncture
provided more than 50% relief in a significant number of
patients. 14 Biofeedback and systematic relaxation were very
useful in migraine and had significantly better long-term
prophylactic effect than propranolol in migraine.15 The doses of
various prophylactic drugs required by our patients is lesser as
compared to Western data.

Use of Abortive Medication Along

with Preventive Treatment
Many patients of migraine can have breakthrough headaches
while on prophylaxis. Such patients, particularly with headaches
during menstruation, should receive abortive medications. It has
been observed that preventive medications make abortive agents
more effective. However, a limited use, not exceeding two times a
week is recommended to prevent medication overuse headache.

Recommendations

Combinations of drugs

The US Headache Consortium has classified drugs into

various groups based on their established clinical efficacy,
significant adverse events, safety profile, and clinical experience
of participants of drug trials:2

A number of conditions have been noted to be comorbid with

migraine, notably psychiatric disorders (anxiety, depression,
panic disorder), epilepsy, asthma, and cardiovascular diseases
(stroke, angina). The presence of a comorbid disease poses
significant therapeutic implications. The goal should be to treat
both the conditions adequately with a single agent wherever
possible (Table 2). If combining a second drug is necessary, care
should be taken while choosing the second drug to avoid drug
interactions and increased adverse effects (Table 3).

Group 1. Medications with proven high efficacy and mild

to moderate adverse events, on the basis of multiple Class-I
randomized controlled trials. They should be considered as first
line drugs for migraine prophylaxis (Level A).
Group 2. Medications with probable efficacy and mild to
moderate adverse events, on the basis of at least one Class I or
two Class II studies. They should be considered as second line
drugs for migraine prophylaxis (Level B).

Limitations of Migraine Prophylaxis

According to the American Migraine Prevalence and

Group 3. Medications with possible efficacy based on one class

28

Group 4
Lamotrigine
Clomipramine, fluvoxamine
Doxepin, imipramine,
nortriptyline
DHE

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Table 3 : Drug combinations

Combinations preferred
First agent
Amitriptyline
Beta blocker
Divalproex/ topiramate
Combinations best avoided
Beta blocker and flunarizine

Second agent
Beta blocker, divalproex, flunarizine
Amitriptyline, divalproex, topiramate
Amitriptyline, beta blocker

References

Prevention (AMPP) study, 38.8% of patients with migraine

merit consideration for migraine prophylaxis therapy. However,
only 13% of all migraineurs use preventive medications to
control their attacks.24 The side-effects, compliance, and cost of
prolonged treatment are important limiting factors. Presence of
co-existing diseases may deter use of some of the first-line drugs.
Migraine preventive medications show a ceiling effect and most
of the drugs provide 50% relief in approximately 50% of patients.

1.

Wang SJ, Chung CS, Chankrachang S, Ravishankar K, Merican JS,

Salazaret G, al. Migraine disability awareness campaign in Asia:
migraine assessment for prophylaxis. Headache 2008; 48;1356-65.

2. Ramadan NM, Silberstein SD, Freitag FG, Gilbert TT, Frishberg B.

Evidence-based guidelines of the pharmacological management for
prevention of migraine for the primary care provider. http:/www.
neurology.org, 1999 (accessed June 25, 2009).

Future Targets
It has been well documented that mutations in the calcium
channel are implicated in familial hemiplegic migraine;
therefore calcium ion transporters are considered as novel
targets for the development of future anti-migraine drugs. The
L-calcium channel blockers (verapamil) and novel calcium
channel antagonists (dotarizine, ziconotide) are being studied
for migraine prophylaxis. Newer serotonergic/noradrenergic
reuptake inhibitors (SNRIs), especially mir tazapine and
duloxetine may potentially prevent migraine attacks. New 5-HT7
modulators and 5-HT4 agonists appear promising for migraine
prophylaxis.18,19
Cortical spreading depression may be inhibited through
the use of sigma R receptor agonists (dextromethorphan,
carbetapentane), non-NMDA (AMPA-kainate) ionotropic
receptor blockers, potassium current modulators, and glycine site
modulators. The chloride channel enhancers and metabotropic
glutamate receptor modulators are also of interest. Tonabersat,
a novel gap junction inhibitor, may have potential value in
migraine prophylaxis.20

3.

Casucci G, Villani V, Frediani F. Central mechanism of action of

antimigraine drugs. Neurol Sci 2008; 29 (Suppl 1):S123-6.

4.

Silberstein SD, Loder E, Forde G, Papadopoulos G, Fairclough

D, Greenberg S. The impact of migraine on daily activities: effect
of topiramate compared with placebo. Curr Med Res Opin 2006;
22:1021-9.

5.

Pascual-Gmez J. The role of neuromodulators in the preventive

treatment of migraine. Rev Neurol 2009; 49:25-32.

6.

Tomkins GE, Jackson JL, OMalley PG, Balden E, Santoro JE.

Treatment of chronic headache with antidepressants: a meta
analysis. Am J Med 2001; 111:54-63.

7.

Shuhender AJ, Lee S, Siu M, Ondovcik S, Lam K, Alabdullatif A, et

al. Efficacy of botulinum toxin type A for the prophylaxis of episodic
migraine headache: a meta-analysis of randomized, double-blind,
placebo-controlled trials. Pharmacotherapy 2009; 29:784-91.

8.

Das SM, Ahuja GK, Narainaswamy AS. Clonidine in prophylaxis

of migraine. Acta Neurol Scand 1979; 60: 214-7.

9.

Ahuja GK, Verma AK. Propranolol in prophylaxis of migraine.

Indian J Med Res 1985; 82:203-5.

10. Thomas M, Behari M, Ahuja GK . Flunarizine in migraine

prophylaxis. Headache 1991; 31:613-5.
11. Shukla R, Garg RK, Nag D, Ahuja RC. Nifedipine in migraine and
tension headache. J Assoc Phys India 1995; 43:770-2.

Conclusion

12. Gupta P, Singh S, Goyal V, Shukla G, Behari M. Low-dose topiramate

versus lamotrigine in migraine prophylaxis (the Lotolamp study).
Headache 2007; 47:402-12.

One-third of patients suffering from migraine require

prophylactic therapy. The preventive drugs with the best
documented effectiveness are the beta blockers, flunarizine,
divalproex, topiramate, and amitriptyline. Choice of drugs
should be made on the basis of efficacy of drug, adverse events,
patient preference, headache profile, and the presence or absence
of coexisting disorders.

13. Rao BS, Das DG, Taraknath VR, Sarma Y. A double-blind controlled
study of propranolol and cyproheptadine in migraine prophylaxis.
Neurol India 2000; 48: 223-6.
14. Chari P. Acupuncture therapy for migraine. Indian J Pain 1992;
6:36-8.
15. Kaushik R, Kaushik RM, Mahajan SK, Rajesh V. Biofeedback
assisted diaphragmatic breathing and systematic relaxation versus
propranolol in long term prophylaxis of migraine. Complement
Ther Med 2005; 13:165-74.

Salient Features

Migraine prophylaxis includes avoidance of trigger factors and
life style advice, followed by consideration of medications.

Medications having the highest level of evidence-based efficacy
should be started first.

Lowest effective dose of the drug should be used and increased
slowly.

After 6 to 12 months of effective prophylaxis, gradual withdrawal
should be considered.

Propranolol 40-160 mg/day or flunarizine 5-10 mg/day is
recommended as first line therapy for prophylaxis in patients with
migraine (Level A).

In patients with episodic and chronic migraine, topiramate 50-100
mg/day is recommended (Level A).

In patients with episodic migraine divalproex 250-750 mg/day is
recommended (Level A).

Amitriptyline 10-75 mg/day is better for patients with mixed
migraine and tension-type headache (Level A).
SUPPLEMENT OF JAPI april 2010 VOL. 58

Most of the drugs provide 50% relief in approximately 50% of

treated patients.
Combination of prophylactic medications for e.g. propranolol and
topiramate may be tried in refractory patients.
Nonpharmacological interventions such as acupuncture, relaxation
training, biofeedback, and cognitive-behavioral therapy may
be considered as alternative treatment options if drugs are not
tolerated.

16. Campbell JK, Penzien D, Wall EM. Evidenced-based guidelines for

migraine headache: behavioral and physical treatments. http://
www.neurology.org, 2000 (accessed June 25, 2009).
17. Linde K, Allais G, Brinkhaus B, Manheimer E, Vickers A, White
AR. Acupuncture for migraine prophylaxis. Cochrane Database
Syst Rev 2009; 21:CD001218.
18. Ramadan NM. Current Trends in Migraine Prophylaxis. Headache
2007; 47: S52-7.
19. Stam AH, Haan J, Frants RR, Ferrari MD, van den Maagdenberg
AM. Migraine: new target options from molecular biology. Expert
Rev Neurother 2005; 5:653-61.
20. Silberstein SD. Tonabersat, a novel gap-junction modulator for the
prevention of migraine. Cephalalgia 2009; 29:28-35.

29