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Review Article

Preventive
Address correspondence to
Dr Stephen D. Silberstein,
Thomas Jefferson University,
Jefferson Headache Center,

Migraine Treatment 900 Walnut Street, Suite 200,


Philadelphia, PA 19107,
stephen.silberstein@jefferson.edu.
Stephen D. Silberstein, MD, FAAN, FACP Relationship Disclosure:
Dr Silberstein receives
honoraria for serving as a
consultant and/or advisory
panel member from Alder
ABSTRACT Biopharmaceuticals Inc;
Allergan, Inc; Amgen Inc;
Purpose of Review: This article reviews the evidence base for the preventive treatment Avanir Pharmaceuticals, Inc;
of migraine. Depomed, Inc; Dr. Reddy’s
Recent Findings: Evidence-based guidelines for the preventive treatment of mi- Laboratories; electroCore
Medical LLC; eNeura Inc; Ipsen
graine have recently been published by the American Academy of Neurology (AAN) Biopharmaceuticals Inc;
and the Canadian Headache Society (CHS), providing valuable guidance for clinicians. Medscape, LLC; Medtronic plc;
Strong evidence exists to support the use of metoprolol, timolol, propranolol, dival- Mitsubishi Tanabe Pharma
Development America, Inc;
proex sodium, sodium valproate, and topiramate for migraine prevention, according to National Institute of Neurological
the AAN. Based on best available evidence, adverse event profile, and expert con- Disorders and Stroke (NINDS);
sensus, topiramate, propranolol, nadolol, metoprolol, amitriptyline, gabapentin, candesartan, St. Jude Medical, Inc; Supernus
Pharmaceuticals, Inc; Teva
Petasites (butterbur), riboflavin, coenzyme Q10, and magnesium citrate received a Pharmaceutical Industries Ltd;
strong recommendation for use from the CHS. and Trigemina, Inc.
Summary: Migraine preventive drug treatments are underutilized in clinical practice. Dr Silberstein is a consultant
on the clinical trials of calcitonin
Principles of preventive treatment are important to improve compliance, minimize side gene-related peptide that are
effects, and improve patient outcomes. Choice of preventive treatment of migraine discussed in this article.
should be based on the presence of comorbid and coexistent illness, patient prefer- Unlabeled Use of
ence, reproductive potential and planning, and best available evidence. Products/Investigational
Use Disclosure:
Dr Silberstein discusses the
Continuum (Minneap Minn) 2015;21(4):973–989. unlabeled/investigational use
of pharmaceuticals for the
preventive treatment of
migraine, none of which are
approved by the US Food and
INTRODUCTION would occur by chance. Conditions that Drug Administration.
Migraine is a chronic neurologic disease occur in patients with migraine with a * 2015, American Academy
higher prevalence than coincidence in- of Neurology.
that varies in its frequency, severity, and
impact on patients’ quality of life. A treat- clude stroke, comorbid pain disorders,
ment plan should consider not only the angina, patent foramen ovale (aura), epi-
patient’s diagnosis, symptoms, and co- lepsy, and certain psychiatric disorders,
existent or comorbid conditions, but also which include depression, mania, anxi-
the patient’s expectations, needs, and ety, and panic disorder.
goals.1 Effective migraine treatment be- The pharmacologic treatment of
gins with making an accurate diagnosis, migraine may be acute (abortive) or pre-
ruling out alternate causes, ordering ap- ventive (prophylactic), and patients with
propriate studies, and addressing the frequent severe headaches require both
headache’s impact on the patient2; edu- approaches. Preventive therapy is used
cating the patient with regard to treat- to reduce the frequency, duration, or
ment options, side effect profile, duration severity of attacks. Additional benefits
of therapy, and expectations for improve- may include enhancement of response
ment; and developing a treatment plan to acute treatments, improvement of a
that considers coincidental and comor- patient’s ability to function, and reduc-
bid conditions.3 Comorbidity is the pre- tion of disability.3 Preventive treatment
sence of two or more disorders, the may also result in reduction of health
association of which is more likely than care costs.4
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Preventive Migraine Treatment

IMPACT OF range of scores with as little as 6 months


PREVENTIVE TREATMENT of treatment.7,8 With a migraine-specific
Silberstein and colleagues4 found that quality-of-life assessment, broad improve-
the addition of migraine preventive drug ments of at least moderate size and an ef-
therapy to therapy that consisted of only fect that persisted over a prolonged period
an acute medication was effective in re- of observation were found across domains.9
ducing resource consumption. During
the second 6 months after the initial pre- PRINCIPLES OF
ventive medication, as compared with PREVENTIVE TREATMENT
the 6 months preceding preventive ther- Preventive treatment can be preemptive,
apy, migraine diagnosisYrelated office short term, or maintenance. Preemptive
and other outpatient visits decreased by treatment is used when a known head-
51.1%, emergency department visits with ache trigger exists, such as exercise or
a migraine diagnosis decreased 81.8%, sexual activity. Patients can be instructed
CT scans decreased 75.0%, MRIs decreased to pretreat prior to the exposure or ac-
88.2%, and other migraine medication tivity. For example, a single dose of
dispensements decreased 14.1%.4 indomethacin can be used to prevent
The cost and consumption of triptan exercise-induced migraine. Short-term
medications is also an important factor prevention is used when patients are un-
and has been evaluated after the addi- dergoing a time-limited exposure to a
tion of preventive medication. Silberstein provoking factor, such as ascent to a high
and colleagues evaluated the medical re- altitude or menstruation. These patients
source utilization and overall cost of care can be treated with daily medication just
among patients treated with topiramate before and during the exposure. For ex-
for migraine prevention in a commercially ample, the perimenstrual use of a non-
insured population that included 2645 plan steroidal anti-inflammatory drug (NSAID)
members. Topiramate utilization was as- or triptan for 3 to 5 days may prevent the
sociated with significantly less triptan uti- emergence of menstrually related mi-
lization. In addition, in postindex period 1, graine. Maintenance prevention is used
results showed a 46% decrease in emer- when patients need ongoing treatment.
gency department visits, a 39% decrease Recent US, Canadian, and European
in diagnostic procedures (eg, CT scans guidelines10Y15 have established the cir-
and MRIs), and a 33% decrease in hos- cumstances under which migraine pre-
pital admissions; physician office visits ventive treatment should be considered.
were unchanged. In postindex period 2, (Refer to Appendix A and Appendix B for
results showed a 46% decrease in emer- summaries of the American Academy of
gency department visits, a 72% decrease Neurology’s evidence-based guidelines
in diagnostic procedures, a 61% decrease for clinicians). These guidelines include:
in hospital admissions, and a 35% dec- & Recurring migraine attacks that
rease in physician office visits.5 significantly interfere with a patient’s
Several studies have examined the im- quality of life and daily routine
pact of migraine prevention therapy on pa- despite trigger management,
tients’ quality of life. These have included appropriate use of acute medications,
specific therapies, such as topiramate, as and lifestyle modification strategies
well as more far-reaching assessment. & Frequent headaches (four or more
Using the SF-36 Health Survey6 to exam- attacks per month or eight or
ine quality of life, studies showed highly more headache days per month)
statistically significant changes across the because of the risk of chronic migraine

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KEY POINTS
& Failure of, contraindication to, nately, the underutilization of migraine h A preventive migraine
overuse of, or troublesome side preventive medications is underscored by drug is considered
effects from acute medications the fact that only 13% of all patients with successful if it reduces
& Patient preference, that is, the migraine currently use preventive therapy migraine attack
desire to have as few acute to control their attacks.11 frequency or days by
attacks as possible The following classes of medications at least 50% within
& Presence of certain migraine are used for migraine prevention: anti- 3 months.
conditions: hemiplegic migraine; epileptic drugs, antidepressants, beta- h Migraine preventive
basilar migraine (now called blockers, calcium channel antagonists, drugs with the
migraine with brainstem aura); serotonin antagonists, botulinum neu- best proven efficacy are
frequent, prolonged, or rotoxins, NSAIDs, and others (including certain beta-blockers,
uncomfortable aura symptoms; riboflavin, magnesium, and Petasites). A divalproex sodium,
or migrainous infarction drug is chosen based on its efficacy, its and topiramate.

A preventive migraine drug is con- adverse event profile, the patient’s pre-
sidered successful if it reduces migraine ference, and the presence of any coex-
attack frequency or days by at least 50% istent or comorbid conditions. Preventive
within 3 months. As illustrated in Case 2-1, drugs with the best proven efficacy for
additional benefits include reduced attack migraine are certain beta-blockers, di-
duration or severity, enhanced response valproex sodium, and topiramate. The
to acute treatments, improved ability to chosen drug should have the best risk-
function, and reduced disability. Accord- to-benefit ratio for the individual patient
ing to the American Migraine Prevalence and, where possible, take advantage of
and Prevention (AMPP) Study, 38.8% of the drug’s side effect profile. An under-
patients with migraine should be con- weight patient would be a candidate for
sidered for (13.1%) or offered (25.7%) one of the medications that commonly
preventive migraine therapy.16 Unfortu- produce weight gain, such as a tricyclic

Case 2-1
A 24-year-old university student presented with chronic daily headache. He had a history of migraine
that began in high school while he was a varsity football player. The frequency of his attacks
increased after starting college. He attributed the increase in frequency to the sleep deprivation and
stress that came with taking 18 credits to graduate. Most of the headaches were moderate or severe,
and while sumatriptan 100 mg helped, it took about 5 hours before he got significant relief and the
headache often came back the next day. He was using sumatriptan 100 mg on about 12 days per month.
He had no significant past medical history or family history. His neurologic examination was normal.
He was started on topiramate 15 mg at bedtime, and the dose was titrated to 50 mg 2 times a day
over the course of 6 weeks. There was a reduction in headache days to about 18 days per month.
Importantly, the duration of attacks was reduced to less than 60 minutes after taking sumatriptan
100 mg. Moreover, he had only required three tablets of sumatriptan per month as the severity
of each attack was reduced. Other attacks were treated with over-the-counter ibuprofen 600 mg.
After 3 months of treatment, he was experiencing only about one headache per week and
using sumatriptan 2 times per month.
Comment. This case illustrates the potential for effective preventive medication to reduce headache
frequency, acute medication consumption, and duration and severity of attacks. It also illustrates
the importance of continuing treatment even if the initial response is considered ‘‘partial,’’ ie, absence
of a 50% reduction in frequency of headache. Headache duration and severity are important
considerations, and significant decrease in these end points can lead to a dramatic reduction in
disability and improved ability to function.

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Preventive Migraine Treatment

KEY POINT
h A full therapeutic trial antidepressant; in contrast, one would
may take 2 to 6 months try to avoid these drugs and consider TABLE 2-1 Migraine Comorbid
before the maximal topiramate when the patient is over- Disease
response to a preventive weight. Tertiary tricyclic antidepressants
migraine treatment that have a sedating effect would be b Cardiovascular
is evident. useful at bedtime for patients with in- Angina/myocardial infarction
somnia. Older patients with cardiac Raynaud disease
disease or patients with significant hypo- Atrial septal defects, pulmonary
tension may not be able to use tricyclic arteriovenous malformations
antidepressants, calcium channel blockers,
Mitral valve prolapse
or beta-blockers, but could use divalproex
sodium or topiramate. Patent foramen ovale
(migraine with aura)
Stroke
General Principles for Instituting
Preventive Therapy b Psychiatric
The following principles will help in- Bipolar disorder
crease the chances of successful pre- Depression
ventive treatment:
Generalized anxiety disorder
& Start the chosen drug at a low dose
and increase it slowly until therapeutic Panic disorder
effects develop, the ceiling dose b Neurologic
is reached, or adverse events
Bell’s palsy?
become intolerable.
& Consider comorbidity and coexistent Epilepsy
illnesses in drug choice. Conditions Fibromyalgia
comorbid with migraine are shown
Positional vertigo
in Table 2-1.
& Avoid exacerbating, overused, and Restless legs syndrome
contraindicated drugs (because of b Gastrointestinal
coexistent or comorbid illnesses).
Irritable bowel syndrome
& Give each treatment an adequate
trial. A full therapeutic trial may take Peptic ulcer disease?
2 to 6 months before the maximal b Other
response to a treatment is evident. Allergies
Case 2-2 demonstrates the benefits
of an adequate course of preventive Asthma
treatment at an adequate dose.
& Set realistic goals. Success is
defined as a 50% reduction in possible risks and avoid preventive
attack frequency or headache days, drugs if at all possible in anticipation
a significant decrease in attack of and during pregnancy.
duration, or an improved response & To maximize compliance, involve
to acute medication. patients in their care. Discuss the
& Reevaluate therapy; migraine rationale for a particular treatment,
may improve or remit independent when and how to use it, and what
of treatment. adverse events are likely. Address
& Be sure that a woman of patient expectations, and set
childbearing age is aware of any realistic goals.

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Case 2-2
A 35-year-old mother of two presented for an evaluation for migraine. Her migraine attacks began at
the age of 13 but were infrequent until the birth of her second child 3 years ago. Attacks occurred
about 2 times per week, but she was never without some type of headache every day. On average, her
ability to function was impaired or impossible on 20 days per month. She also had a history of
postpartum depression, which had not responded to fluoxetine 20 mg per day or bupropion 75 mg per day.
Her Migraine Disability Assessment (MIDAS)17 score was 80, Patient Health Questionnaire (PHQ-9)18
was 13, and Generalized Anxiety Disorder 7-Item Scale (GAD-7)19 was 4. She was started on amitriptyline
25 mg nightly at bedtime, which was continued for 1 month but then discontinued because of
sedation and constipation. She was switched to nortriptyline at a dose of 10 mg, and the dose was
titrated to 75 mg at bedtime over the course of 2 months. After 3 months on 75 mg, she was tolerating
the medication and experiencing only 10 headache days per month, her MIDAS score dropped to 18,
and only half of the headaches were moderately severe, and those responded promptly with rizatriptan
10 mg. However, depression persisted, and her PHQ-9 score was still elevated (12). She was started
on venlafaxine and titrated to a dose of 75 mg 2 times a day over 1 month. She reported a significant
improvement in her mood.
Comment. This case illustrates several of the key principles in the preventive treatment of migraine.
Switching from a tertiary to secondary amine may be better tolerated. Starting at a low dose and
titrating the dose very slowly minimizes side effects and improves adherence, and continuing treatment
for at least 2 to 3 months after the target dose is achieved is important to determine maximal efficacy.
Moreover, a single drug (nortriptyline) failed to adequately treat both the depression and migraine.
Therefore, the addition of an additional antidepressant, including one shown to be effective for migraine
prevention (venlafaxine), may be necessary.

& Set realistic expectations tic adjustments based on the status of


regarding adverse events. Most each illness. For example, tricyclic anti-
are self-limited and dose depressants are often recommended for
dependent, and patients should patients with migraine and depression.20
be encouraged to tolerate the early However, appropriate management of
adverse events that may develop depression often requires higher doses
when a new medication is started. of tricyclic antidepressants, which may
While monotherapy is a treatment be associated with more adverse events.
goal and taking advantage of comorbid A better approach might be to treat the
or coexistent illness may facilitate treat- depression with a selective serotonin re-
ment of both disorders with a single uptake inhibitor (SSRI) or serotonin nor-
drug, limitations exist to using a single epinephrine reuptake inhibitor (SNRI)
medication to treat two illnesses. Giving and to treat the migraine with an anti-
a single medication may not treat two epileptic drug. Migraine and epilepsy
different conditions optimally; although may both be controlled with an anti-
one of the conditions may be adequately epileptic drug, such as topiramate or
treated, the second illness may require a divalproex sodium, which are also the
higher or lower dose, and, therefore, a drugs of choice for the patient with mi-
risk exists that the second illness is not graine and bipolar illness. When indi-
being adequately treated. Therapeutic viduals have more than one disease,
independence may be needed should certain categories of treatment may be
monotherapy fail. Avoiding drug inter- relatively contraindicated. For example,
actions or increased adverse events is a beta-blockers should be used with caution
primary concern when using polyphar- for the patient with migraine and depres-
macy. Polytherapy may enable therapeu- sion, while tricyclic antidepressants or

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Preventive Migraine Treatment

KEY POINTS neuroleptics may lower the seizure thresh- who completed the open-label phase,
h Although monotherapy old and should be used with caution for 514 entered the double-blind phase and
for migraine prevention the patient with migraine and epilepsy. were assigned to topiramate (n = 255)
is preferred, it often
Although monotherapy is preferred, or placebo (n = 259). The mean in-
does not yield the
it often does not yield the desired ther- crease in number of migraine days was
desired therapeutic effect,
and it may be necessary
apeutic effect, and it may be necessary greater in the placebo group (1.19 days
to combine preventive to combine preventive medications. The in 4 weeks, 95% confidence interval 0.71
medications. need for selective treatment of two dis- to 1.66; PG.0001) than in the topiramate
orders is illustrated in Case 2-2, in which group (0.10, confidence interval Y0.36 to
h Patients may relapse
after the discontinuation
a tricyclic antidepressant alone was in- 0.56; P=.5756). Patients in the placebo
of preventive migraine adequate to manage both migraine and group had a greater number of days on
treatment; patients major depression. Antidepressants are acute medication than did those in the
should be cautioned in often used with beta-blockers or calcium topiramate group (mean difference be-
this regard and followed channel blockers, and topiramate or di- tween groups 0.95, confidence interval
carefully for escalating valproex sodium may be used in combi- Y1.49 to Y0.41; P=.0007). Sustained ben-
attack frequency. It is nation with any of these medications. efit was reported after topiramate was
unclear which factors discontinued, although the number of
increase the risk of relapse Guidelines for Stopping
migraine days did increase. In a subse-
or sustained remission. Preventive Therapy
quent analysis of this study, no factors
Preventive migraine therapy should be were identified that predicted consistent
stopped when: relapse after withdrawal of topiramate
& The patient develops intolerable therapy.22 While the authors did find
adverse events or a severe evidence that the likelihood of sustained
drug reaction. relapse was higher when the initial re-
& The drug does not demonstrate sponse to migraine preventive treatment
even partial efficacy after 2 months was more pronounced, the same effect
of therapy and disorders such as was found in the placebo group, leading
acute medication overuse have the authors to speculate that this obser-
been eliminated. vation likely reflected ‘‘regression to the
& The patient has shown significant mean.’’ Wöber and colleagues found that
benefit. If the headaches are well 75% of patients developed increased mi-
controlled for at least 6 months, graine frequency after flunarizine or beta-
slowly taper and, if possible, blockers were stopped.23 Relapse occurred
discontinue the drug. on average 6 months after cessation of
Preventive treatment is often recom- the medication. These findings suggest
mended for 6 to 9 months, but until now, that patients may relapse after the discon-
no randomized placebo-controlled trials tinuation of preventive treatment; pa-
have been performed to investigate mi- tients should be cautioned in this regard
graine frequency after the preventive and followed carefully for escalating
treatment has been discontinued. Diener attack frequency. It is unclear which
and colleagues21 assessed 818 patients factors increase the risk of relapse or
with migraine who were treated with sustained remission.
topiramate for 6 months to see the ef-
fects of topiramate discontinuation. Pa- SPECIFIC MIGRAINE
tients received topiramate in a 26-week PREVENTIVE AGENTS
open-label phase. They were then ran- Specific migraine preventive agents and
domly assigned to continue topiramate their classification per American Academy
or switch to placebo for a 26-week of Neurology (AAN) evidence guide-
double-blind phase. Of the 559 patients lines are listed in Table 2-2. (Refer to
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a
TABLE 2-2 Classification of Migraine Preventive Therapies (Available in the United States)

Level B: Level U: Other:


Level A: Medications Are Level C: Inadequate or Medications That
Medications With Probably Effective Medications Are Conflicting Data to Are Established
Established Efficacy (1 Class I or 2 Possibly Effective Support or Refute as Possibly or
(Q2 Class I Trials) Class II Studies) (1 Class II Study) Medication Use Probably Ineffective
Antiepileptic drugs Antidepressants/ ACE inhibitors Carbonic anhydrase Established as not
SSRI/SNRI/TCA inhibitor effective
Divalproex sodium Amitriptyline Lisinopril Acetazolamide Antiepileptic drugs
Sodium valproate Venlafaxine Angiotensin Antithrombotics Lamotrigine
receptor blockers
Topiramate Beta-blockers Candesartan Acenocoumarol Probably not effective
Beta-blockers Atenolol b
"-Agonists Coumadin Clomipramineb
Metoprolol Nadololb Clonidineb Picotamide Possibly not effective
Propranolol Triptans (MRMc) Guanfacineb Antidepressants/ Acebutololb
SSRI/SNRI
Timololb Naratriptanc Antiepileptic Drugs Fluvoxamineb Clonazepamb
Triptans (MRMc) Zolmitriptanc Carbamazepineb Fluoxetine Nabumetoneb
Frovatriptanc Beta-blockers Antiepileptic drugs Oxcarbazepine
Nebivolol Gabapentin Telmisartan
Pindololb TCAs
Antihistamines Protriptylineb
Cyproheptadine Beta-blockers
Bisoprololb
Ca++ blockers
Nicardipineb
Nifedipineb
Nimodipine
Verapamil
Direct vascular smooth
muscle relaxants
Cyclandelate

SSRI = selective serotonin reuptake inhibitor; SNRI = serotonin norepinephrine reuptake inhibitor; TCA = tricyclic antidepressant; ACE =
angiotensin-converting enzyme; MRM = menstrually related migraine; Ca++ blockers = calcium channel blockers.
a
Modified with permission from Silberstein SD, et al, Neurology.12 B 2012 American Academy of Neurology. www.neurology.org/
content/78/17/1337.long.
b
Classification based on original guideline and new evidence not found for this report.
c
For short-term prophylaxis of menstrually related migraine.

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Preventive Migraine Treatment

KEY POINT
h Beta-blockers are the Appendix A for a summary of the AAN’s defects, Raynaud disease, peripheral vas-
most widely used class evidence-based guideline for clinicians, cular disease, and severe diabetes mellitus.
of drugs in prophylactic Appendix C for the AAN classification of All beta-blockers can produce behavioral
migraine treatment and evidence for the rating of a therapeutic adverse events, such as drowsiness, fatigue,
are about 50% effective study, and Appendix D for the classifi- lethargy, sleep disorders, nightmares,
in producing a greater cation of recommendations.) depression, memory disturbance, and
than 50% reduction in hallucinations.26 Other potential adverse
attack frequency. Beta-Blockers for the events include gastrointestinal symptoms,
Prevention of Migraine decreased exercise tolerance, hypoten-
Beta/blockers are the most widely used sion, bradycardia, and impotence. Al-
class of drugs in prophylactic migraine though stroke has been reported to occur
treatment and are about 50% effective after patients with migraine with aura
in producing a greater than 50% reduc- were started on beta-blockers, neither
tion in attack frequency. Table 2-3 lists an absolute nor a relative contraindica-
beta-blockers and dosages used for the tion to their use by patients with migraine,
prevention of migraine. Evidence has either with or without aura, exists.
consistently demonstrated the efficacy of
the nonselective beta-blocker propran- Antidepressant Medication for
olol and of the selective beta1-blocker Migraine Prevention
metoprolol. Atenolol, bisoprolol, nadolol, Antidepressants consist of a number of
and timolol are also likely to be effective. different drug classes with different mech-
Beta-blockers with intrinsic sympatho- anisms of action. Although the mechanism
mimetic activity (eg, acebutolol, alprenolol, by which antidepressants work to pre-
oxprenolol, pindolol) are not effective vent migraine headache is uncertain, it
for migraine prevention. does not result from treating latent or
The combination of propranolol and undiagnosed depression. Antidepressants
topiramate versus topiramate alone was are useful in treating many chronic pain
examined as a preventive treatment for states, including headache, independent
chronic migraine in the National Insti- of the presence of depression, and the
tute of Neurological Diseases and Stroke response occurs sooner and at lower dos-
(NINDS) Clinical Research Collaboration ages than that expected for an antide-
Chronic Migraine Treatment Trial (CMTT). pressant effect. In animal pain models,
This was a randomized double-blind antidepressants potentiate the effects of
placebo-controlled parallel study to ex- coadministered opioids. The antide-
amine the safety and efficacy of topiramate pressants that are clinically effective in
(up to 100 mg per day) and propranolol headache prevention either inhibit nor-
(up to 240 mg per day long-acting for- epinephrine and 5-hydroxytryptamine
mulation) taken in combination, com- (5-HT) reuptake or are antagonists at the
pared with treatment with topiramate 5-hydroxytryptamine 2 (5-HT2) receptors.
(up to 100 mg per day) and placebo. The Tricyclic antidepressants. Tricyclic
trial was terminated in September 2010, antidepressants are used for migraine
when an interim analysis determined prevention; however, only one tricyclic
that the combination of topiramate antidepressant (amitriptyline) has proven
and propranolol offered no additional efficacy in migraine.
advantage over topiramate alone.24,25 The dosage range for tricyclic antidepres-
Contraindications to the use of beta- sants is wide and must be individualized.
blockers for the treatment of migraine Amitriptyline and doxepin are sedating.
include asthma and chronic obstructive Patients with coexistent depression may
lung disease, atrioventricular conduction require higher doses of these drugs to
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TABLE 2-3 Beta-Blockers and Antidepressants in the Preventive Treatment of Migraine

Class and Agent Daily Dose Comments


Beta-blockers
Atenolol 50Y200 mg Use 1 or 2 times/d
Fewer side effects than propranolol
Metoprolol 100Y200 mg Use the short-acting form 2 times/d
Use the long-acting form once daily
Nadolol 20Y160 mg Use once daily
Fewer side effects than propranolol
Long half-life
Propranolol 40Y240 mg Use the short-acting form 2 or 3 times/d
Use the long-acting form once daily
1Y2 mg/kg in children
Timolol 20Y60 mg Use 2 times/d
Short half-life

Antidepressants (tertiary amines)


Amitriptyline 10Y200 mg Start at 10 mg at bedtime
Doxepin 10Y200 mg Start at 10 mg at bedtime
Antidepressants (secondary amines)
Nortriptyline 10Y150 mg Start at 10 mg at bedtime
If insomnia occurs, take early in the morning
Protriptyline 5Y60 mg Start at 5 mg in the morning
Serotonin Norepinephrine Reuptake Inhibitors
Venlafaxine 75Y225 mg Start at 37.5 mg in the morning

treat underlying depression. Start with a tions, blurred vision, and urinary reten- KEY POINT
low dose of the chosen tricyclic anti- tion. Other adverse events include weight h If the tricyclic antidepressant
depressant at bedtime, except when gain (rarely seen with protriptyline), or- being used for migraine
prevention is too sedating,
using protriptyline, which should be ad- thostatic hypotension, reflex tachycardia,
switch from a tertiary
ministered in the morning (since protrip- palpitations, QT interval prolongation, tricyclic antidepressant
tyline has alerting properties). If the decreased seizure threshold, and seda- (eg, amitriptyline, doxepin)
tricyclic antidepressant is too sedating, tion. Antidepressant treatment may change to a secondary tricyclic
switch from a tertiary tricyclic antide- depression to hypomania or frank mania antidepressant (eg,
pressant (eg, amitriptyline, doxepin) to (particularly in bipolar patients). Older nortriptyline, protriptyline).
a secondary tricyclic antidepressant (eg, patients may develop confusion or delirium.
nortriptyline, protriptyline). Adverse events The antimuscarinic and antiadrenergic
are common with tricyclic antidepres- effects of these agents may pose increased
sant use. Antimuscarinic adverse events risks for cardiac conduction abnormalities,
include dry mouth, a metallic taste, epi- especially in the elderly, and these pa-
gastric distress, constipation, dizziness, tients should be carefully monitored or
mental confusion, tachycardia, palpita- other agents considered.
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Preventive Migraine Treatment

KEY POINT Selective serotonin reuptake inhib- have not shown superiority over placebo
h Evidence for the use of itors and serotonin norepinephrine re- in well-designed clinical trials, and these
selective serotonin uptake inhibitors. Evidence for the use medications cannot be recommended
reuptake inhibitors or of SSRIs or other antidepressants for mi- for migraine prophylaxis.
other antidepressants for
graine prevention is mixed and overall
migraine prevention is
poor. The efficacy analysis summarized Antiepileptic Drugs for the
mixed and overall poor.
in the Agency for Health Care Policy and Prevention of Migraine
Research (AHCPR) Evidence Report did Antiepileptic drugs are increasingly recom-
not indicate a clear benefit of the racemic mended for migraine prevention because
mixture of fluoxetine over placebo.26 One of well-conducted placebo-controlled
class II study showed fluoxetine (racemic) trials (Table 2-4). It is important for the
was significantly better than placebo for clinician to recognize that most antiepi-
migraine prevention, but the results were leptic drugs may substantially interfere
not duplicated in a second study. with the efficacy of oral contraceptives, with
Other antidepressants not effective in the exception of valproic acid, topiramate
placebo-controlled trials were clomipramine (dose less than 200 mg per day), zonisamide,
and sertraline; for other antidepressants, gabapentin, pregabalin, and levetiracetam,
only open or nonYplacebo-controlled among others.
trials are available. Because their tolera- Gabapentin. Gabapentin (1800 mg per
bility profile is superior to that of tricyclic day to 2400 mg per day) showed efficacy
antidepressants, SSRIs may be helpful in a placebo-controlled double-blind
for patients with comorbid depression. trial only when a modified intent-to-treat
The most common adverse events in- analysis was used. Another double-blind
clude sexual dysfunction, anxiety, ner- placebo-controlled trial showed positive
vousness, insomnia, drowsiness, fatigue, results; however, the ability to draw
tremor, sweating, anorexia, nausea, vomit- conclusions from the placebo-controlled
ing, and dizziness or lightheadedness. The studies is limited because of their meth-
combination of an SSRI and a tricyclic odologic and analytical limitations. Recent
antidepressant can be beneficial in treat- reviews, including a Cochrane review,28
ing refractory depression and, in the conclude that further evaluation of gaba-
author’s experience, resistant cases of pentin in migraine prophylaxis is war-
migraine. Some combinations require ranted in order to inform clinical practice.
the tricyclic antidepressant dose to be ad- Silberstein and colleagues29 conducted
justed, because tricyclic antidepressant a randomized double-blind placebo-
plasma levels may significantly increase. controlled trial of gabapentin enacarbil,
Venlafaxine, a selective serotonin a transported prodrug of gabapentin that
and norepinephrine reuptake inhibitor, provides sustained dose-proportional
has been shown to be effective.27 Ad- exposure to gabapentin. No statistically
verse events include insomnia, nervous- significant difference between active treat-
ness, mydriasis, and seizures. ment and placebo was found.
Valproic acid. Valproic acid is a simple
Calcium Channel Antagonists 8-carbon, 2-chain fatty acid. Divalproex
for the Prevention of Migraine sodium (approved by the US Food and
Table 2-4 lists selected calcium channel Drug Administration [FDA] for the treat-
blockers used for the preventive treat- ment of migraine ) is a combination of
ment of migraine. Data from older studies valproic acid and sodium valproate. Sev-
regarding verapamil, nimodipine, nicar- eral subsequent randomized placebo-
dipine, diltiazem, cyclandelate, and other controlled studies have confirmed its
nonselective calcium channel antagonists efficacy, with responder rates ranging
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TABLE 2-4 Selected Calcium Channel Blockers and Selected Antiepileptic Drugs in the
Preventive Treatment of Migraine

Class and Agent Daily Dose Comments


Selected Calcium Channel Blockers
Verapamil 120Y480 mg Start 80 mg 2 or 3 times/d
Sustained release can be given
1 or 2 times/d
Flunarizinea 5Y10 mg Take at bedtime
Weight gain is the most common adverse effect

Selected Antiepileptic Drugs


Carbamazepine 600Y1200 mg 3 times/d
Gabapentin 600Y3600 mg
Topiramate 50Y200 mg Start 15Y25 mg at bedtime
Increase 15Y25 mg per week
Attempt to reach 50Y100 mg
Increase further if necessary
Associated with weight loss, not weight gain
Valproate/divalproex 500Y2000 mg Start 250Y500 mg
Monitor valproic acid levels if compliance is
an issue
Maximum dose is 60 mg/kg/d

a
Flunarizine is not available in the United States.

between 43% and 48% with dosages valproex sodium. Nausea, vomiting, and KEY POINT
ranging from 500 mg per day to 1500 mg gastrointestinal distress are the most h In addition to
per day. Extended-release (ER) divalproex common adverse events; their incidence well-known teratogenic
effects, including neural
sodium has also been shown to be effec- decreases, however, particularly after
tube defects, the US
tive for migraine prevention, and com- 6 months. Tremor and alopecia can, Food and Drug
pliance and side effect profile may be however, occur later. Treatment with Administration recently
more favorable with this formulation. these agents requires careful follow-up issued an alert to health
Since the 2000 AAN guideline30 was pub- and testing because of the risk of pan- care providers and
lished, one double-blind randomized creatitis, liver failure, teratogenicity, patients that medications
class I placebo-controlled 12-week trial and thrombocytopenia and other blood including and related to
showed divalproex sodium ER was su- dyscrasias. In addition to well-known ter- sodium valproate can
perior to placebo without significant dif- atogenic effects, including neural tube cause decreased IQ
ferences between groups in the number defects, the FDA recently issued an alert scores in children
whose mothers took
of treatment-emergent adverse events. to health care providers and patients
the medication
Clinical context. In most headache that medications including and related during pregnancy.
trials, patients taking divalproex sodium to valproate acid can cause decreased IQ
or sodium valproate reported no more scores in children whose mothers took
adverse events than those on placebo. the medication during pregnancy. These
However, weight gain has been clinically drugs are contraindicated and should
observed with the long-term use of di- never be used by pregnant women for

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Preventive Migraine Treatment

KEY POINTS
h Topiramate and dival- the prevention of migraine headaches. been reported in association with an ele-
proex sodium are the In fact, in women of childbearing poten- vation in body temperature; most re-
only two antiepileptic tial, sodium valproate and all related ports have involved children. A risk for
drugs that have US Food drugs should be used with extreme cau- hyperchloremic non-anion gap meta-
and Drug Administration tion. Hyperandrogenism, polycystic ovary bolic acidosis has also been described
approval for migraine syndrome, and obesity are of concern in during topiramate treatment. In 2011,
prevention. young women with epilepsy who use the FDA notified health care professionals
h Topiramate is being valproate. Absolute contraindications and patients of an increased risk of de-
placed in pregnancy are pregnancy (valproic acid/divalproex velopment of cleft lip and cleft palate
category D, which means sodium are pregnancy category X) and (oral clefts) in infants born to women
positive evidence of a history of a hepatic disorder or pan- who were treated with topiramate dur-
human fetal risk exists creatitis. Other contraindications are ing pregnancy. Because of new human
based on human data. thrombocytopenia, pancytopenia, and data that show an increased risk for oral
bleeding disorders. clefts, topiramate is being placed in preg-
Topiramate. Topiramate and dival- nancy category D, which means positive
proex sodium are the only two antiepi- evidence of human fetal risk exists based
leptic drugs that have FDA approval for on human data.
migraine prevention. Topiramate is not Lamotrigine. Although open-label
associated with significant reductions studies have suggested that lamotrigine
in estrogen exposure at doses below may have a select role in the treatment
200 mg per day. At doses above 200 mg of patients with migraine with frequent or
per day, there may be a dose-related prolonged aura, results from a placebo-
reduction in exposure to the estrogen controlled study in migraine without aura
component of oral contraceptives. were negative.32 Both lamotrigine and
Four class I studies and seven class II topiramate may have a special role in the
studies report that topiramate (50 mg per treatment of migraine with aura.
day to 200 mg per day) is effective in
migraine prevention. It is comparable to Other Drugs for the Prevention
amitriptyline in efficacy.31 Topiramate’s of Migraine
most common adverse event is pares- Other drugs used for the prevention of
thesia; other common adverse events are migraine include angiotensin-converting
difficulty with concentration and memory, enzyme inhibitors, angiotensin II recep-
language problems, fatigue, decreased tor antagonists, histamines, antihista-
appetite, nausea, diarrhea, kidney stones, mines, leukotriene receptor antagonists,
weight decrease, taste perversion, hy- aspirin and other NSAIDS, medicinal
poesthesia, and abdominal pain. In the herbs, and vitamins (Table 2-5).
migraine trials, body weight was re- Angiotensin-converting enzyme in-
duced an average of 2.3% in the 50-mg hibitors and angiotensin II receptor
group, 3.2% in the 100-mg group, and antagonists. Schrader and colleagues33
3.8% in the 200-mg group. Renal calculi conducted a double-blind placebo-
can occur with topiramate use. The re- controlled crossover study of lisinopril,
ported incidence is about 1.5%, rep- an angiotensin-converting enzyme inhib-
resenting a twofold to fourfold increase itor, in migraine prophylaxis. Days with
over the estimated occurrence in the migraine were reduced by at least 50%
general population. A very rare adverse in 14 participants for active treatment
event is acute myopia associated with versus placebo and in 17 patients for ac-
secondary angle-closure glaucoma. No tive treatment versus run-in period. Days
cases of this condition were reported in with migraine were fewer by at least 50%
the clinical studies. Oligohidrosis has in 14 participants for active treatment
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TABLE 2-5 Miscellaneous Medications in the Preventive Treatment
of Migraine

Agent Daily Dose Comments


Angiotensin-converting
enzyme and angiotensin
receptor antagonists
Lisinopril 10Y40 mg Positive small controlled trial
Candesartan 16Y32 mg Positive small controlled trial
Feverfew 50Y300 mg Controversial evidence
Riboflavin 400 mg Positive small controlled trial
Coenzyme Q10 300 mg Two positive controlled trials
Magnesium citrate 400Y600 mg Controversial evidence

versus placebo. Tronvik and colleagues34 migraine prevention, with an effect size
performed a randomized double-blind similar to propranolol 160 mg per day.
placebo-controlled crossover study of In a single class II placebo-controlled
candesartan (16 mg), an angiotensin II trial, telmisartan 80 mg per day did not
receptor blocker, in migraine preven- show a significant difference from pla-
tion. In a 12-week period, the mean num- cebo for reduction in migraine days
ber of days with headache was 18.5 with (Y1.65 versus Y1.14).36
placebo versus 13.6 with candesartan Histamines/antihistamines/leukotriene
(P=.001) in the intention-to-treat anal- receptor antagonists. The 2012 AAN guide-
ysis (n = 57). The number of cande- line includes studies of histamines,
sartan responders (reduction of 50% antihistamines, and leukotriene receptor
or more compared with placebo) was antagonists for migraine prevention.13
18 of 57 (31.6%) for days with head- Histamine. Three class II single-center
ache and 23 of 57 (40.4%) for days with studies (all from the same center) show
migraine. Adverse events were similar the efficacy of histamine for migraine
in the two periods. In this study, the prevention. N-"-methyl histamine (1 ng
angiotensin II receptor blocker cande- to 10 ng 2 times a week) subcutaneous
sartan was effective, with a tolerability injections reduced attack frequency from
profile comparable with that of placebo. baseline as compared with placebo.37 His-
A second randomized triple-blind tamine was statistically superior to placebo
double-crossover placebo-controlled trial at all treatment visits through 12 weeks for
with propranolol as an active compara- reduction in migraine frequency, severity,
tor confirmed the preventive efficacy of and duration (PG.0001). Transient itching
candesartan.35 Candesartan was noninferior at the injection site was the only reported
to propranolol. The proportion of re- adverse effect, but it did not reach signif-
sponders was significantly higher on icance. In a second class II study, histamine
candesartan (43%) and propranolol (40%) was shown to be as effective as sodium
than on placebo (23%) (PG.025 and PG.050, valproate in reducing attack frequency
respectively). The authors concluded that and better than sodium valproate in re-
candesartan 16 mg per day is effective for ducing headache duration and intensity.

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Preventive Migraine Treatment

A third study reported the efficacy of his- NSAIDs for migraine prevention was re-
tamine in migraine prevention as com- ported in the original AAN guideline,30
pared with topiramate. Topiramate 100 mg including 23 controlled trials of 10 dif-
per day was compared with histamine ferent NSAIDs that showed a modest but
(1 ng to 10 ng 2 times a week subcutane- significant benefit for naproxen sodium,
ous), and both active treatments showed with similar trends for flurbiprofen,
improvement over baseline measures for ketoprofen, and mefenamic acid. In
attack frequency, intensity, and use of res- the guideline, studies of aspirin had con-
cue medication.38 Eleven percent of sub- flicting results. Since the original report,
jects (5 of 45) treated with histamine two additional class II studies have been
withdrew from the histamine group be- reported. Aspirin was found to be as effec-
cause they were not satisfied with the tive as metoprolol for migraine prevention.
speed of results, although no adverse In a second study, aspirin 100 mg per day,
events were reported. A few subjects in combination with vitamin E 600 IU every
reported transitory burning and itching other day, was compared with placebo in
at the injection site. Similar adverse events combination with vitamin E.40 No differ-
and withdrawal rates (for slow reaction ences were noted between aspirin and
speed) were reported for the sodium placebo treatments for migraine frequency
valproate study. Histamine subcutane- or severity at 12 months or 36 months.
ous was associated with transitory burn- Medicinal herbs and vitamins. Medic-
ing and itching at the injection site. inal herbs and vitamins used for mi-
Cyproheptadine. Cyproheptadine, an graine prevention are listed in Table 2-5
antagonist at the 5-HT2, histamine H1, and discussed in the article ‘‘Nutraceutical
and muscarinic cholinergic receptors, is and Other Modalities for the Treatment
widely used in the prophylactic treatment of Headache’’ by Stewart J. Tepper, MD,
of migraine in children. Cyproheptadine is FAHS, in this issue of .
available as 4-mg tablets. The total dose
ranges from 12 mg per day to 36 mg CANADIAN HEADACHE
per day (given 2 to 3 times per day or at SOCIETY GUIDELINES FOR
bedtime). Common adverse events are MIGRAINE PREVENTION
sedation and weight gain; dry mouth, A comprehensive series of guidelines
nausea, lightheadedness, ankle edema, for migraine prevention were also devel-
aching legs, and diarrhea are less common. oped by the Canadian Headache Society.
Cyproheptadine may inhibit growth in Randomized double-blind controlled
children and reverse the effects of SSRIs. trials and relevant Cochrane reviews were
A single class II study showed cyprohep- graded according to criteria developed
tadine (4 mg per day) was as effective as by the US Preventive Services Task Force.14
propranolol (80 mg per day) in reducing The principles of the Grading of Recom-
migraine frequency and severity.39 mendations Assessment, Development
Montelukast. One class I study of and Evaluation (GRADE) Working Group
montelukast (20 mg per day) for migraine Recommendations were used to develop
prevention reported no significant differ- expert consensus that incorporated
ence between treatments in the percent- the best available evidence, side effect
age of patients with a greater than 50% profile, and migraine characteristics, and
decrease in migraine attack frequency comorbid and coexisting disorders were
per month (15.4% for montelukast versus used to develop final recommenda-
10.3% for placebo). tions for drug selection. In this guide-
Aspirin and other nonsteroidal anti- line, topiramate, propranolol, nadolol,
inflammatory drugs. The efficacy of metoprolol, amitriptyline, gabapentin,
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candesartan, butterbur, riboflavin, coen- liminary efficacy and safety findings be
zyme Q10, and magnesium citrate received duplicated in phase 3 trials.
a strong recommendation for use, while
divalproex sodium, flunarizine, pizotifen, CONCLUSION
venlafaxine, verapamil, and lisinopril re- Preventive therapy plays an important
ceived a weak recommendation. Clini- role in migraine management. When a
cians should exercise caution when preventive medication is added, attack
considering the use of butterbur given frequency may be reduced and response
the recent concerns regarding the po- to acute treatment improved, which can
tential for hepatic toxicity (refer to the result in reduced health care resource
article ‘‘Nutraceutical and Other Modal- utilization and improved quality of life.
ities for the Treatment of Headache’’ by Despite research suggesting that a large
Stewart J. Tepper, MD, FAHS, in this percentage of patients with migraine are
issue of ). candidates for prevention, only a frac-
tion of these patients are receiving or
TRENDS have ever received preventive migraine
Calcitonin Gene-Related medication.
Peptide Antibodies Many preventive medications are
Calcitonin gene-related peptide (CGRP) available, and guidelines for their selec-
is an important emerging migraine target. tion and use have been established. Since
CGRP is a potent vasodilator and impor- comorbid medical and psychological
tant neurotransmitter in the trigemino- illnesses are prevalent in patients with
vascular system. CGRP is released during migraine, one must consider comorbidity
migraine attacks and inhibited after pain when choosing preventive drugs. How-
relief occurs with triptans; when infused ever, optimal treatment of migraine and
systemically, it triggers a migraine attack. a comorbid disorder may require the
Multiple human monoclonal antibodies use of two different medications.
that specifically target either human CGRP No biological markers or clinical char-
or its receptor have been generated, and acteristics are predictive of response to a
the results of two randomized placebo- particular migraine preventive medica-
controlled phase 2 trials have been pub- tion. The impact of prevention on the
lished. A single IV dose of ALD403 1000 mg natural history of migraine remains to
per day, a genetically engineered hu- be fully investigated.
manized anti-CGRP IgG1 antibody, was
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