Download preventive therapy for migraine headache

REVIEW
PREVENTIVE THERAPY FOR MIGRAINE HEADACHE
—
H
Carla Rubingh, PharmD*
ABSTRACT
Headache is one of the most common medical
complaints. It is estimated that the prevalence of
migraine is approximately 13% (18% of women
and 6%–7% of men). Most patients with migraine
require pharmacologic treatment. Preventive
treatments for patients with migraine headache
reduce the frequency, severity, and duration of
headaches. Many medications are used for
migraine prevention, including β blockers, calcium channel blockers, antiseizure medications,
and antidepressants. Most agents reduce
migraine frequency by approximately 40% to
50%. The selection of a preventive strategy is usually based on the patient’s comorbid conditions
and ability to tolerate specific side effects. Several
vitamins, minerals, and herbal remedies also are
used for migraine prevention. Although some of
these may reduce migraine headache frequency,
they are not regulated by the US Food and Drug
Administration and may vary considerably in
potency from lot to lot. Nonpharmacologic therapies are also effective for some patients.
Migraine prevention may help to reduce lost
workplace productivity caused by absenteeism or
impaired job performance. In addition, preventive therapy may help to reduce the need for costly acute migraine headache treatments.
(Adv Stud Pharm. 2007;4(1):15-20)
*Assistant Professor, Department of Pharmacy Practice,
University of Nebraska Medical Center, Clinical PharmacistAmbulatory Care, Veterans Affairs Medical Center, Omaha,
Nebraska.
Address correspondence to: Carla Rubingh, PharmD,
Assistant Professor, Department of Pharmacy Practice,
University of Nebraska Medical Center, Clinical PharmacistAmbulatory Care, Veterans Affairs Medical Center, 986045
Nebraska Medical Center, Omaha, NE 68198-6045.
E-mail: [email protected].
University of Tennessee Advanced Studies in Pharmacy
n
eadache is one of the most common medical complaints. It is estimated that the
prevalence of migraine is approximately
13% (18% of women and 6%–7% of
men).1 Most patients with migraine require pharmacologic treatment.1 Migraine headaches cause significant
pain and disability, in addition to substantial loss of
time spent with family members, at work, or engaged
in leisure activities. Preventive treatments are intended
to reduce the frequency, severity, and duration of
headaches; to increase the response to acute migraine
medications; and to maintain the patient’s ability to
function.2 Preventive medications should be considered if a patient suffers from 2 or more headaches per
month. Other factors that may influence the decision
to use preventive medication include migraines that
significantly interfere with daily routine despite acute
treatment, contraindication to or failure or overuse of
acute therapies, inability to tolerate acute therapies,
and patient preference.3 Only 4 medications—timolol,
propranolol, divalproex sodium, and topiramate—are
approved by the US Food and Drug Administration
(FDA) for the prevention of migraine headache. Many
other agents have been used off-label for migraine
headache prevention, including β blockers, tricyclic
antidepressants (TCA), antiseizure medications, calcium channel antagonists, and selective serotonin reuptake inhibitors (SSRI).3,4 All of the commonly used
preventive agents reduce headache frequency by
approximately 40% to 50%, and all have the potential
for adverse effects.2 Therefore, the selection of a preventive therapy is usually made on the basis of comorbid conditions, side effects, cost, patient preference, or
other considerations. For example, a patient with
migraine headache who also has difficulty sleeping
may benefit from a preventive therapy that causes
drowsiness, whereas a patient with comorbid depression may do well with an antidepressant. Preventive
medications often are selected on the basis of the
patient’s willingness to tolerate the side effects of a par-
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REVIEW
ticular agent. SSRIs effectively reduce migraine frequency for many patients, but produce sexual side
effects that are difficult for many to tolerate. Some
agents (eg, certain β blockers, TCAs, and divalproex
sodium) cause weight gain that may be undesirable to
patients.4 In addition, it is also important to establish
that a preventive treatment is not contraindicated for
the patient’s comorbid conditions and that treatments
being administered for other conditions do not exacerbate migraine.3
There is often an element of trial-and-error in identifying an appropriate preventive therapy, and it is usually
not possible to know in advance how well a particular
therapy will work for a particular patient. A common
mistake made by patients and providers is not giving an
adequate trial to the selected agent being tried for prevention. It should be noted that patients may need to use
preventive therapy for at least 4 to 6 weeks before
headache frequency improves.2 When time for dose titration is added, preventive therapy may take up to 6
months to improve migraine symptoms.5
Medications that are used for migraine prevention
are summarized in the Table.4 β blockers have long
been considered a preferred treatment for migraine
prevention, especially in patients with comorbid
hypertension or angina.2 Common TCAs used in the
United States include amitriptyline and doxepin (both
of which produce sedation) and nortriptyline (which is
less sedating).2 Several nonsteroidal anti-inflammatory
drugs have been shown to reduce migraine frequency,
of which naproxen has been most extensively evaluated. These agents may be especially useful to prevent
headaches that occur predictably, such as migraine
headaches associated with the menstrual cycle.2
Calcium channel antagonists and SSRIs also may be
effective, but have not been evaluated as extensively.2
Recent developments in migraine prevention
include the anticonvulsant topiramate and botulinum
toxin type A. Antiseizure medications have been used
for many years to prevent migraine headaches.
Divalproex sodium, which was approved in 2000 for
this indication, has been shown to significantly reduce
the frequency of migraine headaches in randomized,
double-blind, placebo-controlled clinical trials.6 Other
anticonvulsants have been used off-label for migraine
prevention, including gabapentin and oxcarbazepine.4
Topiramate was approved for migraine prevention in
2004 and was evaluated in 2 large, randomized, double-blind clinical trials of identical design.7,8 In both of
16
these studies, patients with 3 to 12 migraine headaches
during a 28-day baseline period were randomized to
receive placebo or 1 of 3 topiramate doses (ie, 50 mg,
100 mg, or 200 mg/day) for up to 6 months, with
headache frequency evaluated monthly. A total of 483
patients were randomized to treatment in one study,8
and 487 were randomized in the other.7 In both studies, topiramate doses of 100 and 200 mg per day produced significantly greater reduction in headache
frequency than placebo across the 6-month study period (Figure 1).7 The 50-mg dose did not significantly
reduce migraine frequency at most time points.
Increasing the dose to 200 mg did not significantly
improve treatment efficacy compared with the 100-mg
dose. More recently, Wenzel et al reviewed the medical
literature regarding the use of topiramate in migraine
prevention.9 The investigators also found that an optimal topiramate dose appears to be 100 mg per day for
most patients. This dose of topiramate reduced
migraine frequency by an average of approximately 2
headaches per month and also significantly reduced
the number of days per month with migraine
headache and the use of acute migraine medications.
Antiseizure medications may be particularly useful for
patients with comorbid bipolar disorder or seizure disorders.10 Patients should be aware that topiramate may
produce mild cognitive impairment or fatigue, which
are usually transitory.11 Other adverse effects reported
in more than 10% of patients with migraine headache
in placebo-controlled clinical trials include paresthesia,
dizziness, diarrhea, anorexia, and upper respiratory
tract infection.12
Although somewhat controversial, and not US
FDA approved for this purpose, botulinum toxin type
A is used by some specialists to treat migraine.
Botulinum toxin injections are typically administered
once every 3 months, eliminating issues of medication
adherence.13 Some clinical studies have demonstrated
reductions in migraine headache frequency with botulinum toxin injections (Figure 2),14,15 although one
recent randomized, double-blind multicenter trial
found that botulinum toxin injections were no more
effective than placebo.16
Vitamins, herbal preparations, and other natural
products are also sometimes used for migraine
headache prevention. Riboflavin and magnesium have
both been shown to significantly reduce the frequency
of migraine episodes in placebo-controlled clinical trials.14 Some evidence also supports the use of feverfew
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and butterbur.17 Although many individuals prefer
natural remedies, and these agents have improved
migraine symptoms in some studies, herbal products
must be used with caution. Herbal remedies may contain many different ingredients with significant biologic activity, are not regulated by the US FDA, may
Table. Medications Used for Prevention of Migraine Headaches
Drug
β Blockers
Propranolol
Nadolol
Atenolol
Metoprolol
TCAs
Amitriptyline
Nortriptyline
Imipramine
Desipramine
Doxepin
Calcium Channel Blockers
Amlodipine
Verapamil
Examples of NSAIDs
Indomethacin
Naproxen
Celecoxib
SSRIs
Citalopram
Escitalopram
Fluoxetine
Fluvoxamine
Paroxetine
Sertraline
Anticonvulsants
Divalproex sodium
Gabapentin
Oxcarbazepine
Topiramate
MAO Inhibitor
Phenelzine
Daily Dosage
Range
Major Side Effects
Comorbid Considerations
40–240
40–160
50–100
50–200
mg
mg
mg
mg
Fatigue, depression, weight gain, edema,
dizziness, decreased exercise tolerance,
and sexual dysfunction
Hypertension, anxiety disorders,
status-post MI, and tachycardia
10–200
10–150
10–200
10–150
10–200
mg
mg
mg
mg
mg
Dry mouth, dry eyes, constipation,
weight gain, fatigue, and urinary retention
Sleep disorders, depression, and
neuropathic pain
1.25–5 mg
120–480 mg
Constipation, hypotension, and dizziness
Hypertension, connective tissue disorders,
autoimmune disorders, and Raynaud’s disease
75–150 mg
440–1100 mg
100–200 mg
Stomach irritation, ulcer, edema, and
renal problems
Musculoskeletal aches and pains,
inflammatory disorders, and menstrual migraine
10–40 mg
10–20 mg
10–80 mg
50–300 mg
10–50 mg
25–200 mg
GI complaints, tremor, dizziness,
insomnia, and sexual dysfunction
Depression, obsessive-compulsive disorder,
anxiety disorder, panic disorder, and social
phobia
250–2000 mg
GI disturbances, sedation, tremor,
hepatotoxicity, transient hair loss, and
weight gain
Sedation and dizziness
Sedation and dizziness
Bipolar disorder, epilepsy, and PTSD
1800–2400 mg
300–1200 mg
Neuropathic pain and epilepsy
Trigeminal neuralgia, neuropathic pain,
and epilepsy
Epilepsy, obesity, and mood disorders
50–200 mg
Sedation, cognitive/memory problems,
and weight loss
30–75 mg
Dietary precautions, hypotension, nausea,
weight gain, edema, and liver function
Severe depression
Weight gain, sedation, and urinary retention
First-line agent in children and allergic rhinitis
H1 Blocker/Serotonin Antagonist
Cyproheptadine
8–16 mg
Carbonic Anhydrous Inhibitor
Acetazolamide
250–2000 mg
Lightheadedness, frequent urination, and
Pseudotumor cerebri and altitude sickness
taste disturbances with carbonated beverages
GI = gastrointestinal; MAO = monoamine oxidase; MI = myocardial infarction; NSAID = nonsteroidal anti-inflammatory drug; PTSD = post-traumatic stress disorder;
SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant.
Reprinted with permission from Rubingh and Baggaley. Headache: Diagnosis and approaches to treatment. In: Lipman, ed. Pain Management for Primary Care
Clinicians. Bethesda, Md: American Society of Health System Pharmacists; 2004.4
University of Tennessee Advanced Studies in Pharmacy
n
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REVIEW
WORKPLACE PRODUCTIVITY AND
ECONOMIC EFFECTS OF MIGRAINE PREVENTION
Onset of migraine headaches is typically between
the ages of 5 and 40.23 However, frequency of migraine
often increases between the ages of 30 and 45, a time
when many individuals are raising young children and
reaching their peak level of workplace productivity.1
Headache causes significant loss of workplace productivity due to missed work days and, even more importantly, to impaired performance while on the job.24,25
Migraine headaches also produce significant disruption
of childcare and other family responsibilities. Although
workplace and non-workplace productivity have been
shown to benefit from acute treatments (eg, triptans) or
from migraine management programs that incorporate
18
acute and preventive therapies,26,27 the specific effects of
migraine prevention on workplace performance have not
been evaluated in controlled studies.
Direct medical costs associated with migraine
headache are incurred because of the use of medications, physician office or clinic visits, emergency
Figure 1. Mean (Least Squares Value) Change from Baseline
in Monthly Migraine Frequency
Mean change from baseline in
monthly migraine frequency
produce significant interactions with other medications, and may vary considerably in the amount of
active ingredient contained.18
Nonpharmacologic methods also may help to
reduce the impact of migraine headache. Headaches
are often induced by specific triggers, such as certain
foods, odors, behaviors, chemicals, or other environmental factors.19 One way to help reduce the impact of
migraine triggers is to use a headache diary or calendar.19 The diary may be used to record all headache
episodes, headache intensity, any trigger factors, foods
and beverages consumed, and medications used.
Keeping a headache diary may help the patient and the
physician to identify triggers, suggest lifestyle modifications to reduce headache impact, and select an
appropriate pharmacotherapy strategy. Lifestyle modifications that may help to reduce the frequency of
migraine include limiting caffeine consumption,
maintaining a regular sleep schedule, eating regularly
and avoiding fasting, minimizing stress, and avoiding
bright or flashing lights.19 These lifestyle changes along
with the headache diary should be encouraged in all
patients with headache. Other nonpharmacologic
options include relaxation training, biofeedback,
cognitive-behavioral psychotherapy, cervical manipulation, and massage therapy.3,20 Migraine headaches are
often linked to menstrual cycles,21 and some experts
have suggested that reducing the number of menstrual cycles (eg, with an “extended contraceptive” agent
that reduces the number of menstrual cycles to 4
cycles/year) may reduce the number of headaches. At
present, this strategy has not been evaluated in controlled clinical trials.22
0
Placebo
group
-0.5
Topiramate,
50 mg/d,
group
Topiramate,
100 mg/d
group
Topiramate,
200 mg/d
group
-1.0
*
-1.5
*
*
-2.0
-2.5
*
*
0
1
*
*
*
3
4
2
Treatment month
*
*
5
*
*
6
*P <.02 vs placebo; †P = .03 for topiramate, 50 mg/d, vs placebo.
Reprinted with permission from Silberstein et al. Arch Neurol. 2004;61:490-495.7
Figure 2. Mean (Least Squares Value) Change from Baseline
in Monthly Migraine Frequency
70%
60%
50%
40%
30%
20%
10%
0%
1 Month
2 Months
BTX 25
Placebo
3 Months
Percentage of subjects with at least a decrease of 2 headaches in the frequency of
their migraines/month, after treatment with botulinum toxin injections. P <.05 at 3
months.
BTX = botulinum toxin.
Reprinted with permission from Bigal and Lipton. Neurologist. 2006;12:204-213.14
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department visits, laboratory and diagnostic services,
and other services.28 Acute migraine medications are
one of the most significant costs of migraine care.28
Preventive therapy for migraine has been shown to
reduce the use of medical services, and therefore, may
result in lower total treatment cost. For example, preventive therapy for migraine headaches has been
shown to reduce the need for acute triptan medications by more than 20% over a 12-month period, with
an even larger decrease for patients with the most frequent triptan use at baseline.29 It has been suggested
that these reductions in medical resource use may
lower overall treatment costs associated with migraine
headache.13 An economic analysis of antiseizure medications for migraine prevention found that the cost
effectiveness was greatest for patients who had the
most severe migraines at baseline.30 A recent study of
migraine prevention with topiramate found that savings associated with reduced need for acute medications and reduced loss of work offset approximately
70% of the cost of treatment.31
COMBINED THERAPY FOR
MIGRAINE HEADACHE PREVENTION
Preventive therapies reduce the frequency of
migraine headache by approximately 50%, but they
do not eliminate headaches. Therefore, patients should
also receive abortive medications to treat acute attacks
that occur despite their preventive regimens.20 The
goal of combining acute and preventive agents should
be to use preventive therapies so that the patient rarely
needs acute medications.32 Detailed clinical guidelines
to combine acute and preventive therapies have been
developed by several expert consensus groups in the
United States and Europe.20
In some cases, it may be necessary to combine 2 or
more preventive medications. Adding a second preventive agent may be considered for a patient who still
has frequent headaches despite the use of a preventive
agent. The second preventive agent is usually selected
from a different drug category.33 Patients who receive
combination preventive therapy usually have very frequent headaches before preventive treatment.
Although this approach has not been extensively evaluated in controlled trials, some studies have demonstrated additional effectiveness of combining
preventive medications. In one study, the combination
of sodium valproate and a β blocker in patients with
treatment-resistant migraine headaches demonstrated
University of Tennessee Advanced Studies in Pharmacy
n
improvement of at least 50% in headache frequency
from baseline in 56% of patients.34 In a second study,
adding topiramate to existing preventive therapies (ie,
propranolol, flunarizine [not available in the United
States], or both for most patients) significantly
reduced headache frequency from 17 per month to 3
per month and also reduced the average headache
duration and intensity (P <.001).35 Although this
approach may help to control migraine headaches for
some patients who have very frequent headaches, it
also increases the risk for adverse effects and the potential for drug interactions.33
CONCLUSIONS
Only 4 agents are approved by the US FDA for
migraine prophylaxis, although several β blockers,
antiseizure medications, calcium channel blockers,
antidepressants, and other drugs are used to prevent
migraine headaches. Treatment often is selected on the
basis of the patient’s comorbid conditions and desire
to avoid specific side effects. By reducing pain, disability, and the need for acute medications, migraine prevention is cost effective. Some patients continue to
exhibit significant disability on a monotherapy preventive regimen, and the use of combinations of preventive agents are sometimes required to reduce
migraine headache frequency to tolerable levels.
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