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Official reprint from UpToDate®

[Link] © 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Preventive treatment of episodic migraine in adults

Authors: Todd J Schwedt, MD, MSCI, Ivan Garza, MD
Section Editor: Jerry W Swanson, MD, MHPE
Deputy Editor: Richard P Goddeau, Jr, DO, FAHA

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Feb 2023. | This topic last updated: Feb 16, 2023.

INTRODUCTION

Migraine is a common disorder with one-year prevalence estimates of approximately 17 percent

in females and 6 percent in males. (See "Pathophysiology, clinical manifestations, and diagnosis
of migraine in adults", section on 'Epidemiology'.)

The preventive treatment of episodic migraine headache in adults is reviewed here. The clinical
features and management of chronic migraine (defined as ≥15 headache days per month) are
discussed separately. (See "Chronic migraine".)

Other aspects of migraine are reviewed elsewhere. (See "Acute treatment of migraine in adults"
and "Pathophysiology, clinical manifestations, and diagnosis of migraine in adults".)

INDICATIONS

Many migraine sufferers can benefit from preventive migraine treatment. Indications include
the following [1-6]:

● Frequent or long-lasting migraine headaches

● Migraine attacks that cause significant disability or diminished quality of life despite
appropriate acute treatment
● Contraindication to acute therapies
● Failure of acute therapies
● Serious adverse effects of acute therapies

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● Risk of medication overuse headache

● Menstrual migraine

While there are no strict definitions for the precise frequency or duration of migraine
headaches that would prompt preventive therapy, more than four headaches per month or
headaches that last longer than 12 hours are generally considered reasonable thresholds.

The main goals of preventive therapy are to [1,7]:

● Reduce attack frequency, severity, and duration

● Improve responsiveness to treatment of acute attacks
● Improve function and reduce disability
● Prevent progression or transformation of episodic migraine to chronic migraine

Based on expert consensus, preventive migraine therapy also is indicated to reduce the risk of
neurologic damage and/or impairment in the presence of uncommon migraine conditions
including [1]:

● Hemiplegic migraine (see "Hemiplegic migraine")

● Migraine with brainstem aura (see "Migraine with brainstem aura")
● Persistent aura without infarction (see "Pathophysiology, clinical manifestations, and
diagnosis of migraine in adults", section on 'Complications of migraine')
● Migrainous infarction (see "Headache, migraine, and stroke")

In addition, short-term preventive therapy during the perimenstrual period may be useful for
female patients who have menstrual migraine that occurs on a predictable schedule. (See
"Estrogen-associated migraine, including menstrual migraine", section on 'Hormonal therapy'.)

OUR APPROACH

Our approach to choosing preventive treatment of migraine is outlined in the sections that
follow.

Choosing pharmacologic therapy — A number of drug classes are used for the prevention of
migraine. Medications that are effective in controlled trials include:

● Metoprolol, propranolol, and timolol (see 'Beta blockers' below)

● Amitriptyline and venlafaxine (see 'Antidepressants' below)
● Valproate and topiramate (see 'Anticonvulsants' below)

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● Erenumab, fremanezumab, galcanezumab, eptinezumab, rimegepant, and atogepant (see

'CGRP antagonists' below)

For most patients with episodic migraine (≤14 headache days per month) who have an
indication for preventive therapy (see 'Indications' above), we suggest initial treatment with
amitriptyline, venlafaxine, one of the beta blockers (metoprolol or propranolol), or topiramate.
Approximately half of patients given any of these drugs will have a 50 percent reduction in the
frequency of headache, but the doses required may lead to intolerable side effects [8]. The
choice among preventive agents of similar efficacy should be individualized according to
patient-specific characteristics, comorbid conditions, medication side effect profile, medication
cost, and patient values and preferences [9-11].

The calcitonin gene-related peptide (CGRP) antagonists are reasonable options for patients with
marked disability from frequent migraine who do not respond to or cannot tolerate other
options [12]. They may provide earlier benefit than other preventive agents, and the
formulations given by injection may also be helpful for those who have difficulty complying with
preventive medications that require daily pills. However, high cost and barriers to insurance
approval may limit their access.

Valproate should not be used for females of childbearing potential, because it is teratogenic
and is associated with an increased risk of congenital anomalies. However, it may be considered
for those utilizing effective contraception if other options are not effective or tolerated. The
approach to migraine prevention during pregnancy and the postpartum period is discussed
elsewhere. (See "Headache during pregnancy and postpartum", section on 'Preventive
therapies'.)

In some cases, the presence of associated conditions and comorbid disorders can help to guide
the choice of migraine therapy:

● For patients with hypertension who are nonsmokers and ≤60 years of age, reasonable
options include metoprolol, propranolol, or timolol in the absence of contraindications to
beta blockers.

● For patients with hypertension who are smokers or are >60 years of age, options include
verapamil or flunarizine. We suggest not using beta blockers as initial therapy for
migraine prevention in these patients because beta blockers may be associated with a
higher rate of cardiovascular events compared with other antihypertensive drugs in the
primary treatment of hypertension. (See "Choice of drug therapy in primary (essential)
hypertension".)

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● For patients with depression or mood disorder, reasonable options include amitriptyline
or venlafaxine.

● For patients with epilepsy, reasonable options include valproate or topiramate.

● For patients with insomnia, amitriptyline is a reasonable option.

● For patients with obesity, topiramate is a reasonable option.

● For patients with Raynaud phenomenon, reasonable options include verapamil or

flunarizine.

However, comorbid disorders cannot be the sole factor in selecting therapy. A number of issues
may preclude the use of specific agents or classes of medications, including contraindications,
side effects, patient preferences, and cost.

The treatment of chronic migraine (≥15 headache days per month) is reviewed separately. (See
"Chronic migraine", section on 'Management'.)

Principles of preventive therapy — Regardless of the drug chosen, some general principles
may improve the success rate of preventive migraine therapy, improve treatment adherence,
and reduce complications [9]:

● Start an oral migraine preventive medication at a low dose. Increase the dose gradually
until therapeutic benefit is achieved, the maximum dose of the drug is reached, or side
effects become intolerable.

● Give the chosen medication an adequate trial in terms of duration and dosage. Clinical
trials suggest efficacy for some agents may be first noted at four weeks but can continue
to increase for three to six months.

● Avoid overuse of acute headache therapies including analgesics, triptans, and ergots.

● Opioids and barbiturates should not be used for the acute or preventive treatment of
migraine. Opioid use can contribute to development of chronic daily headache and can
interfere with other preventive therapies. (See "Acute treatment of migraine in adults",
section on 'Opioids and barbiturates' and "Medication overuse headache: Etiology, clinical
features, and diagnosis", section on 'Causal medications'.)

● Females of childbearing potential must be warned of any potential risks. Avoid valproate
for this group if possible, avoid topiramate during pregnancy, and choose the medication

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that will have the least adverse effect on the fetus. (See "Headache during pregnancy and
postpartum", section on 'Preventive therapies'.)

● Address patient expectations and consider patient preferences when deciding between
drugs of relatively equivalent efficacy. Discuss the rationale, dosing, and likely side effects
for a particular treatment. Discuss expected benefits of therapy and how long it will take
to achieve them. Preventive migraine therapy requires a sustained commitment on the
part of the patient and physician to achieve benefit.

● Migraine may improve independent of treatment. If migraine is well controlled, slowly

taper the drug if possible. Many patients experience continued relief with either a lower
dose or cessation of the medication.

Treatment failure — We suggest switching to a migraine prevention medication from a

different class for patients who fail to improve despite an adequate trial of initial pharmacologic
therapy. Clinical trials have shown that switching to another preventive agent can be effective
for individuals who have failed prior migraine preventive therapies [4,13-17].

Lifestyle measures — Therapeutic lifestyle measures may be beneficial for controlling

migraine, including good sleep hygiene, routine meal schedules, regular exercise, and
managing migraine triggers. (See 'Nonpharmacologic interventions' below and
"Pathophysiology, clinical manifestations, and diagnosis of migraine in adults", section on
'Precipitating and exacerbating factors'.)

While few high-quality, placebo-controlled trials have evaluated the efficacy of these factors for
migraine prevention, we recommend therapeutic lifestyle measures because they may be
effective and are unlikely to cause any harm. A headache diary is useful for estimating the
number and severity of headaches each month and for identifying precipitating factors so that
so they can be managed. The optimal management of headache trigger factors is uncertain;
traditional teaching emphasizes avoidance, while newer approaches emphasize coping
strategies. (See 'Desensitizing triggers' below.)

INTERVENTIONS

Pharmacotherapy and lifestyle measures are the mainstay of migraine prevention.

Antihypertensives — Data from randomized clinical trials show that beta blockers and
angiotensin II receptor blockers (ARBs) are effective for migraine prevention [2,18-20]. Lower
quality evidence suggests but does not establish that calcium channel blockers and angiotensin

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converting enzyme (ACE) inhibitors are also effective for migraine prevention. There are no
clinical trial data for thiazide diuretics in migraine prevention.

Blood pressure treatment appears to reduce the overall prevalence of headache in general. This
point is illustrated by the results of a meta-analysis of 94 randomized controlled trials
examining four different classes of antihypertensive medications (beta blockers, ACE inhibitors,
ARBs, and thiazides) that also included data on headache prevalence [21]. Patients assigned to
blood pressure treatment had a significant reduction in headache prevalence compared with
placebo treatment (odds ratio [OR] 0.67, 95% CI 0.61-0.74), and headache prevalence was
significantly reduced in each of the four classes of drugs compared individually with placebo.
One limitation is that the individual trials lacked information on headache classification, so the
proportion of migraine versus other types of headaches among the subjects is unknown.
However, it is conceivable that most of the patients had migraine, as the prevalence of
headache among placebo patients (12.4 percent) is similar to the reported prevalence of
migraine in the general population. (See "Pathophysiology, clinical manifestations, and
diagnosis of migraine in adults", section on 'Epidemiology'.)

Beta blockers — Metoprolol, propranolol, and timolol are established as effective for migraine
prevention, while atenolol and nadolol are probably effective [2].

Our suggested doses for migraine prevention with beta blockers are as follows [11,22,23]:

● Propranolol in two divided doses starting at 40 mg daily; dose range 40 to 240 mg daily
● Metoprolol in two divided doses starting at 50 mg daily; dose range 50 to 200 mg daily
● Nadolol starting at 20 mg once a day; dose range 20 to 240 mg daily
● Atenolol starting at 25 mg daily; dose range 25 to 100 mg once daily

Although we generally do not use timolol for migraine prevention, it can be started at 5 mg
once daily; the dose range is 10 to 30 mg daily given in two divided doses.

It can take several weeks for headache improvement to accrue with these drugs [24]; the dose
should be titrated and maintained for at least three months before deeming the medication a
failure.

We suggest not using beta blockers as initial therapy for migraine prevention in patients over
age 60 and in smokers. Compared with other antihypertensive drugs in the primary treatment
of hypertension, beta blockers may be associated with a higher rate of stroke and other
cardiovascular events. (See "Choice of drug therapy in primary (essential) hypertension".)

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The use of beta blockers may be also limited in patients with erectile dysfunction, peripheral
vascular disease, Raynaud phenomenon, and patients with baseline bradycardia or low blood
pressure. They must be used cautiously as well in patients with asthma, diabetes mellitus, or
depression, and in those with cardiac conduction disturbances or sinus node dysfunction. (See
"Major side effects of beta blockers".)

Calcium channel blockers — Calcium channel blockers are used for migraine prevention.
However, the data supporting the efficacy of calcium channel blockers are weak and conflicting
[2,11]. Two methodologically flawed studies showed a small but significant effect of verapamil
(in three divided doses starting at 120 mg daily, dose range 120 to 240 mg daily) for migraine
prevention [25,26]. If there is no response at lower doses, or if tolerance develops, verapamil
can be increased to 480 mg per day in divided doses as tolerated; increased vigilance for
bradycardia and heart block is mandatory with higher verapamil doses.

Flunarizine, a nonspecific calcium channel blocker, also has some evidence of efficacy [3,11].
Based on several controlled studies, the recommended dose of flunarizine is 5 to 10 mg daily.
Flunarizine is not available in the United States.

Tolerance may develop with calcium channel blockers; it occurred after eight weeks of
successful therapy in 42 percent of those treated with nifedipine, 49 percent treated with
verapamil, and 4 percent treated with nimodipine in one report [27]. Tolerance may be
overcome by increasing the dose of medication, or by switching to a different calcium channel
blocker.

ACE inhibitors/ARBs — A double-blind crossover study of 60 patients with two to six migraine
episodes per month found that the ACE inhibitor lisinopril (10 mg/day for one week, then 20
mg/day) significantly reduced the number of hours and days with headache and headache
severity compared with placebo [28].

Candesartan is an ARB that was found to be effective in two blinded crossover trials [19,20].
Approximately 40 percent of patients in both studies were responders to candesartan used at
16 mg once daily.

However, the small size and single-center crossover design of these trials prevent definitive
conclusions regarding the effectiveness of lisinopril and candesartan for migraine prevention.

Antidepressants — In a systematic review of prospective double-blind, randomized controlled

trials of medications for migraine prevention, the tricyclic antidepressant amitriptyline (starting
dose 10 mg at bedtime, dose range 20 to 50 mg at bedtime) was effective for migraine
prevention in four trials [11]. Doses ranging from 10 to 100 mg per day are used in clinical
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practice. In other trials, the serotonin-norepinephrine reuptake inhibitor venlafaxine (starting at

37.5 mg once a day, dose range 75 to 150 mg once a day) was also effective as prevention for
migraine [11]. Similarly, a 2012 guideline from the American Academy of Neurology (AAN)
concluded that amitriptyline and venlafaxine are probably effective for migraine prevention [2].

Although other tricyclic antidepressants (eg, nortriptyline and protriptyline) are used in clinical
practice, amitriptyline is the only tricyclic that has proven efficacy for migraine; there are
insufficient data regarding the other tricyclics [9].

Side effects are common with tricyclic antidepressants. Most are sedating, particularly
amitriptyline and doxepin. Therefore, these drugs are usually used at bedtime and started at a
low dose. Additional side effects of tricyclics include dry mouth, constipation, tachycardia,
palpitations, orthostatic hypotension, weight gain, blurred vision, and urinary retention.
Confusion can occur, particularly in older adults. (See "Tricyclic and tetracyclic drugs:
Pharmacology, administration, and side effects".)

Venlafaxine is used by the author for patients with migraine who have comorbid panic disorder,
generalized anxiety disorder, persistent postural perceptual dizziness, or social anxiety disorder.
(See "Management of panic disorder with or without agoraphobia in adults" and
"Pharmacotherapy for social anxiety disorder in adults" and "Generalized anxiety disorder in
adults: Management".)

Anticonvulsants — The anticonvulsants sodium valproate and topiramate are more effective
than placebo for reducing the frequency of migraine attacks [11,29]. A 2012 guideline from the
AAN concluded that topiramate and sodium valproate are established as effective for migraine
prevention, while evidence is insufficient to determine the effectiveness of gabapentin [2].

Topiramate — Several placebo-controlled studies, a systematic review, and a meta-analysis

have found that topiramate is effective preventive therapy for migraine [18,30-33]. The starting
topiramate dose in most of these studies was 25 mg/day, with slow titration by 25 to 50
mg/week to the maximum of 100 mg twice daily or the highest tolerated dose.

The two largest randomized trials of topiramate for migraine each evaluated over 460 patients
[30,31]. The following observations emerged from these trials [30,31]:

● The mean monthly migraine frequency decreased significantly for patients receiving
topiramate at either 100 or 200 mg/day compared with placebo. For patients receiving
topiramate at 50 mg/day, the reduction in migraine frequency did not achieve statistical
significance.

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● Significant reductions in migraine frequency occurred within the first month at topiramate
doses of 100 and 200 mg/day. The responder rate (proportion of patients with a ≥50
percent reduction in mean migraine frequency) for these doses was about 50 percent of
treated patients. The effectiveness of topiramate at these doses was maintained for the
entire double-blind treatment phase.

● Topiramate treatment-related adverse events, generally mild to moderate in severity,

included paresthesia, fatigue, anorexia, diarrhea, weight loss, hypesthesia, memory
difficulty, language problems, difficulty with concentration, nausea, and taste perversion.
Of these, paresthesia was the most common, occurring in about half of patients receiving
topiramate at 100 or 200 mg/day. Weight loss is a unique side effect of this drug, and it
occurred in 9 to 12 percent of patients taking 100 to 200 mg/day of topiramate.

Adverse events with topiramate were more frequent with the 200 mg/day dose in controlled
trials, leading to withdrawal of therapy in up to 30 percent of patients [11]. Therefore, some
experts recommend using topiramate at no more than 100 mg/day for migraine prevention. We
suggest not using topiramate during pregnancy, since topiramate is associated with an
increased risk of facial clefts and may increase the risk of low birth weight (see "Risks associated
with epilepsy during pregnancy and postpartum period", section on 'Topiramate'). A more
complete review of adverse effects is discussed separately. (See "Antiseizure medications:
Mechanism of action, pharmacology, and adverse effects", section on 'Topiramate'.)

Data from one trial suggest that topiramate has residual benefit for migraine that persists for
up to six months after the drug is discontinued [32].

Limited data from comparative trials suggest that topiramate is as effective as propranolol for
episodic migraine prevention, and may have a modest advantage over valproate [33]. Patients
should be counseled that topiramate doses greater than 100 mg may induce estrogen
metabolism and impact the efficacy of oral contraception.

Valproate — A review of three trials evaluating valproate products (divalproex sodium, sodium
valproate, and valproic acid) at doses ranging from 500 to 1500 mg daily for migraine
prevention found that valproate was significantly more effective than placebo as measured by
the number of patients experiencing a ≥50 percent reduction in migraine frequency (OR 2.74,
95% CI 1.48-5.08) [11]. Subsequent systematic reviews reached similar conclusions [18,34].

Valproate can work well for migraine prevention at doses less than 1000 mg/day; doses up to
1500 mg/day are sometimes needed to achieve a response, but higher doses are associated
with the potential for more adverse effects. Valproate can cause nausea, somnolence, tremor,
dizziness, weight gain, and hair loss. It is contraindicated in pregnancy because of
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teratogenicity. In addition, valproate has been linked to lower intelligence quotient scores
among children with prenatal valproate exposure (see "Risks associated with epilepsy during
pregnancy and postpartum period", section on 'Effect of ASMs on the fetus and neonate').
Therefore, valproate should not be used by females of childbearing age for headache
prevention [35]. A more complete review of adverse effects is discussed separately. (See
"Antiseizure medications: Mechanism of action, pharmacology, and adverse effects", section on
'Valproate'.)

Gabapentin — Gabapentin is used for migraine prevention based on clinical experience as

well as society guideline endorsement [4]. However, a systematic review of five controlled trials
found that gabapentin was not efficacious for episodic migraine prevention in adults [36]. In
addition, a 20-week trial of 523 patients reported no significant difference between treatment
with gabapentin enacarbil (the prodrug of gabapentin) and placebo in change from baseline in
the number of migraine headache days during the last four weeks of treatment [37].

CGRP antagonists — Calcitonin gene-related peptide (CGRP) is a therapeutic target in migraine

because of its role in mediating trigeminovascular pain transmission and neurogenic
inflammation. (See "Pathophysiology, clinical manifestations, and diagnosis of migraine in
adults", section on 'Role of calcitonin gene-related peptide'.)

Large molecules in the form of monoclonal antibodies directed against the CGRP receptor or
ligand are given by injection for migraine prevention. Small-molecule CGRP antagonists
("gepants") are oral agents first shown effective for acute migraine treatment. Rimegepant and
atogepant are orally formulated gepants that have also shown benefit for migraine prevention
[38]. The United States Food and Drug Administration (FDA) approved the monoclonal antibody
CGRP antagonists erenumab [39], fremanezumab [40], and galcanezumab [41] in 2018,
eptinezumab [42] in 2020, and rimegepant and atogepant in 2021 [43,44] for migraine
prevention.

There is little evidence to guide the use of the CGRP antagonists in specific populations (eg,
children, older adults, and pregnant or lactating patients). They should be avoided for those
who are pregnant or likely to become pregnant and for individuals with recent cardiovascular or
cerebrovascular ischemic events, since CGRP has theoretical cardioprotective and vasodilatory
effects [12,45]. Although probably unrelated to treatment, there were three deaths in clinical
trial subjects who received CGRP monoclonal antibodies [46-48]. Additional concerns have been
raised about the potential for adverse cardiovascular, pulmonary, and psychiatric effects with
CGRP antagonists [49], even though these were not observed in randomized trials [50-52].
Cases of angioedema and anaphylaxis have also been reported [53,54]. More data are needed
regarding the long-term safety of this class of medications [49].
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● Erenumab – Erenumab, a human monoclonal antibody that binds to and inhibits the
CGRP receptor, was modestly effective for migraine prevention in a placebo-controlled trial
of over 900 adults with episodic migraine [55]. The trial randomly assigned subjects in a
[Link] ratio to subcutaneous injections of erenumab 70 mg, erenumab 140 mg, or placebo
monthly for six months. At baseline, the mean number of migraine days per month was
8.3 in the overall population. At months four through six, the number of migraine days per
month was reduced by 3.2 in the 70 mg erenumab group, 3.7 in the 140 mg erenumab
group, and 1.8 in the placebo group. The rates of adverse events were similar between the
erenumab and placebo groups.

Another trial evaluated 246 subjects with treatment-resistant episodic migraine who had
failed to respond to or did not tolerate between two and four previous migraine
preventive medications [13]. Subjects were randomly assigned to receive erenumab 140
mg or placebo by subcutaneous injection every four weeks. At 12 weeks, the proportion of
patients who had a 50 percent or more reduction in the mean number of monthly
migraine days was greater for the group assigned to erenumab compared with the group
assigned to placebo (30 versus 17 percent; OR 2.7, 95% CI 1.4-5.2; absolute risk difference
13 percent). In an open-label extension phase of this study, the response rate at 64 weeks
increased in those switching from placebo to erenumab and in those who continued
erenumab (50 and 44 percent, respectively) [56].

Erenumab appears to be effective for patients with episodic migraine either with or
without aura. In a secondary analysis of four clinical trials involving more than 2000
patients with episodic migraine, the effectiveness of erenumab at 70 mg or 140 mg over
placebo, as assessed by the proportion of patients with at least a 50 percent reduction in
the number of monthly migraine days by 12 weeks, was sustained when results were
stratified by patients with migraine with (45 percent for 70 mg, 46 percent for 140 mg, 32
percent for placebo) and without aura (37 percent for 70 mg, 51 percent for 140 mg, 25
percent for placebo) [57]. Adverse effects were mild and similar between groups.

We use erenumab at 140 mg as a subcutaneous injection once monthly in the abdomen,

thigh, or upper arm. Injection site reactions and constipation are the most common
adverse effects [58]. Hypertension, at times causing serious complications, has also been
reported [59]. Patients treated with erenumab should be monitored for the onset or
worsening of hypertension.

● Fremanezumab – Fremanezumab, a human monoclonal antibody that binds to both

isoforms of the CGRP ligand, is effective for prevention of episodic migraine [14,46]. One
trial randomly assigned 875 adults with episodic migraine in a [Link] ratio to subcutaneous
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fremanezumab 225 mg monthly for three months, a single dose of fremanezumab 675 mg
(intended to support a quarterly dose regimen), or placebo [46]. At three months
compared with placebo, the mean number of migraine days per month decreased by 1.5
in the fremanezumab monthly dose group and by 1.3 days in the single higher dose
group. The proportion of patients with at least a 50 percent reduction in the mean number
of monthly migraine days was 48 percent in the fremanezumab monthly dose group and
44 percent in the fremanezumab single higher dose group, compared with 28 percent for
the placebo group. At three months, patients assigned to placebo were rerandomized to
receive monthly or quarterly fremanezumab injections. At 12 months, the reduction in
baseline migraine burden was sustained in both monthly and quarterly fremanezumab
dosing regimens by 5.1 and 5.2 days per month, respectively [60].

The recommended dose of fremanezumab is 225 mg once monthly or 675 mg (given as

three consecutive injections of 225 mg each) every three months administered
subcutaneously in the abdomen, thigh, or upper arm. The most common adverse effects
are injection site reactions.

● Galcanezumab – Galcanezumab, a human monoclonal antibody that binds to the CGRP

ligand, is also effective for episodic migraine prevention, as demonstrated in several
placebo-controlled trials [61-63]. As an example, one of these trials randomly assigned 858
patients with episodic migraine to monthly subcutaneous galcanezumab 120 mg,
galcanezumab 240 mg, or placebo in a [Link] ratio [64]. At six months, the mean number of
migraine days per month decreased by 4.7 and 4.6 for the galcanezumab 120 and 240 mg
groups, respectively, compared with 2.8 days for the placebo group. In another trial of 462
migraine patients who were previously nonresponders to other standard preventive
therapies, those assigned to galcanezumab had fewer migraines compared with placebo
(4.1 versus 1.0 fewer migraine days per month) [63].

Galcanezumab treatment is started with a loading dose of 240 mg, given as two
consecutive doses of 120 mg each, followed by monthly doses of 120 mg, administered
subcutaneously in the thigh, upper arm, or buttocks. Injection site reactions were the
most common adverse events in clinical trials.

● Eptinezumab – Eptinezumab is a monoclonal antibody that binds to both isoforms of the

CGRP ligand. Data from randomized trials support its efficacy for prevention of migraine
[65-67]. The PROMISE-1 trial randomly assigned 888 patients in a [Link] ratio to
intravenous (IV) eptinezumab 30 mg, 100 mg, 300 mg, or placebo administered every 12
weeks for up to four IV doses [65]. The reduction in mean monthly migraine days from
baseline was approximately 4 for each of the eptinezumab dose groups, compared with
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approximately 3 days for the placebo group. In addition, a ≥50 percent reduction in
migraine days was achieved by more patients in the 100 mg and 300 mg eptinezumab
groups (50 and 56 percent, compared with 38 percent in the placebo group).

Eptinezumab given during a migraine may also shorten the time to headache resolution.
In a trial of 480 patients with frequent episodic migraine, those assigned eptinezumab 100
mg within six hours of migraine onset were likelier to be headache free at two hours than
those who received placebo (24 versus 12 percent; OR 2.27, 95% CI 1.4-3.7) [68]. In the
eptinezumab group, use of rescue medications within the subsequent 48 hours was less
frequent (35 versus 64 percent) and the interval to the next migraine headache was longer
(10 versus 5 days).

The recommended dose of eptinezumab is 100 mg given as an IV infusion over

approximately 30 minutes every three months [69]. The label notes that some patients
may benefit from a 300 mg dose. Adverse effects associated with eptinezumab include
upper respiratory tract infections, hypersensitivity, and fatigue.

● Rimegepant – Rimegepant is a small-molecule CGRP receptor antagonist administered

orally that is effective for migraine prevention. In a trial of 1591 patients with migraine,
those assigned to receive rimegepant 75 mg every other day for 12 weeks had a greater
reduction in migraine days per month than those assigned to placebo (-4.3 versus -3.5
days; difference -0.8 days, 95% CI -1.46 to -0.2) [70]. The response rate in those with ≥50
percent reduction in moderate or severe monthly migraine days was also higher among
those who received rimegepant (49 versus 41 percent).

● Atogepant – Atogepant is an oral small-molecule CGRP receptor antagonist that appeared

to be effective in clinical trials for migraine prevention [38,71]. In one study, 834 patients
with 4 to 14 migraine days per month received atogepant daily regimens from 10 mg once
daily up to 60 mg twice daily or placebo for 12 weeks. Atogepant treatment regimens were
associated with a reduction of migraines by nearly four days per month independent of
dose regimen [38]. However, adverse effects were more common in higher dose regimens
with nausea as the most common and none were serious. Another study of 873 patients
with episodic migraine similarly found that patients assigned to atogepant 10 mg, 30 mg,
or 60 mg once daily for 12 weeks had fewer migraine days per month than those assigned
to placebo [71]. In addition, patients assigned to each atogepant dosing regimen were
likelier to achieve at least a 50 percent reduction in the three-month mean number of
monthly migraine days (56 to 61 percent for atogepant regimens versus 29 percent for
placebo). In the initial trial and subsequent open-label extension, the most common
adverse events in patients taking atogepant were nasopharyngitis or sinusitis, upper
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respiratory tract infections, lower urinary tract infections, constipation, and nausea
[71,72].

Other agents — A number of other agents have been studied for migraine prevention.
Guidelines issued in 2012 from the AAN concluded that Petasites (butterbur) is effective for
migraine prevention [73]. In addition, the AAN noted that feverfew, magnesium, certain
nonsteroidal anti-inflammatory drugs, and riboflavin are probably effective.

● Botulinum toxin – Several randomized placebo-controlled trials have found no consistent,

statistically significant benefits for botulinum toxin injection in the treatment of episodic
migraine headache [74-76]. In addition, an evidence-based review published in 2008 by
the AAN concluded that botulinum toxin is probably ineffective for the treatment of
episodic migraine [77]. A 2010 systematic review reached a similar conclusion [11]. Given
these data, the use of botulinum toxin therapy is not recommended for the preventive
treatment of episodic migraine.

In contrast, there is evidence that botulinum toxin type A (onabotulinumtoxinA) injection is

effective for the treatment of chronic migraine (ie, headache on ≥15 days per month for at
least three months, with at least 8 of the 15 headaches per month fulfilling criteria for
migraine without aura). The utility of botulinum toxin injection for chronic migraine is
discussed separately. (See "Chronic migraine", section on 'Second- and third-line agents'.)

● Butterbur – An extract of butterbur (Petasites hybridus) root, a perennial shrub, is an

herbal medicine that is marketed as a food supplement in the United States. The extract
was previously registered as a licensed pharmaceutical medicine in Germany (Petadolex),
but the registration expired and it is no longer available in Germany [78]. At least two
small placebo-controlled clinical trials found some efficacy for Petasites extract in migraine
prevention [79-81]. In the larger of these studies, Petasites at a dose of 150 mg daily
(given in two divided doses) but not 100 mg daily was effective and well tolerated as
preventive therapy for migraine. Gastrointestinal upset, predominately burping, was the
most common side effect [81].

Butterbur contains pyrrolizidine alkaloids that are hepatotoxic and potentially

carcinogenic; they are removed from the commercially prepared Petasites root extract.
However, concerns persist due to the lack of long-term safety data and the absence of a
regulated product. Therefore, we no longer suggest the use of butterbur-containing
compounds.

● Coenzyme Q10 – Interest in coenzyme Q10 (CoQ10) for migraine treatment has been
sparked by the potential role of mitochondrial dysfunction in migraine pathogenesis
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[82,83]. In a small, randomized controlled trial of 42 patients with migraine, CoQ10 was
effective for migraine prevention; significantly more patients treated with CoQ10 (100 mg
three times daily) experienced a ≥50 percent reduction in attack frequency at three
months than patients treated with placebo (47.6 versus 14.4 percent) [84]. CoQ10
treatment was well tolerated. Larger clinical trials are needed to confirm the benefit of
CoQ10 for migraine prevention.

● Riboflavin – Riboflavin used to improve energy metabolism may support the contribution
of mitochondrial dysfunction in the development of migraine [83]. A randomized, double-
blind, placebo-controlled trial of 55 patients who were suffering from two to eight
migraines per month found that the administration of oral vitamin B2 (riboflavin) at a dose
of 400 mg/day compared with placebo resulted in a significantly higher proportion of
patients with greater than 50 percent improvement in the frequency of headaches (54
versus 19 percent), headache days (57 versus 15 percent), and the migraine index
(headache days and mean severity 39 versus 8 percent) [85]. The benefits only became
significant after three months of therapy. Riboflavin was well tolerated. Additional studies
are needed to confirm these results and to determine the optimum dose and patient
population most likely to benefit.

● Feverfew – Feverfew has been the herbal remedy most studied for the prevention of
migraine, but evidence regarding benefit is conflicting. A 2015 systematic review of
feverfew for migraine prevention found six randomized controlled trials with 561 patients
that met the inclusion criteria [86]. Four of the included trials [87-90] found that feverfew
was beneficial, while two trials [91,92] found no significant difference between feverfew
and placebo [86]. There were no major adverse effects associated with the use of feverfew.
A planned meta-analysis was not performed because of heterogeneity among the trials
and the absence of common outcome measures. All trials were considered to be at
unclear or high risk of bias due to small sample size. The review concluded that larger
rigorous trials are needed before firm conclusions can be drawn about the effectiveness of
feverfew for migraine headache.

● Magnesium – There is only limited evidence supporting magnesium supplementation for

migraine prevention in adults [93]. Several small randomized controlled trials using
variable formulations of oral magnesium produced mixed results, with three trials finding
a statistically significant benefit for magnesium [94-96], and one trial finding no benefit
[97]. Magnesium is typically used at 400 to 600 mg daily for migraine prevention [73].
Diarrhea and gastrointestinal discomfort were the most common side effects of
magnesium supplementation in these trials.

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● Melatonin – Small, short-term randomized controlled trials evaluating melatonin for

episodic migraine prevention have provided conflicting results. One such trial found that
melatonin 2 mg (extended release) was not more effective than placebo for reducing
headache frequency [98], while another trial reported that melatonin 3 mg (immediate
release) was more effective than placebo, and equally as effective as amitriptyline, for
reducing headache frequency [99].

● Nonsteroidal anti-inflammatory drugs – A number of older randomized controlled trials

have found that naproxen, a nonsteroidal anti-inflammatory drug (NSAID), is moderately
more effective than placebo for migraine prevention [100-104].

Guidelines issued in 2012 from the AAN concluded that the NSAIDs fenoprofen, ibuprofen,
ketoprofen, and naproxen are probably effective for migraine prevention [73]. This AAN
assessment was based upon an earlier systematic review and meta-analysis from the US
Agency for Health Care Policy and Research (AHCPR), which included 23 controlled trials of
10 different NSAIDs indexed from 1966 through 1996 [105]. The AAN identified no newer
randomized trials of NSAIDs for migraine prevention [73]. However, the AHCPR report
noted that the evidence was strongest for naproxen, with multiple placebo-controlled
trials showing a moderate reduction in headache symptoms [105]. Only one trial
supported the efficacy of ketoprofen [106], while the evidence was less certain for
fenoprofen. The AHCPR review identified no controlled trials of ibuprofen [105].

The use of NSAIDs for the treatment of acute migraine headache is discussed separately.
(See "Acute treatment of migraine in adults", section on 'Nonsteroidal anti-inflammatory
drugs'.)

● Pizotifen – A systematic review identified five placebo-controlled trials evaluating the

serotonin blocker pizotifen for migraine prevention [11]. Although the trials were
heterogeneous and could not be combined for meta-analysis, all five found that pizotifen
(starting at 0.5 mg daily, dosage range 1.5 mg daily to 3 mg daily in three divided doses)
was superior to placebo. Weight gain and sedation were the most common adverse
events in these trials. Pizotifen is not licensed for use in the United States.

● Simvastatin plus vitamin D – In a randomized controlled trial of 57 adults with episodic

migraine, in which participants continued their pre-study abortive and prophylactic
migraine medications, treatment with simvastatin (20 mg twice daily) plus vitamin D3
(1000 international units twice daily) was superior to placebo over a 24-week intervention
period for reduction in the number of days with migraine headache and some secondary
outcome measures [107]. The small size of this trial limits the strength of the findings.

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Nonpharmacologic interventions — Nonpharmacologic therapies with at least moderate-

quality evidence suggesting benefit for migraine headache prevention include aerobic exercise,
biofeedback, other forms of relaxation training, cognitive-behavioral therapies, acupuncture,
and transcutaneous electrical nerve stimulation [108-113]. Several of these are discussed in
greater detail in the sections that follow. (See 'Acupuncture' below and 'Neuromodulation'
below and 'Desensitizing triggers' below.)

Therapeutic lifestyle measures may be beneficial for controlling migraine, including good sleep
hygiene, routine meal schedules, regular aerobic exercise, and managing migraine triggers.
(See 'Lifestyle measures' above.)

Acupuncture — Some evidence suggests that classic acupuncture may have modest benefits
for migraine headache prevention, but data from clinical trials and systematic reviews are
mixed [114-117].

Acupuncture appears to be more effective than oral pharmacologic placebos, but probably not
more effective than sham needling or traditional medical therapy [118]. A randomized
controlled trial with 302 patients found that acupuncture was not more effective than sham
acupuncture (needling at points distant from "true" treatment points and using fewer needles)
in reducing migraine headaches [119]. However, both acupuncture and sham acupuncture were
significantly more effective in reducing days with headache than assignment to a wait-list
control group. In another randomized controlled trial with 794 patients available for intention-
to-treat analysis, the reduction in migraine headache days at 23 to 25 weeks for acupuncture,
sham acupuncture, or standard medical therapy groups (mean reduction 2.3, 1.5, and 2.1 days,
respectively) was statistically significant when compared with baseline, but nonsignificant
across treatment groups [120].

Although the explanation for these results is uncertain, one hypothesis is that, compared with
oral pharmacologic placebos, the placebo effect of sham acupuncture is enhanced by
contextual factors such as more elaborate treatment rituals and higher levels of attention and
physical contact [114,121,122]. Headache improvement related to nonspecific physiologic
effects of needling is another possible mechanism.

Neuromodulation

● Transcutaneous supraorbital nerve stimulation – Although data are limited, the

findings of a controlled trial conducted at five tertiary headache centers in Belgium
suggest that treatment with a supraorbital transcutaneous electrical nerve stimulator is
beneficial for patients with episodic migraine [123]. The trial randomly assigned 69 adults
with migraine (with or without aura) to active or sham stimulation for 20 minutes daily for
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three months. Exclusion criteria included the use of preventive treatment for migraine in
the three months prior to enrollment. At three months of treatment, the responder rate,
defined as the percentage of subjects with a ≥50 percent reduction in migraine days per
month, was significantly higher for the active stimulation compared with the sham
stimulation group (38.2 versus 12.1 percent), as was the mean reduction in monthly
migraine days (-2.1 versus +0.3 days). There were no adverse events in either group.
Limitations to this trial include small effect size, low patient numbers, and uncertainty in
concealing treatment allocation, given that active stimulation causes intense paresthesia.
The device used in this trial is approved for marketing in the United States, Canada,
Europe, and several additional countries.

● Transcranial magnetic stimulation – Limited observational evidence suggests that

single-pulse transcranial magnetic stimulation (sTMS) may be effective for migraine
prevention. An open-label, prospective study of subjects with episodic and chronic
migraine, with and without aura, assessed preventive (four pulses twice daily) and acute
(three pulses repeated up to three times for each migraine attack) sTMS treatment over a
12-week period [124]. During weeks 9 through 12, the mean reduction of headache days
was greater with TMS compared with an estimated placebo response derived from
historical data (-2.75 versus -0.63 days). Adverse events were infrequent, but included
lightheadedness, tingling, and tinnitus. In a meta-analysis of sham-controlled trials,
repetitive TMS over the dorsolateral prefrontal cortex was associated with reduced
functional disability and medication use but no improvement in pain intensity or headache
days [125]. sTMS received FDA approval for the acute and prophylactic treatment of
migraine in 2017.

● Vagal nerve stimulation – Neuromodulation by vagal nerve stimulation was associated

with reduced headache burden in observational studies for patients with episodic
migraine [126,127]. However, a clinical trial failed to confirm a benefit [128]. Additional
studies are needed to identify the role of this intervention for patients with migraine.

Desensitizing triggers — Traditional teaching is that avoidance of known migraine trigger

factors is a useful strategy for migraine prevention, but there is scant evidence to support this
approach. Some studies suggest that avoidance of trigger factors may paradoxically lead to
trigger sensitization, particularly since many known triggers cannot be completely avoided
[112,129]. These reports suggest that coping with headache triggers is potentially a more
valuable strategy than advice to avoid the triggers.

Learning to cope (LTC) is a behavioral method that involves graduated exposure to selected
headache triggers to promote desensitization [112]. In a small, single-center randomized
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controlled trial of patients with migraine or tension-type headache, the group assigned to the
LTC strategy had a significant reduction in both headache and medication use compared with
the control group, while the group assigned to trigger avoidance had no significant reduction in
headache or medication use [130]. A third group assigned to trigger avoidance plus cognitive-
behavioral therapy had a significant reduction in headaches but not medication use. These data
suggest that LTC is a better strategy than avoidance, but further study is needed to establish
whether it is an effective and practical approach to migraine prevention.

Other interventions not recommended

● Surgery – Results from a single-center trial suggested that surgical removal of muscle or
nerve tissue from headache "trigger sites" may be an effective treatment for select
patients with frequent migraine headache [131]. However, the trial results have been
received with skepticism by some headache experts due to small numbers and
methodologic flaws including poor case definition and inadequate controls [132]. In
addition, the proposed mechanism of benefit (trigger site deactivation) does not fit with
current pathophysiologic models of migraine. Given the methodologic flaws in the study
design [132,133], independent confirmation of benefit in more rigorous trials is needed. In
addition, only a minority of patients with frequent migraine (those with identifiable trigger
sites and a positive response to botulinum toxin injection) would appear to be candidates.

● Closure of right-to-left cardiac shunt – There is conflicting evidence regarding a possible

association of migraine with aura and right-to-left cardiac shunts in the setting of a patent
foramen ovale (PFO) or an atrial septal defect (ASD), as reviewed separately. (See
"Pathophysiology, clinical manifestations, and diagnosis of migraine in adults", section on
'Right-to-left cardiac shunt'.)

However, clinical trials have failed to show that PFO/ASD closure is beneficial for migraine.
The multicenter double-blind MIST trial enrolled 147 patients with a PFO who had frequent
migraine with aura that was refractory to two types of preventive medication [134]. At six
months, there was no difference between PFO device closure and sham treatment for the
primary end point of headache cure, which was achieved in each treatment group by three
patients (4 percent). Furthermore, the PFO closure group experienced more serious
adverse events than the sham group. The smaller open-label PRIMA trial, which was
stopped prematurely due to slow recruitment, compared PFO device closure with medical
management among subjects with migraine with aura [135]. At one year, there was no
difference between groups for reduction in monthly migraine days.

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In earlier reports, which were relatively small and largely retrospective, improvement in
migraine after device closure of a PFO or an ASD was noted in some (but not all) studies
[136-146]. Most of the patients treated with shunt closure were selected because of prior
cryptogenic stroke or paradoxical embolism. A majority of study patients were treated
with aspirin and clopidogrel, which may have reduced migraine frequency.

SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Migraine and other
primary headache disorders".)

INFORMATION FOR PATIENTS

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the
Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade
reading level, and they answer the four or five key questions a patient might have about a given
condition. These articles are best for patients who want a general overview and who prefer
short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more
sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading
level and are best for patients who want in-depth information and are comfortable with some
medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print
or e-mail these topics to your patients. (You can also locate patient education articles on a
variety of subjects by searching on "patient info" and the keyword(s) of interest.)

● Basics topics (see "Patient education: Migraines in adults (The Basics)")

● Beyond the Basics topics (see "Patient education: Migraines in adults (Beyond the Basics)"
and "Patient education: Headache treatment in adults (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

● Indications for preventive treatments – Migraine prevention therapy may be indicated

for those with migraine headaches that are frequent (eg, ≥4 headaches/month) or long-

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lasting (eg, ≥12 hours) and those that cause significant disability or diminished quality of
life. (See 'Indications' above.)

The goals of preventive therapy are to reduce the frequency, severity, and duration of
headaches, to improve treatment responsiveness of acute attacks, and to improve overall
function or reduce the risk of neurologic impairment. (See 'Indications' above.)

● Treatment approach – Preventive drugs are started at a low dose and the dose is
gradually increased until therapeutic benefit develops, the maximum dose is reached, or
side effects become intolerable. The choice among preventive agents should be
individualized according to patient-specific characteristics, comorbid conditions,
medication side effect profile, medication cost, and patient values and preferences.
Benefit is often noted for some agents by four weeks and can continue to increase for
three months or longer. (See 'Principles of preventive therapy' above.)

● Pharmacologic options – For patients with migraine who have an indication for
preventive therapy, we suggest treatment with one of the agents effective in controlled
trials rather than other options (Grade 2A). These agents include the following (see 'Our
approach' above):

• Metoprolol and propranolol (see 'Beta blockers' above)

• Amitriptyline and venlafaxine (see 'Antidepressants' above)
• Valproate and topiramate (see 'Anticonvulsants' above)
• Erenumab, fremanezumab, galcanezumab, eptinezumab, rimegepant, and atogepant
(see 'CGRP antagonists' above)

For patients who fail to improve despite an adequate trial of initial pharmacologic therapy,
we suggest switching to a migraine prevention medication from a different class (Grade
2C). (See 'Treatment failure' above.)

Alternative agents that may be effective and are generally well tolerated include the
calcium channel blockers verapamil and flunarizine, angiotensin-converting enzyme
inhibitors/angiotensin receptor blockers, and gabapentin. (See 'Calcium channel blockers'
above and 'ACE inhibitors/ARBs' above and 'Gabapentin' above.)

● Nonpharmacologic options – Nonpharmacologic measures that may be beneficial for

migraine headache prevention include aerobic exercise, biofeedback, other forms of
relaxation training, cognitive-behavioral therapies, acupuncture, and neuromodulation.
(See 'Nonpharmacologic interventions' above.)

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ACKNOWLEDGMENTS

The UpToDate editorial staff acknowledges Ashraf Sabahat, MD, Zahid H Bajwa, MD, and
Jonathan H Smith, MD, who contributed to earlier versions of this topic review.

Use of UpToDate is subject to the Terms of Use.

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Topic 3345 Version 86.0

Contributor Disclosures
Todd J Schwedt, MD, MSCI Equity Ownership/Stock Options: Aural Analytics [Neurology]; Nocira
[Headache]. Grant/Research/Clinical Trial Support: Amgen [Migraine/Headache]. Consultant/Advisory
Boards: AbbVie [Migraine/Headache]; Allergan [Migraine/Headache]; Amgen [Migraine/Headache];
Axsome [Migraine/Headache]; Biodelivery Science [Migraine/Headache]; Biohaven [Migraine/Headache];
Click Therapeutics [Migraine/Headache]; Collegium [Migraine/Headache]; Eli Lilly [Migraine/Headache];
Ipsen [Migraine/Headache]; Linpharma [Migraine/Headache]; Lundbeck [Migraine/Headache]; Novartis
[Migraine/Headache]; Satsuma [Migraine/Headache]; Tonix Pharma [Migraine/Headache]. All of the
relevant financial relationships listed have been mitigated. Ivan Garza, MD No relevant financial
relationship(s) with ineligible companies to disclose. Jerry W Swanson, MD, MHPE Other Financial
Interest: Elsevier [Honorarium as editor of texts about migraine]. All of the relevant financial relationships
listed have been mitigated. Richard P Goddeau, Jr, DO, FAHA No relevant financial relationship(s) with
ineligible companies to disclose.

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
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provided to support the content. Appropriately referenced content is required of all authors and must
conform to UpToDate standards of evidence.

Conflict of interest policy

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