PREVENTIVE TREATMENT OF MIGRAINE IN ADULTS

Authors
Zahid H Bajwa, MD
Jonathan H Smith, MD
Section Editor
Jerry W Swanson, MD, MHPE
Deputy Editor
John F Dashe, MD, PhD
All topics are updated as new evidence becomes available and our peer review
process is complete.
Literature review current through: Jul 2017. | This topic last updated: May 31,
2017.

INTRODUCTION — Migraine is a common disorder that affects approximately 17

percent of women and 6 percent of men. (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 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 [1-5]:

●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
●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 [1,6]:

●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 in the presence of uncommon migraine conditions
including [1]:

●Hemiplegic migraine (see "Hemiplegic migraine")

●Migraine with brainstem aura (see "Migraine with brainstem aura (basilar-type
migraine)")
●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", section on
'Migrainous stroke')

In addition, short-term preventive therapy during the perimenstrual period may be

useful for women who have menstrual migraine that occurs on a predictable
schedule. (See "Estrogen-associated migraine", section on 'Menstrual migraine'.)

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)

We suggest initial therapy with one of these agents for most patients with episodic
migraine (≤14 headache days per month) who have an indication for preventive
therapy (see 'Indications' above). Approximately 50 to 75 percent 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 [7]. The choice among
preventive agents of similar efficacy should be individualized according to patient-
specific characteristics, comorbid conditions, medication side effect profile, and
patient values and preferences [8-10].

In the absence of contraindications, we prefer amitriptyline, one of the beta blockers

(metoprolol, propranolol, or timolol), or topiramate for initial treatment. For women
of childbearing age, reasonable options include verapamil or flunarizine. In this
group, valproate is problematic because it is teratogenic and is associated with an
increased risk of birth defects. However, it can be considered for women utilizing
effective contraception if other options are not effective or tolerated.
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 stroke and other cardiovascular events compared
with other antihypertensive drugs in the primary treatment of hypertension. (See
"Choice of drug therapy in primary (essential) hypertension", section on 'Beta
blockers'.)
●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 and reduce
complications [8]:

●Start the drug at a low dose. Increase the dose gradually until therapeutic benefit
develops, 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 is often first noted at four weeks and can continue
to increase for three 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'.)
●Women of childbearing potential must be warned of any potential risks. Avoid
valproate for this group if possible, and choose the medication that will have the
least adverse effect on the fetus. (See "Headache in pregnant and postpartum
women", 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 headaches may improve independent of treatment. If the headaches
are 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. However, there is no good evidence from randomized
trials to guide therapy for patients who fail to respond to preventive therapy [4].

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 (form 1). The optimal
management of headache trigger factors is uncertain; traditional teaching
emphasizes avoidance, while newer approaches emphasize coping strategies. (See
'Coping with headache triggers' below.)

INTERVENTIONS — Pharmacotherapy and lifestyle measures are the mainstay of

migraine prevention.

Antihypertensives — Data from randomized clinical trials show that beta blockers,
particularly metoprolol, propranolol, and timolol, are effective for migraine
prevention [2,11]. Lower quality evidence suggests but does not establish that
calcium channel blockers, angiotensin converting enzyme (ACE) inhibitors, and
angiotensin II receptor blockers (ARBs) are 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 [12]. Patients assigned to blood pressure treatment had a
significant reduction in headache prevalence compared with placebo treatment
(odds ratio 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
[10,13,14]:

●Propranolol in two divided doses starting at 40 mg daily; dose range 40 to 160

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 [15];
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", section on 'Beta blockers'.)

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 widely used for migraine
prevention. However, the data supporting the efficacy of calcium channel blockers
are weak and conflicting [2,10]. 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 [16,17]. Nevertheless, one
author of this topic (ZB) frequently employs verapamil as the first choice for
preventive therapy based upon ease of use and a favorable side effect profile [18].
Flunarizine, a nonspecific calcium channel blocker, also has some evidence of efficacy
[3,10]. 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 [19].
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, placebo-controlled, 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 [20].
Another crossover trial of 60 patients from the same group of investigators reported
similar results with the ARB candesartan (16 mg once daily) [21]. 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.
They are not widely used for this purpose.

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, dosage range 20 to 50 mg at bedtime)
was effective for migraine prevention in four trials [10]. In other trials, the serotonin-
norepinephrine reuptake inhibitor venlafaxine (starting at 37.5 mg once a day,
dosage range 75 to 150 mg once a day) was also effective as prevention for migraine
[10]. Similarly, a 2012 guideline from the American Academy of Neurology (AAN)
concluded that amitriptyline and venlafaxine are probably effective for migraine
prevention [2].

The tricyclic antidepressants most commonly used for migraine prevention include
amitriptyline, nortriptyline, doxepin, and protriptyline. Amitriptyline is the only
tricyclic that has proven efficacy for migraine; there are insufficient data regarding
the other tricyclics [8].
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, a serotonin-norepinephrine reuptake inhibitor, is used by one author

(JS) for patients with migraine who have comorbid panic disorder, generalized anxiety
disorder, or social anxiety disorder. However, evidence of efficacy in migraine
prevention is weak [4,22]. (See "Pharmacotherapy for panic disorder with or without
agoraphobia in adults" and "Pharmacotherapy for generalized anxiety disorder in
adults" and "Pharmacotherapy for social anxiety disorder in adults".)

Anticonvulsants — The anticonvulsants sodium valproate and topiramate are more

effective than placebo for reducing the frequency of migraine attacks [10,23]. 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
[11,24-28]. 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 [24,25]. The following observations emerged from these trials [24,25]:

●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.
●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 [10].
Therefore, some experts recommend using topiramate at no more than
100 mg/day for migraine prevention.

Data from one trial suggest that topiramate has residual benefit for migraine that
persists for up to six months after the drug is discontinued [27].

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 [28]. However, topiramate is much more expensive than beta blockers
or valproate.

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 (odds ratio 2.74, 95% CI 1.48-5.08) [10]. Subsequent
systematic reviews reached similar conclusions [11,29].

Valproate can cause nausea, somnolence, tremor, dizziness, weight gain, and hair
loss. It is contraindicated in pregnancy because of teratogenicity. In addition,
valproate has been linked to lower intelligence quotient scores in children of women
who used valproate during pregnancy (see "Risks associated with epilepsy and
pregnancy", section on 'Effect of antiseizure drugs on the fetus'). Therefore, valproate
should not be used by women of childbearing age for headache prevention [30].

Gabapentin — A systematic review of five controlled trials found that gabapentin

was not efficacious for episodic migraine prevention in adults [31]. 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 [32].

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 [33]. In addition, the AAN noted that
feverfew, magnesium, certain nonsteroidal anti-inflammatory drugs, riboflavin, and
subcutaneous histamine 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 [34-36]. 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 [37]. A 2010 systematic review
reached a similar conclusion [10]. Given these data, the use of botulinum toxin
therapy is not recommended for the preventive treatment of episodicmigraine.

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 3 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 [38].
At least two small placebo-controlled clinical trials found some efficacy for Petasites
extract in migraine prevention [39-41]. 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 [41].

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) and riboflavin (see 'Riboflavin'
below) for migraine treatment has been sparked by the potential role of
mitochondrial dysfunction in migraine pathogenesis [42].

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) [43].
CoQ10 treatment was well tolerated. Larger clinical trials are needed to confirm the
benefit of CoQ10 for migraine prevention.

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 [44]. Four of the included trials [45-48] found
that feverfew was beneficial, while two trials [49,50] found no significant difference
between feverfew and placebo [44]. 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 [51]. Several small randomized
controlled trials using variable formulations of oral magnesium produced mixed
results, with three trials finding a statistically significant benefit for magnesium [52-
54], and one trial finding no benefit [55]. Diarrhea and gastrointestinal discomfort
were the most common side effects of magnesium supplementation in these trials.

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 [56], 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 [57].

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 [58-62].

Guidelines issued in 2012 from the AAN concluded that the NSAIDs fenoprofen,
ibuprofen, ketoprofen, and naproxen are probably effective for migraine prevention
[33]. 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
[63]. The AAN identified no newer randomized trials of NSAIDs for migraine
prevention [33]. However, the AHCPR report noted that the evidence was strongest
for naproxen, with multiple placebo-controlled trials showing a moderate reduction
in headache symptoms [63]. Only one trial supported the efficacy of ketoprofen [64],
while the evidence was less certain for fenoprofen. The AHCPR review identified no
controlled trials of ibuprofen [63].

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 [10]. Although the trials were
heterogeneous and could not be combined for meta-analysis, all five found that
pizotifen (in three divided doses starting at 1.5 mg daily, dosage range 1.5 to 3 mg
daily) 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.

Riboflavin — 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) [65]. 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.

Simvastatin plus vitamin D — In a randomized controlled trial of 57 adults with

episodic migraine, in which participants continued their prestudy abortive and
prophylactic migraine medications, treatment with simvastatin (20 mg twice daily)
plus vitamin D3 (1000 IU 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 [66]. The small size of this trial limits the strength
of the findings.

Calcitonin gene-related peptide antibodies — The calcitonin gene-related peptide

(CGRP) is a therapeutic target in migraine because of its hypothesized role in
mediating trigeminovascular pain transmission and the vasodilatory component of
neurogenic inflammation (see "Pathophysiology, clinical manifestations, and
diagnosis of migraine in adults", section on 'Role of calcitonin gene-related peptide').
Preliminary trials of several different monoclonal antibodies to CGRP have shown
promising results for migraine prevention [67-71]. Larger trials of longer duration are
needed to confirm the efficacy and safety of these agents.

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
[72-76]. Several of these are discussed in greater detail in the sections that follow.
(See 'Acupuncture' below and 'Transcutaneous nerve stimulation' below and 'Coping
with headache triggers' below.)

The benefit of migraine trigger site deactivation surgery is controversial. (See

'Surgery' below.)

There appears to be no benefit with closure of a right-to-left cardiac shunt in terms

of migraine prevention. (See 'Closure of right-to-left cardiac shunt' below.)

Therapeutic lifestyle measures may be beneficial for controlling migraine, including

good sleep hygiene, routine meal schedules, regular exercise, and managing
migraine triggers. (See 'Lifestyle measures' above.)

Acupuncture — Clinical trial evidence suggests that classic acupuncture for migraine
headache is more effective than oral pharmacologic placebos, but probably not more
effective than sham needling or traditional medical therapy [77-81]. The following
reports support this conclusion:

●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
[82]. 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 [83].

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 [80,84,85]. Headache improvement
related to nonspecific physiologic effects of needling is another possible mechanism.

Transcutaneous 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 [86]. The trial randomly assigned 69 adults with
migraine (with or without aura) to active or sham stimulation for 20 minutes daily for
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.

Coping with headache 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 [76,87]. These reports suggest that coping
with headache triggers is potentially a more valuable strategy than advice to avoid
the triggers.
Since there is an important behavioral component to many of the known headache
triggers, behavioral therapies are a potentially useful means of coping with these
triggers. One behavioral method, learning to cope (LTC), involves graduated
exposure to selected headache triggers to promote desensitization [76]. In a small,
single-center randomized 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 [88]. 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.

Surgery — Results from a single-center, blinded, randomized controlled trial suggest

that surgical removal of muscle or nerve tissue from headache "trigger sites" may be
an effective treatment for select patients with frequent migraine headache [89].
However, the trial results have been received with skepticism by some headache
experts due to methodologic flaws including poor case definition [90]. In addition,
the proposed mechanism of benefit (trigger site deactivation) does not fit with
current pathophysiologic models of migraine.

The trial screened 317 patients with frequent moderate to severe migraine headache
(with or without aura) and found 76 who were eligible for inclusion, which required
both identification of the predominant "trigger site" where "migraine pain started
and settled consistently" and a positive response to botulinum toxin injection at the
trigger site [89]. Eligible patients, who had approximately 10 migraine headaches per
month at baseline, were randomly assigned to treatment with either actual surgery
(n = 49) or sham surgery (n = 26) at their trigger site.

Actual surgery involved removal of glabellar muscles from patients with frontal
trigger sites, removal of a segment of the zygomaticotemporal branch of the
trigeminal nerve from those with temporal trigger sites, and resection of a segment
of the semispinalis capitis muscle (under general anesthesia) from those with occipital
trigger sites [89]. The sham surgery group had exposure but not resection of the
muscles and nerves through a similar incision. At 12 months, actual surgery was
statistically superior to sham surgery on a variety of outcome measures, including
complete elimination of migraine headaches (57 versus 4 percent), and a reduction
of ≥50 percent in the migraine headache index, calculated by multiplying the
headache frequency, intensity, and duration (84 versus 58 percent) [89]. Confidence
intervals were not reported. Improvement with surgery was independent of trigger
site. The surgery was well tolerated.

Given the methodologic flaws in the study design [90,91], 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, as reviewed
separately. (See "Pathophysiology, clinical manifestations, and diagnosis of migraine
in adults", section on 'Right-to-left cardiac shunt'.)

However, there is evidence from randomized controlled trials that PFO/ASD closure
is not an effective treatment 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 [92]. Patients with prior stroke or
transient ischemic attack were excluded. During a three-month healing phase,
patients in both treatment groups received aspirin plus clopidogrel. 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 [93]. At
one year, there was no statistically significant difference between groups for
reduction in monthly migraine days.

In earlier reports, which were relatively small and largely retrospective, improvement
in migraine after device closure of a PFO or an atrial septal defect was noted in some
(but not all) studies [94-104]. 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.

In summary, the observational studies that reported improvement in migraine with

PFO closure were flawed, and the only randomized controlled trial found no benefit.

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".)

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

SUMMARY AND RECOMMENDATIONS

●The main indications for migraine prevention therapy are frequent or long lasting
migraine headaches and migraine headaches that cause significant disability or
diminished quality of life. In addition, preventive migraine therapy is indicated to
reduce the risk of neurologic damage in the presence of uncommon migraine
conditions including hemiplegic migraine, migraine with brainstem aura, and
migraine with prolonged aura. (See 'Indications' above.)
●Therapeutic lifestyle measures including good sleep hygiene, routine meal
schedules, regular exercise, and management of migraine triggers are appropriate
for all patients with migraine. (See 'Our approach' above.)
●For patients with migraine who have an indication for preventive therapy, we
suggest treatment with one of the agents effective in controlled trials (Grade 2A),
a list which includes the following (see 'Our approach' above):
•Metoprolol, propranolol, and timolol (see 'Beta blockers' above)
•Amitriptyline and venlafaxine (see 'Antidepressants' above)
•Valproate and topiramate (see 'Anticonvulsants' above)
Alternatives include calcium channel blockers including verapamil and flunarizine,
which may be less effective but are generally safe and well tolerated. (See 'Calcium
channel blockers' above.)
We suggest selecting one of these agents as initial therapy according to individual
patient characteristics and preferences, medication side effect profile, and the
presence of comorbid conditions including but not limited to hypertension,
depression or mood disorder, epilepsy, insomnia, obesity, and Raynaud
phenomenon. (See 'Choosing pharmacologic therapy' 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.)
●Preventive migraine therapy requires a sustained commitment on the part of the
patient and physician to achieve benefit. In general, 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. Benefit
is often noted first at four weeks and can continue to increase for three months.
(See 'Principles of preventive therapy' above.)
 ●Nonpharmacologic measures that may be beneficial for migraine headache
prevention include aerobic exercise, biofeedback, other forms of relaxation
training, cognitive-behavioral therapies, acupuncture, and transcutaneous
electrical nerve stimulation. (See 'Nonpharmacologic interventions' above.)

ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge

Ashraf Sabahat, MD, who contributed to an earlier version of this topic review.