Migraine Headache Prophylaxis

Introduction

Migraine headaches affect approximately 1% of the US population and can be a debilitating condition.
Goals of migraine prophylaxis:
- Reduction in headache severity and frequency.
- Improved response to acute treatment without need for escalation.
- Fewer days with disability.
- Improvement in quality of life.
- Empowerment of patients with a sense of control over the condition.
Indications for preventive therapy:
- Frequent headaches (4 or more headaches per month; 3 or more significant headaches per month; 2 or more severe headaches per month).
- Headaches significantly interfere with daily activities despite acute treatment.
- Failure of or contraindication to acute treatments.
- Overuse of acute treatments (10 or more days per month for ergot derivatives, triptans, opioids, combination analgesics, and a combination of drugs from different classes that are not individually overused; 15 or more days per month for nonopioid analgesics, acetaminophen, and nonsteroidal anti-inflammatory drugs).
- Patient preference.
First-line medications:
- Propranolol
- Metoprolol
- Topiramate
- Divalproex
- Valproate
- Calcitonin gene–related peptide receptor antagonists (limited by cost and insurance coverage)
Second-line medications:
- Amitriptyline (greater number of adverse events)
- Venlafaxine (less supporting evidence)
OnabotulinumtoxinA (Botox) injection is approved for chronic migraine prophylaxis.
- As effective as other medications, well-tolerated, and has lower discontinuation rates.
Common migraine triggers:
- Alcohol
- Anxiety
- Dehydration
- Excessive caffeine
- Eye strain
- Hunger
- Sleep deprivation
- Stress
Nonpharmacologic therapies:
- Cognitive behavior therapy
- Acupuncture
- Neural stimulators
- Exercise (supported by varying levels of evidence)
Alternative agents:
- Feverfew
- Magnesium
- Melatonin (have shown effectiveness and are generally well tolerated)
Migraine headaches typically are unilateral and pulsating and may be associated with photophobia, phonophobia, nausea, or vomiting.
One-third of patients will have preceding aura.
The prevalence of migraines in the US population is approximately 1%; about 7% of patients with the diagnosis meet criteria for chronic migraine.
Approximately 2.5% of patients with episodic migraine will develop chronic migraine.

Pharmacologic Therapy

Beta Blockers

Established efficacy in episodic and chronic migraine treatment.
Most widely used drug class for migraine prophylaxis.
Propranolol and metoprolol are more effective than placebo for the prevention of episodic migraine.
- Propranolol resulted in an average reduction of 1.5 migraine days per month at 8 weeks of treatment.
- Appeared to be as effective as flunarizine and topiramate for chronic migraine treatment. (Flunarizine is not approved by the US FDA).
Other beta blockers (atenolol, bisoprolol, and timolol) have shown weak evidence of benefit in migraine prophylaxis.

Antiepileptics

Topiramate, divalproex, and valproate are considered first-line medications for migraine headache prophylaxis.
Topiramate:
- Associated with a significantly greater reduction in migraine frequency compared with placebo in several RCTs.
- Twice as likely as placebo to reduce monthly migraine days by 50%, with an average reduction of 1.5 headache days at 8 weeks of treatment.
- Studies comparing topiramate and propranolol have shown similar effectiveness and reductions in migraine frequency.
Valproate and Divalproex:
- Effective in reducing migraine frequency compared with placebo.
- Appear to be equally or slightly less effective compared to topiramate and propranolol.

Antidepressants

Amitriptyline and venlafaxine are commonly used for migraine prevention.
Amitriptyline:
- Considered probably effective for migraine prophylaxis.
- More effective than placebo in achieving at least a 50% reduction in monthly migraine days, with an average reduction of monthly headache days of 1.24.
- May be superior to other oral agents for prophylaxis, but this was not confirmed in head-to-head clinical trials.
- Appears to be as effective as propranolol or topiramate but is associated with a greater number of adverse events.
Venlafaxine:
- Also considered effective; however, its supporting data are less robust.
- Results in fewer adverse events than amitriptyline.

Angiotensin Receptor Blocker

Candesartan is effective for the prevention of episodic and chronic migraines.
Several RCTs have demonstrated superiority of candesartan over placebo, with one trial showing a reduction of 5 headache days per month.
At least noninferior to propranolol.
A systematic review found a reduction in headache frequency of 1.12 days per month in patients taking candesartan compared with placebo.
The 2023 US Department of Veterans Affairs/US Department of Defense clinical practice guidelines on headache management cite strong evidence for candesartan in episodic migraine prevention.

OnabotulinumtoxinA

OnabotulinumtoxinA (Botox) is approved by the FDA for chronic migraine prophylaxis.
Phase III Research Evaluating Migraine Prophylaxis Therapy study:
- Patients received 31 injections in seven head and/or neck muscles every 12 weeks for five treatments.
- Resulted in a greater than 50% reduction in monthly headache days for 50% of patients after one treatment cycle and an additional 10% to 15% of patients after second and third treatment cycles.
At least as effective as topiramate and had a significantly lower discontinuation rate.
Follow-up analyses:
- Appear to have sustained benefits, with 74% of patients still responding to treatments at 2 years.
The effectiveness in the prevention of episodic migraines is not well established.

Calcitonin Gene–Related Peptide Antagonists

Calcitonin gene–related peptide (CGRP) is released during migraine headaches.
Antibodies to this peptide or its receptor decrease vasodilatory effects on meningeal vessels and neuronal modulation of pain that can induce migraine.
Erenumab (Aimovig) is a large-molecule monoclonal antibody to this receptor that was approved by the FDA for migraine prophylaxis in 2018.
Fremanezumab (Ajovy) and galcanezumab (Emgality), two monoclonal antibodies targeting the CGRP molecule, were approved for this indication shortly thereafter.
Atogepant (Qulipta) and rimegepant (Nurtec) are examples of medications approved for migraine prophylaxis that antagonize the receptor.
A systematic review and network meta-analysis of 74 trials that included more than 32,000 patients showed that medications targeting the CGRP pathway (with gepants and topiramate) have the highest efficacy for migraine prevention and the lowest incidence of adverse events compared with beta blockers, amitriptyline, and topiramate.
Recent updates to guidelines from the European Headache Federation and AHS advise that these should be considered first-line medications for episodic or chronic migraine prevention, particularly if the patient cannot tolerate or has contraindications to other first-line drugs.
These drugs are well-tolerated and at least as effective as standard prophylactic treatments.
However, they are costly and restricted by insurance coverage to third- or fourth-line medications for episodic or chronic migraine prevention in the United States and Europe.

Nonpharmacologic Therapy

Migraine Trigger Avoidance

Physicians should recommend identification and management of migraine triggers.
Common causes include alcohol, anxiety, dehydration, excessive caffeine, eye strain, hunger, sleep deprivation, and stress.
There is insufficient evidence to recommend avoidance of specific foods.
Weight management is recommended, given that increased frequency and severity of migraines are associated with a higher body mass index.
Several studies have shown high- and low-impact exercise to be noninferior to some pharmacotherapies.

Behavior Therapies

Cognitive behavior therapy, biofeedback, mindfulness training, and relaxation training are not recommended for migraine prophylaxis due to a lack of high-quality supporting evidence, but these treatments are generally accepted as effective and should be considered for all patients.
Patient access to physicians who teach these therapies may be limited; however, once the techniques are learned, patients can implement them independently.

Other Therapies

A 2016 systematic review demonstrated that acupuncture can reduce headache frequency when combined with usual symptomatic treatment (number needed to treat = 4).
Acupuncture is at least noninferior to pharmacotherapy based on moderate-quality evidence (risk ratio of 1.24 at 3 months and 1.11 at 6 months, both favoring acupuncture).
Fewer participants dropped out of the studies due to adverse effects from acupuncture compared with medication.
Acupuncture may be a reasonable prophylactic therapy for patients who experience adverse drug effects or prefer to avoid the use of pharmacotherapy.
Multiple types of neural stimulation devices, differing in treatment mechanism and location applied, have been studied for migraine prophylaxis.
A systematic review of RCTs investigating neural stimulators found that some devices appeared to be effective based on poor-quality evidence (limited by poor control of confounders and short-term follow-up).
Three devices are currently approved by the FDA; however, their use is limited by high cost and lack of insurance coverage in the United States.

Supplements

Supplements such as coenzyme Q10, magnesium, feverfew, melatonin, and vitamin B2 have been proposed as effective migraine prevention treatments with relatively favorable safety profiles.
Combination supplements (e.g., feverfew, 5-hydroxytryptophan, magnesium) have been studied in Europe with promising results and are available in the United States.
Although butterbur has been established as effective for migraine prevention, its safety profile is concerning due to the possible presence of hepatotoxic and carcinogenic pyrrolizidine alkaloids, even if it reportedly has been purified.
In 2018, a review of over-the-counter butterbur products found that seven of 21 tested products had toxic levels of pyrrolizidine alkaloids.
Six of the products had no detectable levels of the active ingredient petasin.
The 2012 AAN/AHS guideline on complementary treatments for migraine prevention was retired in 2015 due to concerns about the safety of butterbur.
Overall, studies on supplements continue to have small sample sizes and short durations.
Although the safety of supplements is generally accepted, they are not regulated in the United States.
Physicians should ensure that patients understand the limitations of the evidence for supplements while remembering that they are generally well-tolerated and frequently more affordable than other options for migraine prophylaxis.

Special Populations

Pregnant and Breastfeeding Patients

The increase in estrogen levels that occurs during pregnancy improves control of migraines without aura but has been associated with increased frequency of migraine with aura.
Family physicians should carefully distinguish between migraines and dangerous causes of headaches in pregnant patients and counsel them about when to seek emergency care.
Prophylactic pharmacotherapy for migraines in pregnancy is highly controversial and poorly studied.
Use of CGRP antagonists for migraine prophylaxis in pregnancy is not recommended by any guidelines, and these drugs should be discontinued at least 5 to 6 months before attempting to conceive.
Retrospective and prospective studies on use of onabotulinumtoxinA for migraines in pregnancy have shown no adverse pregnancy outcomes, manufacturers recommend against its use in pregnant patients.
Neural stimulators have not been extensively studied in pregnant patients with migraines. Use of neural stimulators in pregnancy theoretically is low risk, but more research is needed.
Breastfeeding patients have fewer restrictions on options for migraine prophylaxis than pregnant patients. Propranolol, amitriptyline, magnesium, and onabotulinumtoxinA can be used safely.
There is insufficient evidence regarding the safety of the use of CGRP antagonists in breastfeeding patients and breastfed infants.

Patients With Menstrual Migraines

Menstrual migraines affect fewer than 10% of menstruating patients with migraine and are thought to be related to the decrease in estrogen level during the menstrual cycle.
Short-term daily use of frovatriptan (Frova) or naratriptan (Amerge) in addition to naproxen (5 to 7 days, starting 2 days before menses) can be beneficial.
Studies are currently ongoing to investigate the use of CGRP antagonists for menstrual migraines.
Continuous combined hormonal contraceptives are a common and effective method of suppressing hormone cycling, thereby limiting menstrual migraines. Use of this option should be limited to patients with migraine without aura. Migraine with aura is a contraindication to use of combined hormonal contraceptives.

Children and Adolescents

The 2019 AAN/AHS guideline on pharmacotherapy for migraine prevention in children found insufficient evidence to recommend pharmacotherapy. Notably, nonpharmacotherapies and lifestyle changes appear to have more benefit for children.
The guideline recommends that children and adolescents with migraine be screened for comorbid mood and anxiety disorders and that clinicians discuss management options with patients with these disorders.

Key Clinical Recommendations

Prophylactic therapy for migraines should be considered in patients who meet indication criteria per the American Headache Society clinical practice guideline.
Propranolol, metoprolol, topiramate, divalproex, valproate, and calcitonin gene–related peptide antagonists are effective for migraine prevention and should be offered as first-line treatments.
OnabotulinumtoxinA is an effective treatment for chronic migraine prophylaxis.
Nonpharmacologic treatments such as exercise, cognitive behavior therapy, biofeedback, mindfulness training, and relaxation training are effective options for migraine prevention.
The addition of acupuncture to usual symptomatic treatment can decrease migraine headache frequency.