Valproic acid (Depakene) and its related compound divalproex (Depakote, Depakote ER) are approved by the U.S. Food and Drug Administration (FDA) for migraine prevention.

These drugs are also used for management of epilepsy and bipolar disorder (formerly referred to as manic depression). In this context, the term valproic acid will also include its related compound divalproex.

Indications

Migraine prevention is a strategy that involves lifestyle modifications, such as getting enough sleep and avoiding dietary triggers. If you have more than four days of migraines per month, or if you are taking migraine medication more than once per week on average, then you and your healthcare provider need to talk about the possibility of using prescription medication for migraine prophylaxis as well. 

Valproic acid is one of several medications indicated for migraine prevention. Antidepressants, as well as some other anticonvulsants, are used off-label for this purpose. Several injectable medications described as anti-CGRP drugs were approved for migraine prophylaxis in 2018. 

Your healthcare provider will discuss several things with you in deciding if you would benefit from preventative medications and whether valproic acid would be right for you. Factors such as your overall health, your migraine frequency, your improvement with medications taken during an attack (abortive medications), and whether you experience side effects or have contraindications to abortive medications are all taken into account.

How It Works

Valproic acid increases the level of gamma-Aminobutyric acid (GABA), an inhibitory neurotransmitter in the brain. It does this by blocking the enzyme that normally breaks down GABA. This neurotransmitter reduces the nerve cell excitability and firing that normally leads to a seizure. 

A few possible mechanisms through which valproic acid may prevent migraines. Migraines are associated with an alteration in the electrical activity of the brain described as cortical spreading depression. One mechanism by which valproic acid may thwart migraines is by preventing cortical spreading depression, possibly due to its effect on GABA. 

Valproic acid may also inhibit neuron excitation mediated by glutamate and NMDA receptors.

One of the theories that has been examined is whether valproic acid has an effect on blood flow in the brain because vasodilation (widening of the blood vessels) may play role in migraines. Also, medications such as beta-blockers reduce migraine frequency by affecting blood flow. However, research suggests that valproic acid does not have a major effect on blood flow in the brain, which goes against this theory. 

Dosing

Valproic acid is approved at a lower dose when used for migraine prevention than when used for bipolar disorder or for epilepsy.

  • Valproic acid (Depakene): The starting dose is 250 mg twice a day; dose can be increased to 500 mg twice a day if need be.Divalproex sodium (Depakote): The starting dose is 250 mg twice per day, which may be increased as needed (with supervision from your healthcare provider) up to a maximum of 1,000 mg per day. An extended release form also exists (Depakote ER) with a starting dose of 500 mg per day. It can be increased to 1,000 mg per day if necessary.

Side Effects

Valproic acid is known for having a number of side effects when used at high doses. When used at relatively low doses for migraine prevention, these side effects are less common. Nevertheless, you should be aware of them.

Common side effects of valproic acid include:

  • NauseaSleepinessTrouble sleepingTremorDizzinessWeight gainHair loss

If you experience any of the common side effects of valproic acid, they may resolve after some time. But some side effects, such as weight gain, tend to persist.

Discuss your side effects with your healthcare provider as you decide whether continuing valproic acid is right for you. 

Adverse Events 

Some effects of valproic acid are less common but more concerning.

Anticonvulsants can cause a serious skin reaction called Stevens-Johnson syndrome (SJS), which starts with a rash and causes severe peeling of the skin, resembling a severe burn. This condition can worsen rapidly, causing dehydration and even death if not treated. If you develop a rash while using valproic acid, get medical attention promptly. 

Valproic acid can also cause liver failure or pancreatitis. These conditions can cause skin bruising, abdominal pain, nausea, vomiting, jaundice (yellow color of the skin and/or eyes), or problems with your blood count. Be sure to call your practitioner if you experience any of these symptoms. 

This medication has also been associated with suicidal ideation, which is a state of thinking about or planning suicide. If you develop these symptoms, discuss them with your healthcare provider or call a suicide hotline immediately. Be aware that suicidal ideation is caused by a chemical imbalance and professional intervention can help you keep these symptoms under control.

Interactions

Valproic acid may interact with certain drugs, such as aspirin, Elavil (amitriptyline), Pamelor (nortriptyline), the carbapenem class of antibiotics, other anti-seizure medications, and Coumadin (warfarin).

Be sure to inform your healthcare provider and pharmacist of all the medications you are taking, including prescription and over-the-counter medicine. Remember to include supplements, herbs, and vitamins on your medication list as well.

Since valproic acid may cause drowsiness, be sure to let your healthcare provider know if you consume alcohol or take medications that make you sleepy, such as narcotic pain medication, cold or allergy drugs, or sleep aids.

Contraindications

Valproic acid is contraindicated during pregnancy. It has been linked to birth defects (especially neural tube defects, like spina bifida) as well as lower intelligence quotient (IQ) scores in babies of mothers who took this medication during pregnancy. 

Because the nervous system begins to develop very early during pregnancy, often before a woman knows that she is pregnant, it is not recommended that valproic acid be taken by women of childbearing age.

You cannot use valproic acid if you have any of the following health conditions:

  • Liver disease
  • An allergy to valproic acid
  • Urea cycle disorder (for example, ornithine transcarbamylase deficiency—a rare genetic disease)

A Word From Verywell

Migraine prophylaxis relies on taking medication consistently. If you have frequent migraines, prophylaxis can give you a break from having too many episodes, providing you with comfort and avoidance of symptoms. Prophylaxis can also allow you to reduce the frequency and amount of medication you take for an acute migraine attack, which helps prevent side effects including medication overuse headaches.