Preventive Agents for Migraine: Focus on the Antiepileptic Drugs
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What You Need to Know About Migraine and Seizures
Migraine attacks and seizures are both events related to the brain, but exactly how the two are related to each other is something that experts are still trying to unravel.
“There times when a patient experiences an event, and it’s not immediately apparent if they’ve had a seizure or a migraine,” says Lauren Doyle Strauss, DO, a headache specialist and an assistant professor at Wake Forest Baptist Health in Winston Salem, North Carolina.
“That’s because there can be an overlap in some of the ways that people describe both of those problems,” Dr. Strauss explains.
There is evidence that the two disorders are associated with each other: The prevalence of migraine in children with epilepsy — which causes seizures — is estimated at 8 to 24 percent, which is approximately double the risk found in the general population, according to a paper published in the Journal of Headache and Pain.
What Is Migralepsy?
Migralepsy is an older term that has been used to describe when a person has both migraine and epilepsy, says Strauss. The term was first used in a paper published in 1960 to describe a condition in which “ophthalmic migraine with perhaps nausea and vomiting was followed by symptoms characteristic of epilepsy,” according to a paper published in the Journal of Headache Pain.
This type of seizure, which is triggered by a migraine attack with aura, is considered a rare but real complication of migraine, according to the International Headache Society (ICHD-3).
A Seizure Can Be Part of Epilepsy or Migraine
To better understand the connection between migraine and seizures, it’s helpful to understand what a seizure is, says Strauss. “You could describe it as a sudden surge of electrical activity in the brain,” she says.
Johns Hopkins Medicine defines a seizure as “a burst of uncontrolled electrical activity between brain cells (also called neurons or nerve cells) that causes temporary abnormalities in muscle tone or movements (stiffness, twitching, or limpness), behaviors, sensations, or states of awareness.”
People are diagnosed with epilepsy after they have had two or more unprovoked seizures, according to the Centers for Disease Control and Prevention (CDC).
RELATED: Seizures Not Caused by Epilepsy
Seizures Are Different Depending on Where They Occur in the Brain
There are two categories of seizures: generalized seizures, which affect both sides of the brain, and focal seizures (also called partial seizures), which take place is just one part of the brain, according to the CDC.
Depending on which part of the brain is affected, that's the area that will manifest symptoms, explains Strauss.
“For example, if the area of the brain that controls your language is affected, then that makes sense that your language may not be normal during the seizure. It could cause you to stutter or have trouble with your words,” she says. Similarly, if someone had a seizure in the area of the brain that controls your vision, that may correlate with visual symptoms, says Strauss.
Just because the seizure begins in one part of the brain doesn’t mean it stays there. “A seizure can start in one area of the brain and can quickly spread to other areas or across the entire brain,” she says.
People can experience a seizure in a lot of different ways, says Strauss. “You can have a change in your awareness; others may notice that you're staring. You may have amnesia, where you forget or are unaware there's been a change in your surroundings, or you don’t even know that a seizure happened,” she says.
“Your whole body can shake — that's called a grand mal seizure, and it’s often what people think about when they when they think of seizure. You can also have shaking in one arm or just one leg,” says Strauss.
RELATED: What to Do and What Not to Do if You Witness a Seizure
Can a Migraine Attack Cause Someone to Have a Seizure?
“We don’t fully understand what provokes a migraine and what provokes a seizure; it could be possible that something provokes both,” says Strauss.
Headaches can occur on their own and be unrelated to seizures, or a headache can be a symptom that happens before, during, or after a seizure, says Strauss. “We use the terms ‘preictal,’ which is before the seizure, ‘ictal,’ which is during the seizure, and ‘postictal,’ which is after the seizure,” she says.
Preictal and ictal headaches are relatively rare and usually don’t last long, according to the Epilepsy Foundation. Headaches that occur after a seizure are more common. A survey of 372 patients attending an epilepsy clinic found that 45 percent of them had experienced a postictal headache, and more than 1 in 5 always had one.
Is It a Migraine Attack or a Seizure?
“If a person is having migraine symptoms that aren’t responding to migraine therapies, and they have neurologic symptoms associated with the headaches, it’s reasonable to take a step back and say, ‘Are we sure these are migraines?’” says Strauss.
If you have a grand mal seizure, it’s usually clear that it’s a seizure, she says. “However, with focal seizures or partial seizures or complex partial seizures, these more subtle seizures where it's only affecting one part of the brain, it can be difficult to always know: Is this migraine, or is this seizure?”
There are some differences between headaches associated with seizures and the headache of a migraine attack that can help a doctor distinguish between the two, says Strauss, including the following:
- Prodrome symptoms can occur with either migraine or seizure. The prodrome is the warning that the migraine is going to happen, says Strauss. “In migraine, a person can have nausea, vomiting, weakness, stiff neck, paleness, and yawning, which can occur starting hours or days before the pain portion of the migraine.” In seizures, symptoms such as a “rising” feeling in the stomach, perception of certain smells, feeling of numbness, or a sense of déjà vu may precede motor symptoms.
- Automatism suggests a seizure. “In seizures, we can have something called an automatism, which is where there can be involuntary movements. This can include things like chewing movements or a movement that looks like you’re picking lint off your clothes — fidgety movements,” Strauss says. There aren’t automatisms with migraine, and so if you experience that, it suggests a seizure-related headache, she says.
- Visual disturbances may differ between migraine and seizure. You can experience visual disturbances in both seizures and migraine, says Strauss. “When it’s related to seizures, these are usually going to be very short in duration, and patients will describe things like circular colored scribbles that can move horizontally to the other side,” she says. Visual disturbances in migraine emerge more gradually, over minutes to hours, and are most commonly scintillating scotoma, where the disturbance stays in one spot and grows from that point, says Strauss.
- Memory loss usually suggests a seizure. “Headaches can cause confusion in both cases, but if the person actually can’t remember that the headache happened, we would think it may have been related to seizure,” says Strauss. However, transient global amnesia, or a sudden, temporary episode of memory loss, can occur with migraine.
- Onset of headache differs between migraine and seizure. “Migraine pain tends to come on gradually, whereas a headache related to seizure can come on very suddenly; it hits you hard and fast,” says Strauss.
- Unusual tastes or smells suggest a seizure. If a person has a strange smell or a strange taste along with the headache, that would be consistent with seizure and not usually migraine, says Strauss. “People will describe smells like burnt fire or bananas or they taste something metallic. It’s usually something strange and noxious, and no one else around them is smelling it or tasting it,” she says.
Can Hemiplegic Migraine Cause Seizures?
Sporadic hemiplegic migraine is a very rare form of migraine that has different associated genes with it, says Strauss. There have been reports that some people can have alterations in consciousness with this type of migraine, according to the National Organization for Rare Disorders (NORD).
It’s not certain how many people have this type of migraine, but studies in a population of Denmark estimated it affects about 1 in 10,000 people in the general population.
This type of migraine can have a very long aura phase — lasting anywhere from an hour to as long as a week. The hallmark symptom of hemiplegic migraine is weakness on one side of the body that happens just before or during the headache phase. In severe attacks, hemiplegic migraine can cause confusion, memory loss, personality or behavioral changes, seizures, and even coma, according to MedlinePlus.
Patients can sometimes be concerned about whether they have hemiplegic migraine or seizures — there is some interesting overlap, says Strauss. “We have to be careful we’re not missing a diagnosis of seizure; just because you have headache and you have weakness with it, you don’t want to assume that it’s hemiplegic migraine,” she says.
For example, people who have focal seizures that affect the motor control center in the brain when the seizure ends can get weakness in their arm, their leg, or both, says Strauss.
The best way to distinguish between hemiplegic migraine and seizures is to do an electroencephalogram (EEG).
Topamax for Migraine Prevention
Topamax (topiramate) is an anticonvulsant, meaning it's used to prevent seizures for people who have epilepsy and related disorders. It's also prescribed to prevent certain types of migraine headaches for adults and adolescents age 12 and older. A migraine is more severe than a headache and often lasts longer (up to 72 hours).
Because it has been proven in studies to be highly effective as a prophylactic migraine medication, it is approved for this use by the U.S. Food and Drug Administration (FDA), as well as by drug regulatory agencies in numerous other countries.
Besides Topamax, topiramate is sold under two other brand names—Qudexy XR and Trokendi XR—and is also available in a generic form.
Medications for Preventing Episodic Migraines
How It Works
Topamax blocks channels in the body that deliver electrical impulses to nerve, muscle, and brain cells. This may enhance the activity of a neurotransmitter known as gamma-aminobutyric acid (GABA), which is involved in regulating motor control, vision, and anxiety.
Researchers aren't certain how this process works to prevent migraine headaches or seizures, but it does so effectively, and it is considered safe.
Topamax prevents episodic migraines, meaning those that occur fewer than 15 days per month.
Topamax is available in 25 milligram (mg), 50 mg, 100 mg, and 200 mg tablets. It's also available in 15 mg and 25 mg capsules that contain a powdered form of the medication. The capsules can be swallowed whole or opened up and sprinkled onto soft food.
Based on research comparing the effectiveness of 100 mg vs. 200 mg per day of Topamax for preventing migraines, the target dose for most people is 100 mg (50 mg taken twice a day). The dosage range recommended in guidelines set by the American Headache Society and the American Academy of Neurology is 25 mg to 200 mg per day.
If your healthcare provider prescribes this medication for you, they likely will start you on a relatively low dose of 25 mg once a day for a week, and then increase your dose by 25 mg per week until you're taking a therapeutic dose.
Gradually titrating the dose of Topamax in this way will help to prevent side effects. It takes time for Topamax to work when you first start using it. It may take 1 month for your migraine attacks to become less frequent and 2 to 3 months for Topamax to become fully effective.
Likewise, if you've been taking Topamax and would like to quit, it's advisable to first consult with your healthcare provider, who will guide you through tapering down your dose to lower the risk of side effects that can occur if you stop cold turkey. Withdrawal seizures are a potential side effect of stopping abruptly, even if you do not have epilepsy.
How to Avoid Side Effects
- It is important to have adequate fluid intake to minimize the risk of kidney stones.
- Topamax may make you sweat less, making you more likely to get heatstroke. Avoid doing things that may cause you to overheat, such as hard work or exercise in hot weather, or using hot tubs. When the weather is hot, drink a lot of fluids and dress lightly. If you overheat, quickly look for a place to cool down and rest.
Topamax has been shown to cause a host of side effects. Most are mild to moderate in severity and temporary; as your body gets used to the medication, some side effects are likely to disappear. Call your healthcare provider if they don't.
There also are a number of potentially serious side effects associated with Topamax, all of which you should let your healthcare provider know about right away.
Numbness, tingling, or burning in hands or feet
Slowed reaction time/muscle weakness
Uncontrollable shaking or eye movements
Changes in ability to taste food
Teary or dry eyes
Pain in bones or muscles
Back or leg pain
Heavy menstrual bleeding or missed periods
Blurred or double vision/loss of vision
Eye pain or redness
Chills/low body temperature
Difficulty concentrating, confusion, memory problems
Trouble speaking or thinking of specific words
Loss of coordination
Pounding or irregular heartbeat
Shortness of breath/trouble breathing/fast, shallow breathing
Inability to respond to things around you
Excessive tiredness or insomnia
Nausea/diarrhea/vomiting/loss of appetite
Stomach, back, or side pain
Bloody, cloudy, or foul-smelling urine/frequent, difficult, or painful urination
Reduced ability to sweat and increased body temperature
Serious skin reactions (Steven-Johnson's Syndrome or Toxic Epidermal Necrolysis)
In addition to side effects, Topamax has been linked to several serious complications:
- Metabolic acidosis: This is a build-up of acid in the blood caused by an imbalance of bicarbonate in the body. Symptoms include nausea, vomiting, fast breathing, and lethargy. This condition may cause kidney stones, so it's important to drink plenty of fluids while on Topamax. If left untreated, metabolic acidosis can lead to coma and death. It most often occurs in children 15 and under.
- Glaucoma: Symptoms usually appear within a month of starting treatment and may be recognized by the sudden blurring of vision, eye pain, redness, and abnormally dilated pupils.
- Kidney failure: This is most likely to occur in folks over age 65 who have an underlying kidney disorder. For this reason, people taking Topamax should have routine kidney function tests.
- Suicidal thoughts and behavior
- Cognitive/neuropsychiatric reactions: use caution when operating machinery, including cars. Depression and mood problems may occur. Alcohol or marijuana (cannabis) can worsen these effects.
It's possible that taking Topamax along with other medications could lead to problems. Your healthcare provider will ask you what other drugs you take before prescribing Topamax; this means over-the-counter and prescription medications, as well as nutritional and herbal supplements and natural remedies.
The medications most likely to interact with Topamax include:
- Diamox (acetazolamide)
- Lanoxin (digoxin)
- Microzide, Oretic (hydrochlorothiazide)
- Lamictal (lamotrigine)
- Lithobid (lithium)
- Medications for motion sickness, ulcers, or urinary problems
- Fortamet, Glucophage, and others (metformin)
- Other anti-seizure medications
Taking Topamax may decrease the effectiveness of hormonal contraceptives. If you become pregnant while taking the drug, call your healthcare provider right away.
Over-the-counter Migraine Medications
Be careful about using Topamax if you're trying to conceive, are expecting a baby, or you're breastfeeding.
Migraine Medications That Are Safe During Pregnancy
Among others who should be cautious about taking Topamax or who shouldn't take it all are those who have:
- Metabolic acidosis
- Kidney stones
- A history of self-harm or suicidal thoughts
- Conditions in which bones are brittle or soft (osteopenia, osteomalacia, or osteoporosis
- Any condition that affects breathing, such as asthma
- Depression or another mood disorder
- A growth problem
A Word From Verywell
If your healthcare provider prescribes Topamax for you, it's vital that you take it correctly and report any side effects without delay.
And do not stop taking Topamax abruptly, unless there is an urgent need and you are under the guidance of your healthcare provider. For most people who get episodic migraine headaches, Topamax is safe, effective, and may well be the key to having fewer headaches per month.
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Silberstein SD. Topiramate in Migraine Prevention. Headache. 2005 Apr;45 Suppl 1:S57-65. doi: 10.1111.j.1526-4610.2005.4501005.x
U.S. Food and Drug Administrtion. Medication Guide: Topamax. https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020505s038s039,020844s032s034lbl.pdf
1. About topiramate
Topiramate is a medicine used to treat epilepsy. These are also called anti-epileptic medicines.
It can also be taken to prevent migraine.
This medicine is only available on prescription. It comes as tablets or capsules.
2. Key facts
- It's usual to take topiramate twice a day. You can take it with or without food.
- Common side effects of topiramate include feeling sleepy, dizziness, diarrhoea and feeling sick. These are usually mild and go away by themselves.
- If taking topiramate for epilepsy, it usually takes a couple of weeks for it to work. If taking topiramate to prevent migraines, it can take up to 3 months for it to work fully.
- Topiramate is also called by the brand name Topamax.
3. Who can and can't take it
Topiramate can be taken by adults and children aged 2 years and over.
Topiramate is not suitable for some people.
Tell your doctor before starting the medicine if you:
- have ever had an allergic reaction to topiramate or any other medicines in the past
- have kidney problems, especially kidney stones
- have a blood disorder called acute porphyria
- have a history of blood metabolic acidosis, where the body produces too much acid or cannot remove it properly
- have eye problems, especially glaucoma
- have liver problems
- need to take high doses of vitamin C or calcium supplements
- are pregnant
4. How and when to take it
Topiramate is a prescription medicine.
It's important to take it as instructed by your doctor.
How much will I take?
How much you take will depend on what you're using topiramate for.
It's usual to start topiramate at a low dose of 25mg to 50mg a day.
This will be increased over several weeks to the usual doses for:
- epilepsy - 100mg to 200mg a day, taken as 2 doses
- epilepsy (if you take another epilepsy medicine with topiramate) - 200mg to 400mg a day, taken as 2 doses
- migraines - 50mg to 100mg, taken as 2 doses
In children, the dose of topiramate will depend on the weight of your child.
Your doctor will be able to give the right dose to your child.
How to take it
It's usual to take topiramate twice a day. You can take topiramate at any time of day, but try to take your doses at the same time each day.
Try to space your doses evenly through the day. For example, first thing in the morning and in the evening.
Topiramate tablets can be taken with or without food. Swallow your tablets whole with a glass of water. Do not chew them.
Topiramate capsules can be swallowed whole or they can be opened and sprinkled on a teaspoon of soft food, like porridge or yoghurt.
What if I forget to take it?
If you forget to take a dose, take one as soon as you remember.
If it's less than 8 hours before the next dose is due, it's better to leave out the missed dose and take your next dose as normal.
Do not take 2 doses at the same time to make up for a forgotten dose.
If you forget doses often, it may help to set an alarm to remind you.
You could also ask your pharmacist for advice on other ways to help you remember to take your medicine.
What if I take too much?
Ask your doctor for advice straight away. Taking too much topiramate by accident can lead to serious side effects.
Urgent advice: Call your doctor straight away if you take too much topiramate and:
- feel dizzy or sleepy
- have difficulties talking
- have blurred vision
- have stomach pain
- feel confused or your normal behaviour changes
7. Pregnancy and breastfeeding
There's no firm evidence that topiramate is harmful to an unborn baby.
But for safety your doctor will only advise you to take it in pregnancy if the benefits of the medicine outweigh the risks.
It's important for you and your baby to stay well during pregnancy.
If you become pregnant while taking topiramate, tell your doctor or nurse straight away.
Do not stop taking it without talking to your doctor first.
If you have epilepsy, it's very important that it's treated during pregnancy as fits (seizures) can harm you and your unborn baby.
If you're pregnant, or trying to get pregnant, and taking topiramate, you're recommended to take a higher dose of folic acid, a vitamin that helps your baby grow normally.
Your doctor might prescribe a high dose of 5mg a day for you to take while you're trying to get pregnant and during the first 12 weeks of pregnancy.
For more information about how topiramate can affect you and your baby during pregnancy, read the leaflet about the best use of medicines in pregnancy (BUMPS).
Topiramate and breastfeeding
If your doctor or health visitor says your baby is healthy, topiramate can be taken while you're breastfeeding.
Topiramate passes into breast milk, but it's unlikely to cause any side effects in your baby.
It's been linked with side effects in very few breastfed babies.
If you notice that your baby's not feeding as well as usual, or seems unusually sleepy, or you have any other concerns about them, talk to your pharmacist, health visitor or doctor as soon as possible.
Non-urgent advice: Talk to your doctor if you're:
- trying to get pregnant
8. Cautions with other medicines
There are some medicines that may interfere with the effects of topiramate.
Tell your doctor if you're taking any of these medicines:
- medicines used to treat diabetes, such as metformin, glibenclamide and pioglitazone
- medicines used to treat depression or anxiety, such as venlafaxine and amitriptyline
- medicines for heart or blood pressure, such as diltiazem, hydrochlorothiazide and propranolol
- antipsychotic medicines, such as risperidone
- any other epilepsy medicines
Mixing topiramate with herbal remedies and supplements
Do not take St John's wort, the herbal remedy for depression, while you're being treated with topiramate.
This is because St John's wort may make topiramate less effective.
Tell your doctor or pharmacist if you're taking any other medicines, including herbal remedies, vitamins or supplements.
9. Common questions
Epilepsy migraine medication
There’s nothing more frustrating than being told to "take a painkiller and drink a glass of water” when you have a migraine. After all, if it was that simple, you probably wouldn’t be here.
We know that finding the right migraine treatment takes time. There’s no quick fix and there's no one-size-fits-all solution. And what makes it even harder is that there's not a lot of information out there to help you figure it out.
That’s why Cove exists. Our mission is to make it easier for migraine sufferers to get ongoing support and access to the care they need. And that's why we're breaking down the most common migraine treatments and explaining them to you in a language that actually makes sense. So let’s talk about anticonvulsant medications, a preventive treatment that’s been proven to work for migraine headaches.
As you might know (or suspect), anticonvulsants are a prescription medication that’s most commonly prescribed for the treatment of epilepsy. However, the anti-epileptic drug also helps prevent migraines.
While it’s not entirely understood why that’s the case, some researchers believe epilepsy and migraines share some of the same traits.
There are two types of anticonvulsants used to treat migraines:
Anticonvulsants are preventive medication, which means it takes about one to two months for them to start working to prevent migraines (as opposed to acute medication like triptans and NSAIDs which begin working to relieve migraine pain within two hours).
According to the NIH, an anticonvulsant can be considered successful if your migraine frequency is reduced by 50%. (This is why using migraine tracking tools is so important.)
You might be doing the 50% math now and thinking that you'd like that number to be much closer to 100%. We wish that was the case, too. But until science finds a cure that prevents migraines 100% of the time, we recommend speaking to your doctor about combining your preventive treatment with acute treatment.
You should take your anticonvulsant daily with water, with or without food. The daily dosage varies by person, so make sure to ask your doctor what’s right for you and then it as prescribed.
Anticonvulsants are a good treatment option for migraine sufferers who suffer from several migraines a month, who need additional treatment support beyond acute medication, or who can’t take acute treatment at all.
While anticonvulsants are generally considered safe and effective, there are people who should consider other migraine treatments.
- People are currently using certain types of birth control (some anticonvulsants might prevent the birth control from working)
- People who are pregnant or planning to become pregnant
- People who haven't tried any acute migraine treatments before
That said, everyone’s different and we recommend speaking with your doctor about your specific needs and concerns. (We know, you’d prefer to get all the answers now, but were committed to providing you with the best migraine care, and in this case, that means not making any claims we can’t stand by.)
While anticonvulsants are generally considered safe, like many medications, there are possible side effects.
These are the most common side effects:
- attention issues
- drowsiness and fatigue
- kidney stones
- weight loss
Note that you cannot abruptly stop taking anticonvulsants as it puts you at risk of having rebound seizures. So talk to your doctor before decreasing your usage.
You should immediately contact your doctor if you experience signs of serious allergic reaction, dizziness, or difficulty breathing while taking these medications.
Weighing Depakote® (a.k.a. Epilim®) vs. Topamax®? They’re both effective migraine prevention treatments, but they do have different side effects. Depakote® can cause hair thinning, nausea, tremors, and weight gain. You also shouldn’t take Depakote® if you’re considering getting pregnant, because it can cause birth defects.
That’s not to say that Topamax® (a.k.a. topiramate) doesn’t have side effects. Its side effects can include numbness, tingling, difficulty finding your words, and, in some cases, weight loss.
Reading through these two descriptions might feel like you have to pick the lesser of the two evils. Dr. Philip Bain, a headache expert and Cove medical advisor, says it’s important to note that these side effects “are seen more at the doses that are used for seizures (e.g. 500 mg – 2000mg daily) than those producing benefit for migraine headache (usually 250 -1000mg max).”
Since migraines are so personal, it’s difficult to know in advance what medication will work best for you. Discuss your options with your doctor, make the best choice you can, and don’t be afraid to make changes if something doesn’t feel right.
Cove currently offers topiramate, which is considered to be the most effective FDA-approved anticonvulsant for migraine treatment.
We know this can feel like a lot of information and you may still have questions. That’s why we work with licensed physicians to help each and every person find a treatment that'll actually work for them (and provide ongoing support for as long as you need it). If you’d like to speak to a Cove physician about your headaches, simply click here.
If you'd like to keep exploring your options, we recommend reading about other migraine treatments: triptans, NSAIDs, beta blockers, and antidepressants.
The information provided in this article is not a substitute for professional medical advice, diagnosis, or treatment. You should not rely upon the content provided in this article for specific medical advice. If you have any questions or concerns, please talk to your doctor.
Topiramate is an oral medications used used to prevent migraine headaches. Call your doctor right away if you have a fever or you do not sweat during activities or in warm temperatures. Patients who take this drug may be at a greater risk of having thoughts or actions of suicide. The risk may be greater in people who have had these thoughts or actions in the past. Call the doctor right away if signs like low mood (depression), nervousness, restlessness, grouchiness, panic attacks, or changes in mood or actions are new or worse. Call the doctor right away if any thoughts or actions of suicide occur. Very bad and sometimes deadly liver problems have happened with this drug. Call your doctor right away if you have signs of liver problems like dark urine, feeling tired, not hungry, upset stomach or stomach pain, light-colored stools, throwing up, or yellow skin or eyes. This drug may cause very bad eye problems. If left untreated, this can lead to lasting eyesight loss. You can read more about topiramate’s side effects, warnings, and precautions here. Full prescribing information for topiramate is available here. You are encouraged to report negative side effects of prescription drugs to the FDA. Visit MedWatch: https://www.fda.gov/Safety/MedWatch/default.htm or call 1-800-FDA-1088.
Photo by Frank Park on Unsplash.
Antiepileptic drugs (AEDs) are frequently used as a preventive treatment for the management of migraine. Topiramate (TPM) and valproic acid (VPA) are 2 AEDs that have demonstrated efficacy in reducing the frequency of migraine attacks, and both carry US Food and Drug Administration indications for the prevention of episodic migraine, based on level A evidence.1
“Topiramate is the most common migraine preventive in the world, used on a prescription basis, and valproic acid would be the next best choice,” Peter MacAllister, MD, told Neurology Advisor. Dr MacAllister is Medical Director of the New England Institute for Neurology and Headache and Chief Medical Officer of the New England Institute for Clinical Research and Ki Clinical Research in Stamford, Connecticut. “Other AEDs that are used for migraine but show less evidence include zonisamide and levetiracetum,” he stated.
According to Matthew Robbins, MD, a clinical neurologist at Weill Cornell Medicine and New York-Presbyterian Medical Center in New York City, “Lamotrigine may have a niche for migraine with aura specifically, but not migraine overall.” He told us that while gabapentin (GBP) is prescribed frequently, data supporting its use as a migraine preventive agent is not as strong as that of other AEDs. This was reinforced in a 2019 review by Parikh and Silberstein1 stating that, “clinical evidence has suggested that GBP is not beneficial in migraine prevention.” Similarly, they reported that oxcarbazepine “is likely ineffective for migraine prophylactic treatment.”
Levetiracetam has provoked interest compared to other AEDs, due to a unique mechanism of action of binding to the synaptic vesicle protein SV2A, and thereby blocking neuronal hyperexcitability of voltage-gated N-type calcium channels that have been implicated in migraine pathogenesis.1 Small studies of levetiracetam have indicated good efficacy and tolerability, although the evidence from multiple trials is conflicting and somewhat inconclusive, strongly suggesting the need for intensive large-scale study of this agent.1
Why AEDs Work for Migraine
Epilepsy and migraine show a 2-fold higher than average risk for comorbidity, supporting the use of AEDs for treatment of both conditions; however, the mechanisms of these drugs in migraine are not well understood.1-3 It is thought that AEDs are able to block excitation leading to cortical spreading depression that may be a central precipitator in migraine through actions on voltage- and receptor-gated ion channels that promote stabilization of neuronal membranes.1 A unique property of TPM is that it inhibits neuro-excitatory glutamate receptor activity at the cellular level, which has a pronounced effect in migraine as well as in epilepsy. A study in 2017 by Heberstreit and May3 in 27 patients found that TPM reduced blood oxygen level-dependent responses in several areas of the brain responsible for pain transmission, while also improving functional connectivity between the thalamus and somatosensory regions.3 These theories all draw an incomplete picture of how TPM works in migraine, and none have been proven as yet.
Adverse Effects of AEDs
Dr MacAllister observed that most AEDs work well when used with other agents used to treat migraine. “The biggest problem is adherence,” he said, “For example, 70% or more of migraineurs on [TPM] … stop it on their own within 6 months, due to side effects.” Spritzer et al1 reported that, “it is not uncommon in clinical practice for TPM when used for migraine prevention to be given once daily, often at night, in an attempt to improve tolerability.”
The known adverse effects of TPM include a range of cognitive symptoms, such as difficulties with word-finding, concentration, memory, and slowed mental processing, as well as fatigue, dizziness, somnolence, and suicidal ideations.1 More systemic responses may include renal calculi, hypokalemia, and metabolic acidosis, with disturbances to taste (often leading to weight loss) and vision.
Zonisamide has demonstrated efficacy that is potentially comparable to TPM, with improved tolerability. The main side effects appear at doses of 200 mg/d to 500 mg/d, accumulated for more than 24 months.1 These include decreased appetite and weight, memory loss, and reduced hemoglobin levels. Rapid titration of zonisamide was also associated with potential risks for Stevens-Johnson syndrome or toxic epidermal necrolysis.
Contrary to weight loss observed with other AEDs, VPA, given at doses of 500 mg/d to 1000 mg/d for migraine prevention often produced weight gain, along with nausea, fatigue, dizziness and tremor.1 More serious effects include the potential for pancreatitis and liver failure.
Levetiracetam is associated with adverse effects, such as mood swings including irritability, hostility, and hyperactivity, as well as dizziness and somnolence.1
Of greater concern are the substantial teratogenic risks with all AED use. Both VPA and TPM have been shown to produce major congenital abnormalities that are likely to occur within the first 60 days after conception occurs.1 Unless used as a last resort, VPA and TPM “should both be avoided as a preventive agent in women of childbearing age, given their potential for birth defects and other consequences,” Dr Robbins cautioned. If AEDs are used, he noted, then contraception is highly recommended, although at higher doses, TPM can also interact negatively with contraceptives.4
“The decision to use an antiepileptic agent, or any migraine preventive agent, is based on individual factors, including side effects, route of administration, comorbidities, and most importantly for women, pregnancy considerations,” Dr Robbins said. “There is very little evidence that one preventive agent is really better than another,” he added.
1. Parikh SK, Silberstein SD. Current status of antiepileptic drugs as preventive migraine therapy. Curr Treat Options Neurol. 2019;21:16.
2. Spritzer SD, Bravo TP, Drazkowski JF. Topiramate for treatment in patients with migraine and epilepsy. Headache. 2016;561081-1085.
3. Heberstreit JM, May A. Topiramate modulates trigeminal pain processing in thalamo-cortical networks in humans after single dose administration. PLoS One. 2017;12(10):e0184406.
4. Reimers A, Brodtkorb E, Sabers A. Interactions between hormonal contraception and antiepileptic drugs: Clinical and mechanistic considerations. Seizure. 2015;28:66-70.
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