What is oxcarbazepine used for. How does oxcarbazepine work. What are the main side effects of oxcarbazepine. Is oxcarbazepine safe during pregnancy. Can oxcarbazepine interact with other medications.

What is Oxcarbazepine and How Does it Work?

Oxcarbazepine is an anticonvulsant medication primarily used to treat and prevent certain types of seizures. It belongs to a class of drugs known as dibenzazepine carboxamides. Once ingested, oxcarbazepine is metabolized in the liver to form an active compound called MHD (monohydroxy derivative), which also contributes to its antiseizure effects.

How exactly does oxcarbazepine work? While the precise mechanism is not fully understood, it is believed to function by stabilizing nerve membranes and reducing repetitive firing of neurons. This action helps to control abnormal electrical activity in the brain that can lead to seizures.

Key Points About Oxcarbazepine’s Mechanism:

• Metabolized to active compound MHD in the liver
• Stabilizes nerve membranes
• Reduces repetitive neuronal firing
• Controls abnormal brain electrical activity

Approved Uses and Off-Label Applications of Oxcarbazepine

The U.S. Food and Drug Administration (FDA) has approved oxcarbazepine for several specific uses in epilepsy treatment. What are the main indications for oxcarbazepine? The medication is primarily used to:

1. Treat and prevent partial seizures in adults, either as monotherapy or in combination with other antiepileptic drugs
2. Serve as sole therapy for partial seizures in children 4 years and older
3. Function as adjunctive therapy for partial seizures in children 2 years and older

Beyond its FDA-approved uses, oxcarbazepine may sometimes be prescribed off-label for other conditions. These off-label applications can include:

• Treatment of bipolar disorder
• Management of migraine headaches

It’s important to note that while these off-label uses exist, they are not officially sanctioned by the FDA and should be discussed thoroughly with a healthcare provider.

Advantages and Formulations of Oxcarbazepine

Oxcarbazepine offers several advantages as an antiepileptic medication. What makes oxcarbazepine a preferred choice for some patients and healthcare providers? Here are some key benefits:

• Versatility in treatment options (monotherapy or combination therapy)
• Availability in both tablet and suspension forms for easier administration
• No apparent development of dependence or tolerance
• Generic versions available, potentially reducing costs

Oxcarbazepine is marketed under brand names such as Trileptal and Oxtellar. The availability of generic versions can make this medication more accessible and affordable for many patients.

Common Side Effects and Safety Considerations

Like all medications, oxcarbazepine can cause side effects. What are the most common adverse reactions associated with oxcarbazepine use? The central nervous system (CNS) is often affected, leading to symptoms such as:

• Dizziness
• Sleepiness and fatigue
• Difficulty concentrating
• Slowed information processing
• Coordination problems
• Speech and language difficulties

Other frequently reported side effects include:

• Nausea and vomiting
• Double vision
• Headache
• Nystagmus (rapid involuntary eye movements)

While rare, serious allergic reactions such as anaphylaxis can occur. Patients should be aware of the signs of severe allergic reactions and seek immediate medical attention if they occur.

Hyponatremia Risk

One significant safety concern with oxcarbazepine is the potential for hyponatremia (low sodium levels in the blood). This condition can be life-threatening if severe. Hyponatremia typically develops within the first three months of treatment but can occur at any time. Regular monitoring of sodium levels may be necessary, especially in patients at higher risk.

Drug Interactions and Special Populations

Oxcarbazepine can interact with various medications and may require special considerations in certain patient populations. What should patients and healthcare providers be aware of regarding drug interactions and special populations?

Drug Interactions

Oxcarbazepine can inhibit certain liver enzymes, particularly CYP2C19 and CYP3A4/5. This inhibition may affect the plasma levels of other medications metabolized by these enzymes. Notable interactions include:

• Oral contraceptives (potentially reduced effectiveness)
• Felodipine (possible increased plasma levels)

Special Populations

Certain groups may require special consideration when using oxcarbazepine:

• Patients with kidney disease may need dosage adjustments
• Individuals with a history of mental health issues should be monitored closely
• Patients of Asian descent may have a higher risk of serious skin reactions (Stevens-Johnson syndrome and toxic epidermal necrolysis) if they carry the HLA-B 1502 allele

Pregnancy and Breastfeeding Considerations

The use of oxcarbazepine during pregnancy and breastfeeding requires careful consideration. Is oxcarbazepine safe for use during pregnancy? There is limited data on human pregnancy outcomes, but animal studies have shown potential risks including:

• Higher rates of structural abnormalities
• Increased risk of spontaneous abortions
• Growth retardation
• Fetal malformations
• Decreased fetal body weight

Oxcarbazepine and its active metabolite can cross the placenta. Given its structural similarity to carbamazepine (a known teratogen), oxcarbazepine should only be used during pregnancy if the potential benefits outweigh the risks.

For breastfeeding mothers, it’s important to note that oxcarbazepine and its active metabolite are found in breast milk. However, the effects on breastfed infants are not well understood. Mothers should discuss the risks and benefits with their healthcare provider before breastfeeding while taking oxcarbazepine.

Discontinuation and Withdrawal Considerations

Proper discontinuation of oxcarbazepine is crucial to avoid potential complications. How should oxcarbazepine be discontinued? The medication should be withdrawn gradually unless there is an emergency situation. Abrupt discontinuation has been associated with:

• Increased seizure frequency
• Risk of status epilepticus (prolonged seizures)

Healthcare providers typically develop a tapering schedule to safely reduce the dosage over time. This gradual approach helps minimize the risk of withdrawal symptoms and seizure recurrence.

Monitoring and Long-Term Management

Effective use of oxcarbazepine requires ongoing monitoring and management. What aspects of treatment should be regularly assessed? Key areas for monitoring include:

• Serum sodium levels, especially in the first three months of treatment
• Liver and kidney function
• Mental health status, including mood changes and suicidal thoughts
• Effectiveness in seizure control
• Occurrence and severity of side effects

Long-term management may involve periodic adjustments to the dosage or treatment regimen based on the patient’s response and tolerability. Regular follow-up appointments with the healthcare provider are essential for optimal management of epilepsy with oxcarbazepine.

Suicidality Risk

Like other antiepileptic drugs, oxcarbazepine has been associated with an increased risk of suicidal thoughts and behaviors. Patients and their caregivers should be alert to any changes in mood or behavior and report these promptly to their healthcare provider.

Patient Education and Support

Effective use of oxcarbazepine relies heavily on patient education and support. What information should patients receive about their treatment? Key points to cover include:

• Proper dosing and administration instructions
• Potential side effects and when to seek medical attention
• Importance of regular follow-up appointments
• Need for gradual discontinuation if stopping treatment
• Potential interactions with other medications or supplements
• Lifestyle considerations (e.g., avoiding alcohol, operating machinery)

Support groups and educational resources can be valuable for patients and families dealing with epilepsy. These resources can provide additional information, coping strategies, and a sense of community for those affected by seizure disorders.

Future Directions and Research

As with many medications, research into oxcarbazepine continues to evolve. What areas of research are currently being explored? Some key areas of interest include:

• Further understanding of the precise mechanism of action
• Exploration of potential new indications
• Development of extended-release formulations
• Investigation of genetic factors influencing response and side effects
• Long-term safety and efficacy studies

Ongoing research may lead to improved treatment strategies, better patient selection criteria, and potentially new applications for oxcarbazepine in the future.

Comparative Efficacy and Alternative Treatments

Oxcarbazepine is one of several medications available for treating epilepsy. How does it compare to other antiepileptic drugs? The choice of medication often depends on various factors, including:

• Type and frequency of seizures
• Patient’s age and overall health
• Potential side effects and drug interactions
• Cost and availability

Some alternative treatments for epilepsy include:

1. Other antiepileptic medications (e.g., carbamazepine, valproic acid, levetiracetam)
2. Dietary therapies (e.g., ketogenic diet)
3. Surgical interventions
4. Neurostimulation devices

The most appropriate treatment approach should be determined through careful consultation between the patient and their healthcare provider, considering individual circumstances and preferences.

Oxcarbazepine: 7 things you should know

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Medically reviewed by Carmen Fookes, BPharm. Last updated on Dec 30, 2022.

1. How it works

• Oxcarbazepine is an anticonvulsant that reduces the frequency of certain types of seizures.
• Once in the body, it is metabolized in the liver to another compound, called MHD, which also helps to reduce seizure frequency. The exact way oxcarbazepine and its active metabolite exert their antiseizure activity is not known; however, it is thought to be by stabilizing nerve membranes, which reduces repetitive firing.
• Oxcarbazepine belongs to the class of medicines known as dibenzazepine carboxamides.

2. Upsides

• May be used for the treatment and prevention of partial seizures in adults, either alone or in addition to other anti-seizure medicines.
• May be used as the sole therapy for the treatment and prevention of partial seizures in children over the age of four, or in addition to other medications for epilepsy in children over the age of two.
• It may be used off-label (not an FDA-approved use) to treat other conditions such as bipolar disorder or migraine.
• Oxcarbazepine does not appear to cause dependence or tolerance, although a slow withdrawal is recommended to avoid precipitating seizures. The abuse potential of oxcarbazepine is unknown.
• Oxcarbazepine is available in tablet form or as a suspension.
• Brand names of oxcarbazepine include Trileptal and Oxtellar.
• Cost-saving, generic oxcarbazepine is available.

3. Downsides

If you are between the ages of 18 and 60, take no other medication or have no other medical conditions, side effects you are more likely to experience include:

• Central nervous system (CNS) side effects, including a slowing in the speed of information processing, difficulty with concentration, dizziness, speech and language problems, sleepiness and fatigue, and coordination difficulties including muscle movement disorders and gait disturbances.
• Nausea, vomiting, double vision, headache, and nystagmus (rapid side-to-side eye movements) are also common. Anaphylaxis (serious allergic reactions) is rare.
• Oxcarbazepine can inhibit some liver enzymes (notably CYP2C19 and CYP3A4/5), which may affect plasma levels of some other medications, including oral contraceptives and felodipine.
• Although dosages greater than 1200 mg/day in adults have shown greater efficacy, most people cannot tolerate the CNS side effects that occur with these dosages.
• The dosage of oxcarbazepine needs reducing in people with kidney disease.
• Oxcarbazepine may cause low sodium levels (hyponatremia), usually during the first three months of therapy, although hyponatremia may occur at any time. May be life-threatening. Hyponatremia generally resolves once oxcarbazepine has been discontinued.
• The risk of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (both serious dermatological reactions) may be greater in people carrying the HLA-B 1502 allele (predominantly found in people from China, the Philippines, Malaysia, Thailand, India, and Korea).
• As with other drugs used to treat epilepsy or depression, oxcarbazepine has been associated with a higher risk of suicidal thoughts and behaviors. Monitor for the emergence of worsening mood or unusual behaviors.
• Oxcarbazepine is best withdrawn slowly on discontinuation unless it is an emergency. Sudden discontinuation has been associated with an increase in seizure frequency and status epilepticus.
• May not be suitable for everybody including those with liver or kidney disease, previous mental health issues, or planning to become pregnant.
• There are no controlled data in human pregnancy. Animal studies have reported higher rates of structural abnormalities, spontaneous abortions, growth retardation, fetal malformations, decreased fetal body weight, and maternal toxicity in fetuses of animals exposed to oxcarbazepine. Oxcarbazepine and its active metabolite, MHD, cross the human placenta and oxcarbazepine is structurally related to carbamazepine, which is a known human teratogen. Do not use during pregnancy unless the benefits outweigh the risks. If a woman inadvertently becomes pregnant while taking oxcarbazepine, encourage her to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling the toll-free number 1-888-233-2334 or online at http://www.aedpregnancyregistry.org/. Oxcarbazepine and its active metabolite (MHD) are found in breastmilk, but the effects on a breastfed infant are unknown.

Note: In general, seniors or children, people with certain medical conditions (such as liver or kidney problems, heart disease, diabetes, seizures) or people who take other medications are more at risk of developing a wider range of side effects. View complete list of side effects

Oxcarbazepine is an antiseizure medication that is used either alone or in combination with other antiseizure medications to reduce seizure frequency in people with partial seizures and sometimes other seizure types. CNS side effects (including concentration difficulties, sleepiness, and confusion) are the main side effects associated with its use.

5. Tips

• May be taken with or without food.
• Oxcarbazepine suspension may be substituted for oxcarbazepine tablets in people or children who have difficulty swallowing (the dosages are equivalent).
• Oxcarbazepine may make you sleepy or impair your reaction times and affect your ability to drive or operate machinery. Do not drive or operate machinery if oxcarbazepine affects you in this way. Alcohol may make these effects worse.
• Talk to your doctor if you experience any signs of hyponatremia (low blood sodium levels) such as confusion, headache, nausea, tiredness, or an increase in seizure frequency.
• Seek urgent medical advice if you develop any allergic-type reactions including facial swelling or a rash. 25-30% of people who are allergic to carbamazepine will also be allergic to oxcarbazepine. Also seek urgent advice if you develop any unusual bruising or bleeding, swollen lymph nodes, abdominal pain, painful mouth sores, yellowing of the skin, frequent or persistent infections, or different or more frequent seizures.
• If you are taking hormonal contraceptives, talk with your doctor. Your dosage may need to be increased or an alternative method of contraception may be needed.
• Do not stop oxcarbazepine suddenly, unless your doctor has told you to do so. It is best to discontinue oxcarbazepine slowly.
• Tell your doctor if you are pregnant, intending to become pregnant, or breastfeeding because oxcarbazepine may not be suitable for you.

6. Response and effectiveness

• Oxcarbazepine is completely absorbed after oral administration with over 70% being converted to its active metabolite, MHD. MHD is responsible for more antiseizure effects than oxcarbazepine. Peak concentrations of MHD are reached within 3 to 13 hours (average time of 4.5 hours).
• Food does not affect the absorption of oxcarbazepine. Reductions in seizure frequency have been noted within ten days of regular administration of oxcarbazepine.

7. Interactions

Medicines that interact with oxcarbazepine may either decrease its effect, affect how long it works for, increase side effects, or have less of an effect when taken with oxcarbazepine. An interaction between two medications does not always mean that you must stop taking one of the medications; however, sometimes it does. Speak to your doctor about how drug interactions should be managed.

Common medications that may interact with oxcarbazepine include:

• antidepressants, such as citalopram, sertraline, St John’s Wort, and monoamine oxidase inhibitors
• cyclosporine
• HIV combination drugs such as elvitegravir/cobicistat
• other medications for seizure control such as phenytoin or phenobarbital
• other medications that cause drowsiness, such as anti-anxiety medications, muscle relaxants, narcotics, psychiatric medications, sedating antihistamines, or sleeping pills
• oral contraceptives (oxcarbazepine may make them less effective)
• proton pump inhibitors such as lansoprazole, omeprazole, or pantoprazole
• some heart medications, such as amiodarone, calcium channel blockers (eg, amlodipine, felodipine, nifedipine).

Alcohol may also increase drowsiness associated with oxcarbazepine, so is best avoided.

Note that this list is not all-inclusive and includes only common medications that may interact with oxcarbazepine. You should refer to the prescribing information for oxcarbazepine for a complete list of interactions.

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Other brands

Trileptal, Oxtellar XR

Professional resources

• Prescribing Information

Related treatment guides

• Borderline Personality Disorder
• Anxiety
• Bipolar Disorder
• Cyclothymic Disorder

References

• Oxcarbazepine. Revised 11/2022. Major Pharmaceuticals. https://www.drugs.com/pro/oxcarbazepine.html

Further information

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use oxcarbazepine only for the indication prescribed.

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

Copyright 1996-2023 Drugs.com. Revision date: December 30, 2022.

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Its uses, side effects, and FAQs

1. Does oxcarbazepine cause weight loss?

Both weight loss and weight gain are listed as side effects caused by oxcarbazepine. A study showed that children with seizures on oxcarbazepine alone showed significant weight gain. This medication has many side effects, such as loss of appetite, abdominal pain, etc., which can cause weight loss.

2. Does oxcarbazepine cause hair loss?

Hair loss or alopecia is one of the lesser-known side effects of oxcarbazepine. It occurs very rarely as a result of this drug. If you experience hair fall as a side effect, it is generally less severe.

3. How long does oxcarbazepine stay in your system?

Oxcarbazepine gets converted to licarbazepine during its metabolism in the liver. Licarbazepine is responsible for decreasing seizures. The half-life of oxcarbazepine is 1-5 hours, and the half-life of licarbazepine is 8-10 hours. Half-life is the time the body takes to remove half of the amount of drug.

4. Will oxcarbazepine affect getting pregnant?

There is not enough data that confirms the effects of oxcarbazepine on fertility. A study had inconclusively shown the results of this drug on the fetus. Few animal studies showed birth defects in animals exposed to oxcarbazepine during pregnancy.

5. Is oxcarbazepine a benzo?

No, oxcarbazepine is not a benzo (Benzodiazepine). It belongs to the class of drugs called anticonvulsants.

6. Is oxcarbazepine a narcotic?

No, it is not a narcotic. Narcotics are used to provide pain relief. Even though oxcarbazepine can provide relief for nerve pain, it is not considered a narcotic.

7. Is oxcarbazepine like Xanax?

Xanax (alprazolam) is a medication used to treat anxiety and panic disorders. It belongs to a group of drugs called benzodiazepines. Oxcarbazepine reduces the effects and the blood levels of Xanax. Therefore, it is useful in treating patients with benzodiazepine withdrawals.

8. Can divalproex sodium and oxcarbazepine take together?

Both are anticonvulsant drugs that can treat seizures. Divalproex sodium is also used for manic episodes and migraines. There are many drug interactions with both of these drugs. Therefore, it is essential to inform your doctor before taking one of them with the other.

9. How does oxcarbazepine cause urinary incontinence?

Urinary incontinence is not a known side effect of oxcarbazepine. It can cause other related side effects like urinary tract infections, excess urination, blood in urine, etc.

10. How does oxcarbazepine work for trigeminal neuralgia?

Trigeminal neuralgia is a condition that causes sudden and unilateral pain along the trigeminal nerve. Oxcarbazepine blocks the over-firing of the nerves and stabilizes the excited nerve membranes. Therefore, it can treat trigeminal neuralgia with fewer side effects.

11. Is oxcarbazepine a mood stabilizer?

Yes, oxcarbazepine can treat mood disorders like bipolar disorder. It is used during a manic episode of bipolar disorder and to prevent future manic episodes of bipolar disorder. One of the off-label uses of this drug is to stabilize the mood.

Consult our medical experts for a free second opinion.

Controlled-release monotherapy with oxcarbazepine and carbamazepine for newly diagnosed adult focal epilepsy (open comparative study) | Azhigova

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Antiepileptic drugs outside of epilepsy (use of anticonvulsants in the treatment of pain syndromes)

Anticonvulsants, or anticonvulsants, according to one definition – a group of different the chemical structure of drugs that have the ability to prevent or reduce seizures. Anticonvulsants include a number of substances with hypnotic and sedative effects (for example, bromides, chloral hydrate, phenobarbital), as well as substances that have a selective anticonvulsant effect [3]. The first description of the use of potassium bromide as an anticonvulsant dates back to 1857, and synthetic selective antiepileptic therapy dates back to 1912, when the antiepileptic properties of phenobarbital were discovered, discovered when prescribing the drug as a hypnotic. The next important step in the development of the pharmacology of anticonvulsants was the discovery of phenytoin, which was synthesized in 1908, and studied and described as an antiepileptic agent without a hypnotic effect in 1938 by Merrit and Putnam. Further attempts to find a less toxic drug for the relief of convulsive syndromes led to the discovery of ethosuximide in 1958 g. In the 1960s, carbamazepine, valproic acid, and benzodiazepines entered the practice of treating epilepsy. A new era in the development of antiepileptic drugs (AEDs) begins in 1975, when a program was established in the United States to study the latest anticonvulsant molecules. Since 1990, 16 new AEDs have been registered in Europe and the United States, constituting the current generation of anticonvulsants, such as: tiagabine, vigabatrin, gabapentin, topiramate, oxcarbazepine, felbamate, zonisamide, levetiracetam, pregabalin, lacosamide, rufinamide, and others. molecules are under development [11].

In the years since the introduction of the first anticonvulsants, an extensive evidence base and experience in the use of these drugs in the treatment of various forms of epilepsy has emerged, while at the same time a number of points of application for these drugs in the treatment of other diseases have emerged. The literature contains the results of a study of the effectiveness of AEDs in the following diseases and syndromes: neuropathic pain and fibromyalgia, migraine, anxiety and bipolar disorders, schizophrenia, essential tremor [21].

Prerequisites for the use of anticonvulsants in neuropathic pain

Neuropathic pain, according to the current definition, is a pain syndrome caused by damage to the somatosensory nervous system due to a variety of reasons [33]. The pathophysiological basis for the occurrence of neuropathic pain syndrome is disturbances in the mechanisms of generation and conduction of a nociceptive signal in nerve fibers, as well as the processes of controlling the excitability of nociceptive neurons in the structures of the brain and spinal cord. Due to nerve damage, the number of sodium and calcium channels on the nerve fiber membrane increases, and zones of generation of ectopic impulses appear. The increased impulsation from the periphery also disorganizes the work of the central structures, resulting in the so-called “central sensitization” [1, 2].

A number of pathophysiological mechanisms characteristic of neuropathic pain have analogues in epilepsy. For example, similarities have been found between the phenomenon of “winding up” that occurs in the posterior horns of the spinal cord in neuropathic pain, central sensitization, and the phenomenon of “kindling” or the formation of “pathological excitation generators” in hippocampal neurons in epilepsy. It is believed that both phenomena, along with other mechanisms, arise due to the activation of NMDA receptors. Not surprisingly, anticonvulsants show their effectiveness both in terms of reducing the number of epileptic seizures and in terms of suppressing the intensity of the pain syndrome [13, 17, 37].

Mechanisms of action of anticonvulsants in pain syndromes

The mechanisms of action of anticonvulsants in neuropathic pain are different. The anti-pain effect of drugs such as carbamazepine, phenytoin, oxcarbazepine, lamotrigine, valproate, topiramate is usually explained by a decrease in high-frequency repetitive neuron firing by blocking voltage-dependent sodium and calcium channels in peripheral nerves. A number of drugs (eg, phenobarbital, tiagabine, topiramate, vigabatrin, and valproate) increase nerve transmission of pain-suppressing impulses or directly block nerve transmission of excitatory impulses. Pregabalin and gabapentin have a fundamentally different mechanism of action associated with the effect on the alpha-2-delta subunit of voltage-gated calcium channels and the suppression of central sensitization processes in the dorsal horn of the spinal cord and in the brain. Summarized data on the mechanisms of action of anticonvulsants are presented in tab. 1 .

In addition to those listed in Table. 1 of the proposed mechanisms of action of anticonvulsants, their possible indirect effects on various neurotransmitter systems and effects on intracellular processes are also considered. Today, the question is being discussed whether the mechanism of realization of the therapeutic effect of the same anticonvulsant in different conditions: epilepsy, pain syndromes, anxiety, etc. is the same through similar mechanisms or these mechanisms differ [21].

The first publication on the use of anticonvulsants for the treatment of neuropathic pain appeared in 1942, when M. Bergouignan showed the effectiveness of phenytoin in the treatment of neuropathic pain in trigeminal neuralgia [8]. 20 years later, since the early 1960s, carbamazepine was successfully introduced into the practice of treating the same trigeminal neuralgia, which became one of the first drugs officially registered for the treatment of this condition [9]. The beginning of the 1990s was characterized by a kind of boom in the study of antidepressants, which led to the emergence of new effective and safer drugs. A large number of evidence-based randomized controlled trials have been published, allowing further meta-analysis of the data obtained. Summarized results of systematic reviews and meta-analyses are presented in tab. 2 [17]. Attention is drawn to a large number of studies on the effectiveness of the latest generation of anticonvulsants – pregabalin and gabapentin.

Based on the meta-analysis and systematic reviews, such authoritative international organizations as the European Federation of Neurological Societies, the Group for the Study of Neuropathic Pain of the International Association for the Study of Pain, etc., have published recommendations for the treatment of neuropathic pain and identified several directions (lines) of therapy for this condition . In most documents, first-line drugs are distinguished, i.e. those drugs with which to start treatment, and if ineffective or intolerable, change to another drug of the same line, as well as second and third line drugs, and some recommendations even suggest that fourth-line drugs be allocated. The authors of the recommendations agree on one thing: to date, among anticonvulsants, only pregabalin and gabapentin are first-line drugs in the treatment of neuropathic pain. Evidence for the effectiveness of carbamazepine is only available for trigeminal neuralgia [32] (Table 3) .

It is important to emphasize that the considered approach to the treatment of neuropathic pain is based on evidence obtained in studies that took into account not only the experience of each specialist, but also summarized the relevant world data [32]. The same positions are reflected in the recommendations of a group of Russian experts [4].

In Russia today a huge number of anticonvulsants are registered – more than 200 trade names of various forms of release as of 03/01/13. Most of these drugs are indicated for the treatment of various forms of epilepsy as monotherapy or in combination with other drugs. Neuropathic pain is among the indications for use only in a very limited number of drugs in this group. These include: phenytoin, which is registered for the treatment of trigeminal neuralgia, and carbamazepine, indicated for the treatment of trigeminal neuralgia, glossopharyngeal neuralgia, and painful diabetic polyneuropathy. Pregabalin (lyrica) and its predecessor gabapentin are the only drugs registered for the treatment of all types of neuropathic pain in adults ^[1] . Let’s consider each of these drugs in more detail.

Phenytoin (Difenin) is one of the very first AEDs. In addition to anticonvulsant and analgesic, it has a membrane-stabilizing, antiarrhythmic and hypotensive effect. Its bioavailability is low and is 20-50%. It is metabolized in the liver and is an inducer of the isoenzymes CYP3A4, CYP3A5. As an anesthetic, the drug is indicated for the treatment of only trigeminal neuralgia, in which it is prescribed 100-300 mg 1-3 times a day. Of the side effects, ataxia, nystagmus, dizziness, tremor, muscle weakness, nausea, vomiting, toxic hepatitis and others are most characteristic. Very rarely, the development of Stevens-Johnson syndrome and acute epidermal necrolysis is possible. The drug should be prescribed with caution in patients with algoholism, diabetes mellitus, chronic heart and liver failure. In addition, the drug is characterized by a high risk of adverse events due to drug interactions [1].

Carbamazepine (tegretol, finlepsin, actinerval, zeptol, etc. ) belongs to the first generation of AEDs and is similar in chemical structure to tricyclic antidepressants. Carbamazepine has a wide range of indications, including conditions accompanied by neuropathic pain, trigeminal neuralgia, glossopharyngeal neuralgia, and painful diabetic polyneuropathy, among other diseases. Most well-designed studies have been conducted in patients with trigeminal neuralgia and facial pain, where the drug has proven effective. Data on its effectiveness in other types of neuropathic pain are limited (few trials conducted and patients included). In this regard, in a number of recommendations for the treatment of neuropathic pain, carbamazepine is recommended as a first-line drug only for trigeminal neuralgia [17]. Carbamazepine is usually taken with or without food, with a small amount of liquid. In adults, treatment is recommended to start with a dose of 100-200 mg 1 or 2 times a day, gradually increasing it by no more than 200 mg per day, until pain relief (on average, 800-1200 mg per day), and then reduce it to minimum effective dose. In some cases, a dose of 1600 mg per day may be required, which requires careful titration and monitoring of the patient. Carbamazepine is contraindicated in atrioventricular blockade, hematopoietic disorders, acute intermittent porphyria, including history, as well as simultaneously with monoamine oxidase inhibitors.

When using carbamazepine, a number of serious side effects have been registered, such as Stevens-Johnson syndrome (544 cases were registered in the world in 1999), acute epidermal necrolysis, agranulocytosis, aplastic anemia, hepatitis, impaired renal function, endocrine disorders. The most common side effects (10% or more) of carbamazepine include: dizziness, ataxia, drowsiness, urticaria, multi-organ hypersensitivity reactions, vasculitis, leukopenia, nausea, vomiting, edema, weight gain. The risk of developing these phenomena is increased when taking into account adverse drug interactions. With caution, carbamazepine should be prescribed in elderly patients [5, 6].

Therefore, carbamazepine should only be used under regular medical supervision. Before starting treatment, it is recommended to do a urinalysis, a detailed biochemical blood test, including the level of urea. These indicators should be monitored first weekly and then monthly. During treatment, it is also necessary to regularly monitor liver function, blood status, including the concentration of electrolytes in the serum [14].

Oxcarbazepine (trileptal) is structurally similar to carbamazepine. It is believed that the effectiveness of these drugs in epilepsy is quite comparable, but oxcarbazepine is better tolerated. For example, when using the drug, not a single case of Stevens-Johnson syndrome has been registered. Several clinical studies have been conducted with oxcarbazepine in trigeminal neuralgia with positive results. Recommended dosing regimen 900-1800 mg per day. A number of recommendations for the treatment of neuropathic pain indicate that oxcarbazepine is the first-line drug for trigeminal neuralgia. Oxcarbazepine is not registered in Russia for this indication [17].

Gabapentin is recognized as a first-line drug for the treatment of neuropathic pain in a number of international recommendations [32]. In addition to the original drug Neurontin, a number of generics have been registered in Russia: gapentek, tebantin, gabagamma, convalis, etc. In 9 large randomized placebo-controlled trials, the effectiveness of gabapentin in postherpetic neuralgia and diabetic polyneuropathy was shown. One placebo-controlled study was conducted for phantom pain, Guillain-Barré syndrome, neuropathic pain of various etiologies, neuropathic pain caused by cancer, and spinal cord injury. According to the results of clinical trials, the drug showed its superiority over placebo in pain relief and its good tolerability by patients [26].

The mechanism of action of gabapentin is based on the ability to bind to an additional subunit of the alpha-2-delta voltage-dependent Ca2 ⁺ channels, which is located on the extracellular side of the channel. Strong binding at this site reduces calcium influx to nerve endings, leading to inhibition of the release of a number of neurotransmitters, including glutamate and substance P.

In the absence of neurotransmitters in the synaptic cleft, the impulse propagation to the next neuron is blocked [13, 23].

Gabapentin can be taken with or without food. There is no need to measure serum concentrations to optimize treatment. The drug should be titrated starting at 300 mg per day and then increasing the dose by 300 mg per day to a target daily dose of 1800-3600 mg (the titration period to the maximum dose usually takes 12 days). The time between successive doses of the drug should not exceed 8 hours. Elderly patients may require dose adjustment, as they often have impaired renal function. The most common side effects include dizziness, drowsiness and ataxia. To avoid falls, the doctor needs to warn patients, especially the elderly, about the possibility of these side effects. Other characteristic side effects are nystagmus, diarrhea, headache, nausea, peripheral edema and asthenia are less common.

Pregabalin (lyric) is currently positioned in all international and Russian recommendations for the treatment of neuropathic pain and painful diabetic polyneuropathy as a first-line drug [4, 32]. Pregabalin, like gabapentin, belongs to a class of drugs that have a high affinity for alpha-2-delta protein in the central nervous system. Pregabalin is a derivative of GABA and is essentially its analogue. In studies on the background of taking the drug, a decrease in the release of a number of neurotransmitters (including glutamate, norepinephrine and substance P) in hyperexcited neurons was demonstrated. This is believed to be caused by modulation of the function of the alpha-2-delta subunit of voltage-gated calcium channels. Pregabalin, by reducing the release of neurotransmitters, thus slows down the transmission of a nerve impulse to the next neuron, which results in a reduction in pain. It is important to note that pregabalin has an effect only under conditions of hyperexcitation of neurons in pathological conditions; its modulating action leads to the transition of neurons to the normal state [13, 18, 23].

Despite the similarities between pregabalin and gabapentin, the pharmacokinetic profile of pregabalin has some differences compared to the profile of gabapentin. Unlike gabapentin, pregabalin has a linear pharmacokinetics, which ensures the predictability of changes in plasma concentrations of the drug with increasing or decreasing doses. Pregabalin is rapidly absorbed into the blood and has a higher bioavailability (90%) compared to gabapentin (33-66%). As a result, the drug is effective in smaller doses, and the likelihood of side effects is much less. A meta-analysis of conducted randomized clinical trials of both drugs showed that the effectiveness of pregabalin is similar to that of gabapentin in reducing pain intensity, but at significantly lower dosages. It has been demonstrated that the maximum dose of gabapentin (3600 mg) is as effective as the average therapeutic dose of pregabalin – 450 mg (for pregabalin the maximum dose is 600 mg) [36]. In addition, pregabalin is characterized by a shorter time to reach maximum concentration with a long period of absorption. This circumstance allows the use of a two-time dose of the drug, in contrast to gabapentin, which is required to be taken 3 times a day. The time to reach a stable concentration of pregabalin is shorter, therefore, a shorter titration period is required, and the therapeutic concentration and, accordingly, the clinical effect are reached faster [1].

Pregabalin has been shown to be highly effective in neuropathic pain in clinical trials. In total, more than 10,000 patients were treated in them. The main studies on the effectiveness of pregabalin have been conducted in postherpetic neuralgia and painful diabetic neuropathy, since these diseases have been accepted by the US Food and Drug Administration – FDA – as standard models of neuropathic pain. All studies, 4 in postherpetic neuralgia, 5 in diabetic neuropathy, and 1 in these conditions, were randomized, double-blind, placebo-controlled, up to 13 weeks in duration. The dosage of pregabalin was flexible or fixed at 75 to 600 mg per day. In all studies without exception, at all doses, pregabalin showed a significantly higher efficacy compared to placebo, up to 60% or more; it not only reduced the intensity of pain, but also normalized sleep and improved the quality of life of patients. According to the results of a somewhat later meta-analysis, the effect of the drug was observed already by the end of the 2nd or the beginning of the 3rd day of therapy, continuing until the end of the study, and the number of responders with a 50% or more reduction in pain intensity was about 65%. Some of the studies described above were continued in the open phase, the average duration of pregabalin use was 15 months, and the maximum duration was 3.5 years. These data allow us to speak about pregabalin as an effective and safe agent for long-term treatment of neuropathic pain [22, 25, 28, 29].

There is extensive post-marketing experience with pregabalin in the literature. Thus, in Germany, it was studied in the treatment of 10,300 patients with such forms of pathology as diabetic polyneuropathy, back pain with a neuropathic component, postherpetic and trigeminal neuralgia, alcoholic polyneuropathy, various other polyneuropathies and neuropathic pain due to a tumor. Significant reduction in pain intensity was noted as early as the 1st week of therapy. By the 6th week of treatment with pregabalin, pain intensity decreased by an average of 62%, while patients improved their sleep and mood [24].

There is experience with the use of the drug in patients with severe, not relieved by other means, pain. In one open-label study [24], in patients with pain refractory to gabapentin, tricyclic antidepressants, or other drugs, pregabalin significantly reduced visual analog scale pain and anxiety and sleep disturbances [25].

The drug was also studied in central neuropathic pain in patients with spinal cord injury in a 12-week randomized placebo-controlled trial. Against the background of pregabalin therapy, pain intensity in this group of patients decreased starting from the 1st week of therapy, and the effect persisted until the end of the course of treatment. In parallel with anesthesia, the use of the drug caused a persistent improvement in sleep. In another study, pregabalin was more effective than placebo in patients with central post-stroke pain [30, 34].

As already mentioned, pregabalin is well tolerated. The most common side effects are dizziness and drowsiness. According to data from clinical studies, dizziness and drowsiness while taking pregabalin are transient in nature, occurring after 1–2 days of administration and stopping at 2–4 weeks of therapy [25]. Other side effects include: ataxia, dysarthria, impaired attention, euphoria, irritability, diplopia, dry mouth, fatigue, edema, transient weight gain. Pregabalin is not metabolized in the liver and does not bind to plasma proteins, so the risk of interaction with other drugs is minimal.

The range of daily therapeutic doses of pregabalin is 300-600 mg divided into 2 doses. The drug can be taken regardless of food intake. In Russia, the drug is sold in capsules of 25, 75, 150 and 300 mg. In the treatment of neuropathic pain, the recommended starting dose is 150 mg per day. Depending on the effect and tolerability, the dose can be increased to 300 mg per day after 3-7 days. If necessary, you can increase the dose to a maximum (600 mg per day) after another 7 days. In patients with impaired renal function, treatment is recommended to be started and carried out at lower doses. According to the experience gained in clinical studies, in case of discontinuation of the drug, it is recommended to reduce the dose gradually over a week.

Other anticonvulsants for the treatment of neuropathic pain . Lamotrigine (lamiktal, convulsan, lamolep, lamictor) is a second-generation anticonvulsant and is registered for the treatment of epilepsy and bipolar disorder. In neuropathic pain, the effectiveness of the drug has been shown in the painful form of diabetic neuropathy, spinal injury, trigeminal neuralgia, central post-stroke pain, however, in some other studies, conflicting results have been obtained. Topiramate (Topamax, Topiromax, Maxitopyr, etc.) has been shown to be effective in reducing pain in diabetic neuropathy and spinal injury, but in other studies the effect was insufficient. Lacosamide (Vimpat), which at the stage of clinical trials instilled certain hopes for effectiveness, did not live up to expectations in relation to the treatment of pain syndromes. The absence of neuropathic pain in the official list of indications for all three drugs should also be taken into account [18, 20, 38, 39].

Anticonvulsant use for migraine, anxiety disorders and fibromyalgia

The use of anticonvulsants for migraine is only considered in the context of prophylactic treatment of attacks. According to the recommendations of the American Academy of Neurology, in order to start preventive therapy, there should be at least 2 such attacks per month, or the attacks should be severe, refractory to treatment and leading to maladjustment of the patient [31]. Among the possible mechanisms of the preventive action of anticonvulsants, their influence on the GABA-glutamate system or on intracellular mediators (ATP, c-AMP, protein kinase C, etc.) by affecting the calcium or sodium channels of the synapse is considered. In the United States, topiramate and valproate are registered by the FDA for the prevention of migraine, but in Russia these indications do not appear [31, 37].

The hypothetical possibility of using most anticonvulsants in anxiety disorders is associated with an effect on GABA transmission. The most proven anti-anxiety effects are tiagabine, gabapentin, and pregabalin, with the latter officially registered in both the US and Russia for the treatment of generalized anxiety disorder. The mechanism of the anxiolytic action of pregabalin is associated with presynaptic inhibition of the release of excitatory neurotransmitters, and more than 7 randomized placebo-controlled trials have been published as evidence of its effectiveness [35].

One disease that is also to some extent treatable with anticonvulsants is fibromyalgia, or as it is also called, the syndrome of individual hypersensitivity to pain, a disease that is most difficult to treat. Of the currently known anticonvulsants in his treatment, only pregabalin has proven its effectiveness, studied both in short, 8-week studies and in long-term studies lasting more than a year. The presence of sufficient evidence allowed the European League against Rheumatism to recommend the inclusion of this drug in the complex therapy of fibromyalgia. The mechanism of action of pregabalin in fibromyalgia is associated with the effect on the processes of central sensitization [12, 19].

Thus, the use of anticonvulsants today is possible not only for epilepsy, but also for many other diseases and syndromes. Among these forms of clinical pathology, neuropathic pain stands out, in which anticonvulsants are especially well studied. The first-line drugs for such pain are pregabalin and gabapentin; with trigeminal neuralgia – carbamazepine. Topiramate and valproate are registered in the United States for the prevention of migraine attacks, and pregabalin is increasingly being used to treat generalized anxiety disorder. Pregabalin is also the first and only anticonvulsant in the United States and Russia to date registered for the treatment of such a difficult condition as fibromyalgia. Conducted in recent years in the world of research on the latest anticonvulsants allow us to hope for further expansion of the scope of these drugs in a variety of pain syndromes.

^[1] Instructions for the medical use of the drug http://grls.rosminzdrav.ru/ Instructions for the medical use of the Vimpat preparation. Approved 11/16/09; instructions for the medical use of the drug depakine chrono. Approved 03/29/12; instructions for the medical use of the drug difenin. Approved 09.06.09; instructions for the medical use of the drug lamictal. Approved 28.08.12; Instructions for medical use of Lyrica. Approved 29.09.11; instructions for medical use of the drug Neurontin.