Anticonvulsant

Approval

The usual method of achieving approval for a drug is to show it is effective when compared against placebo, or that it is more effective than an existing drug. In monotherapy (where only one drug is taken) it is considered unethical by most to conduct a trial with placebo on a new drug of uncertain efficacy. This is because untreated epilepsy leaves the patient at significant risk of death. Therefore, almost all new epilepsy drugs are initially approved only as adjunctive (add-on) therapies. Patients whose epilepsy is uncontrolled by their medication (i.e., it is refractory to treatment) are selected to see if supplementing the medication with the new drug leads to an improvement in seizure control. Any reduction in the frequency of seizures is compared against a placebo. The lack of superiority over existing treatment, combined with lacking placebo-controlled trials, means that few modern drugs have earned FDA approval as initial monotherapy. In contrast, Europe only requires equivalence to existing treatments and has approved many more. Despite their lack of FDA approval, the American Academy of Neurology and the American Epilepsy Society still recommend a number of these new drugs as initial monotherapy.

Drugs

In the following list, the dates in parentheses are the earliest approved use of the drug.

Aldehydes

• Paraldehyde (1882) One of the earliest anticonvulsants. It is still used to treat status epilepticus, particularly where there are no resuscitation facilities.

Aromatic allylic alcohols

• Stiripentol (2007) Indicated for the treatment of Dravet syndrome.

Barbiturates

Barbiturates are drugs that act as central nervous system (CNS) depressants, and by virtue of this they produce a wide spectrum of effects, from mild sedation to anesthesia. The following are classified as anticonvulsants:

• Phenobarbital (1912) See also the related drug primidone.
• Methylphenobarbital (1935) Known as mephobarbital in the US. No longer marketed in the UK.
• Barbexaclone (1982) Only available in some European countries.

Benzodiazepines

The benzodiazepines are a class of drugs with hypnotic, anxiolytic, anticonvulsive, amnestic and muscle relaxant properties. Benzodiazepines act as a central nervous system depressant. The relative strength of each of these properties in any given benzodiazepine varies greatly and influences the indications for which it is prescribed. Long-term use can be problematic due to the development of tolerance to the anticonvulsant effects and dependency. Of many drugs in this class, only a few are used to treat epilepsy:

• Clobazam (1970)
• Clonazepam (1974)
• Clorazepate (1972)

The following benzodiazepines are used to treat status epilepticus:

• Diazepam (1963) Can be given rectally by trained care-givers.
• Midazolam (N/A) Increasingly being used as an alternative to diazepam. This water-soluble drug is squirted into the side of the mouth but not swallowed. It is rapidly absorbed by the buccal mucosa.
• Lorazepam (1972) Given by injection in hospital.

Nitrazepam, temazepam, and especially nimetazepam are powerful anticonvulsant agents, however their use is rare due to an increased incidence of side effects and strong sedative and motor-impairing properties.

Bromides

• Potassium bromide (1857) The earliest effective treatment for epilepsy. There would not be a better drug until phenobarbital in 1912. It is still used as an anticonvulsant for dogs and cats but is no longer used in humans.

Carbamates

• Felbamate (1993) This effective anticonvulsant has had its usage severely restricted due to rare but life-threatening side effects.
• Cenobamate (2019)

Carboxamides

The following are carboxamides:

• Carbamazepine (1963) A popular anticonvulsant that is available in generic formulations.
• Oxcarbazepine (1990) A derivative of carbamazepine that has similar efficacy and is better tolerated and is also available generically.
• Eslicarbazepine acetate (2009)
• Photoswitchable analogues of carbamazepine (2024) are research compounds developed to control its pharmacological activity locally and on demand using light, with the purpose to reduce adverse systemic effects. One of these compounds (carbadiazocine, based on a bridged azobenzene) has been shown to produce analgesia with noninvasive illumination in a rat model of neuropathic pain.

Fatty acids

The following are fatty-acids:

• The valproates — valproic acid, sodium valproate, and divalproex sodium (1967)
• Vigabatrin (1989)
• Progabide (1987)
• Tiagabine (1996)

Vigabatrin and progabide are also analogs of GABA.

Fructose derivatives

• Topiramate (1995)

Gabapentinoids

Gabapentinoids are used in epilepsy, neuropathic pain, fibromyalgia, restless leg syndrome, opioid withdrawal and generalized anxiety disorder (GAD). Gabapentinoids block voltage-gated calcium channels, mainly the N-Type, and P/Q-type calcium channels. The following are gabapentinoids:

• Pregabalin (2004)
• Mirogabalin (2019) (Japan only)
• Gabapentin (1993)
• Gabapentin enacarbil (Horizant) (2011)
• Gabapentin extended release (Gralise) (1996)

Gabapentinoids are analogs of GABA, but they do not act on GABA receptors. They have analgesic, anticonvulsant, and anxiolytic effects.

Hydantoins

The following are hydantoins:

• Ethotoin (1957)
• Phenytoin (1938)
• Mephenytoin
• Fosphenytoin (1996)

Oxazolidinediones

The following are oxazolidinediones:

• Paramethadione
• Trimethadione (1946)
• Ethadione

Propionates

• Beclamide

Pyrimidinediones

• Primidone (1952)

Pyrrolidines

• Brivaracetam (2016)
• Etiracetam
• Levetiracetam (1999)
• Seletracetam

Succinimides

The following are succinimides:

• Ethosuximide (1955)
• Phensuximide
• Mesuximide

Sulfonamides

• Acetazolamide (1953)
• Sultiame
• Methazolamide
• Zonisamide (2000)

Triazines

• Lamotrigine (1990)

Ureas

• Pheneturide
• Phenacemide

Valproylamides

• Valpromide
• Valnoctamide

Other

• Perampanel
• Pyridoxine (1939)

Non-pharmaceutical anticonvulsants

The ketogenic diet and vagus nerve stimulation are alternative treatments for epilepsy without the involvement of pharmaceuticals. The ketogenic diet consists of a high-fat, low-carbohydrate diet, and has shown good results in patients whose epilepsy has not responded to medications and who cannot receive surgery. The vagus nerve stimulator is a device that can be implanted into patients with epilepsy, especially that which originates from a specific part of the brain. However, both of these treatment options can cause severe adverse effects. Additionally, while seizure frequency typically decreases, they often do not stop entirely.

Treatment guidelines

According to guidelines by the American Academy of Neurology and American Epilepsy Society, mainly based on a major article review in 2004, patients with newly diagnosed epilepsy who require treatment can be initiated on standard anticonvulsants such as carbamazepine, phenytoin, valproic acid/valproate semisodium, phenobarbital, or on the newer anticonvulsants gabapentin, lamotrigine, oxcarbazepine or topiramate. The choice of anticonvulsants depends on individual patient characteristics. Both newer and older drugs are generally equally effective in new onset epilepsy. The newer drugs tend to have fewer side effects. For newly diagnosed partial or mixed seizures, there is evidence for using gabapentin, lamotrigine, oxcarbazepine or topiramate as monotherapy. Lamotrigine can be included in the options for children with newly diagnosed absence seizures.

History

The first anticonvulsant was bromide, suggested in 1857 by the British gynecologist Charles Locock who used it to treat women with "hysterical epilepsy" (probably catamenial epilepsy). Bromides are effective against epilepsy, and also cause impotence, which is not related to its anti-epileptic effects. Bromide also suffered from the way it affected behaviour, introducing the idea of the "epileptic personality" which was actually a result of medication. Phenobarbital was first used in 1912 for both its sedative and antiepileptic properties. By the 1930s, the development of animal models in epilepsy research led to the development of phenytoin by Tracy Putnam and H. Houston Merritt, which had the distinct advantage of treating epileptic seizures with less sedation. By the 1970s, a National Institutes of Health initiative, the Anticonvulsant Screening Program, headed by J. Kiffin Penry, served as a mechanism for drawing the interest and abilities of pharmaceutical companies in the development of new anticonvulsant medications.

Marketing approval history

The following table lists anticonvulsant drugs together with the date their marketing was approved in the US, UK and France. Data for the UK and France are incomplete. The European Medicines Agency approves drugs throughout the European Union. Some of the drugs are no longer marketed.

Pregnancy

Many of the commonly used anticonvulsant/anti-seizure medications (ASMs), such as valproate, phenytoin, carbamazepine, phenobarbital, gabapentin have been reported to cause an increased risk of birth defects including major congenital malformations such as neural tube defects. The risk of birth defects associated with taking these medications while pregnant may be dependent on the dose of the drug and on the timing of gestation (how well developed the baby is). While trying to conceive a child and during pregnancy, medical advice should be followed to optimize the management of the person's epilepsy in order to keep the person and the unborn baby safe from epileptic seizures and also ensure that the risk of birth defects due to in utero exposure of anticonvulsants is as low as possible. Anticonvulsant medications should be carefully monitored during use in pregnancy. For example, since the first trimester is the most susceptible period for fetal development, planning a routine antiepileptic drug dose that is safer for the first trimester could be beneficial to prevent pregnancy complications.

Valproic acid, and its derivatives such as sodium valproate and divalproex sodium, causes cognitive deficit in the child, with an increased dose causing decreased intelligence quotient and use is associated with adverse neurodevelopmental outcomes (cognitive and behavioral) in children. On the other hand, evidence is conflicting for carbamazepine regarding any increased risk of congenital physical anomalies or neurodevelopmental disorders by intrauterine exposure. Similarly, children exposed lamotrigine or phenytoin in the womb do not seem to differ in their skills compared to those who were exposed to carbamazepine.

There is inadequate evidence to determine if newborns of women with epilepsy taking anticonvulsants have a substantially increased risk of hemorrhagic disease of the newborn.

There is little evidence to suggest that anticonvulsant/ASM exposure through breastmilk has clinical effects on newborns. The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study showed that most blood concentrations in breastfed infants of mothers taking carbamazepine, oxcarbazepine, valproate, levetiracetam, and topiramate were quite low, especially in relationship to the mother's level and what the fetal level would have been during pregnancy. (Note: valproic acid is NOT a recommended ASM for people with epilepsy who are considering having children.)

Infant exposure to newer ASMs (cenobamate, perampanel, brivaracetam, eslicarbazepine, rufinamide, levetiracetam, topiramate, gabapentin, oxcarbazepine, lamotrigine, and vigabatrin) via breastmilk was not associated with negative neurodevelopment (such as lower IQ and autism spectrum disorder) at 36 months.

Several studies that followed children exposed to ASMs during pregnancy showed that a number of widely used ones (including lamotrigine and levetiracetam) carried a low risk of adverse neurodevelopmental outcomes (cognitive and behavioral) in children when compared to children born to mothers without epilepsy and children born to mothers taking other anti-seizure medications. Data from several pregnancy registries showed that children exposed to levetiracetam or lamotrigine during pregnancy had the lowest risk of developing major congenital malformations compared to those exposed to other ASMs. The risk of major congenital malformations for children exposed to these ASMs were within the range for children who were not exposed to any ASMs during pregnancy.

People with epilepsy can have healthy pregnancies and healthy babies. However, proper planning and care is essential to minimize the risk of congenital malformations or adverse neurocognitive outcomes for the fetus while maintaining seizure control for the pregnant person with epilepsy. If possible, when planning pregnancy, people with epilepsy should switch to ASMs with the lowest teratogenic risk for major congenital malformations as well as the least risk of adverse neurodevelopmental outcomes (e.g., lower IQ or autism spectrum disorder). They should also work with their healthcare providers to identify the lowest effective ASM dosage that will maintain their seizure control while regularly checking medication levels throughout pregnancy.

Data from studies conducted on women taking antiepileptic drugs for non-epileptic reasons, including depression and bipolar disorder, show that if high doses of the drugs are taken during the first trimester of pregnancy then there is the potential of an increased risk of congenital malformations.

Research

The mechanism of how anticonvulsants cause birth defects is not entirely clear. During pregnancy, the metabolism of many anticonvulsants is affected. There may be an increase in the clearance and resultant decrease in the blood concentration of lamotrigine, phenytoin, and to a lesser extent carbamazepine, and possibly decreases the level of levetiracetam and the active oxcarbazepine metabolite, the monohydroxy derivative. In animal models, several anticonvulsant drugs have been demonstrated to induce neuronal apoptosis in the developing brain.