Novel Uses of the Antiepilepsy DrugsThe anticonvulsant, or antiepilepsy, drugs (AEDs) have been utilized since the 17th century, but recent attention has turned to using the AEDs for more novel uses. This is particularly true for the newer-generation agents. For many years, phenobarbital and phenytoin were the mainstay treatments for seizures. The 1970s and beyond saw the development of the newer-generation agents, which we will focus on in this article. Nontraditional, alternative uses of AEDs have ranged from adjuvant therapy in providing analgesia for the treatment of chronic or cancer pain, to treatment of bipolar disorders, migraine headache, peripheral neuropathies, and reflex sympathetic dystrophy. Carbamazepine and valproic acid have been used for behavior symptoms associated with dementia (i.e., aggressive behavior). Other potential uses are for anxiety disorders, trigeminal neuralgia, major depression, and intermittent explosive disorder.
History and ClassificationThe evolution of anticonvulsant therapy began in the 17th century with medications such as elk’s claw and powdered human skull. In 1857, Sir Charles Locock evaluated the use of potassium bromide to control aberrant behaviors in the mentally ill. It later became the first drug in the treatment of seizure disorders due to its unexpected anticonvulsant properties. In 1921, another accidental discovery led to the development of phenobarbital, which was an even more effective anticonvulsant and was widely used until the development of phenytoin in 1938. A number of years passed without the introduction of another effective AED.In the 1960s and 1970s, drugs purported to be as effective as anticonvulsants but with less toxic side effects were introduced.1,2 The drugs clonazepam, carbamazepine, sodium divalproex, gabapentin, lamotrigine, topiramate, tiagabine, and, more recently, levetiracetam were introduced. These drugs comprise the new generation of anticonvulsant drugs. Research into different uses for these medications has provided the impetus for the alternative pharmacotherapies. The AEDs are divided into classes based on their mechanisms of action. These include sodium channel–blocking agents, benzodiazepines, barbiturates, and gamma amino butyric acid (GABA) inhibitors. The barbiturates, such as sodium phenobarbital, reduce neuron excitability by reducing the excitatory postsynaptic potentials. Carbamazepine is an iminostilbene that exerts a depressant effect on transmission of the impulses through the thalamus. Clonazepam, a benzodiazepine, decreases cortical hyperexcitability. Valproic acid is a branched-chain carboxylic acid that inhibits transmission of impulses from neuron to neuron. Gabapentin appears to inhibit postsynaptic responses and post-tetanic potentiation (PTP). In general, these medications are metabolized in the liver and excreted primarily through the kidneys. The AEDs are rapidly absorbed from the gastrointestinal tract, with the exception of carbamazepine, which has slow and often erratic absorption.3
GabapentinGabapentin is structurally related to GABA. The mechanism of action is unknown, but gabapentin appears to act via the gabapentin-binding sites in the neocortex and hippocampus. This relatively new anticonvulsant medication has also been shown to be effective as an adjuvant therapy in pain management—a use not approved by the Food and Drug Administration (FDA)—bipolar disorder, and reflex sympathetic dystrophy. The most common side effect is sedation, but this is usually tolerable if gabapentin therapy is started and titrated slowly over a period of a month or more. Gabapentin usually provides excellent pain relief for patients with reflex sympathetic dystrophy.The most common side effects of gabapentin are drowsiness, dizziness, fatigue, ataxia, nystagmus, tremor, nausea, and rhinitis. Administering the initial dose at bedtime assists in avoiding somnolence. Abrupt withdrawal should be avoided by tapering off medication over one to two weeks.
CarbamazepineCarbamazepine was introduced into clinical usage in 1962 for the treatment of trigeminal neuralgia, but it was also recognized for its anticonvulsant properties. In addition, carbamazepine has been used in the treatment of bipolar disorder, other affective disorders, schizophrenia, alcohol withdrawal, restless leg syndrome, and agitated or aggressive behavior associated with dementia.4 It has also been used to relieve peripheral neuropathies related to diabetes and peripheral nerve damage.Carbamazepine has anticholinergic, antineuralgic, antidiuretic, muscle relaxant, and antiarrythmic properties. It is structurally related to the tricyclic antidepressants. While its exact mechanism of action is unknown, it causes some depression of PTP. In addition, it may inhibit an increase in cyclic adenosine monophosphate. It relieves the pain of neuralgia by reducing synaptic transmission in the nuclei of affected nerves. It also stimulates the release of antidiuretic hormone. The most common side effects of carbamazepine are dizziness, drowsiness, ataxia, nystagmus, blurred vision, slurred speech, confusion, headache, and nausea and vomiting. It has the serious adverse effect of bone marrow suppression, which may lead to aplastic anemia, agranulocytopenia and/or thrombocytopenia, hyponatremia, hepatitis, and pancreatitis.
ClonazepamClonazepam, a benzodiazepine, possesses anxiolytic, sedative-hypnotic, and anticonvulsant properties. Clonazepam is indicated in the treatment of panic and anxiety disorders, restless leg syndrome, Parkinson’s dysarthria, and multifocal tic disorders, and also as adjunct therapy in schizophrenia. In addition, clonazepam has been used for reflex sympathetic dystrophy and neuropathic and deafferentation pain syndromes, even though these are non–FDA-approved uses. Clonazepam has been found to be effective in the treatment of bipolar disorder and, to a lesser degree, schizoaffective disorder. Although the specific mechanism of action is not clearly understood, carbazepine potentiates the effects of the inhibitory neurotransmitter GABA.The most common side effects of carbamazepine are drowsiness, ataxia, dizziness, headache, hypotension, nystagmus, xerostomia, slurred speech, and tremors. More serious adverse events are anemia, leukocytosis, and thrombocytopenia. When discontinuing the medication, it should be tapered off over a period of one week or more.
Divalproax sodium/valproic acidValproic acid and its derivative sodium divalproax, discovered in 1963, act by increasing the nerve impulse transmitter GABA, thereby suppressing the spread of abnormal electrical activity. Valproic acid is used in the treatment of bipolar disorder and in the prophylaxis of migraine headaches. It may also relieve symptoms of bipolar schizoaffective disorder, panic disorder, and certain agitated/aggressive behaviors associated with dementia.4,5 Its potential efficacy and tolerable side effect profile are useful when treating the elderly with behavioral disturbances of physical aggression and agitation.Because divalproax has been associated with birth defects, women in childbearing years should be advised to use reliable birth control methods. The most common side effects of valproic acid are nausea and vomiting, drowsiness, sedation, weight gain, amenorrhea, and rash. Serious adverse effects include hepatic failure, anemia, leukopenia, thrombocytopenia, Stevens-Johnson syndrome, pancreatitis, and encephalopathy.
ConclusionOftentimes we get caught up in the new medications that are released and forget some of the medications that have been on the market for a few years. In many cases, the effects and adverse effects of the old standbys are more predictable, because they have been tried and tested.In the search for newer and better treatments for disorders such as migraine headaches, bipolar disorder, and behaviors associated with dementia, as well as analgesia for cancer pain, it appears that the AEDs have found a new niche. With further study and research, perhaps additional uses of these mainstays for seizure control will be discovered.
Phyllis M. Parks-Veal, PharmD
References
American Society of Consultant Pharmacists. |
Forum