Antiepileptic drugs (AEDs) have been used in the treatment of chronic pain syndromes for more than 50 years.1–4 Phenytoin, in particular, has been extensively used for the treatment of neuropathic pain during that time.5–9 Carbamazepine was the first AED used and extensively studied specifically for the treatment of trigeminal neuralgia.10–12 Since then a variety of neuropathic syndromes have been treated with AEDs, including:
The AEDs include the older drugs such as phenytoin, carbamazepine, and valproic acid and newer agents such as gabapentin, lamotrigine, felbamate, topiramate, vigabatrin, tiagabine, levetiracetam, zonisamide, and oxcarbazepine.
The individual AEDs are briefly reviewed here, and general guidelines for their use in pain control are provided.
Neuropathic pain is defined as pain caused by dysfunction of the nervous system in the absence of ongoing tissue damage.13
The pain typically is characterized as sharp, shooting, or burning and is usually felt in the area of sensory deficit.
The pain is typically worsened by mild stimuli that normally would not produce pain, such as light touch or cool air.
The pain tends to be chronic and causes considerable patient discomfort.
These symptoms have led to various hypotheses about the pathophysiologic mechanisms of neuropathic pain with relevance to AEDs.14 When peripheral nerves become damaged, axons grow toward the formerly innervated area directed by an intact connective tissue sheath. If this sheath is also damaged, then axon extensions grow without any direction and become tangled into a structure called a neuroma.
Neuromas can generate ectopic electrical impulses at the regenerating tips in the damaged primary nociceptive afferents at various levels in the nervous system, from the dorsal root ganglia to demyelinated regions of a root or nerve.15 Because nerves have been damaged, there is a potential disruption in the balance of the excitatory (e.g., glutamate) and inhibitory (e.g., γ-aminobutyric acid [GABA]) neurotransmitters. This disruption leads to hyperexcitability of the neuronal membrane sodium channels and voltage-dependent calcium channels, causing rapid ectopic firing. The AEDs have varying mechanisms of action, many of which are directed at sodium and calcium-dependent channels and GABA metabolism.
Although the AEDs provide at least partial pain relief in a large percentage of patients with a variety of neuropathic pain syndromes, their use is limited by side effects in a substantial percentage of patients. In addition, the older AEDs (phenytoin, carbamazepine, and valproic acid) also require monitoring of blood counts and liver function tests (LFTs) because of their hematologic and hepatic toxicity, leading to poor compliance. The newer AEDs (with the exception of felbamate) generally are not associated with life-threatening side effects and are easier to use.
Phenytoin (5,5-diphenyl-2,4-imidazolidinedione) is an AED used to control generalized tonic-clonic and complex partial seizures. For years it was the most commonly used AED for the treatment of a wide variety of pain syndromes.
Phenytoin has been reported to be effective in the treatment of the following:
Diabetic neuropathy
Trigeminal neuralgia
Neuropathic cancer pain
Postherpetic neuralgia
Complex regional pain syndrome (CRPS) types 1 and 2
The proposed mechanism of action is reduction of neuronal hyperexcitability by decreasing the activity of sodium channels, thereby stabilizing the neural membrane.16
Phenytoin is supplied as 30- and 100-mg capsules. The recommended dosage of phenytoin for epilepsy in most patients is 300 mg/day. An exact dosage needed to achieve adequate analgesia has not been defined. Use of phenytoin as a neuropathic analgesic should follow the guidelines for its use for epilepsy. Phenytoin has the advantage of once-a-day dosing and is relatively inexpensive. Absorption orally is slow and variable; peak concentrations may occur as early as 3 hours or as long as 12 hours. It is about 90% bound to plasma proteins and is metabolized primarily by the liver. Phenytoin has a half-life of 20 to 60 hours at therapeutic concentrations. However, a narrow therapeutic window and its short- and long-term side effects limit use.
Fosphenytoin (5,5-diphenyl-3-[(phosphonooxy)methyl]-2,4-imidazolidine-dione disodium salt) is a prodrug of phenytoin. It is indicated for short-term parenteral administration when other means of phenytoin administration are unavailable.17
Complete blood counts (CBCs), LFTs, and serum drug levels need to be closely monitored, particularly in the first 6 months. Long-term use can result in cosmetic side effects (e.g., gingival hyperplasia, hirsutism, coarsening of the facial features) and, rarely, cerebellar atrophy and peripheral neuropathy.
Carbamazepine (5H-dibenz(b,f)azepine-5-carboxamide) is considered to be a primary drug for partial and tonic-clonic seizures. It has structural similarities to the tricyclic antidepressants, making it a particularly desirable drug for treating chronic pain syndromes.
It has been widely prescribed as the drug of choice for trigeminal neuralgia10–12 and is considered the best neuropathic analgesic for lancinating or electric-like pain.15
Carbamazepine is effective in other neuropathic pain syndromes such as glossopharyngeal neuralgia, diabetic neuropathy, and pain syndromes associated with multiple sclerosis.18–21
It has also been used for the treatment of migraine headaches in pediatric populations.22
Carbamazepine enhances antidepressant effects and is an effective mood stabilizer. Its mechanism of action is similar to that of phenytoin in stabilizing neuronal membranes.
Carbamazepine is available as 100-mg chewable tablets; 100-, 200-, and 400-mg extended-release tablets; and 100 mg/5 mL suspension. The initial starting dosage of carbamazepine is between 100 and 200 mg/day; the dosage can be slowly increased over several weeks as needed to a maximum total dose of 1200 mg/day. It is absorbed slowly orally, and peak concentrations may be observed in 4 to 8 hours but may be delayed 24 hours. It is about 75% bound to plasma proteins. Carbamazepine is metabolized to 10,11-epoxycarbamazepine, which is an active metabolite. Its half-life is between 10 and 20 hours depending on induction of hepatic enzymes. Carbamazepine, similar to phenytoin, has a narrow therapeutic window. Before initiating therapy, a baseline CBC and LFTs should be obtained, with frequent monitoring thereafter, particularly in the first 6 months.
Agranulocytosis and aplastic anemia rarely occur; patients should be advised to report any episodes of fever while taking the drug so that a CBC can be checked. Other side effects of concern are hypersensitivity reactions manifesting as Stevens-Johnson syndrome with lymphadenopathy and rare cases of liver failure.
Oxcarbazepine (10,11-dihydro-10-oxo-5H-dibenz[b,f]azepine-5-carboxamide) is a new antiepileptic that is chemically similar to carbamazepine and may prove to be a neuropathic analgesic.23 Oxcarbazepine is a prodrug, which means its metabolite is the active substance. It is indicated for monotherapy or adjunctive therapy in the treatment of partial seizures.24
Oxcarbazepine blocks voltage-sensitive sodium channels, resulting in stabilization of hyperexcited neural membranes, inhibition of repetitive neuronal firing, and diminution of synaptic impulse propagation.25 It may modulate high-voltage activated calcium channels and increase potassium conductance.
A small study demonstrated the efficacy of oxcarbazepine in trigeminal neuralgia.26
Further controlled studies are under way to determine its efficacy and optimal dose in the treatment of neuropathic pain.
Oxcarbazepine is available as 150-, 300-, and 600-mg tablets. The starting dosage of oxcarbazepine is 150 to 600 mg/day divided into two doses, up to a maximum of 2400 mg/day. Monitoring of hepatic enzymes or hematologic parameters is not required with oxcarbazepine to the same degree as with carbamazepine. It does not extensively undergo oxidative metabolism and has low protein binding (40%). Oxcarbazepine is metabolized to 10,11-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide (MHD), which is responsible for the pharmacologic effects of oxcarbazepine. The peak serum levels of oxcarbazepine and MHD are reached in 4.5 hours after oral administration. The half-life of MHD is 9 hours.
Side effects associated with oxcarbazepine are primarily related to the nervous system and digestive system. The symptoms are somnolence, headache, dizziness, diplopia, ataxia, nystagmus, abdominal pain, anorexia, nausea, vomiting, and rash.
Valproic acid (n-dipropylacetic acid) is a broad-spectrum AED used to treat a number of epileptic syndromes; although it has been used in the management of chronic pain.27
It has been mainly indicated in the preventive treatment of migraine, cluster, and tension-type headaches.28,29
Valproic acid has several proposed mechanisms of action, including increasing GABA brain concentrations by inhibition of GABA aminotransferase and succinic semialdehyde dehydrogenase (enzymes involved in the synthesis and degradation of GABA), selectively enhancing postsynaptic GABA responses, direct effects on neuronal membranes, and reduction of excitatory transmission by aspartate.30 Valproic acid, similar to carbamazepine, is an effective mood stabilizer.
Valproic acid is available as 250-mg capsules and 250 mg/5 mL syrup. The starting dosage of valproic acid is usually 250 mg/day; it is titrated slowly upward to a maximum dosage of 1000 to 2000 mg/day, usually in divided doses. Valproic acid is absorbed rapidly orally, and peak concentrations are observed in 1 to 4 hours. It is about 90% bound to plasma proteins. It is metabolized hepatically with potent antiseizure metabolites. Valproic acid has an approximately 15-hour half-life.
Limitations for the use of this agent include drug interactions and drug-related side effects, such as central nervous system (CNS) depression, and hepatic and hematologic toxicity. Frequent monitoring of these parameters should continue during the first year of therapy and occasionally thereafter.
Clonazepam (5-(o-chlorophenyl)-1,3-dihidro-7-nitro-2H-1,4-benzodiazepin-2-one) is a benzodiazepine that has been used successfully in providing relief for both chronic malignant and nonmalignant pain syndromes:
Clonazepam acts by enhancing GABA receptor–mediated chloride channels. It is particularly effective when used in combination with other neuropathic analgesics and in patients with prominent anxiety disorder and insomnia.
Clonazepam is available as 0.5-, 1-, and 2-mg tablets. The dose of clonazepam should initially be 0.5 mg at bedtime, with the dose being slowly increased to 0.5 to 1 mg three times per day. Dosages of up to 20 mg/day have been used in epilepsy; 1 to 6 mg/day is generally successful in treating headache and pain. It is absorbed rapidly orally with peak concentrations in 1 to 4 hours. Clonazepam is approximately 85% bound to plasma proteins. It is metabolized hepatically and has a half-life of about 24 hours.
The most common side effects are drowsiness, dizziness, fatigue, and sedation. As with other benzodiazepines, clonazepam may produce physical and psychological dependence; abrupt discontinuation is prohibited.
Gabapentin (1-(aminomethyl)cyclohexanacetic acid) is one of the newer AEDs that has been approved for adjunctive treatment of partial seizures. In recently published anecdotal reports followed by multicenter, randomized, placebo-controlled studies, the drug was effective in the treatment of the following:
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