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Antiepileptic drugs (AEDs) have been used in the treatment of chronic pain syndromes for more than 50 years.1–4Phenytoin, in particular, has been extensively used for the treatment of neuropathic pain during that time.5–9Carbamazepine 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 diabetic neuropathy, postherpetic neuralgia, glossopharyngeal neuralgia, post-sympathectomy neuralgia, and post-thoracotomy pain syndromes.1–4 The AEDs include the older drugs like phenytoin, carbamazepine, and valproic acid, and newer agents such as gabapentin, lamotrigine, felbamate, topiramate, vigabatrin, tiagabine, levetiracetam, zonisamide, and oxcarbazepine.

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The individual AEDs are briefly reviewed here, as well as general guidelines for their use in pain control.

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Neuropathic pain is defined as pain due to 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. It 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 Since 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.

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Although 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, older AEDs (phenytoin, carbamazepine, and valproic acid) also require monitoring of blood counts and liver function tests because of their hematologic and hepatic toxicity, leading to poor compliance. Newer AEDs (with the exception of felbamate) generally are not associated with life-threatening side effects and are easier to use.

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Phenytoin

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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.

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