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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 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 (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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