This week's article covers some of the current and recent research into the nature of neuropathic pain and its treatment and what can be done to abate this pain completely. The original author is GARY J. BENNETT, of the Allegheny University of the Health Sciences
INTRODUCTION
Some of the first discoveries have concerned antiepileptic medications borrowed for possible benefit against neuropathic pain. In certain respects, these disorders resemble one another. For one, injured sensory fibers may discharge spontaneously, though with a clocklike regularity unlike the irregular pattern of an epileptiform burst in cortical neurons. In both cases, the discharge is probably due in part to abnormal distribution or activation of voltage-gated sodium channels at the neuronal cell-surface membrane.
Anticonvulsant Drugs
The standard anticonvulsant carbamazepine has long been used against neuropathic pain - in particular, tic douloureux, which is one of the rarest of neuropathic pain syndromes. Against neuropathic pain, as against epilepsy, the drug is thought to have dual modes of action: blockade of sodium channels (in the manner of lidocaine) along with potentiation of GABAergic neurotransmission (in the manner of a barbiturate). Cells utilizing GABA as their inhibitory neurotransmitter are known to affect the dorsal-horn neurons that receive primary sensory afferents and emit ascending fibers. In both neuropathic pain and epilepsy, use of the drug has been impeded by need to monitor liver function.
A new generation of anticonvulsant medications is beneficial in seizure disorders resistant to standard drugs. Tested in CCI rats, some of them also exhibit dramatic effects against neuropathic pain When felbamate was first tested, we were intrigued by descriptions of its mechanisms, which cited voltage-gated sodium-channel blockade. This is a slight potentiation of GABAergic neurotransmission, and a third action: blockade of a type of glutamate receptor known as the NMDA receptor (owing to its capacity to bind not only glutamate but also N-methyl-D-aspartate [NMDA]). Nociceptive C fibers are known to use glutamate to signal dorsal-horn neurons, which express NMDA receptors (along with other known types of glutamate receptor). In all three mechanisms, therefore, the drug might counteract abnormalities involved in neuropathic pain, at least as modeled in CCI rats.
Felbamate
The effects were impressive. At intra-peritoneal doses of up to 600 mg/kg (the drug's antiepileptic range in rats), the high doses completely abolished abnormal pain sensations in the four ways we could measure them: heat hyperalgesia, mechanical hyperalgesia, mechanical allodynia, and hindpaw guarding. Heat hyperalgesia was tested by noxious heat to the hindpaw, as described. The presence of mechanical hyperalgesia was tested for by the tip of a safety pin - which was pushed slowly until it dimpled the hindpaw skin. The presence of mechanical allodynia was tested for by von Frey hairs. All effects lasted two to 12 hours. In the control hindpaw, all responses were unaffected, indicating that the drug acted specifically against neuropathic pain rather than being broadly analgesic. With only limited solubility in intrathecal media, felbamate could not be tested directly for a spinal site of action.
