Neuropathic Pain Control: Anti-convulsants and anti-depressants

[Guest guest]

Handb Exp Pharmacol. 2007;(177):145-77.

Anti-convulsants and anti-depressants.

Dickenson AH, Ghandehari J.

Dept. Pharmacology, University College London, Gower Street, London

WC1E 6BT, UK.

Damage to a nerve should only lead to sensory loss. While this is

common, the incidence of spontaneous pain, allodynia and

hyperalgesia indicate marked changes in the nervous system that are

possible compensations for the loss of normal function that arises

from the sensory loss.

Neuropathic pain arises from changes in the damaged nerve which then

alter function in the spinal cord and the brain and lead to

plasticity in areas adjacent to those directly influenced by the

neuropathy. The peripheral changes drive central compensations so

that the mechanisms involved are multiple and located at a number of

sites. Nerve damage increases the excitability of both the damaged

and undamaged nerve fibres, neuromas and the cell bodies in the

dorsal root ganglion.

These peripheral changes are substrates for the ongoing pain and the

efficacy of excitability blockers such as carbamazepine, lamotrigine

and mexiletine, all anti-convulsants. A better understanding of ion

channels at the sites of injury has shown important roles of

particular sodium, potassium and calcium channels in the genesis of

neuropathic pain. Within the spinal cord, increases in the activity

of calcium channels and the receptors for glutamate, especially the

N-methyl-D-aspartate (NMDA) receptor, trigger wind-up and central

hyperexcitability.

Increases in transmitter release, neuronal excitability and

receptive field size result from the damage to the peripheral

nerves. Ketamine and gabapentin/pregabalin, again with anti-

convulsant activity, may interact with these mechanisms. Ketamine

acts on central spinal mechanisms of excitability whereas gabapentin

acts on a subunit of calcium channels that is responsible for the

release of pain transmitters into the spinal cord.

In addition to these spinal mechanisms of hyperexcitability, spinal

cells participate in a spinal-supraspinal loop that involves parts

of the brain involved in affective responses to pain but also

engages descending excitatory and inhibitory systems that use the

monoamines. These pathways become more active after nerve injury and

are the site of action of anti-depressants. This chapter reviews the

evidence and mechanisms of drugs, both anti-depressants and anti-

convulsants, that are believed to be effective in pain control, with

a major emphasis on the neuropathic state.