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.