If a chronic neuropathic pain condition is already well established, treatment is more difficult. Sensitisation (e.g. "wind-up") is presumed to have already occurred, so the ideal medication would include an NMDA receptor antagonist. Ketamine non-competitively antagonises NMDA receptors. Although it has proven beneficial in the treatment of neuropathic pain, side-effects tend to be unacceptable. NMDA receptor antagonists are known to induce psychomimetic reactions in adults and induce behavioural disturbances such as learning and memory impairments, sensorimotor disturbances, stereotypical behaviour and hyperactivity and pathomorphological changes in neurones of the posterior cingulate/retrosplenial (PC/RS) cortex of the adult rat.
Recent animal studies have reported that pre-emptive intrathecal ketamine delayed mechanical hyperalgesia but did not prevent it. Also, case reports suggest that epidural administration of a "very low dose" of ketamine is sufficient to block activated NMDA receptors and is an effective choice for the management of neuropathic pain, without undesirable side-effects.
Calcium channel blockers
Activation of NMDA receptors leads to calcium entry into the cell and initiates a series of central sensitisation. This sensitisation may be blocked not only with NMDA receptor antagonists, but also with calcium channel blockers that prevent Ca2+ entry into cells. A double-blind study revealed that epidural verapamil and bupivacaine reduced the amount of self-administered postoperative analgesic versus epidural bupivacaine alone. It is suggested that epidural verapamil may prevent central sensitisation by surgical trauma.