Cold allodynia and hyperalgesia in neuropathic pain: the effect of N-methyl-D-aspartate (NMDA) receptor antagonist ketamine--a double-blind, cross-over comparison with alfentanil and placebo.

Cold allodynia and hyperalgesia are frequent clinical findings in patients with neuropathic pain. While there have been several clinical studies showing the involvement of central sensitization mechanisms and N-methyl-D-aspartate (NMDA) receptor activation in mechanical allodynia/hyperalgesia and ongoing pain, the mechanisms of thermal allodynia and hyperalgesia have received less attention. The aim of the present study was to examine the effect of the NMDA-receptor antagonist ketamine on thermal allodynia/hyperalgesia, ongoing pain and mechanical allodynia/hyperalgesia in patients with neuropathic pain (11 patients with post-traumatic neuralgia and one patient with post-herpetic neuralgia). All the patients were known to suffer from severe cold allodynia (cold pain detection threshold (CPDT): 23.8 degrees C, median value). The mu-opioid agonist alfentanil was used as an active control. The study design was double-blind and placebo-controlled and the drugs were administered i.v. (bolus dose and infusion). CPDT in the asymptomatic contralateral area was found to be significantly decreased (cold allodynia) compared to CPDT in site- and age-matched normal controls. Heat pain detection thresholds were found to be normal and no consistent heat hyperalgesia occurred. Alfentanil significantly reduced cold allodynia (by increasing CPDT) in symptomatic area (P=0.0076). Ketamine did not significantly increase the threshold. Significant and marked reductions of hyperalgesia to cold (visual analogue score at threshold value) were seen following both alfentanil (4.5 before, 1.4 after, median value) and ketamine (6.8 before, 0.4 after, median value). Alfentanil and ketamine also significantly reduced ongoing pain and mechanical hyperalgesia. It is concluded that NMDA-receptor mediated central sensitization is involved in cold hyperalgesia, but since CPDT remained unaltered, it is likely that other mechanisms are present.