The effect of Ketamine on stimulation of primary and secondary hyperalgesic areas induced by capsaicin -- a double-blind, placebo-controlled, human experimental study

Abstract

The non-competitive NMDA-antagonist, Ketamine, was infused (i.v.) in healthy volunteers to study the effect on central excitability with the presence of cutaneous hyperalgesia. Hyperalgesia was established experimentally on the dorsum of the foot by topical application of capsaicin (1%). Different thermal and mechanical conditioning stimuli were applied to the primary and secondary hyperalgesic areas to modulate the central nociceptive excitability monitored by the nociceptive reflex. When the elicited reflex was combined with an activation of the secondary hyperalgesic area by continuous, non-painful, electrical stimulation, a facilitation of the reflex was observed. This indicates that summation of activity in non-nociceptive and nociceptive afferents can occur under mild pathological conditions. Conditioning thermal stimuli of the primary hyperalgesic area were employed to intensify the allodynia prior to testing this interaction between tactile and nociceptive activity. The same reflex facilitation was inhibited by Ketamine. Furthermore, Ketamine decreased the pain intensity associated with the stimuli eliciting the reflex. Psychophysical measures to single and repeated electrical and thermal (laser) stimuli applied within the hyperalgesic areas were also obtained. The intensity of pain sensations produced by single, painful, electrical stimuli applied to the primary hyperalgesic region was reduced after Ketamine infusion. Finally, five repeated, electrical stimuli applied to the secondary hyperalgesic area were used to assess the temporal summation threshold. Ketamine caused an increase in the summation threshold compared to the placebo treatment. In conclusion, these results demonstrate that (1) summation of activity in non-nociceptive and nociceptive afferents occurs under hyperalgesic conditions and, (2) this summation can be inhibited by NMDA-antagonists. Therefore, the study shows an apparent involvement of NMDA-receptors in some of the central mechanisms underlying secondary hyperalgesia.

Assessing efficacy of non‐opioid analgesics in experimental pain models in healthy volunteers: an updated review

“…One study evaluated the hyperalgesia with laser heat and electrical stimulation. Here only the electrical stimulation in the secondary hyperalgesic area was sensitive to the drug [60].…”

Human Experimental Pain Models for Assessing the Therapeutic Efficacy of Analgesic Drugs

“…Hyperalgesia to stroking and pinprick were affected by systemic but not locally applied ketamine (Sethna et al, 1998;Gottrup et al, 2000a,b;Wallace et al, 2002b). One study evaluated the hyperalgesia with laser heat and electrical stimulation; only the electrical stimulation in the secondary hyperalgesic area was sensitive to the drug (Andersen et al, 1996). Hyperalgesia evoked by burn injury is decreased by ketamine, and substantial effects could be seen on hyperalgesia in response to pinprick and allodynia in response to stroking (Ilkjaer et al, 1996;Warncke et al, 1997;Schulte et al, 2004).…”

Assessing analgesic actions of opioids by experimental pain models in healthy volunteers – an updated review

“…In models evoking hyperalgesia, the sensitization of the pain system can be assessed in different ways.Hyperalgesia can be seen as an increased pain response to painful stimulation or a lowering of the pain detection threshold [40,41]. Often such models also evoke allodynia, for example, to gently stroking of the skin by a cotton wool tip [42,43].…”