Effect of systemic N-methyl-D-aspartate receptor antagonist (ketamine) on primary and secondary hyperalgesia in humans

Abstract

Ketamine reduces nociception by binding noncompetitively to the N-methyl-D-aspartate (NMDA) receptor, activation of which increases spinal hypersensitivity. We studied 19 healthy, unmedicated male volunteers, aged 20-31 yr. Burn injuries were produced on the medial surface of the dominant calf with a 25 x 50 mm rectangular thermode. On 3 separate days, at least 1 week apart, subjects received a bolus of either ketamine 0.15 mg kg-1, ketamine 0.30 mg kg-1 or placebo, delivered by a mechanical infusion pump over 15 min. The bolus was followed by continuous infusion of ketamine 0.15 mg kg-1 h-1, ketamine 0.30 mg kg-1 h-1 or placebo, respectively, for 135 min. Ketamine reduced the magnitude of both primary and secondary hyperalgesia, and also pain evoked by prolonged noxious heat stimulation, in a dose-dependent manner. In contrast, ketamine did not alter phasic heat pain perception (perception of transient, painful, thermal stimuli) in undamaged skin. The analgesic effects of ketamine in the burn injury model are in agreement with results from experimental studies, and can be distinguished from those of local anaesthetics and opioids. Side effects caused by continuous infusion of ketamine 0.15 and 0.30 mg kg-1 h-1 were frequent but clinically acceptable.

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

“…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). Allodynia and hyperalgesia from continuous electrical stimulation were all affected by ketamine (Koppert et al, 2001), which should be expected because the inflicted pain is strong and longlasting, and it probably activates the NMDA receptors.…”

Cetamina e analgesia preemptiva

“…Also in rats, racemic ketamine has decreased peripheral hyperalgesia triggered by thermal stimulation 80 . In volunteers submitted to burns, racemic ketamine decreases central sensitization both by intravenous 82,83 and subcutaneous 84 routes. This effect has not been observed with oral administration 85 .…”

“…Também em ratos, a cetamina racêmica diminui a hiperalgesia periférica provocada por estímulo térmico 80 . Em voluntários submetidos a queimaduras, a cetamina racê-mica reduz a sensibilização central tanto pela via venosa 82,83 como pela via subcutânea 84 . Esse efeito não foi observado por via oral 85 .…”

Safety of opioid patch initiation in Australian residential aged care

“…There is experimental evidence for beneficial effects of ketamine (Ilkjaer et al, 1996) and dextromethorphan on hyperalgesia, and clinical evidence of an opioid-sparing effect with clonidine (Viggiano et al, 1998 Level II).…”