The Effect of N-Methyl-D-aspartate Antagonist (Ketamine) on Single and Repeated Nociceptive Stimuli

Abstract

Ketamine is a noncompetitive N-methyl-D-aspartate (NMDA) receptor channel blocker known to inhibit "wind-up" and hence central hyperexcitability of dorsal horn neurons. We sought to assess the effect of ketamine on single and repeated nociceptive stimuli. A placebo-controlled, human (12 volunteers) experimental study was conducted in which several psychophysical (pain detection and tolerance thresholds, magnitude ratings) and electrophysiologic (withdrawal reflex) techniques were used 1) to investigate whether a ketamine (0.5 mg/kg) bolus followed by a 20-min infusion (9 micrograms.kg-1.min-1) inhibits central temporal summation to repeated nociceptive electrical stimuli, and 2) to assess quantitatively the hypoalgesic potency using several experimental nociceptive stimuli (argon laser, pressure, electrical). Facilitation of the withdrawal reflex to and pain rating of repeated electrical stimuli (five pulses at 2 Hz) were inhibited by ketamine. Reflex and pain rating to a single stimulus did not change. The pressure pain detection and tolerance thresholds were increased significantly by ketamine, whereas the laser heat pain and tolerance thresholds remained stable compared with placebo. The stimulus response function showed that ketamine reduced the responses to the highest electrical stimulus intensities (1.4, 1.6, and 1.8 times the reflex threshold). We conclude that ketamine inhibits central temporal summation in humans and has a marked hypoalgesic effect on high intensity nociceptive stimuli.

A Translational Study of the Effects of Ketamine and Pregabalin on Temporal Summation of Experimental Pain

“…In the current study, ketamine, the active control, attenuated the TS pain detection threshold and pain following suprathreshold TS stimulation in humans as expected, 8,9 showing the importance of the NMDA receptor for mediating central integration in humans.…”

“…A loading dose of ketamine of 0.5 mg/kg was used, followed by infusion of 9 Kg/kg per minute for 20 minutes. 8 Ketamine was not administered after pregabalin dosing because of the potential of a carryover effect from pregabalin; therefore, only the placebo infusion was administered after oral pregabalin dosing. Subjects attended the clinic on 6 separate occasions: screening; training session; at study periods 1, 2, and 3; and follow-up.…”

“…Compounds efficient in blocking central sensitization associated with neuropathic pain have been shown to modulate TS, for example, gabapentin, 10 ketamine, 8 imipramine, 11 and venlafaxine. 21 It is therefore of basic and clinical interest to know if pregabalin has an effect on this mechanism of action.…”

Effect of oral ketamine on secondary hyperalgesia, thermal and mechanical pain thresholds, and sedation in humans

“…No exact corresponding test is described in the literature. Arendt-Nielsen et al 38 described the lack of effect of ketamine on high-intensity laser pulses as well as brief electrical pulses. Investigating the effects of ketamine on heat stimulation of short duration (2 seconds), Arendt-Nielsen et al 37 found reduction of pain intensity after infusion of ketamine compared with placebo.…”

Effects of Gabapentin on Experimental Somatic Pain and Temporal Summation

“…14 This is interesting, as we have previously shown that drugs that affect central sensitization inhibit temporal summation. [15][16][17] As facilitated temporal summation is a feature in neuropathic pain patients, 18,19 temporal summation may be a biomarker of drug effects on neuropathic pain.…”