Mapping of punctuate hyperalgesia around a surgical incision demonstrates that ketamine is a powerful suppressor of central sensitization to pain following surgery

Abstract

Background: Tissue injury induces central sensitization in the spinal cord dorsal horn neurons via mechanisms involving N-methyl-D-aspartate (NMDA) receptors, leading to secondary hyperalgesia. Using punctuate mechanical hyperalgesia as a measure of central sensitization, we examined whether induction and maintenance of central sensitization after surgery could be prevented by a low-dose infusion of the NMDA-receptor antagonist ketamine.

Methods: Twenty living kidney donors were included in a randomized, double-blind, parallel, two-group study. Before start of surgery 10 patients received an i.v. bolus of racemic ketamine 0.5 mg.kg-1, followed by a continuous i.v. infusion of ketamine 2 micrograms.kg-1.min-1 for 24 h, thereafter 1 microgram.kg-1.min-1 for another 48 h. The control group received placebo bolus and infusion. A standard general anaesthesia including fentanyl was used. Patient-controlled (PCA) i.v. morphine was used for postoperative analgesia. Punctuate mechanical hyperalgesia and temporal summation of mechanical stimuli causing "wind-up pain" were measured using von Frey filaments.

Results: The area of punctuate mechanical hyperalgesia was significantly reduced in the ketamine group 1, 3 and 7 d after the operation (P < 0.01-0.001). "Wind-up pain" was also reduced by ketamine (P < 0.05). PCA morphine consumption and pain intensity (visual analogue scale) differed between groups only during the first hours after surgery, in favour of ketamine. The ketamine patients scored significantly higher on a global satisfaction score. Side-effects were most frequent in the placebo group.

Conclusion: Low-dose i.v. infusion of ketamine during and after surgery reduces mechanical punctuate hyperalgesia surrounding the surgical incision. These results indicate that blockade of NMDA receptors prevents the central sensitization caused by nociceptive input during and after surgery.