The effect of ketamine on opioid-induced acute tolerance: Can it explain reduction of opioid consumption with ketamine-opioid analgesic combinations?

Ketamine administered intraoperatively in very small doses reduces postoper ative opioid consumption. We suggest that this effect is the result of atte nuation of acute tolerance to the analgesic effect of opioids. We sought to demonstrate that acute tolerance induced by alfentanil infusion can be att enuated by a dose of ketamine that is too small to produce a direct antinoc iceptive effect. The experiments were conducted in rats with the use of an infusion algorithm designed to maintain a constant plasma level of the opio id for 4 h. The degree of acute tolerance was determined on the basis of de cline in the level of analgesia measured with a tail compression test. Keta mine (10 mg/kg) did not change the baseline pain threshold and did not incr ease the peak of alfentanil-induced analgesia. At the same time, it attenua ted the development of acute tolerance to analgesia during alfentanil infus ion and suppressed rebound hyperalgesia observed the day after the infusion . These effects were similar to those observed with dizocilpine (0.1 mg/kg) . The development of acute tolerance to analgesia induced by the infusion o f an opioid can be attenuated by ketamine administered in doses that are no t large enough to provide a direct antinociceptive effect. Therefore, ketam ine has the potential to reduce opioid consumption even in subanalgesic dos es.