Drs. Al-Samsam and Chelly have suggested that a study by Katz and Siffert 1invalidates our model. To the contrary, the Katz and Siffert study actually helps support our model. Although it may be unreliable to compare a nonrandomized, unblinded laboratory study of cefazolin kinetics (human half-life 90–150 min) in 10 mongrel dogs to a blinded, randomized, controlled-trial of ketorolac tromethamine (half-life 120–480 min) in humans, it is nice to have confirmation that drugs administered systemically after tourniquet inflation do not reach the target limb in any significant amount. This was a major point of our study design. To quote, “because ketorolac exerts its analgesic effects primarily at the peripheral level, 2the latter dose would function as a poststimulus dose, since it would not reach the site of action until after the tourniquet was deflated at the end of surgery” (emphasis added). The tourniquets in Katz and Siffert's study were never deflated because this study was undertaken to determine if cefazolin administered after tourniquet inflation reached the tissues in significant amounts. This study did not examine tissue drug levels after tourniquet deflation, hence we see no need to “modulate” our conclusions.
Drs. Manoir and Fletcher suggest that our results cannot be attributed to preemptive analgesia because they are not long-lived. We disagree. The definition of preemptive analgesia is the phenomenon by which analgesia administered before a painful stimulus decreases the intensity of the subsequent pain. 3There is no requirement that these effects must persist for a certain period of time. Our paper presents several possible explanations for the relatively short duration of the observed preemptive analgesic effects. Particularly important are the effects of ongoing tissue inflammation caused by surgical trauma. This inflammation, like repeat injury, will obscure preemptive effects, as discussed by Woolf and Chong. 3Optimal preemptive analgesia may necessitate continuing therapy into the postoperative period.