Effect of multiple dosing on the analgesic action of diflunisal in rats

This investigation was designed to compare the analgesic effect of the initial dose of a repetitively dosed non-narcotic analgesic with the analgesic effect of a subsequent dose given 3 days later. To exclude gradual drug accumulation as a variable, the first ("loading") dose was larger than the maintenance doses. Male Sprague-Dawley rats received 100 mg/kg diflunisal i.v. as the first dose and 70 or 75 mg/kg every 12 hours thereafter. The analgesic effect of the first and seventh doses was determined as the pain threshold (voltage) upon electrical stimulation of the tail every 15 to 30 minutes from the third to the ninth hour after dosing. Blood samples for drug assay were obtained at 3 and 9 hours. A control group received injections of solvent for 6 doses and 100 mg/kg diflunisal as the seventh dose. There were no statistically significant differences between the area under the total or free (unbound) drug concentration versus time curves of the first and seventh dose but the average analgesic effect (area under the voltage increase versus time) of the seventh dose was only 28 percent that of the first dose. The areas under the drug concentration and analgesic effect versus time curves of the diflunisal dose given as the seventh injection to the control rats were similar to those produced by the first dose given to the multiple dosed rats. The results of this investigation show that the analgesic effect of a non-narcotic drug decreases substantially during repeated dosing in an animal model of experimental pain. This change in pharmacologic response has the characteristics of functional rather than pharmacokinetic tolerance in that there was no change in the drug concentration profile with time and no effect of the manipulations as such (i.e., repeated pain threshold determinations and blood withdrawals) on diflunisal-induced analgesia. These observations may have important implications for the evaluation and use of non-narcotic analgesics in the management of clinical pain.