Single versus multiple infusions of fentanyl analogues in a rat EEG model

Administration of anesthetic agents to rats produces a loss of righting (LOR) which is predictive of clinical anesthesia. Following bolus i.v. administration of fentanyl, sufentanil, alfentanil, and remifentanil, the ED100 doses for LOR were 0.035, 0.003, 0.05, and 0.020 mg/kg, respectively. For the EEG infusion studies, rats were implanted with jugular catheters and 5 cortical electrodes on the surface of the dura mater. Each agent was infused at a rate of 0.02 ml/min such that each animal received the ED100 dose every 60 seconds until LOR was observed and the infusion was stopped. Following a single infusion to LOR, the difference in time from the return of righting (ROR) to baseline EEG for fentanyl, sufentanil, alfentanil, and remifentanil was 30.9, 35.3, 14.9, and 1.3 minutes, respectively. Following a three hour washout period, multiple infusions (three successive infusions to LOR) were administered. Following ROR (after the third LOR) the return to baseline EEG for fentanyl, sufentanil, alfentanil, and remifentanil was 56.1, 58.5, 13.6, and 2.9 minutes, respectively. There were no statistically significant differences between the single and multiple infusions for the return to baseline EEG for alfentanil and remifentanil, but there were significant increases in time to return to baseline following multiple infusions of fentanyl and sufentanil. These results show that there was no cumulation of alfentanil and remifentanil with respect to EEG effects but cumulation was observed for fentanyl and sufentanil.