Pharmacokinetic-pharmacodynamic modelling of the analgesic effect of alfentanil in the rat using tooth pulp evoked potentials.

The purpose of the present study was to develop an animal model for the investigation of the concentration-effect relationship of alfentanil using tooth pulp evoked potentials (TPEP). Six chronically instrumented, freely moving rats received a computer-controlled intravenous infusion of alfentanil resulting in seven pseudo-steady-state blood concentration levels, each maintained for 30 min. At each concentration level, the tooth pulp of the rat upper incisor was electrically stimulated in a time-randomized order with different current intensities (400-800 microA, 1 msec duration) and the electroencephalogram (EEG) was recorded concomitantly. Arterial blood samples were collected serially and assayed for alfentanil using RIA. Repetitive evoked EEG responses were averaged per stimulus intensity and per session. The decrease of the area under the negative peak 15 msec after stimulation (% of preadministration value) was used as pharmacological endpoint. The concentration-TPEP effect of alfentanil was investigated by nonlinear mixed effect modeling (NONMEM). When the observed TPEP effect was plotted versus the alfentanil blood concentration no hysteresis or proteresis was observed, and the two could directly be related to each other on the basis of the sigmoidal Emax pharmacodynamic model. The (population) pharmacodynamic estimates were (+/-S.E.): Emax = 108 +/- 10%, EC50 = 24 +/- 17 ng/ml, Hill factor = 0.81 +/- 0.37. A large interindividual variability for EC50 (omegaEC50) of 164 +/- 107% was observed. The residual variability was 14 +/- 10%. It is concluded that the TPEP is a useful tool for the systematic investigation of the concentration-analgesic effect relationship of centrally acting analgesics in the freely moving rat.