BACKGROUND The question whether some opioids exert less respiratory depression than others has not been answered conclusively. We applied pharmacokinetic/pharmacodynamic (PKPD) modeling to obtain an estimate of the C50 for the depression of CO2 elimination as a measure of the respiratory depressant potency of alfentanil and piritramide, two opioids with vastly different pharmacokinetics and apparent respiratory depressant action. METHODS Twenty-three patients received either alfentanil (2.3 microg x kg(-1) x min-1, 14 patients, as published previously) or piritramide (17.9 microg x kg(-1) x min(-1), nine patients) until significant respiratory depression occurred. Opioid pharmacokinetics and the arterial PCO2 (PaCO2) were determined from frequent arterial blood samples. An indirect response model accounting for the respiratory stimulation due to increasing PaCO2 was used to describe the PaCO2 data. RESULTS The following pharmacodynamic parameters were estimated with NONMEM [population means and interindividual variability (CV)]: k(elCO2) (elimination rate constant of CO2) 0.144 (-) min(-1), F (gain of the CO2 response) 4.0 (fixed according to literature values) (28%), C50 (both drugs) 61.3 microg l-1 (41%), k(eo alfentanil) 0.654 (-) min(-1) and k(eo piritramide) 0.023 (-) min(-1). Assigning separate C50 values for alfentanil and piritramide did not improve the fit compared with a model with the same C50. CONCLUSIONS Since the C50 values did not differ, both drugs are equally potent respiratory depressants. The apparently lower respiratory depressant effect of piritramide when compared with alfentanil is caused by slower equilibration between the plasma and the effect site. Generalizing our results and based on simulations we conclude that slowly equilibrating opioids like piritramide are intrinsically safer with regard to respiratory depression than rapidly equilibrating opioids like alfentanil.