Background: Although respiratory depression is the most well-known and dang
erous side effect of opioids, no pharmacokinetic-pharmacodynamic model exis
ts for its quantitative analysis. The development of such a model was the a
im of this study.
Methods: After institutional approval and informed consent were obtained, 1
4 men (American Society of Anesthesiologists physical status I or II; media
n age, 42 yr [range, 20-71 yr]; median weight, 82.5 kg [range, 68-108 kg])
were studied before they underwent major urologic surgery. An intravenous i
nfusion of alfentanil (2.3 mu g . kg(-1). min(-1)) was started while the pa
tients were breathing oxygen-enriched air (fraction of inspired oxygen [FIO
2] = 0.5) over a tightly fitting continuous positive airway pressure mask T
he infusion was discontinued when a cumulative dose of 70 mu g/kg had been
administered, the end-expiratory partial pressure of carbon dioxide (PECO2)
exceeded 65 mmHg, or apneic periods lasting more than 60 s occurred. Durin
g and after the infusion, frequent arterial blood samples were drawn and an
alyzed for the concentration of alfentanil and the arterial carbon dioxide
pressure (Pa-CO2). A mamillary tno-compartment model was fitted to the phar
macokinetic data. The Pa-CO2 data were described by an indirect response mo
del The model accounted for the respiratory stimulation resulting from incr
easing Pa-CO2. The model parameters were estimated using NONMEM. Simulation
s were performed to define the respiratory response at steady state to diff
erent alfentanil concentrations.
Results: The indirect response model adequately described the time course o
f the Pa-CO2. The following pharmacodynamic parameters were estimated (popu
lation means and Interindividual variability): EC50, 60.3 mu g/l (32%); the
elimination rate constant of carbon dioxide (K-cl), 0.088 min(-1) (44%); a
nd the gain in the carbon dioxide response, 4 (28%) (fixed according to lit
erature values). Simulations revealed the pronounced role of Pa-CO2 in main
taining alveolar ventilation in the presence of opioid.
Conclusions: The model described the data for the entire opioid-Pa-CO2 resp
onse surface examined. Indirect response models appear to be a promising to
ol for the quantitative evaluation of drug-induced respiratory depression.