Optimal Timing of Intravenous Acetaminophen Administration for Postoperative Analgesia
Acetaminophen (APAP) is widely used as an analgesic for postoperative pain relief. However, the pharmacokinetic-pharmacodynamic (PK-PD) properties of intravenous APAP administration remain unclear. We developed a PK-PD model in adult volunteers. APAP (1 g) was intravenously administered to 15 healthy volunteers. The pain equivalent current (PEC) was then measured using the pulse current, corresponding to the quantitative value of pain perception. The PK model was developed using a 2-compartment model, and the PD model was developed using a linear model and an effect compartment model. APAP plasma concentration peaked just administration, whereas PEC significantly increased at 90 minutes and lasted through the experimental period (300 minutes). APAP plasma concentrations and PEC were processed for use in the PK-PD model. The developed PK-PD model delineates the analgesic effect profile, which peaked at 188 minutes and lasted until 327 minutes. We developed the PK/PD model for APAP administered intravenously. The analgesic effect can be expected ∼90 minutes after administration and to last >5 hours. It is suggested that APAP be administered ∼90 minutes prior to the onset of anticipated postoperative pain.
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Schematic structure of the pharmacokinetic-pharmacodynamic (PK-PD) model.
Drug administered into and eliminated from a central compartment: X1 and X2 are drug amounts in the central and peripheral compartments, and V1 and V2 are distribution volumes of the central or peripheral compartments, respectively; Cp is the plasma drug concentration. CL is the clearance from the central compartment, and Q2 is the intercompartmental clearance. The central compartment is connected to an effect compartment by a first-order equilibration rate constant: Ce is the drug concentration in the effect compartment. The ke0 parameter describes the equilibration rate constant between the central compartment and the effect compartment.
Rate of change in current perception threshold (CPT) (A) and pain equivalent current (PEC) (B) in the acetaminophen (APAP) and control groups.
No significant difference in the rate of CPT change was seen between the APAP and control groups (Figure 1A). On the other hand, the rate of PEC change was significantly higher in the APAP group than in the control group, and the PEC in the APAP group differed significantly at time points between 90 and 300 minutes compared with the PRE value (Figure 1B).
* P < .05 (vs PRE value).
Relationship between plasma acetaminophen (APAP) concentration and pain equivalent current (PEC) value (Figure 2B).
The plasma APAP concentration reached its highest level immediately after administration, but the analgesic effect peaked at 180 minutes after administration. Note that the target effect was substantially delayed after the peak of the plasma concentration.
The pharmacokinetic-pharmacodynamic (PK-PD) model developed using the acetaminophen (APAP) plasma concentration and pain equivalent current (PEC) data.
The PK model (A) was developed using a 2-compartment model, and PD model (B) was developed using a linear model and an effect compartment model. The symbols represent the mean and standard error (SE) that were obtained in 15 subjects. Open circles and the dashed line represent the duration of the analgesic effect of APAP estimated by PK-PD model.
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