Objective:

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.

Methods:

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.

Results:

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.

Conclusion:

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.

Acetaminophen (APAP) is an analgesic that is widely used to relieve postoperative pain. APAP is thought to act as a substrate for the peroxidase activity of cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) and to exert its anti-inflammatory and analgesic effects by decreasing prostaglandin H2 through competition with prostaglandin G2.1  Furthermore, the similarity of its in vivo action to that of selective COX-2 inhibitors has been confirmed.2,3  Although APAP was originally thought to act peripherally, accumulating data now support an analgesia effect on the central nervous system (CNS). APAP is now thought to stimulate serotonergic pathways involved in pain inhibition,4  activate cannabinoid receptors indirectly, and have activity on NMDA and substance P receptors in the spinal cord.5,6 

The antipyretic effect of APAP reportedly occurs 2 hours after its peak plasma concentration has been reached.7  The analgesic effect of APAP can also be delayed for 1 to 2 hours after administration even though peak plasma concentration is observed just after administration.8,9  Thus, the plasma concentration is not considered to be an effect site. This hypothesis is supported by the measurement of APAP concentrations in cerebrospinal fluid after intravenous (IV) administration in children and adults.10,11  Based on these findings, the administration of APAP 1 to 2 hours before anticipated pain and fever has been recommended in children.12  Although the early administration of APAP is recommended for the purpose of postoperative analgesia, pharmacokinetic and pharmacodynamic studies of APAP and its exerted effect on postoperative pain are rare. The available pharmacokinetic-pharmacodynamic (PK-PD) models for APAP have been developed mainly for oral administration in children.7,12,13  The PK-PD model for IV administration in adults has not yet been explored.

The intraoperative use of APAP is left to the discretion of each anesthetist. APAP might not be optimally administered because an effective regimen for APAP has not yet been proposed. Determining the optimal timing of APAP administration could provide valuable information for evaluating the potency of APAP against postoperative pain and could help to reduce opioid use for postoperative analgesia. An adjuvant to opioids for postoperative pain relief is eagerly awaited to avoid the various adverse effects of opioid use and delay in hospital discharge.

We investigated the PK-PD profile of APAP in volunteers and examined the relationship between the PK-PD profile and the effect of APAP on pain perception.

Ethics and Study Design

This study was approved by the Showa University Clinical Research Review Board (approval number: CRB3200002) and was registered at jRCT (https://jrct.niph.go.jp; registration number: jRCTs031200321, Akiko Nishimura, January 21, 2021).

The study design was a randomized, single-blinded, crossover trial comparing IV APAP (Acelio Intravenous Injection, 1000 mg/100 mL bag, Terumo Corp) and a saline placebo. This study was conducted at Showa University Clinical Institute for Clinical Pharmacology and Therapeutics (Tokyo, Japan), from January 21, 2021, to March 9, 2021. The testing period was 2 days followed by a 1-week washout period. After obtaining informed consent, the institute staff registered study participants using an identification code for anonymization and random allocation to 1 of 2 groups. Participants were divided according to sex and then randomly assigned in a 1:1 ratio to receive either APAP or saline on the first day of testing; the randomization was performed using a random number table without stratification. Subjects' height, weight, and vital signs were measured. A cannula was inserted in the dominant arm for blood sampling and in the nondominant arm for drug administration. In total, 1000 mg of APAP or an equivalent volume of saline placebo was intravenously infused for 15 minutes using an infusion pump. Vital signs were measured at 60, 120, and 240 minutes after administration. The analgesic effect and the plasma APAP concentration were also evaluated.

Subjects

Fifteen subjects aged 20 to 60 years with an American Society of Anesthesiologists (ASA) physical status of I were enrolled. All subjects provided written informed consent. The exclusion criteria included a known allergy to APAP; peptic ulcer disease; serious blood coagulation disorders; serious liver, renal, or cardiac dysfunction; aspirin-induced asthma; pregnancy or breastfeeding; the presence of an electronic implant; or any medical concerns that might impact the study.

Evaluation of Analgesic Effect and Plasma Concentration

We used the PainVision PS-2100 device (Nipro Corp) to evaluate analgesia. The PainVision device was developed to evaluate pain and sensory perception quantitatively and can be used to evaluate the effects of treatment and medication.1416  This device selectively stimulates Aβ and Aδ sensory fibers by sending pulses of electric current along the surface of the body and then records the participant's sensory threshold. The electrode is attached to the ulnar side of the forearm opposite the dominant hand, and the subject holds a hand switch in the other hand. The subject then presses the hand switch when he or she perceives a current or feels pain. The current perception threshold (CPT) was defined as the minimum current that could be perceived by the subject. The pain equivalent current (PEC) was defined as the current at which the subject first felt pain. The CPT and PEC were obtained before APAP administration (PRE values) and at 0, 30, 60, 90, 120, 180, 240, and 300 minutes after administration.

Parameters were each measured 3 times with different current rise times to prevent the subject from becoming acclimated (CPT: 60, 80, and 100 seconds; PEC: 30, 40, and 50 seconds). When outliers appeared, the parameter was remeasured using the same current rise time; a maximum of 3 remeasurements were allowed. The closest 3 values were averaged. The change in each value relative to the PRE value was calculated and used for analysis. The subjects practiced before the actual measurement. We used the PEC value as the pain threshold, which was considered to reflect the intensity of the analgesic effect of APAP. In this manner, the PEC values were used in the PK-PD study modeling as a value reflecting the pharmacological target effect of APAP.

Blood samples (5 mL) were obtained before APAP administration (PRE) and at 0, 15, 30, 45, 60, 90, 120, 180, 240, and 300 minutes after administration. The blood samples were collected into vacuum tubes, and the plasma was separated by centrifugation at 1520 × g for 10 minutes. The plasma samples were refrigerated until analysis. The human plasma concentrations of APAP were measured using an enzyme immunoassay (EIA) method and the Clinical Chemistry Automatic Analyzer Cobas 6000 (Roche Diagnostics KK) at BML Inc (Tokyo, Japan).

PK-PD Modeling

The PK-PD analysis was performed based on the time profiles of the plasma APAP concentrations and the analgesic effects after the IV infusion of APAP (1 g) to 15 healthy subjects. A PK-PD model incorporating an effect compartment was constructed using Phoenix WinNonlin 8.3 software (Certara; Figure 1), and the model parameters for each subject were estimated.

Figure 1.

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.

Figure 1.

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.

Close modal

The PK profile of APAP was also analyzed using a linear 2-compartment model. APAP was infused intravenously into the central compartment for 15 minutes, and the time profile of the plasma APAP concentration (Cp) for each subject was fitted to the above PK model. The PK-related parameters in the model were estimated for each subject and consisted of the distribution volume of the central compartment (V1), the distribution volume of the peripheral compartment (V2), the total clearance (CL), and the intercompartmental clearance (Q2). In addition, the volume of distribution (Vd) and the elimination half-life (T1/2) were calculated as secondary PK parameters using the estimated parameters.

The rate of change in PEC was used as the analgesic effect. By incorporating the effect compartment with a first-order equilibration rate constant (ke0) into the PK model, the delay in the effect was described.17  The APAP concentrations in the effect compartment and the rate constant between the central compartment and the effect compartment were represented as Ce and ke0, respectively. The rate of change in Ce () was defined using ke0 according to the following previously reported equation.18 
formula
Regarding the PD model connected to Ce, a linear effect model was used to describe the PD of AAP as follows:
formula
where E is the effect, E0 represents the effect at baseline (PRE; set at 0 in this study), and β is a proportional constant of the linear relationship between the APAP concentrations in the effect compartment and the analgesic effect, or the rate of PEC change. The PD model parameters (ke0 and β) were estimated for each subject by applying the observed time-effect profile to the PK-PD model with the estimates obtained in the above-described PK analysis. All fitting procedures were performed using a nonlinear least square method and Phoenix WinNonlin software.

Statistical Analysis

The data obtained were analyzed using JMP clinical 6.1 (SAS Institute Inc). All data were reported as the mean ± SD or number of subjects. Continuous data were checked for equality of variance using the Shapiro-Wilk test, and nonparametric data were reported as the median (interquartile range). A P value of < 0.05 was considered to indicate statistical significance.

The differences between the APAP and control groups were tested using a multivariate analysis of variance (MANOVA). A Kruskal-Wallis test was used for the statistical analysis for the intragroup difference in the PEC values in the APAP and control groups. A Dunn post-hoc test of multiple comparisons was used to determine whether a significant difference existed at each time point if a significant difference was first indicated using a Kruskal-Wallis test.

Sample Size Calculation

Although no previous studies have verified the analgesic effect of acetaminophen using the PainVision device, 1 article in Japanese examining the analgesic effect of NSAIDs using the CPT obtained using PainVision (data not shown) has been reported. This previous report was used to determine an appropriate sample size. An a priori power analysis showed that 6 patients were required to detect a difference at a power of 80% using a 2-sided significance level of .05. Although no previous reports have examined the analgesic effect using PEC, 1 study showed that the rate of change in PEC was larger than the rate of change in CPT.19  The sample size was estimated using a t-test and a χ2 test with G* power software version 3.1.9.2.

A total of 16 subjects were scheduled to participate, but 1 subject withdrew. An additional subject was not enrolled because a post-hoc power analysis resulted in a value of 98.6% at a .05 level of significance. The background characteristics of the 15 subjects were as follows: age 29 ± 3 years; sex (M/F) 7/8; height 165 ± 10 cm; and weight 58.3 ± 8.3 kg. All subjects met the eligibility criteria, and the BMI range was from 17 to 26 kg/m2. None of the subjects experienced an adverse event, and all the subjects exhibited normal vital signs.

In both groups, the CPT remained unchanged throughout the experimental period (Figure 2A). The PEC in the APAP group was significantly higher than that in the control group throughout the experimental period. No significant difference in PEC was observed between the PRE and 300-minute time points in the control group, but a significant difference was observed in the APAP group. Compared with the PRE value, the PEC in the APAP group differed significantly at time points between 90 and 300 minutes after APAP administration, suggesting that the onset of the analgesic effect occurred 90 minutes after administration (Figure 2B).

Figure 2.

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).

Figure 2.

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).

Close modal

The plasma concentration peaked just after APAP administration, whereas the PEC peaked 180 minutes after administration (Figure 3). Thus, a substantial significant time lag, as high as 180 minutes, was confirmed between the peak plasma concentration and the peak analgesic effect.

Figure 3.

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.

Figure 3.

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.

Close modal

The PK of IV APAP was described using a 2-compartment model (Figure 1). The PK-PD parameter estimates for the plasma concentration and pharmacological analgesic effect of APAP derived using the plasma concentration and the PEC of the 15 subjects, respectively (Figure 3), are shown in the Table. The fitted time-concentration/effect profiles are delineated (Figure 4), the descending slope were slower than the ascending slope. According to this PK-PD model, the effect reached the peak at 188 minutes, then gradually decreased. It is estimated from this model that the time that reached the corresponding value on the ascending slope at 90 minutes was at 327 minutes on the descending slope (Figure 4).

PK-PD Parameters Estimated in Healthy Adults*

PK-PD Parameters Estimated in Healthy Adults*
PK-PD Parameters Estimated in Healthy Adults*
Figure 4.

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.

Figure 4.

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.

Close modal

APAP has been recommended for use as an adjuvant to opioids in practice guidelines for acute pain management in perioperative settings published by the ASA in 2012. These guidelines state that “the ASA members agree and the consultants strongly agree that acetaminophen should be considered as part of a postoperative multimodal pain management regimen”.20  Although the efficacy of APAP as an alternative analgesic for postoperative pain has been recognized, the optimal utilization of APAP has yet to be determined. Most studies recommend around-the-clock administration every 4 to 6 hours.2123  However, timing for the optimal administration of IV APAP to target the peak of postoperative pain yet to be reported.

The onset of APAP's efficacy has been shown to be 1 or 2 hours, which is relatively late.24  The delay in the analgesic effect of APAP was first confirmed in relation to its use as an antipyretic. Kelley et al7  reported that body temperature decreased 2 hours after the peak plasma concentration had been reached. This unique property of APAP suggests a central action. APAP has been confirmed to exert its analgesic effect by acting on receptors involving NMDA and substance P in the spinal cord.25,26  The cerebrospinal concentrations of APAP have been measured in both children10  and adults.11  Because of these studies examining the effect of APAP on the central nervous system, we were motivated to confirm the time-course of the analgesic effect of APAP and whether the analgesic effect corresponded with the pharmacokinetic properties associated with the cerebrospinal concentration.

PK-PD models of APAP have been previously studied in children,12,13  since APAP has been mainly used as an antipyretic for children and as an alternative to NSAIDs. PK-PD studies in adults have been rare. APAP has been mainly used as an oral medication; thus, most PK-PD models in adults have been proposed for oral administration.27  To the best of our knowledge, our proposed model for IV APAP use in adults is therefore quite unique. An advantage and novel point of our PK-PD model was that it was based on the pain perception of patients, and not the effect site concentration of the agent. Therefore, we think that our model was able to explain the clinical manifestations of the analgesic effect of APAP.

The PK parameters such as clearance and distribution volume that were obtained in the present study were comparable with previously reported values.2830  The t1/2 was ∼2 hours, indicating the prompt elimination of APAP from the plasma. A counterclockwise hysteresis was observed between the APAP plasma concentrations and the effect (ie, the rate of change in PEC), suggesting the delayed onset of the analgesic effect. Therefore, the effect compartment was incorporated into the model to express the delayed drug action mathematically. Previous reports also suggest that the analgesic effect of APAP is correlated with its concentration at the effect site rather than its plasma concentration.10,11,27  Some previous reports24,27  used the sigmoid Emax model to describe the relationship between the APAP concentration in the effect compartment (Ce) and the effect (E). However, in this study, a linear model was used for the PK-PD relationship, since a saturation phase of the effect was not apparent and analyses using an Emax model or a log-linear model did not provide a reliable convergence of PD parameters. The population PK model formulas for APAP reported by Würthwein et al28  include body weight as a covariate, and Imaizumi et al29  reported that these formulas also described the pharmacokinetics of APAP in Japanese patients undergoing elective surgery. In addition, Allegaert et al30  reported that size (ie, total body weight and fat free mass) and age are important covariates for APAP pharmacokinetics to explain the variabilities of clearance and distribution volume variability in adults, including healthy volunteers. The ages of the healthy adults and the patients in this study were within the same range; therefore, a simulation based on the standardization of PK parameters according to body weight would be appropriate.

We utilized the PainVision device to evaluate pain quantitatively. This apparatus delivers a pulsed current with a pulse width of 0.3 milliseconds and a pulse frequency of 50 hertz; the intensity of the current was controllable. The CPT and PEC parameters were then used to quantitate the thresholds of sensory perception and pain perception, respectively. The latter parameter was then confirmed using the VAS score.31  The intensity of pain perception can be quantitatively evaluated by the pain generated by a current. Subjects are asked to push a button when they feel pain. The PainVision is a useful means of quantitative assessing pain in healthy subjects without chronic pain.31,32  We considered the pain thresholds to reflect the analgesic effect of APAP.

We demonstrated that the analgesic effect of IV APAP can be expected ∼90 minutes after administration in adults, and its effect lasts longer than 5 hours. Planned continuous maintenance of APAP medication based on the PK/PD model should result in an optimal administration regimen and could reduce the unnecessary or excessive use of NSAIDs and opioids for postoperative pain management.

The developed PK-PD model of IV APAP suggests the appropriate timing for administration to maximize postoperative analgesia. At least 90 minutes is required to achieve the analgesic effect of IV APAP.

The authors would like to thank Ms Myrna Harrod for help with English spelling and grammar. The authors would also like to thank Dr Kakei Ryu, Dr Takuya Mizukami, Dr Takehiko Sanbe, and staff of Showa University Clinical Institute for Clinical Pharmacology and Therapeutics for assistance with the experiment on healthy adults.

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