Optimal Timing of Intravenous Acetaminophen Administration for Postoperative Analgesia

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.

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.

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.^14–16  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).

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.

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 (V_d) and the elimination half-life (T_1/2) were calculated as secondary PK parameters using the estimated parameters.

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.

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).

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.

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).

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.^21–23  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.^28–30  The t_1/2 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 reports^24,27  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.