PDF
Citation
Print
INTRODUCTION
Robot-assisted laparoscopic radical prostatectomy (RALP) is the standard treatment for localized prostate cancer, with clear advantages over open surgery, including less blood loss, shorter hospital stays, and better cosmetic results [1,2]. However, RALP still causes moderate to severe postoperative pain from trocar insertion and peritoneal irritation [3]. Inadequate pain control is associated with higher rates of postoperative complications, prolonged hospital stays, and the development of persistent postsurgical pain that impairs patient quality of life [4]. While opioids have traditionally been the main treatment, their adverse effects, including nausea, vomiting, sedation, and respiratory depression, can slow recovery and increase costs, making multimodal opioid-sparing analgesia the preferred approach [5,6].
The timing of analgesic administration has been suggested to influence central sensitization, which involves enhanced responsiveness of nociceptive neurons after tissue injury and can lead to persistent pain states [7,8]. Preemptive analgesia, administered before surgical incision, aims to prevent the initial establishment of central sensitization by blocking nociceptive input [9]. In contrast, preventive analgesia maintains analgesic coverage throughout the perioperative period, recognizing that sensitization can develop from ongoing inflammatory responses after surgery [10]. However, studies comparing these timing strategies have reported conflicting results, possibly due to variations in surgical procedures, analgesic agents, and study methodologies [8,10].
A new intravenous combination of acetaminophen (1,000 mg) and ibuprofen (300 mg) works better than either drug alone through complementary mechanisms [11,12]. Acetaminophen exerts its analgesic effect mainly via central modulation of pain pathways, while ibuprofen provides peripheral anti-inflammatory effects [13]. However, the optimal timing for this combination in RALP patients remains unclear. This knowledge gap is clinically significant because RALP patients face unique challenges, as the minimally invasive nature often leads to underestimation of postoperative pain [14]. Moreover, with the increasing emphasis on enhanced recovery protocols and same-day discharge, opioid-sparing pain control is more critical, as poor pain management can delay recovery and contribute to chronic postsurgical pain development [4,15].
This double-blinded randomized controlled trial was conducted to compare preemptive versus preventive administration of intravenous acetaminophen/ibuprofen combination in patients undergoing RALP. The hypothesis of this study is that preemptive administration would provide superior opioid-sparing analgesic effects, as reflected by reduced fentanyl consumption within 24 hours after surgery, compared with preventive administration.
MATERIALS AND METHODS
1. Study design
This study was a prospective, single-center, double-blinded, randomized controlled trial conducted at Seoul National University Hospital, a tertiary academic medical center in South Korea. The study protocol was approved by the Institutional Review Board (IRB) of the hospital (IRB no. H-2210-134-1374) and registered at ClinicalTrials.gov (NCT05685342) before enrollment of the first participant. All participants provided written informed consent. The study adhered to the Consolidated Standards of Reporting Trials (CONSORT) guidelines [16].
2. Participants
Male patients aged 19–80 years undergoing RALP for prostate cancer between February 2023 and February 2025 were included in the study. Patients with an ability to understand the study protocol and write an informed consent document were assessed for eligibility. The following patients were excluded: (1) the American Society of Anesthesiologists (ASA) physical status III or above; (2) chronic usage of opioid analgesics; (3) moderate to severe pain from other causes before surgery; (4) allergies to the anesthetic or analgesic medications used in this study; (5) anticipated blood loss larger than 2 liters; (6) need for intensive care after surgery; (7) history of gastric ulcer, gastrointestinal bleeding, or bronchial asthma; (8) history of liver failure, renal failure or heart failure; (9) current alcoholism; (10) taking anti-coagulation drugs or a history of coagulation disease; (11) taking barbiturate or tricyclic antidepressants; and (12) any other medical or psychological disease that could affect the treatment response. Participants dropped out of the study if they withdrew their consent to participate, if unplanned laparotomy was performed, or if the surgery was postponed or canceled.
3. Randomization and blinding
Participants were randomly assigned in a 1:1 ratio to either the preemptive group or the preventive group using a computer-generated randomization table created with R software (version 4.2.2). The randomization utilized block sizes of 4 and 6 and was managed by a research nurse not involved in patient care or outcome assessment. Based on group allocation, study medications were prepared by the research nurse to ensure blinding of patients, anesthesiologists, surgeons, and outcome assessors. The study medication consisted of acetaminophen 1,000 mg and ibuprofen 300 mg in 100 mL solution (Maxigesic IV®; Kyongbo Pharmaceutical) or an identical-appearing placebo (100 mL normal saline). All study medications were labeled only by timing of administration (“Drug #1: before incision” and “Drug #2: end of surgery”) without revealing their contents.
4. Intervention
Participants in the preemptive group received the acetaminophen/ibuprofen combination (Drug #1) intravenously over 15 minutes after anesthesia induction, followed by normal saline placebo (Drug #2) over 15 minutes at the start of fascial closure. Participants in the preventive group received a normal saline placebo (Drug #1) after anesthesia induction and the acetaminophen/ibuprofen combination (Drug #2) at the start of fascial closure.
5. Anesthesia and surgical management
No premedication was administered. Standard monitoring included pulse oximetry, non-invasive blood pressure, electrocardiography, and bispectral index monitoring. Anesthesia was induced with target-controlled infusion of remifentanil, followed by 1–2 mg/kg propofol and 0.6–1.0 mg/kg rocuronium. For prevention of postoperative nausea and vomiting, 0.075 mg palonosetron and 5 mg dexamethasone were administered. Anesthesia was maintained with sevoflurane or desflurane guided by bispectral index monitoring, and remifentanil was titrated to maintain blood pressure within ± 20% of baseline values. Following robotic docking to the patients, continuous rocuronium infusion (0.3 mg/kg/hr) was initiated to prevent movement during robot-assisted surgery. Other intraoperative management was provided at the discretion of the attending anesthesiologist, who was blinded to group allocation.
Surgery was performed using the da Vinci surgical system with a standard multiport technique. Four 8-mm ports were placed around the umbilicus and lower abdomen, with additional 5-mm and 12-mm assistance ports. Pneumoperitoneum was established with CO₂ insufflation at 15 mmHg in the Trendelenburg position.
6. Postoperative pain management
At the start of fascial closure, all patients were connected to an intravenous patient-controlled analgesia (IV-PCA) device (Accumate® 1200; Woo Young Medical) containing fentanyl 20 μg/mL in 100 mL total volume, with a bolus dose of 20 μg and a lockout interval of 10 minutes. A loading dose of 50 μg fentanyl was administered intravenously. The PCA device automatically recorded bolus attempts, actual doses delivered, and cumulative consumption.
Pain intensity was assessed using the 11-point numeric rating scale (NRS), where 0 indicates no pain and 10 represents the worst imaginable pain. Patients were instructed to press the PCA button when pain intensity exceeded 3 on the NRS. For breakthrough pain with NRS > 7 while fasting, 50 μg intravenous fentanyl was administered as first-line rescue analgesia, followed by 25 mg intravenous pethidine as second-line therapy. After resumption of oral intake, 650 mg extended-release acetaminophen tablets were administered orally as a rescue analgesic medication. For severe nausea or vomiting, 0.3 mg intravenous ramosetron was available as a rescue antiemetic.
With the widespread implementation of opioid-sparing analgesia, the routine postoperative pain protocol was updated in August 2023, which occurred during the study period when 51 patients had already been enrolled, to allow the postoperative use of intravenous mixed solution containing acetaminophen (1,000 mg) and ibuprofen (300 mg) on the day of surgery. Because this medication could influence the intensity of postoperative pain, the incidence of administration was prospectively recorded. All other perioperative management was provided according to the institutional routine protocol.
7. Outcome measures
The day before surgery, the participants completed the Korean version of the Quality of Recovery-15 questionnaire (QoR-15K) [17]. Baseline demographics, medical history, current medications, and routine preoperative laboratory tests were recorded. Preoperative levels of laboratory tests such as serum creatinine, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) were also obtained.
The primary outcome was total intravenous fentanyl consumption via IV-PCA within 24 hours postoperatively. Secondary outcomes included: (1) cumulative fentanyl consumption at 2, 6, and 48 hours; (2) PCA bolus attempt counts at 2, 6, 24, and 48 hours; (3) pain intensity using the 11-point NRS at rest at 2, 6, 24, and 48 hours, and during movement at 6, 24, and 48 hours; (4) frequency and dosage of rescue analgesics; (5) incidence of opioid-related adverse events (nausea, vomiting, dizziness, sedation, respiratory depression) at 24 and 48 hours; and (6) quality of recovery assessed by QoR-15K at 24 hours postoperatively. Safety outcomes included postoperative liver function tests and serum creatinine levels on postoperative day 1. All outcomes were assessed by investigators blinded to group allocation.
8. Statistical analysis
Sample size calculation was based on data from 291 patients who underwent robot-assisted prostatectomy at the authors’ institution, showing a mean 24-hour fentanyl consumption of 410 ± 250 μg. Based on previous studies on preemptive analgesia, the authors assumed a clinically significant difference of 30% between the groups [18,19]. With an α of 0.05, power of 80%, and 10% dropout rate, a required sample size of 77 patients per group (total 154 patients) was calculated using the Mann–Whitney U-test.
All statistical analyses followed the modified intention-to-treat principle. Continuous variables were tested for normality using the Shapiro–Wilk test and presented as mean ± standard deviation (SD) or median [interquartile range, IQR] as appropriate. Between-group comparisons were performed using Mann–Whitney U-tests. Categorical variables were expressed as numbers (percentages) and compared using chi-squared or Fisher’s exact tests. Effect sizes were reported as median differences or relative risks with 95% confidence intervals (CIs). Median differences between groups were estimated using nonparametric bootstrap resampling (1,000 iterations) with percentile-based CIs.
To strengthen the study’s findings, the authors conducted sensitivity analyses including: (1) subgroup analyses stratified by postoperative acetaminophen/ibuprofen combination administration (both patients who did and did not receive the combination), (2) multivariable regression analysis with interaction term to assess whether postoperative combination modified the timing effect, treating postoperative combination as an independent variable with log-transformed fentanyl consumption to address skewness, and (3) nonparametric repeated-measures analysis using the nparLD package to evaluate longitudinal outcomes. The f1.ld.f1 function assessed between-group, within-subject (time), and group × time interaction effects without normality assumptions, using ANOVA-type statistics with appropriate degrees of freedom adjustments.
All analyses were performed using R software (version 4.3.3) with significance set at P < 0.05. The boot package (version 1.3.30) was used for bootstrap resampling and nparLD package (version 2.2) for nonparametric repeated-measures analysis.
RESULTS
A total of 200 patients were assessed for eligibility, and 154 were enrolled and randomized (Fig. 1). After randomization, one patient was excluded due to a previously unknown medication history meeting exclusion criteria, and another declined IV-PCA use postoperatively. Consequently, 152 patients (76 for each group) completed the study and were included in the final analysis. The mean ± SD age of the entire cohort was 67.9 ± 6.0 years. Baseline characteristics were well balanced between groups (Table 1), with no significant differences in demographics, comorbidities, or preoperative parameters.
The primary outcome of median [IQR] cumulative fentanyl consumption within 24 hours postoperatively was 260 µg [130–480 µg] in the preemptive group vs. 320 µg [140–560 µg] in the preventive group (median difference: –60 µg [95% CI –140 to 60 µg], P = 0.409), showing no statistically significant difference between groups. Cumulative fentanyl consumption at other time points (2, 6, and 48 hours) showed no significant differences between the groups (Fig. 2).
PCA bolus attempt frequency was similar between the groups at all time points (Table 2). At 24 hours, the median [IQR] bolus attempt count was 19 [10–37.5] in the preemptive group compared to 20 [11–48.5] in the preventive group (P = 0.573). At 48 hours, bolus attempt counts were 28 [12.5–56] and 38 [16–73.5] respectively (P = 0.113). Pain scores assessed using the NRS showed comparable results between the groups at most time points. The resting NRS pain score at 48 hours was significantly lower in the preemptive group (median difference: –1.0 [95% CI –1.0 to 0.0], P = 0.040). No significant differences were observed in pain scores at 2, 6, and 24 hours at rest, or during cough at 24 and 48 hours. Rescue analgesic use in the post-anesthesia care unit (PACU) and ward was comparable between the groups. In the PACU, 13 patients (17.1%) in the preemptive group and 19 patients (25.0%) in the preventive group received additional fentanyl (P = 0.320). Ward-based rescue analgesic administration occurred in similar frequencies across all time intervals, with no significant differences between the groups (Table 2).
Preoperative and postoperative QoR-15K scores are presented in Fig. 3. At 24 hours postoperatively, there was no significant difference in QoR-15K scores between the groups (median difference: 6.5 [95% CI –2.0 to 12.0], P = 0.253).
Opioid-related adverse effects and hepatorenal function parameters are summarized in Table 3. The incidence of nausea and dizziness was similar between groups at all time points, with no statistically significant differences. Laboratory parameters measured on postoperative day 1, including AST, ALT, and serum creatinine levels, showed no significant differences between groups. No clinically significant hepatotoxicity or nephrotoxicity was observed in either group.
Sensitivity analyses further supported the primary findings. Subgroup analysis stratified by postoperative acetaminophen/ibuprofen combination administration revealed no significant differences between the preemptive and preventive groups in either subgroup (Supplementary Table 1). Multivariable regression analysis incorporating postoperative combination as a covariate demonstrated a main effect of the combination reducing opioid consumption (β = –0.326, P = 0.021) but no significant interaction with timing group (β = 0.067, P = 0.706). Nonparametric repeated-measures analysis demonstrated significant time effects for most longitudinal outcomes (all P < 0.001 except rescue analgesics), however, no significant between-group differences or group × time interactions were observed for any endpoints (Supplementary Table 2).
DISCUSSION
This randomized controlled trial showed that there is no significant difference in 24-hour postoperative fentanyl consumption between preemptive and preventive intravenous administration of fixed-dose acetaminophen/ibuprofen in patients undergoing RALP. This result was consistent in the subgroup analysis limited to patients who received postoperative acetaminophen/ibuprofen combination. This finding suggests that the timing of analgesic administration relative to surgical incision may be less critical in opioid-sparing analgesia, while ensuring adequate analgesic coverage throughout the perioperative period could be of greater clinical relevance. The lack of difference in the primary outcome aligns with previous studies questioning the superiority of preemptive over preventive analgesia strategies, particularly when using multimodal approaches that address pain through multiple mechanisms [20–22].
The findings of this study are consistent with recent systematic reviews and meta-analyses that have challenged the traditional concept of preemptive analgesia. Recent network meta-analysis of 188 RCTs (randomized controlled trials) demonstrated that while preemptive analgesia showed modest benefits over placebo, the differences between preemptive and preventive timing strategies were minimal when multimodal approaches were employed [23]. In patients undergoing RALP, Sisa et al. [24] showed that adding a preoperative dose of pregabalin to a multimodal regimen did not reduce postoperative opioid consumption or other outcomes. These findings, together with study results, highlight that although preemptive analgesia has strong theoretical support through central sensitization mechanisms, its clinical impact remains modest. In contrast, accumulating evidence underscores that consistent multimodal analgesia across the perioperative period may hold greater clinical importance than reliance on a single-intervention strategy.
The comparable efficacy between timing strategies in this study can be explained by the complementary mechanisms of the acetaminophen/ibuprofen fixed-dose combination. Acetaminophen is metabolized to p-aminophenol and converted centrally by fatty acid amide hydrolase into AM404, which activates TRPV1 channels and modulates CB1 receptors, thereby engaging descending inhibitory pain pathways [25]. Ibuprofen exerts peripheral analgesic effects through cyclo-oxygenase inhibition, reducing prostaglandin-mediated inflammatory nociception [26]. This central–peripheral dual mechanism underpins the synergistic effect observed when the two drugs are combined, as supported by randomized trials showing superior analgesia and lower opioid use with the fixed-dose combination compared to either drug alone [11,27,28]. These trials demonstrated that the dual mechanisms of acetaminophen and ibuprofen can exert synergistic effects. In the present study, postoperative pain within 24 hours was well controlled at mild to moderate levels in both groups, and in this context, differences in opioid consumption according to timing of administration may have been difficult to detect.
The unique pain characteristics of RALP may explain why timing optimization showed limited additional benefit. RALP primarily causes visceral and inflammatory pain from CO₂ insufflation and peritoneal stretching, rather than the severe somatic pain associated with open procedures [29]. Studies specific to RALP demonstrate relatively low baseline opioid requirements, with Lee et al. [30] showing that 57.5% of patients can be managed entirely without opioids using comprehensive multimodal protocols. The moderate pain intensity and lower opioid requirements in RALP patients may create a ceiling effect, where the baseline analgesic approach provides sufficient pain control [31].
The authors’ findings have important implications for clinical practice, suggesting that efforts should focus on ensuring consistent analgesic coverage rather than optimizing precise timing. The ERAS (Enhanced Recovery After Surgery) Society guidelines emphasize that successful implementation depends more on adherence to multimodal principles than on exact timing of individual components [32]. This approach offers practical advantages, as rigid timing requirements can complicate workflow and potentially delay surgery. This study’s results support a more flexible approach where the acetaminophen/ibuprofen combination can be administered at either time point based on clinical convenience, provided adequate perioperative analgesia is maintained.
Several limitations may have influenced the authors’ results. First, the postoperative pain management protocol consisted primarily of opioid-based PCA with rescue non-opioid analgesics rather than a true multimodal analgesic regimen with scheduled non-opioid components. This distinction is important as scheduled multimodal analgesia might have provided more consistent baseline analgesia, potentially allowing timing differences to emerge more clearly. Second, the primary outcome measure of 24-hour fentanyl consumption may have lacked the sensitivity to detect subtle differences, as PCA use depends on multiple factors including patient education, frequency of button presses, and individual pain tolerance [33]. Third, the study did not account for patient-specific variables such as catastrophizing, anxiety, or genetic polymorphisms, which may be stronger predictors of postoperative pain trajectories than procedural factors [34]. While the study’s randomized design ensured equal distribution of these unmeasured variables between groups, preserving internal validity, future research incorporating predictive modeling and pharmacogenetic testing may help develop more personalized perioperative analgesic strategies [35,36]. Fourth, the implementation of an updated postoperative pain protocol during the study period, allowing postoperative acetaminophen/ibuprofen administration, may have created a ceiling effect that obscured timing-related differences. Fifth, the type of inhalational anesthetic used during surgery was not standardized though no significant difference existed between groups (P = 0.824). Sixth, intraoperative remifentanil dosing was guided by hemodynamic parameters rather than nociception monitoring devices, which may represent a more ideal approach. Finally, the sample size calculation was based on detecting a 30% difference in opioid consumption, which may have been insufficient to identify smaller but clinically meaningful effects.
In conclusion, this study’s findings demonstrate that the timing of acetaminophen/ibuprofen administration (preemptive vs. preventive) does not significantly affect postoperative opioid consumption in RALP patients. Both preemptive and preventive administration of the fixed-dose combination resulted in similar postoperative analgesic outcomes, with no significant difference in opioid consumption between timing strategies. Future research should focus on developing personalized pain management strategies based on individual patient risk factors rather than pursuing universal timing optimization.
XML Download