Abstract
Background
Intraoperative multimodal analgesia with non-opioid agents is standard in perioperative pain management. However, evidence directly comparing triple, dual, and single agent regimens remains limited.
Methods
This retrospective single-center study analyzed adult patients undergoing minor general surgery, setting in which opioids are not routinely employed for postoperative pain management. The primary outcome was the use of rescue analgesics within 4 hours after surgery, comparing triple (acetaminophen [AAP] + nonsteroidal anti-inflammatory drugs [NSAIDs] + nefopam), dual (AAP + NSAIDs, AAP + nefopam, or NSAIDs + nefopam), and single agent regimens. Comparisons among individual dual agent combinations and among individual single agents were performed as secondary analyses. Outcomes were estimated using multivariable regression with inverse probability of treatment weighting (IPTW).
Results
Among 5,601 patients included, 37.9% received single, 58.5% dual, and 3.6% triple agent regimens. Rescue analgesic use occurred in 75.1%, 58.8%, and 43.8% of these groups, respectively. After IPTW adjustment, the triple regimen was associated with significantly lower rescue analgesic use compared with dual regimens (odds ratio, 0.48; 95% confidence interval, 0.32–0.70; P < 0.001), with adjusted probabilities of 31.4% (triple), 49.1% (dual), and 67.2% (single). Among dual regimens, the lowest rescue probability was observed with NSAIDs + nefopam (39.7%), followed by AAP + NSAIDs (53.2%), and AAP + nefopam (58.7%).
Conclusions
Triple agent intraoperative non-opioid analgesia was associated with the greatest reduction in postoperative rescue analgesic use, with a stepwise benefit observed across single, dual, and triple regimens. These findings support the active use of multimodal non-opioid analgesia in minor general surgery.
Keywords: Acetaminophen; Analgesia; Analgesics, Non-Narcotic; Anti-Inflammatory Agents, Non-Steroidal; Nefopam; Postoperative Pain; Propensity Score
INTRODUCTION
Multimodal analgesia has become the standard approach in perioperative pain management [1–3]. Among the various agents available, basic analgesics such as nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen (AAP) are widely recommended as routine components unless contraindicated [4,5]. The combination of these two agents provides superior analgesic efficacy compared with either agent alone [6,7].
Nefopam, another non-opioid analgesic, has long been used in perioperative settings but has yet to be firmly established as a standard component. Nefopam acts centrally, and a 20 mg parenteral dose has been shown to provide analgesic potency comparable to 7–12 mg of parenteral morphine [8,9]. It possesses several favorable characteristics that make it an attractive adjunct for perioperative pain management, including the absence of respiratory depression and additional anti-shivering effects [10,11]. However, given the widespread adoption of NSAID and AAP combinations, the additional benefit of nefopam or its role as an alternative component remains uncertain. A previous multicenter study attempted to address this issue but was terminated early, partly because the control group protocol did not reflect the currently accepted standard of multimodal analgesia, thus failing to provide a definitive answer to this question [12].
At the authors’ institution, non-opioid multimodal analgesics—including AAP, NSAIDs, and nefopam—are increasingly used intraoperatively, either alone or in dual/triple combinations, for minor general surgical procedures involving limited incisions. This study analyzed 5 years (2020–2024) of single-center data to compare analgesic effect of single, dual, and triple multimodal analgesia (combinations of AAP, NSAIDs, and nefopam) in terms of reducing immediate postoperative rescue analgesic use.
MATERIALS AND METHODS
1. Design and setting
This study adhered to the principles of the Declaration of Helsinki (as revised in 2024), and received approval from the Institutional Review Board of Chungnam National University Hospital (IRB no. CNUH 2025-03-025) with a waiver for informed consent.
This single-center retrospective study included adult patients aged 20 years or older who underwent minor general surgery—such as hernia repair, appendectomy, cholecystectomy, or thyroidectomy—under general anesthesia between January 2020 and December 2024 at a teaching university hospital. Patients were excluded if they met any of the following criteria: (1) American Society of Anesthesiologists physical status greater than III; (2) body mass index (BMI) less than 15 kg/m2 or greater than 40 kg/m2; (3) postoperative use of patient-controlled analgesia (PCA); (4) absence of any intraoperatively administered non-opioid analgesics; (5) surgery duration (from induction of anesthesia to emergence) exceeding 150 minutes; (6) combined or more than one surgery performed on the same day; (7) comorbidities that contraindicated the use of the study drugs (AAP, NSAIDs, or nefopam), including coronary artery disease or heart failure, renal dysfunction, estimated glomerular filtration rate < 60 mL/min/1.73 m2, liver cirrhosis, abnormal liver function test (aspartate aminotransferase [AST] or alanine aminotransferase [ALT] > 80 U/L), or gastric ulcer; (8) incomplete post-anesthesia care unit (PACU) data or transfer to the intensive care unit; or (9) insufficient data.
As no universally accepted definition of minor general surgery exists, the classification in this study was pragmatically defined based on the nature of the surgical procedures. The authors identified surgeries that typically involve a limited extent of surgical dissection, where non-opioid analgesics serve as the primary modality of postoperative pain management rather than regional analgesia or opioid-based strategies. Because opioids are not routinely employed in this setting, the effect of non-opioid multimodal combinations on rescue analgesic use can be evaluated more clearly. Breast surgery was not included, as institutional practice at the authors’ center routinely employs PCA for these cases, which does not align with the framework of this study. Exclusion criteria—including prolonged surgery duration, and use of PCA—were applied to further exclude cases that, despite being classified as minor by procedure name, represented atypical complexity or perioperative management.
2. Data acquisition
All data were retrieved from the institutional electronic health records. The dataset comprised patient demographics, pre- and postoperative laboratory findings (liver function test, serum creatinine), comorbidities, surgery-related variables (type and duration), intraoperative analgesic administration, and postoperative data (postoperative analgesic use, length of PACU stay, pain scores, vital sign, and adverse events).
3. Study objectives and outcomes
The primary outcome was the use of any rescue analgesic administered within 4 hours after surgery (including PACU stay). This was used to assess differences in immediate postoperative rescue analgesic use across triple (AAP + NSAIDs + nefopam), dual (AAP + NSAIDs, AAP + nefopam, or NSAIDs + nefopam), and single agent regimens.
Secondary outcomes were: (1) the number of rescue analgesic doses administered per patient within 4 hours after surgery; (2) rescue opioid use within 4 hours after surgery; (3) rescue non-opioid analgesic use within 4 hours after surgery; (4) maximum pain score (numeric rating scale, NRS) during PACU stay; and (5) length of PACU stay.
Adverse outcomes included: (1) postoperative nausea and vomiting (PONV), assessed by PACU nursing records or the use of rescue antiemetics (metoclopramide) within 4 hours after surgery; (2) hemodynamic and respiratory adverse events within 4 hours after surgery, including desaturation (SpO2 ≤ 94%), tachycardia (heart rate ≥ 120 beats/min), tachypnea (respiratory rate ≥ 30 breaths/min), and hypertensive events (systolic blood pressure ≥ 180 mmHg); (3) drug-induced liver injury (DILI), defined as ALT ≥ 5 times the upper limit of normal (ULN; ≥ 200 U/L), or ALT ≥ 3 times ULN (≥ 120 U/L) with concurrent total bilirubin ≥ 2 times ULN (≥ 2.0 mg/dL), assessed within 7 postoperative days; and (4) acute kidney injury (AKI), defined according to the Kidney Disease: Improving Global Outcomes (KDIGO) criteria as an absolute increase in serum creatinine of ≥ 0.3 mg/dL within 48 hours, or an increase to ≥ 1.5 times the preoperative baseline within 7 postoperative days.
4. Perioperative management
During the study period, standard institutional anesthesia management consisted of balanced anesthesia using an inhalational agent in combination with a continuous infusion of remifentanil. No preemptive analgesia protocols or regional analgesic techniques were used in the cases included in this study. The selection of intraoperative non-opioid analgesic was determined at the discretion of the attending anesthesiologist. For AAP, intravenous (IV) paracetamol was administered at a dose of 1 g, or 15 mg/kg for patients with body weight less than 50 kg. For NSAIDs, IV ketorolac 30 mg was administered. Beginning in November 2022, a fixed-dose combination of IV AAP 1,000 mg and ibuprofen 300 mg (Maxigesic® IV; Kyongbo Pharmaceutical) became available and was subsequently used according to physician preference. IV nefopam 20 mg was diluted in 100 mL of normal saline and infused over 15 to 30 minutes. The adoption of multimodal analgesia increased significantly during the study period, with a marked rise observed from 2021 onward (Supplementary Fig. 1). In certain cases, additional opioids (fentanyl or pethidine) were administered intraoperatively as deemed necessary by the anesthesiologist. Routine PONV prophylaxis with intraoperative ramosetron 0.3 mg or palonosetron 0.075 mg was administered to all patients without contraindications. Dexamethasone was not part of the routine perioperative protocol during the study period.
Postoperative rescue analgesics were administered when patients complained of pain exceeding the mild range (NRS ≥ 4) or requested additional pain intervention. In the PACU, either non-opioid agents not previously administered intraoperatively, or small bolus doses of opioids (fentanyl or pethidine) were used. Discharge from the PACU was allowed once the post-anesthetic recovery score reached ≥ 9, or if deemed suitable by the anesthesiologist.
On the general ward, the administration of rescue analgesics was directed by the surgical team under the same general principle: rescue analgesics were administered when patients reported pain of NRS ≥ 4 or requested intervention. IV non-opioid analgesics (NSAIDs, AAP, or nefopam) were preferred as first-line options regardless of the type of surgery, with opioids reserved for severe or refractory pain. Patients were routinely assessed for pain upon ward arrival and subsequently as needed. When pain was tolerable, dosing was spaced at intervals of at least 4 to 6 hours, taking into account the timing of the most recent intraoperative or PACU dose. There were no formal changes in postoperative analgesic management principles during the study period.
5. Covariates
To control potential confounding in the outcome analysis, multivariable regression models were built using covariates selected based on a directed acyclic graph (DAG) derived from domain knowledge and institutional practice patterns (Supplementary Fig. 2). Age, sex, weight, Charlson comorbidity index [13], surgery type, and duration were treated as confounders, as they were assumed to influence both the exposure and the outcome. Body weight, rather than BMI, was selected as a covariate because the non-opioid analgesics used in this study are typically administered at fixed unit doses (e.g., per ampule) in routine clinical practice, rather than weight-based dosing. As a result, the actual drug exposure per kilogram of body weight varies directly with body weight, potentially leading to relative overdosing in underweight patients and underdosing in overweight patients, which may influence both the choice of analgesic agents and the analgesic outcome. The year of procedure was considered a variable affecting the exposure, reflecting the trend toward increased use of multimodal agents (Supplementary Fig. 1). Diabetes mellitus is assumed to affect only the outcome [14,15]. Intraoperative opioid administration (excluding remifentanil) was regarded as an intermediate variable, as non-opioid analgesics were typically selected first by the attending anesthesiologist, with opioids added selectively when additional analgesia was deemed necessary. The attending anesthesiologist was assumed to influence analgesic selection and intraoperative opioid use only, with no direct path to the outcome; therefore, no adjustment was required.
6. Statistical analysis
All statistical analyses were performed using R (version 4.5.2; R Foundation for Statistical Computing). Continuous variables were summarized as median [Q1, Q3], considering their distributions, and categorical variables as number (%). Crude (unweighted) group comparisons were conducted using the Kruskal–Wallis test for continuous variables and Pearson’s χ² test or Fisher’s exact test for categorical variables, as appropriate. For pairwise comparisons, the Wilcoxon rank-sum test was used for continuous variables, and the χ² test or Fisher’s exact test for categorical variables. For pairwise comparisons, P values were adjusted using the Bonferroni correction to account for multiple testing.
The required sample size was estimated through simulation across a range of plausible assumptions for baseline rescue analgesic rate, treatment effect size, and group allocation ratio (Supplementary Fig. 3), and the resulting estimate was adopted as an approximate reference for determining the study period and target data size.
Inverse probability of treatment weighting (IPTW) with propensity scores (PS) was used to balance baseline characteristics across intraoperative multimodal groups (single, dual, triple) using the “twang” and “survey” packages. The PS model included covariates prespecified by a DAG, following established guidance on covariate selection [16,17], specifically confounders and outcome-associated variables. Adequate balance was defined as a standardized mean difference (SMD) < 0.1. The outcome model additionally adjusted for intraoperative opioid use (other than remifentanil), which was not included in the PS model, to estimate the direct effect of intraoperative non-opioid analgesic use on postoperative rescue analgesic use, following the approach of Petersen et al. [18]; this covariate adjustment in the outcome model also served to address potential residual imbalance not fully resolved by weighting alone.
Adjusted marginal probabilities (risks) of rescue analgesia use were estimated for each multimodal group based on the IPTW-weighted logistic regression model using the ‘emmeans’ package. Pairwise group comparisons on the log-odds scale yielded odds ratios [ORs] with 95% confidence intervals (CIs); P values were multiplicity-adjusted using the Tukey method.
The same analytic framework, comprising separate PS models and IPTW, was applied in two secondary analysis: one comparing individual dual-agent combinations, and the other comparing individual single agents.
7. Sensitivity analysis
To assess the robustness of their findings, the authors conducted six types of sensitivity analyses.
(1) To assess dependence on the estimation strategy, an unweighted logistic regression was fitted using the same covariates as in the primary IPTW analysis.
(2) To examine the influence of extreme weights, the authors applied weight truncation (capping) to the stabilized IPTW at the 99th, 97.5th, 95th, and 90th percentiles and refit the weighted outcome models [19].
(3) To restrict inference to the region of common support, arm-specific lower-tail PS trimming was implemented using a multinomial Stürmer–style rule with a threshold of 0.033 (i.e., removing the lowest 3.3% within each observed arm) [20], re-estimated the multinomial PS on the trimmed sample, recomputed stabilized IPTW, and refit the outcome model [21].
(4) To assess the potential influence of temporal shifts in practice patterns, calendar year was included as a categorical covariate in both the PS and outcome models; because triple agent use was negligible in 2020 (n = 1), this analysis was restricted to 2021–2024.
(5) As the year 2024 coincided with a period of severely reduced medical staffing at the authors’ institution [22], which may have compromised consistency of clinical practice and altered rescue analgesic use patterns (Supplementary Fig. 1), they conducted an analysis excluding cases from 2024.
(6) To evaluate the potential influence of intraoperative opioid administration on the primary outcome, an analysis was conducted excluding patients who received intraoperative supplemental opioids.
8. Exploratory analysis
In this study, two types of intraoperative NSAIDs were used: ketorolac 30 mg or ibuprofen 300 mg co-formulated with AAP 1 g (Maxigesic®). As the analgesic efficacy of these two types of NSAIDs cannot be assumed to be equivalent, a post hoc exploratory analysis was conducted among patients who received an NSAID-containing multimodal regimen (dual or triple) to compare outcomes according to the type of NSAID administered.
RESULTS
A total of 7,964 cases were assessed for eligibility, of which 2,265 were excluded based on the predefined criteria. During data processing, an additional 98 cases were excluded due to procedure type (n = 87; robotic surgery, biopsy, soft tissue excision, or other miscellaneous procedures) which were heterogeneous in nature and yielded sparse cell counts, precluding reliable group comparison, and due to unclassifiable analgesic administration (n = 11; concurrent administration of more than one agent from the same analgesic class). Consequently, 5,601 cases were included in the final analysis. Regarding analgesic regimens, 2,123 cases (37.9%) received single agent, 3,277 (58.5%) dual agent, and 201 (3.6%) triple agent non-opioid analgesia (Fig. 1).
Fig. 1.
Patient flow diagram. *Some cases met multiple exclusion criteria; therefore, the total number of excluded cases does not equal the sum of cases listed for each reason. “Relevant comorbidities” refer to conditions that may contraindicate the use of the study drugs (AAP, NSAIDs, or nefopam), including coronary artery disease, heart failure, renal dysfunction, estimated glomerular filtration rate < 60 mL/min/1.73 m2, liver cirrhosis, abnormal liver function test (aspartate aminotransferase or alanine aminotransferase > 80 U/L), or gastric ulcer. AAP: acetaminophen, NSAIDs: nonsteroidal anti-inflammatory drugs. ASA: American Society of Anesthesiologists, BMI: body mass index, PCA: patient-controlled analgesia, ICU: intensive care unit.
Laparoscopic cholecystectomy was the most common procedure type (52.3%, predominantly cholecystectomy with a small number of other laparoscopic biliary procedures), followed by thyroidectomy (24.4%, predominantly thyroid lobectomy or total thyroidectomy with a small number of other neck procedures), laparoscopic hernia repair (9.7%, predominantly inguinal), laparoscopic appendectomy (8.5%), stoma-related surgery (2.8%, including ileostomy and colostomy creation, closure, and revision), and open hernia repair (2.3%, including umbilical, ventral, and incisional hernia).
1. Triple vs. dual vs. single regimens
Baseline characteristics before and after IPTW are summarized in Table 1. PS distributions showed sufficient overlap across all three arms (Supplementary Fig. 4A). After weighting, most covariates achieved adequate balance, except for thyroidectomy (SMD = 0.102). Intraoperative supplemental opioid use was more common in the single agent group than in the dual or triple agent groups (10.6% vs. 4.2% and 5.0%, respectively, P < 0.001). Intraoperative or immediate postoperative dexamethasone was administered in only 50 of 5,601 cases (0.9%). Given its rarity, dexamethasone was not included as a covariate.
Table 1.
Baseline covariate balance before and after IPTW
| Covariates | Unweighted | Weighted | |||||||
|---|---|---|---|---|---|---|---|---|---|
| Single (n = 2,123) |
Dual (n = 3,277) |
Triple (n = 201) |
SMD | Single (n* = 1,959.0) |
Dual (n* = 3,193.4) |
Triple (n* = 166.2) |
SMD | ||
| Age (yr) | 58.00 [47.00, 69.00] |
57.00 [46.00, 68.00] |
54.00 [43.00, 64.00] |
0.209 | 58.00 [46.00, 68.00] |
57.00 [46.00, 68.00] |
57.00 [45.00, 67.00] |
0.045 | |
| Sex (male) | 959 (45.2) | 1,462 (44.6) | 107 (53.2) | 0.115 | 887.2 (44.7) | 1,437.8 (45.0) | 79.8 (48.0) | 0.044 | |
| Weight (kg) | 64.55 [56.86, 73.20] |
64.40 [56.40, 73.30] |
68.75 [59.00, 78.30] |
0.189 | 64.50 [56.80, 73.41] |
64.50 [56.70, 73.40] |
65.09 [57.83, 74.00] |
0.028 | |
| DM | 270 (12.7) | 399 (12.2) | 25 (12.4) | 0.011 | 251.5 (12.7) | 390.0 (12.2) | 15.5 (9.3) | 0.071 | |
| CCI | 2.00 [1.00, 3.00] |
2.00 [1.00, 3.00] |
2.00 [0.00, 3.00] |
0.060 | 2.00 [1.00, 3.00] |
2.00 [1.00, 3.00] |
2.00 [1.00, 3.00] |
0.041 | |
| Surgery duration (min) | 67.00 [57.00, 80.00] |
64.00 [54.00, 75.00] |
64.00 [54.00, 81.00] |
0.103 | 64.00 [55.00, 77.93] |
64.00 [55.00, 78.00] |
64.00 [54.00, 79.68] |
0.015 | |
| Surgery type | |||||||||
| Lap-appendectomy | 231 (10.9) | 233 (7.1) | 13 (6.5) | 0.105 | 174.2 (8.8) | 260.5 (8.2) | 13.0 (7.8) | 0.023 | |
| Lap-cholecystectomy | 1,157 (54.5) | 1,655 (50.5) | 118 (58.7) | 0.110 | 1,048.0 (52.8) | 1,674.7 (52.4) | 97.8 (58.8) | 0.086 | |
| Lap-hernia repair | 179 (8.4) | 345 (10.5) | 18 (9.0) | 0.048 | 182.3 (9.2) | 316.9 (9.9) | 16.3 (9.8) | 0.017 | |
| Open-hernia repair | 47 (2.2) | 75 (2.3) | 5 (2.5) | 0.012 | 44.2 (2.2) | 69.8 (2.2) | 2.7 (1.6) | 0.030 | |
| Stoma-related | 40 (1.9) | 109 (3.3) | 10 (5.0) | 0.115 | 50.6 (2.5) | 91.8 (2.9) | 6.1 (3.7) | 0.044 | |
| Thyroidectomy | 469 (22.1) | 860 (26.2) | 37 (18.4) | 0.126 | 487.2 (24.5) | 780.8 (24.4) | 30.3 (18.2) | 0.102 | |
Values are presented as median [Q1, Q3] or number (%). In the single-agent group: AAP (n = 116), NSAIDs (n = 943), nefopam (n = 1,064). In the dual-agent group: AAP + NSAIDs (n = 1,206), AAP + nefopam (n = 1,818), NSAIDs + nefopam (n = 253). “Lap-cholecystectomy” predominantly comprises cholecystectomy with a small number (0.2%) of other laparoscopic biliary procedures (e.g., common bile duct exploration). “Thyroidectomy” predominantly comprises thyroid lobectomy or total thyroidectomy with a small number (2.5%) of other neck procedures (e.g., parathyroidectomy).
IPTW: inverse probability of treatment weighting, SMD: standardized mean difference, DM: diabetes mellitus, CCI: Charlson comorbidity index, Lap-: laparoscopic, AAP: acetaminophen, NSAIDs: nonsteroidal anti-inflammatory drugs.
*Effective sample size.
Crude rates of rescue analgesic use were 75.1%, 58.8%, and 43.8% in the single, dual, and triple agent groups, respectively (P < 0.001 for overall and all pairwise comparisons; Table 2). The majority of rescue analgesics were administered on the general ward, and group differences were predominantly driven by ward-based administration. The median number of rescue analgesic doses was lowest in the triple agent group. Rescue opioid use differed across groups (single, 13.3%; dual, 8.1%; triple, 7.0%; overall P < 0.001), primarily driven by the higher rate in the single agent group. When stratified by procedure type, the pattern of decreasing rescue analgesic use from single to dual to triple agent groups was consistent across all surgical categories (Supplementary Fig. 5).
Table 2.
Crude rates of rescue analgesic use and number of doses by intraoperative multimodal group
| Outcome (within 4 hours after surgery) |
Single (n = 2,123) | Dual (n = 3,277) | Triple (n = 201) | P (overall) | P (S vs. D) | P (S vs. T) | P (D vs. T) |
|---|---|---|---|---|---|---|---|
| Any rescue analgesic use | 1,594 (75.1) | 1,927 (58.8) | 88 (43.8) | < 0.001 | < 0.001 | < 0.001 | < 0.001 |
| PACU | 288 (13.6) | 286 (8.7) | 14 (7.0) | < 0.001 | < 0.001 | 0.032 | > 0.999 |
| Ward | 1,504 (70.8) | 1,793 (54.7) | 81 (40.3) | < 0.001 | < 0.001 | < 0.001 | < 0.001 |
| Rescue opioid use | 283 (13.3) | 267 (8.1) | 14 (7.0) | < 0.001 | < 0.001 | 0.040 | > 0.999 |
| PACU | 206 (9.7) | 200 (6.1) | 13 (6.5) | < 0.001 | < 0.001 | 0.508 | > 0.999 |
| Ward | 88 (4.1) | 76 (2.3) | 1 (0.5) | < 0.001 | < 0.001 | 0.051 | 0.392 |
| Rescue non-opioid use | 1,513 (71.3) | 1,797 (54.8) | 81 (40.3) | < 0.001 | < 0.001 | < 0.001 | < 0.001 |
| PACU | 102 (4.8) | 102 (3.1) | 1 (0.5) | < 0.001 | 0.006 | 0.024 | 0.169 |
| Ward | 1,472 (69.3) | 1,742 (53.2) | 80 (39.8) | < 0.001 | < 0.001 | < 0.001 | < 0.001 |
| No. of rescue doses | 1.0 [1.0, 1.0] | 1.0 [0.0, 1.0] | 0.0 [0.0, 1.0] | < 0.001 | < 0.001 | < 0.001 | < 0.001 |
Values are presented as number (%) or median [Q1, Q3]. Patients may have received rescue analgesics in both PACU and ward; therefore, PACU and ward subcategory counts may not sum to the total. P values are Bonferroni-adjusted for pairwise comparisons.
PACU: post-anesthesia care unit, S: single, D: dual, T: triple.
In the IPTW-adjusted logistic regression, triple-agent non-opioid analgesia was associated with significantly lower odds of rescue analgesic use compared with dual agent analgesia (OR, 0.48; 95% CI, 0.32–0.70; P < 0.001). The IPTW-adjusted probability of rescue analgesic use was lowest in the triple-agent group, at 31.4% (95% CI, 23.5%–40.5%), followed by the dual agent group, at 49.1% (95% CI, 42.3%–55.8%), and highest in the single-agent group, at 67.2% (95% CI, 61.1%–72.8%) (Fig. 2A). The complete group-wise comparisons are summarized in Table 3.
Fig. 2.
Crude and adjusted probabilities of rescue analgesic use by intraoperative non-opioid analgesic regimen. (A) Comparison by number of agents (single, dual, triple). (B) Comparison among dual agent combinations. (C) Comparison among single agents. Blue bars represent crude (observed) proportions; red bars represent IPTW-adjusted probabilities with 95% confidence intervals. Adjusted estimates were derived from separate IPTW-weighted logistic regression models for each comparison. All pairwise comparisons in (A) and (B) were statistically significant. In (C), no significant differences were observed among single agents. P values were adjusted for multiple comparisons using the Tukey method. IPTW: inverse probability of treatment weighting, AAP: acetaminophen, NSAIDs: nonsteroidal anti-inflammatory drugs.
Table 3.
IPTW-adjusted ORs and predicted probabilities of rescue analgesic use by number of intraoperative non-opioid analgesic agents
| Value | 95% CI | P value | |
|---|---|---|---|
| Comparison (OR) | |||
| Triple/dual | 0.48 | 0.32–0.70 | < 0.001 |
| Triple/single | 0.22 | 0.15–0.33 | < 0.001 |
| Dual/single | 0.47 | 0.40–0.55 | < 0.001 |
| Group (adjusted probability, %) | |||
| Triple | 31.4 | 23.5–40.5 | - |
| Dual | 49.1 | 42.3–55.8 | - |
| Single | 67.2 | 61.1–72.8 | - |
OR were estimated from an IPTW-weighted logistic regression model. Adjusted probabilities and their 95% CIs were derived from the model-based predictions. P-values were adjusted for multiple comparisons.
IPTW: inverse probability of treatment weighting, OR: odds ratio, CI: confidence interval, - : not applicable.
Other secondary and safety outcomes are summarized in Table 4. PACU length of stay was longest in the single agent group (median 38.0 minutes) compared with the dual and triple groups (median 35.0 and 36.0 minutes, respectively; P < 0.001 for single vs. dual and single vs. triple), whereas no difference was observed between dual and triple groups. Maximum NRS during PACU stay followed a similar pattern. The incidence of PONV did not differ across groups. Tachycardia was more frequent in the triple group (7.5%) than in the single group (2.9%, P = 0.004) and dual group (3.2%, P = 0.009); other hemodynamic and respiratory events did not differ significantly. Among patients with available postoperative creatinine, AKI occurred in 6.5%, 2.7%, and 0.6% in the single, dual, and triple groups, respectively (overall P < 0.001). DILI was rare across all groups with no significant differences.
Table 4.
Secondary and adverse outcomes by multimodal analgesic group (crude comparison)
| Outcome | Single (n = 2,123) | Dual (n = 3,277) | Triple (n = 201) | P (overall) | P (S vs. D) | P (S vs. T) | P (D vs. T) |
|---|---|---|---|---|---|---|---|
| Secondary outcome | |||||||
| PACU max NRS | 2.0 [2.0, 3.0] | 2.0 [2.0, 2.0] | 2.0 [2.0, 2.0] | < 0.001 | < 0.001 | < 0.001 | 0.438 |
| PACU LOS (min) | 38.0 [33.0, 44.0] | 35.0 [33.0, 40.0] | 36.0 [33.0, 40.0] | < 0.001 | < 0.001 | < 0.001 | > 0.999 |
| Adverse outcome | |||||||
| PONV* | 126 (5.9) | 172 (5.2) | 8 (4.0) | 0.356 | 0.926 | 0.984 | > 0.999 |
| Tachycardia (PR ≥ 120)* | 62 (2.9) | 106 (3.2) | 15 (7.5) | 0.002 | > 0.999 | 0.004 | 0.009 |
| Tachypnea (RR ≥ 30)* | 67 (3.2) | 110 (3.4) | 7 (3.5) | 0.910 | > 0.999 | > 0.999 | > 0.999 |
| Hypertension (SBP ≥ 180)* | 175 (8.2) | 254 (7.8) | 10 (5.0) | 0.247 | > 0.999 | 0.401 | 0.575 |
| Desaturation (SpO2 ≤ 94)* | 240 (11.3) | 314 (9.6) | 21 (10.4) | 0.125 | 0.139 | > 0.999 | > 0.999 |
| AKI (KDIGO)** | 101/1,552 (6.5) | 66/2,418 (2.7) | 1/177 (0.6) | < 0.001 | < 0.001 | 0.008 | 0.257 |
| DILI** | 18/1,552 (1.2) | 29/2,418 (1.2) | 4/177 (2.3) | 0.436 | > 0.999 | 0.819 | 0.840 |
Values are presented as median [Q1, Q3] or number (%). Pairwise P values were adjusted using Bonferroni correction. AKI was defined according to KDIGO criteria as an absolute increase in serum creatinine of ≥ 0.3 mg/dL within 48 hours, or an increase to ≥ 1.5 × the baseline value within 7 postoperative days. DILI was defined as ALT ≥ 5× ULN (≥ 200 U/L) or ALT ≥ 3× ULN (≥ 120 U/L) with total bilirubin ≥ 2 × ULN (≥ 2.0 mg/dL) within 7 postoperative days.
PACU: post-anesthesia care unit, NRS: numeric rating scale, LOS: length of stay, PONV: postoperative nausea and vomiting, PR: pulse rate, RR: respiratory rate, SBP: systolic blood pressure, AKI: acute kidney injury, KDIGO: Kidney Disease: Improving Global Outcomes, DILI: drug-induced liver injury, ALT: alanine aminotransferase, ULN: upper limit of normal, S: single, D: dual, T: triple.
*Within 4 hours after surgery. **Postoperative laboratory data available: single 1,552/2,123 (73.1%), dual 2,418/3,277 (73.8%), triple 177/201 (88.1%).
2. Sensitivity analysis
The primary comparison across triple, dual, and single regimens remained stable across all sensitivity analyses (Supplementary Fig. 6).
3. Between dual regimens
Among the 3,277 cases in the dual agent groups, 1,206 (36.8%) received AAP + NSAIDs, 1,818 (55.5%) received AAP + nefopam, and 253 (7.7%) received NSAIDs + nefopam. Baseline characteristics before and after IPTW are summarized in Supplementary Table 1. PS distributions showed adequate overlap (Supplementary Fig. 4B). After weighting, all covariates achieved adequate balance.
Crude rates of rescue analgesic use were 56.6%, 62.0%, and 46.6% in the AAP + NSAIDs, AAP + nefopam, and NSAIDs + nefopam groups, respectively (Fig. 2B). In the IPTW-adjusted analysis, all pairwise comparisons showed statistically significant differences in the use of rescue analgesics (Table 5). The adjusted probability was lowest with NSAIDs + nefopam at 39.7% (95% CI, 30.9%–49.2%), followed by the AAP + NSAIDs at 53.2% (95% CI, 45.4%–60.8%), and highest in the AAP + nefopam group at 58.7% (95% CI, 51.0%–65.9%) (Fig. 2B).
Table 5.
IPTW-adjusted ORs and predicted probabilities of rescue analgesic use by dual non-opioid analgesic groups
| Value | 95% CI | P value | |
|---|---|---|---|
| Comparison (OR) | |||
| AAP + nefopam/ AAP + NSAIDs | 1.25 | 1.04–1.50 | 0.014 |
| NSAIDs + nefopam/ AAP + NSAIDs | 0.58 | 0.39–0.86 | 0.004 |
| NSAIDs + nefopam/ AAP + nefopam | 0.46 | 0.31–0.69 | < 0.001 |
| Group (adjusted probability, %) | |||
| NSAIDs + nefopam | 39.7 | 30.9–49.2 | - |
| AAP + NSAIDs | 53.2 | 45.4–60.8 | - |
| AAP + nefopam | 58.7 | 51.0–65.9 | - |
ORs were estimated from an IPTW-weighted logistic regression model. Adjusted probabilities and their 95% CIs were derived from the model-based predictions. P values were adjusted for multiple comparisons.
IPTW: inverse probability of treatment weighting, OR: odds ratio, CI: confidence interval, AAP: acetaminophen, NSAIDs: nonsteroidal anti-inflammatory drugs, - : not applicable.
4. Between single regimens
Among the 2,123 cases in the single agent group, 116 (5.5%) received AAP, 943 (44.4%) received NSAIDs, and 1,064 (50.1%) received nefopam. Baseline characteristics before and after IPTW are summarized in Supplementary Table 2. PS overlap was limited for the AAP subgroup (Supplementary Fig. 4C). After weighting, covariate balance improved; however, residual imbalance persisted for age (SMD = 0.151), weight (SMD = 0.139), and Charlson comorbidity index (SMD = 0.189), reflecting the small size and distinct clinical profile of the AAP subgroup, which comprised older patients with a lower body weight and higher comorbidity burden. Balance for surgery duration and surgery type was adequate (SMDs < 0.1).
Crude rates of rescue analgesic use were 67.2%, 74.9%, and 76.1% in the AAP, NSAIDs, and nefopam groups, respectively (Fig. 2C). In the IPTW-adjusted analysis, no significant differences in rescue analgesic use were observed among the three groups.
5. Exploratory analysis
In the exploratory analysis comparing NSAID types, rescue analgesic use within 4 hours did not differ significantly between ketorolac and ibuprofen (Maxigesic®) in either the dual (55.1% vs. 56.6%, P = 0.951) or the triple group comparison (38.2% vs. 48.2%, P = 0.201) (Supplementary Table 3).
DISCUSSION
In this single-center cohort of minor general surgery, the triple agent regimen consisting of AAP, NSAIDs, and nefopam was associated with a significantly lower need for immediate postoperative rescue analgesics compared with dual agent combinations. After IPTW adjustment, the triple agent regimen yielded the lowest predicted probability of rescue analgesic use (31.4%) compared with the dual agent (49.1%) and single agent (67.2%) regimens; the triple vs. dual contrast corresponded to an OR of 0.48 (95% CI, 0.32–0.70). While most previous investigations examined single agents or dual-agent combinations, few have directly compared triple agent therapy with dual or single regimens within the same cohort [6,12,23].
Multimodal analgesia has drawn sustained interest in perioperative care because it improves patient comfort and recovery while addressing broader societal concerns that inadequate acute pain control may progress to chronic postsurgical pain, prolonged opioid exposure, and, in some cases, opioid dependence [3,24–27]. Despite guidelines recommending multimodal analgesia as standard practice, its adoption remains inconsistent in clinical practice [28,29]. Habitual practice patterns and unfounded concerns about adverse effects may partly account for this slow adoption [30].
The present findings clearly illustrate the benefit of multimodal non-opioid analgesia: beyond the standard AAP + NSAIDs combination, alternative dual regimens incorporating nefopam showed comparable or even superior efficacy, and triple therapy provided further incremental benefit. Notably, the incidence of most adverse events did not differ across regimens. Nevertheless, judicious use with appropriate monitoring remains essential; tachycardia was more frequent in the triple group, consistent with the known pharmacological profile of nefopam, and potential interactions with serotonergic agents should be considered [31–33].
From an opioid-sparing perspective, the difference between dual and triple regimens was not substantial (Table 2), which may raise questions about the incremental value of triple therapy. However, the clinical significance of the triple regimen should not be evaluated solely in terms of opioid reduction. In this cohort, where opioids are not routinely required, the relevant outcome is whether patients experience unnecessary pain despite multimodal analgesia. The findings in this study indicate that even with dual non-opioid regimens, a considerable proportion of patients required additional pain relief. In the context of enhanced recovery after surgery, effective pain control in the immediate postoperative period facilitates deep breathing and early mobilization—key components of accelerated recovery [29].
The differential efficacy observed across dual regimens may be explained by their distinct mechanisms of action. Combinations that span central and peripheral mecha-nisms (AAP + NSAIDs or NSAIDs + nefopam) should engage a broader array of nociceptive pathways than a purely central pairing (AAP + nefopam), consistent with our dual-agent findings. Prospective randomized studies are needed to confirm these mechanistic inferences.
This study has several limitations. First, it was a single-center retrospective analysis, and local practice patterns may limit generalizability and introduce residual confounding. Notably, when all three agents were used intraoperatively, available rescue options may have narrowed, lowering clinicians’ propensity to administer rescue analgesia and biasing the association in favor of the triple regimen. Second, the cohort comprised minor general-surgery cases, so extrapolation to other surgical populations remains uncertain. Third, the triple-agent regimen was relatively uncommon, yielding asymmetric group sizes and a smaller effective sample for the triple group; nonetheless, PS distributions showed adequate overlap and covariate balance across the three arms, and estimates were directionally consistent across sensitivity analyses. Fourth, residual confounding cannot be excluded, as data on preoperative psychological status, chronic pain, and prior opioid use were unavailable. However, regimen selection in routine practice was driven largely by anesthesiologist preference and growing familiarity with multimodal analgesia rather than formal pain-risk stratification, consistent with the temporal increase in multimodal use. Moreover, if triple therapy was preferentially assigned to patients anticipated to have greater postoperative pain, this would bias against the triple group; that it nevertheless showed the lowest rescue rates suggests the observed effect is conservative rather than overestimated. Fifth, systematic NRS assessment was available only during PACU stay, precluding direct assessment of pain severity at the time of rescue administration. Sixth, rescue analgesic use was defined operationally as any IV analgesic given within the 4-hour observation window rather than by prospective labeling, which may overestimate true rescue demand; however, this window matches the expected duration of the intraoperative agents, and the substantial between-group variation in rescue rates suggests the estimates reflect actual analgesic need rather than routine dosing. Lastly, adverse-effect data were crude, unadjusted incidences, and inconsistently charted events (e.g., dizziness, sweating) may have been missed; consequently, the safety profile of the non-opioid regimens could not be fully evaluated.
In conclusion, increasing the number of intraoperative non-opioid analgesic agents was associated with a stepwise reduction in postoperative rescue analgesic use, with triple agent regimens showing the greatest benefit. These findings support the active adoption of multimodal non-opioid analgesia in patients undergoing minor general surgery.
SUPPLEMENTARY MATERIALS
Supplementary materials can be found via https://doi.org/10.3344/kjp.26009.
ACKNOWLEDGMENTS
We thank the use of the Medical Data Core of the Regional Medical Research Capability Enhancement Project, Biomedical Research Institute, Chungnam National University Hospital, for providing technical assistance, instrumentation, and data analysis support.
Footnotes
DATA AVAILABILITY
The data that support the findings of this study are available on request from the corresponding author.
CONFLICT OF INTEREST
Chaeseong Lim and Chahyun Oh have received research (financial) support from Kyongbo Pharmaceutical, South Korea. Boohwi Hong is a section editor of the Korean Journal of Pain. However, he was not involved in the selection of peer reviewers, the evaluation, or the decision-making process for this article. Other authors declare that they have no competing interests.
FUNDING
This study was supported by Kyongbo Pharmaceutical, South Korea.
AUTHOR CONTRIBUTIONS
Concept and design: Chahyun Oh, Hyunjeong Ki, Boohwi Hong. Methodology: Hyunjeong Ki, Boohwi Hong. Investigation: Chahyun Oh, Hyunjeong Ki. Resources: Jeong Yeon Lee. Data visualization: Chahyun Oh, Jeong Yeon Lee. Writing – original draft: Chahyun Oh. Writing – review and editing: Hyunjeong Ki, Jeong Yeon Lee, Boohwi Hong, Chaeseong Lim. Supervision: Boohwi Hong, Chaeseong Lim. Project administration: Chaeseong Lim. Funding acquisition: Chahyun Oh, Chaeseong Lim.
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