Tegileridine versus Sufentanil for Patient-Controlled Intravenous Analgesia After Cesarean Delivery: A Randomized Double-Blind Trial

Abstract

Background

Postoperative nausea and vomiting (PONV) remains one of the most common opioid-related adverse events after cesarean delivery despite multimodal analgesia. Tegileridine, a biased μ-opioid receptor agonist, may offer effective analgesia with fewer opioid-related adverse events. This randomized, double-blind trial compared tegileridine versus sufentanil for patient-controlled intravenous analgesia (PCIA) after cesarean delivery.

Methods

Chinese Clinical Trial Registry number: ChiCTR2600123056. Ninety-four parturients scheduled for elective cesarean were randomized to receive PCIA with tegileridine 5 mg or sufentanil 100 μg. The primary outcome was the 48-hour incidence of PONV. Secondary outcomes included other opioid-related adverse events (ORAEs), pain scores, PCIA bolus counts, rescue analgesia, Quality of Recovery 15 (QoR-15) scores, ambulation time, and hospital stay.

Results

Ninety-two participants completed the study. Compared with the sufentanil group, the tegileridine group had a lower incidence of PONV (6.5% vs 23.9%; RR = 0.27 (95% CI: 0.08–0.91); OR = 0.22 (95% CI: 0.06–0.86); ARD = −17.4% (95% CI: −31.6 to −3.1%); P=0.039) and dizziness (6.5% vs 26.1%; P=0.022). Postoperative pain scores, PCIA bolus counts, rescue analgesic requirements, ambulation time, and hospital stay showed no statistically significant differences between groups. QoR-15 scores at 48 h were higher in the tegileridine group (median 125 vs 113; P<0.001).

Conclusion

Among women undergoing cesarean delivery, tegileridine-based PCIA was associated with a lower incidence of PONV and dizziness and improved postoperative recovery quality compared with sufentanil, while postoperative analgesic outcomes were not significantly different between groups. These findings warrant confirmation in larger multicenter studies before routine clinical adoption.

Introduction

Cesarean delivery is one of the most frequently performed major surgical procedures worldwide. According to data from the National Obstetric Medical Quality Control Center, the cesarean delivery rate in China reached 44.1% in 2020.1 Effective postoperative pain management is critical for maternal recovery, early mobilization, and the quality of early maternal-infant interaction. Although opioids such as intrathecal morphine or intravenous sufentanil provide effective analgesia, they are frequently associated with opioid-related adverse events (ORAEs). Postoperative nausea and vomiting (PONV) is one of the most common complications, with an estimated incidence of 20–30% after cesarean delivery.2,3 PONV not only compromises the quality of recovery but can also lead to dehydration, electrolyte imbalance, increased wound tension, and interference with early breastfeeding and maternal-infant bonding.4

In recent years, the implementation of Enhanced Recovery After Cesarean (ERAC) pathways in obstetrics has standardized perioperative management.5 The Society for Obstetric Anesthesia and Perinatology (SOAP) recommend multimodal analgesia as a core component of ERAC, with the explicit goal of reducing opioid consumption and ORAEs.6 Tegileridine, a novel biased μ-opioid receptor agonist, was approved by China National Medical Products Administration (NMPA) in January 2024 for the management of moderate-to-severe acute pain.7 It preferentially activates the G-protein signaling pathway while minimizing the recruitment of the β-arrestin-2 pathway, a mechanism hypothesized to maintain analgesic efficacy while reducing classical ORAEs. Clinical studies have demonstrated that tegileridine provides comparable analgesia to oliceridine and morphine, with significantly fewer ORAEs in patients undergoing abdominal surgery.8,9 However, analgesic safety, efficacy, and appropriate dosage of tegileridine have not been adequately studied in obstetric populations.

Therefore, we conducted this randomized, double-blind, clinical trial to compare the efficacy and safety of tegileridine versus sufentanil for patient-controlled intravenous analgesia (PCIA) in parturients undergoing cesarean delivery. Our primary hypothesis was that tegileridine-based PCIA reduces the incidence of PONV and has a favorable safety profile. Secondarily, we aimed to compare postoperative analgesic outcomes and maternal postoperative recovery quality between the two groups.

Materials and Methods

Ethics Statement

This prospective, randomized, double-blind clinical trial was conducted at the Guangzhou Women and Children’s Medical Center Liuzhou Hospital from May to June 2026. The study was approved by the Medical Ethics Committee of GWCMCLH (2026103) and registered at the Chinese Clinical Trial Registry (ChiCTR2600123056) on 21^st April 2026, prior to enrolment of the first participant. Written informed consent was obtained from all participants, and the trial was conducted in accordance with the Declaration of Helsinki and reported following the Consolidated Standards of Reporting Trials (CONSORT) guidelines.

Study Design and Patient Enrollment

Patients scheduled for elective cesarean delivery were enrolled in this study. Inclusion criteria comprised American Society of Anesthesiologists (ASA) physical status I–III and aged over 18 years. Exclusion criteria were as follows:1. Refusal to participate in the clinical trial; 2. Known allergy to opioids or local anesthetics; 3. Chronic pain conditions requiring preoperative opioid use; 4. Contraindications to spinal or epidural anesthesia; 5. History of dementia, psychiatric disorders, or other central nervous system diseases; 6. Poor general condition, including significant dysfunction of the cardiovascular, respiratory, digestive, urinary, or central nervous systems. Participants were withdrawn from the study under the following circumstances: 1. The attending anesthesiologist determined that continuation posed a safety risk due to a serious adverse event; 2. Discontinuation or removal of the PCIA device by the patient prior to the scheduled end of postoperative analgesia; 3. Loss to follow-up.

Randomization and Blinding

Eligible patients were randomly assigned in a 1:1 ratio to receive either tegileridine or sufentanil for PCIA. Randomization was performed using a computer-generated table, and group allocations were concealed in sequentially numbered, opaque, sealed envelopes. To maintain blinding, a nurse who was not otherwise involved in the trial opened the envelope in sequence and prepared the appropriate medications (5mg tegileridine or 100μg sufentanil) for PCIA pump. The two formulations were indistinguishable in appearance, and all labeling used only the study identification number. Throughout the study, all patients, anesthesiologists, surgeons, postoperative assessors and data analysts remained blinded to group assignment. Blinding was maintained until database lock and completion of the final statistical analysis. In the event of a serious adverse reaction requiring unblinding, the randomization code could be broken by the principal investigator, and the reason and time of unblinding were documented in the case report form.

Trial Procedure

This trial was conducted in accordance with the ERAC pathway, as recommended by the SOAP.6 Before surgery, patients fasted for 6 hours for solids and 2 hours for clear liquids, received standardized education, and signed written informed consent. In the operating room, standard monitoring was established, prophylactic antibiotics were administered before skin incision, and a prophylactic phenylephrine infusion was titrated to prevent hypotension. Combined spinal-epidural anesthesia was performed at the L3-L4 interspace, with 2.6 mL of 0.5% ropivacaine injected intrathecally. After delivery, oxytocin was given to promote uterine contraction, and ondansetron 4 mg was administered intravenously to prevent nausea. Postoperative analgesia included a single epidural injection of hydromorphone 0.6 mg, followed by a PCIA pump containing 5 mg of tegileridine or 100 μg of sufentanil, along with 200 μg of dexmedetomidine, in a total volume of 100 mL of normal saline. The pump was programmed with a continuous infusion rate of 2 mL/h, a patient-controlled bolus of 2 mL per activation, and a lockout interval of 15 minutes. The pump was not refilled during the postoperative observation period. In the ward, patients with a visual analogue scale (VAS) score ≥4 received a rescue diclofenac sodium suppository. Postoperative ERAC care included early oral intake, early mobilization, early urinary catheter removal, and promotion of breastfeeding. Dr. Hu, an outcome assessor blinded to group allocation, followed up with patients at 12-hour intervals within 48 hours postoperatively. The assessor recorded VAS pain scores at rest and with movement, as well as during uterine contraction, documented adverse events, PCIA bolus counts, postoperative recovery parameters, and administered the QoR-15 questionnaire10 at 48 hours.

During the perioperative period, adverse events such as hypotension (NBP decrease >20% from baseline), excessive sedation (Ramsay score ≥4), respiratory depression (SpO₂ <90% without oxygen), and others (dizziness, pruritus, constipation) were managed with atropine, vasopressors, oxygen, or routine care, respectively. For pain (VAS ≥4), a PCIA bolus was used; if pain persisted after 15–30 min, diclofenac sodium suppository 50 mg was given rectally. For vomiting/retching (PONV grade ≥2), ondansetron 4 mg IV was administered, with dexamethasone for refractory cases.

Primary and Secondary Outcomes

The primary outcome was the incidence of PONV within 48 hours after cesarean delivery. PONV was defined as the occurrence of nausea, retching, or vomiting within 48 postoperative hours, and its severity was graded using a 4-point ordinal scale: 0 = no symptoms; 1 = mild (mild nausea or vomiting once or twice); 2 = moderate (vomiting 3–5 times); 3 = severe (vomiting >5 times).11

The secondary outcomes encompassed the incidence of other ORAEs, including dizziness, pruritus, constipation, and chest tightness within 48 hours postoperatively; the QoR-15 score assessed at 48 hours postoperatively, comprising five subdomains (physical comfort, physical independence, psychological support, pain, and emotional state), with total scores ranging from 0 (extremely poor recovery) to 150 (excellent recovery); Pain intensity was evaluated using the VAS score (0–10cm) at predefined intervals (12, 24, 36, 48h postoperatively) at rest, with movement, and during uterine contraction, and the overall pain burden was summarized as the area under the curve (AUC) for the 12–48 h period using trapezoidal rule; PCIA demanded and effective bolus counts, the time to first PCIA bolus request; time to first postoperative ambulation; the proportion of patients requiring rescue analgesia with diclofenac sodium suppositories on postoperative day; and length of hospital stay, including both total and postoperative duration.

Sample Size and Statistical Analysis

The sample-size calculation was performed using MedSci Sample Size Tools (MSST), based on a two-group comparison of independent proportions. Sample size was calculated based on the primary outcome—the incidence of PONV within 48 hours. Based on previously published estimates3,12 and pilot study, we assumed a 26% PONV rate in the control group and hypothesized that tegileridine would reduce this incidence to 5%. Using a two-sided test with α = 0.05 and 80% power (β = 0.2), and accounting for an anticipated 10% dropout, the calculated sample size was 47 patients per group.

Data analyses were conducted using SPSS (version 27.0) and R (version 4.5.1). Analyses were based on the modified intention-to-treat (mITT) population, comprising all randomized participants who received the allocated intervention and had at least one post-baseline assessment. Data normality was assessed using the Shapiro–Wilk test. Continuous variables are presented as mean (standard deviation, SD) for normally distributed data and as median (interquartile range, IQR) for non-normally distributed data. Categorical variables are expressed as frequencies (percentages). Group comparisons were performed using Student’s t-test for normally distributed continuous variables; for non-normally distributed variables, the Mann–Whitney-U test was used, and median differences between groups with their 95% CIs were estimated using the Hodges–Lehmann method. Categorical variables were analyzed with the Chi-square test or Fisher’s exact test when expected frequencies were less than 5. Postoperative VAS scores were analyzed using linear mixed models with REML estimation. Fixed effects included group, time (categorical: 12, 24, 36, 48 h), group-by-time interaction, and covariates (age, BMI, duration of surgery). Random intercept per patient and an AR (1) covariance structure for repeated measures were specified. Residuals were graphically checked and met model assumptions. Pairwise comparisons were adjusted using Bonferroni correction. The time to first PCIA request data were analyzed by the Kaplan–Meier method, with survival curves compared via the Log rank test. A post hoc best-/worst-case sensitivity analysis was performed for the two participants with missing primary-outcome data: missing PONV was alternatively classified as absent or present in each treatment group, and two-sided Fisher’s exact tests were used to assess the resulting between-group differences. A mediation analysis (5000 bootstrap replications) was conducted to explore whether the beneficial impact on recovery quality was mediated by reductions in vomiting episodes or by analgesic efficacy. Mediator and outcome regression models were adjusted for age and BMI. Given limited sample size and few vomiting events, this analysis is labelled exploratory. A p-value < 0.05 was considered statistically significant.

Results

The CONSORT flowchart was presented in Figure 1. A total of 94 parturients were assessed for eligibility between May 2026 and June 2026. 1 patient was lost to follow-up, and 1 patient discontinued the PCIA device, neither of the two participants completed any post-baseline assessment. Consequently, 92 patients (46 in each group) were included in the final analysis. There were no statistically significant differences in baseline demographic and clinical characteristics between the two groups (Table 1).

Figure 1.

Consolidated Standards of Reporting Trials (CONSORT) flowchart.

Table 1.

Patient Demographics, Clinical Characteristics, and Surgical Characteristics

Demographic	Sufentanil Group (n=46)	Tegileridine Group (n=46)	P-value
Age, mean (SD), year	33.8(4.4)	33.6(4.9)	0.715
Height, mean (SD), cm	157.0(5.9)	156.9(5.0)	0.731
Weight, median (IQR), kg	68.9(62.1,75.9)	69.5(61.5,73.6)	0.994
BMI, median (IQR), kg/m2	27.4(25.6,30.4)	27.4(24.9,30.9)	0.978
Education level			0.456
High school or below	9(19.6%)	12(26.1%)
College or above	37(80.4%)	34(73.9%)
ASA physical status, n (%)			0.328
II	37(80.4%)	33(71.7%)
III	9(19.6%)	13(28.3%)
Gravidity, median (IQR)	3(1,3)	3(1,3)	0.783
Parity, median (IQR)	1(0,1)	1(0,1)	0.741
Gestational age, mean (SD), wk	38.5(1.1)	38.6(1.4)	0.201
IVF pregnancy, n (%)	12(26.1%)	16(34.8%)	0.365
Comorbidities, n (%)
Gestational hypertension	5(10.9%)	2(4.3%)	0.434
GDM	9(19.6%)	8(17.4%)	1
ICP	4(8.7%)	3(6.5%)	1
Anemia	4(8.7%)	7(15.2%)	0.522
Duration of surgery, median (IQR), min	60.5(48.3,76.2)	55(45,80)	0.649
Estimated blood loss, median (IQR), mL	350(350,350)	350(300,362)	0.614

Abbreviations: ASA, American Society of Anesthesiologists; BMI, body mass index; SD, standard deviation; IQR, interquartile range; GDM, Gestational diabetes mellitus; ICP, Intrahepatic cholestasis of pregnancy.

Primary Outcome

The incidence of PONV within 48 hours after cesarean delivery was significantly lower in the tegileridine group compared with the sufentanil group (3 (6.5%) vs 11 (23.9%); RR = 0.27 (95% CI: 0.08–0.91); OR = 0.22 (95% CI: 0.06–0.86); Absolute risk difference (ARD) = −17.4% (95% CI: −31.6% to −3.1%); P=0.039). Regarding PONV severity, there were no statistically significant differences in the severity of PONV between the two groups (mild: P = 0.158; moderate: P = 0.617; severe: P = 1.000) (Table 2). A post hoc best-/worst-case sensitivity analysis was consistent with the direction of the primary finding. When the missing outcome was assumed to be PONV-free in the tegileridine group and PONV-positive in the sufentanil group (best-case scenario for tegileridine), the PONV incidence was 6.4% versus 25.5% (P = 0.022). Under the opposite worst-case assignment, the incidences were 8.5% versus 23.4% (P = 0.089), indicating that statistical significance was not maintained under the most conservative assumption (Supplementary Table S2).

Table 2.

Adverse Events Between Groups

N(%)	Sufentanil Group, n(%) (n=46)	Tegileridine Group, n(%) (n=46)	P-value
Primary outcome
Nausea and vomiting	11(23.9%)	3(6.5%)	0.039
PONV grade
Mild	7(15.2%)	2(4.3%)	0.158
Moderate	3(6.5%)	1(2.2%)	0.617
Severe	1(2.2%)	0(0)	1
Secondary outcome
Dizziness	12(26.1%)	3(6.5%)	0.022
Pruritus	8(17.4%)	2(4.3%)	0.09
Constipation	1(2.2%)	5(10.9%)	0.203
Chest tightness	2(4.3%)	1(2.2%)	1

Notes: Categorical variables were presented as number (%) and compared using Pearson’s chi-square or Fisher’s exact test as appropriate. PONV: “0”, no symptoms of nausea or vomiting; “1” (mild), mild nausea or vomiting occurred once or twice; “2” (moderate), vomiting 3–5 times; “3” (severe), more than 5 times.

Abbreviation: PONV, postoperative nausea and vomiting.

Secondary Outcomes

The incidence of other ORAEs is summarized in Table 2. Compared with the sufentanil group, the tegileridine group had a significantly lower incidence of dizziness (3 (6.5%) vs 12 (26.1%); P = 0.022). The incidence of pruritus was also lower in the tegileridine group (2 (4.3%) vs 8 (17.4%)), although this difference did not reach statistical significance (P = 0.090). No significant differences were observed between the two groups in the incidence of constipation (5 (10.9%) vs 1 (2.2%)); P = 0.203) or chest tightness (1 (2.2%) vs 2 (4.3%); P = 1.000). No respiratory depression or excessive sedation occurred in either group. Secondary outcomes were not adjusted for multiple testing and are therefore considered exploratory.

The visual analogue scale (VAS) pain scores at rest, with movement, and during uterine contraction were measured at 12, 24, 36, and 48 hours postoperatively (Figure 2). Linear mixed models revealed that all three types of pain scores decreased significantly over time in both groups (time effect, all P < 0.001). However, the overall group effect was not significant for any of the three pain measures (VAS-R: P = 0.079; VAS-U: P = 0.590; VAS-M: P = 0.367), indicating that the average pain levels did not differ between the two treatment groups. Notably, significant group-by-time interactions were observed for VAS-U (P = 0.003) and VAS-M (P= 0.004), suggesting that the temporal decline in these pain scores differed between groups although the overall treatment effect was not significant. For VAS-R, the interaction did not reach statistical significance (P = 0.050). In addition, age (P = 0.021) and BMI (P = 0.004) emerged as significant covariates for VAS-M. Estimated treatment differences with 95% confidence intervals at each time point are provided in Supplementary Table S1. No significant differences were observed between the two groups in the area under the curve (AUC) for VAS scores at rest, with movement, or during uterine contraction over the 12–48 h postoperative period (Table 3). There were no significant differences between the two groups in total PCIA bolus counts (median [IQR]: 6 [1–15] vs 4 [1–11]) or effective PCIA bolus counts (5 [1–11] vs 3 [1–9]) (P > 0.05 for both; Table 3). The time to first PCIA request did not differ significantly between the two groups (median [95% CI]: 31.0 [27.7–34.3] hours in the sufentanil group vs 35.0 [30.6–39.4] hours in the tegileridine group; log-rank P = 0.454), Figure 3). At 48 hours, 9 participants in the sufentanil group and 11 participants in the tegileridine group were censored. The proportion of patients requiring rescue analgesia with diclofenac suppositories did not differ significantly on either POD 1 (52.2% vs 50.0%) or POD 2 (32.6% vs 47.8%) (both P > 0.05). Similarly, no significant differences were observed in time to first ambulation (P = 0.736) or length of hospital stay (P > 0.05) (Table 3).

Figure 2.

The mean changes in VAS-R (A), VAS-U (B) and VAS-M (C) in sufentanil and tegileridine group patients over time after cesarean delivery. Error bars represent 95% CI of the mean.

Abbreviations: VAS-R, visual analog scales at rest, VAS-U, visual analog scales of uterine contractions pain, VAS-M, visual analog scales in the movement-evoked mainly by changing position in bed.

Table 3.

Perioperative Measurements Between Groups

outcomes	Sufentanil Group (n=46)	Tegileridine Group (n=46)	Median Difference (95% CI)	P-value
QoR-15 score at 48h	113(105,124)	125(117,131)	−10(−14,-5)	<0.001
Physical comfort	40(37,44)	44(40,46)	−2(−5,0)	0.018
Physical independence	12(7,16)	14(11,17)	−2(−4,0)	0.019
Psychological support	17(16,18)	19(18,20)	−2(−2,-1)	<0.001
Pain	11(10,15)	15(10,16)	−2(−4,0)	0.075
Emotional state	32(29,36)	34(32,37)	−2(−4,0)	0.034
Rest VAS AUC 12–48h	51(14,95)	33(12,60)	12(0,36)	0.118
Movement VAS AUC 12–48h	144(111,156)	114(84,159)	15(−6,36)	0.164
Uterine contraction VAS AUC 12–48h	51(17,110)	66(41,96)	0(−30,18)	0.781
Total PCIA boluses count	4(1,11)	6(1,15)	−1(−4,1)	0.362
Effective PCIA bolus count	3(1,9)	5(1,11)	−1(−3,1)	0.357
Time to first postoperative ambulation(h)	15(11,17)	14(11,18)	0(−1,2)	0.736
Diclofenac sodium suppositories, n (%)
POD1	23(50%)	24(52%)	/	0.835
POD2	22(48%)	15(33%)	/	0.137
Length of hospital stay, (d)	5(5,6)	5(5,5)	0(0, 0)	0.248
length of postoperative hospital stay	4(4,4)	4(4,4)	0(0, 0)	0.946

Notes: Data are expressed as median (IQR), or number (%); Median differences (Sufentanil group − Tegileridine group) and their 95% CIs were estimated using the Hodges–Lehmann method.

Abbreviations: QoR-15, quality of recovery-15; POD, post-operative day; AUC, area under the curve; PCIA, patient-controlled intravenous analgesia.

Figure 3.

Kaplan–Meier curves for time to first PCIA request.

Note: The event was defined as the first PCIA request. Participants who did not request PCIA during the 48-hour observation period were censored at the end of follow-up. Numbers at risk are presented in Supplementary Table S3.

Abbreviation: PCIA, patient-controlled intravenous analgesia.

The Quality of Recovery-15 (QoR-15) score assessed at 48 hours postoperatively was significantly higher in the tegileridine group compared with the sufentanil group (median [IQR]: 125 [117–131] vs 113 [105–124]; median difference, –10; 95% CI, –14 to –5; P < 0.001), indicating better recovery quality. The tegileridine group showed significantly higher scores in four QoR-15 domains (physical comfort, physical independence, psychological support, and emotional state) at 48 hours postoperatively (all P < 0.05), whereas no significant difference was observed in the pain domain (Table 3).

Mediation analysis showed that tegileridine significantly improved the 48-h QoR-15 score (total effect about 9, all P < 0.05). However, the indirect effects via vomiting episodes (0.25, P = 0.636), resting pain (0.66, P = 0.483), and movement-evoked pain (1.02, P = 0.222) were all non-significant, with proportions mediated of only 2.8%, 7.3%, and 11.3%, respectively (Table 4). These exploratory findings indicate that we did not detect evidence of mediation through vomiting episodes or pain scores for the beneficial effect of tegileridine on recovery quality after cesarean delivery.

Table 4.

Mediation Analysis

Model	Total Association		Direct Association		Indirect Association via Pain		Proportion Mediated
	β (95% CI)	P	β (95% CI)	P	β (95% CI)	P	β (95% CI)	P
Model 1	9(3.75, 14.08)	<0.001	8.75(3.59,13.68)	<0.001	0.25(−1.3,1.56)	0.636	2.75%(−17.8%,18.8%)	0.634
Model 2	9.02(3.77,13.97)	<0.001	8.36(2.84,13.83)	0.002	0.66(−1.45,2.46)	0.483	7.28%(−17.3%,35.1%)	0.483
Model 3	9.02(3.77,13.97)	<0.001	8.0(2.44,13.63)	0.005	1.02(−0.63,3.08)	0.222	11.32%(−6.7%,45.5%))	0.222

Notes: Total, direct, and indirect association of use of tegileridine with postoperative QoR-15 mediated via postoperative number of vomiting episodes (Model 1), pain score at rest (Model 2) and with movement (Model 3) at 48 h after surgery. Adjusted for age and BMI.

Abbreviation: BMI, body mass index.

Discussion

This prospective, randomized, double-blind trial demonstrated that PCIA with tegileridine significantly reduced the incidence of ORAEs like PONV, dizziness compared with sufentanil, while providing analgesic efficacy that showed no statistically significant differences as reflected by pain scores and rescue analgesic requirements. Furthermore, tegileridine was associated with significantly higher QoR-15 scores at 48 hours postoperatively. Collectively, these results indicate that tegileridine offers a favorable safety profile and effective analgesia in the post-cesarean delivery, which aligns with the goals of ERAC pathways.

PONV is influenced by well-established risk factors, including female sex, non-smoking status, and postoperative opioid use. Cesarean delivery patients are technically considered a high-risk population for PONV, as they possess all three of these characteristics. Literature reports that the incidence of PONV after cesarean delivery varies widely, ranging from 15% to 38% across studies.4 This variability is attributed to multiple contributing factors: the routine use of neuraxial or systemic opioids for post-cesarean analgesia, pregnancy-induced hormonal fluctuations, delayed gastric emptying, uterine contraction, and surgical peritoneal irritation.2,13 In our study, the incidence of PONV was significantly lower in the tegileridine group (6.5%) compared with the sufentanil group (23.9%). However, the wide confidence intervals (RR 95% CI: 0.08–0.91) indicate that the precision of this estimate is limited by the small number of events, and the observed effect size should be interpreted with caution until confirmed in larger studies. The pharmacological profile of tegileridine provides a mechanistic basis for our findings. As a biased μ-opioid receptor agonist, tegileridine preferentially activates G-protein signaling while minimizing β-arrestin-2 recruitment. This distinctive mechanism is hypothesized to preserve potent analgesic efficacy while reducing classical ORAEs such as respiratory depression, gastrointestinal dysmotility, and emesis.14 Consistent evidence across multiple surgical populations demonstrates that tegileridine significantly reduces PONV compared with conventional opioids. In a Phase 3 abdominal surgery trial, tegileridine showed a favorable safety profile with lower nausea and vomiting rates versus morphine.8 In laparoscopic sleeve gastrectomy, tegileridine reduced nausea (23% vs 36%) and vomiting (11% vs 33%) compared with sufentanil.14 In total laparoscopic hysterectomy, tegileridine lowered PONV incidence from 54.3% with oxycodone to 27.3%.15 Nevertheless, when interpreting the magnitude of PONV reduction in our study, it is important to consider the standardized antiemetic prophylaxis administered to both groups. All participants received ondansetron 4 mg intravenously to prevent PONV. As a 5-HT₃ receptor antagonist, ondansetron effectively lowers the overall PONV rate,16 thereby exerting a comparable dampening effect on the baseline risk in both arms, which might dilute the observed effect size. In the absence of such prophylaxis, the PONV reduction with tegileridine relative to sufentanil might have been more pronounced. Nevertheless, because the prophylactic strategy was applied identically to all participants, it does not introduce systematic bias. Importantly, despite this potentially conservative background, the tegileridine group still demonstrated a significantly lower incidence of PONV, indicating that the benefit of tegileridine in reducing PONV remained discernible even under standardized antiemetic coverage.

Despite the significant reduction in PONV, no statistically significant differences in analgesic efficacy were observed between tegileridine and sufentanil. Post-cesarean pain is multifaceted, encompassing incisional pain, movement-evoked pain, and visceral pain from uterine contraction.17 Uterine contraction pain is related to the use of postpartum oxytocin, postpartum breast-feeding, delivery times, and other factors.18 These pains not only increase maternal discomfort but also affect maternal postoperative recovery, potentially leading to refusal to breastfeed early and an increased risk of postoperative depression.19 Sufentanil is widely used for PCIA after cesarean delivery. However, the relatively high incidence of adverse reactions limits its applicability in ERAC pathways,20 which emphasize minimizing ORAEs to facilitate early recovery.

In our study, linear mixed models revealed no significant overall group effect for any of the VAS at rest, with movement or uterine contraction, indicating that average pain levels did not differ between the two groups over the 48-hour postoperative period. This finding is consistent with prior comparative studies. Clinical studies have demonstrated that tegileridine has a rapid onset of action (within 5 minutes), a half-life of approximately 6–7 hours, and a potency approximately nine times that of morphine.7 Several studies have demonstrated that tegileridine-based PCIA provides effective postoperative analgesia across various surgeries, including minimally invasive esophagectomy, laparoscopic sleeve gastrectomy, and laparoscopic abdominal tumor surgery in older patients. Its analgesic efficacy is comparable or slightly superior to that of conventional opioids such as oliceridine, sufentanil, and morphine, with no significant differences in PCIA consumption or rescue analgesic requirements.9,14 The analgesic findings of this trial should be interpreted within the multimodal analgesic context in which they were generated. Given its known effects in reducing postoperative pain, opioid consumption, and PONV,21 dexmedetomidine was co-administered in the PCIA pump to both groups. Similarly, the addition of epidural hydromorphone provides sustained baseline analgesia and reduces the need for supplemental systemic opioids and their associated side effects,22 while rescue diclofenac offers additional non-opioid analgesia. Importantly, because all co-interventions were applied identically to both groups, they may have attenuated the absolute effect sizes but are unlikely to have introduced systematic bias; their balanced distribution across treatment arms ensures that they do not confound between-group comparisons. Thus, our trial essentially compares two opioid strategies against an identical multimodal background, supporting its generalizability to ERAC practice.

The significantly higher QoR-15 score at 48 hours postoperatively in the tegileridine group (median 125 vs 113; median difference, –10; 95% CI, –14 to –5; P < 0.001) exceeded the proposed minimal clinically important difference (MCID) threshold of 8.0 at the point estimate.23 However, the width of the confidence interval precludes a definitive conclusion of clinical importance, and this finding should be confirmed in larger studies. The tegileridine group showed significantly higher scores in four of the five QoR-15 domains (physical comfort, physical independence, psychological support, and emotional state), while the absence of a significant difference in the pain domain is consistent with the observation of no statistically significant between-group differences in analgesic outcomes, suggesting that the overall improvement in recovery quality might be related to improvements in physical and emotional well-being. Interestingly, we did not detect evidence of mediation through reductions in vomiting episodes or pain scores for the beneficial effect of tegileridine on QoR-15 scores, suggesting that the improvement in recovery quality may be mediated by other factors, possibly the reduction in dizziness or the preservation of normal gastrointestinal function, a finding that warrants further investigation in larger studies with more comprehensive assessments of recovery domains.

The overall safety profile of tegileridine in this trial was favorable, with a significantly lower incidence of dizziness and a trend toward reduced pruritus compared with sufentanil, and no cases of respiratory depression were observed in either group, consistent with the safety profiles reported in prior studies.8,15

This study has several limitations. First, this was a single-center trial with a small sample size, which may limit the generalizability of our findings to other institutions or diverse patient populations. Second, the optimal dosing regimen for tegileridine in the obstetric population remains undefined. We selected a fixed dose of 5 mg based on previous studies,8,24 but dose-finding studies are needed to determine the ideal dose that maximizes analgesic efficacy while minimizing adverse effects in postpartum women. Third, our follow-up period was limited to 48 hours postoperatively, which may not capture delayed ORAEs or the longer-term impact on recovery, including chronic postsurgical pain. Extended follow-up would be valuable to assess the durability of the recovery benefits observed with tegileridine. Fourth, the use of multimodal analgesia, including epidural hydromorphone and rescue diclofenac, may have confounded the assessment of the pure analgesic effect of tegileridine. While this reflects real-world clinical practice and aligns with ERAC principles, it may have diluted the differences between groups in terms of pain scores and opioid consumption. Fifth, we did not assess neonatal safety outcomes, maternal sedation levels, or the impact of the study drugs on breastfeeding initiation and quality. These are clinically relevant endpoints in the obstetric population and should be addressed in future investigations. Sixth, we did not perform a formal cost-effectiveness analysis. Given the novelty and potentially higher acquisition cost of tegileridine, economic evaluations are necessary to determine its value in the context of limited healthcare resources. Seventh, the lack of systematic recording of total infused volume and infusion duration precluded precise quantification of cumulative opioid consumption. Therefore, a direct comparison of cumulative opioid exposure between groups was not possible and should be considered when interpreting the analgesic findings. Finally, although the best-/worst-case sensitivity analysis preserved the direction of the primary PONV effect, statistical significance was not maintained under the most conservative missing-data assumption. This underscores the potential impact of missing data and highlights the need for larger confirmatory trials to validate this finding. In summary, while this trial provides promising evidence for the use of tegileridine in post-cesarean analgesia, our findings should be interpreted within the context of these limitations. Future multi-center, dose-finding, and long-term studies in more diverse populations are warranted to confirm and extend our results.

Conclusion

In conclusion, our study suggested that tegileridine for PCIA significantly reduced the incidence of PONV and dizziness compared with sufentanil in women after cesarean delivery, whereas no statistically significant differences in analgesic efficacy were observed between groups. Moreover, tegileridine was associated with a statistically significant improvement in postoperative recovery quality as measured by QoR-15, suggesting its value as a component of multimodal analgesia within ERAC pathways. However, given the small sample size and single-center design of this trial, larger multicenter studies, formal dose-finding investigations, and thorough maternal-neonatal safety assessments are required before routine clinical adoption can be recommended.

Data Sharing Statement

The individual deidentified participant data in support of the results reported in this study are available upon reasonable request to the corresponding author.

Ethics Approval and Informed Consent

This study was approved by the Medical Ethics Committee of Guangzhou Women and Children’s Medical Center Liuzhou Hospital (2026103) and registered at the Chinese Clinical Trial Registry (ChiCTR2600123056) on 21^st April 2026, prior to enrolment of the first participant. Written informed consent was obtained from all participants.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors report no conflicts of interest in this work.