Analgesic Efficacy and Adverse Effects of Epidural Ropivacaine Combined with Equipotent Alfentanil or Sufentanil for Labor Analgesia: A Multicenter Randomized Controlled Single-Blind Trial

Abstract

Introduction

Epidural analgesia has shown high maternal–fetal safety and satisfactory analgesia. Sufentanil is associated with a high risk of pruritus, nausea, and vomiting for epidural labor analgesia. Alfentanil is characterized by a rapid onset and is also used for labor analgesia. The study aimed to compare the analgesic efficacy and adverse effects of epidural ropivacaine combined with equipotent doses of alfentanil or sufentanil for labor analgesia, and to provide evidence for optimizing obstetric analgesic regimens.

Methods

In this multicenter, randomized, controlled, single-blind trial conducted at four tertiary hospitals in China between June 2023 and June 2024, 442 nulliparous women with singleton, term pregnancies were enrolled. Participants were randomly assigned (1:1) to receive epidural 0.075% ropivacaine combined with either 4 μg/ml alfentanil (group A) or 0.2 μg/ml sufentanil (group S). Analgesia was delivered via a programmed intermittent epidural bolus (PIEB) plus patient-controlled epidural analgesia (PCEA) regimen (10 ml bolus, 50-min interval, 3 ml/h background infusion, 8-ml patient-controlled bolus, 20-min lockout). The onset of analgesia, defined as the median time from drug administration to the first recording of a visual analogue scale (VAS) score ≤ 3 within 30 min was the primary outcome. Hemodynamic parameters, labor characteristics, analgesic consumption, maternal satisfaction, neonatal outcomes, and adverse events were recorded as secondary outcomes.

Results

The median onset time of analgesia was significantly shorter in the alfentanil group compared with the sufentanil group (8.0 min vs. 10.0 min, P < 0.001). No significant differences were observed between groups in blood pressure, heart rate, SpO₂, fetal heart rate, Bromage scores, VAS scores at subsequent time points, uterine pressure, sensory block level, body temperature, duration of analgesia, labor duration, mode of delivery, oxytocin use, total drug consumption, maternal satisfaction, or neonatal Apgar scores (all P > 0.05). Adverse events such as pruritus, nausea, vomiting, urinary retention, and lower limb numbness were infrequent and comparable between groups.

Conclusions

Both alfentanil and sufentanil, when combined with 0.075% ropivacaine, provide effective and safe epidural labor analgesia. However, alfentanil offers the advantage of a faster onset of analgesia, making it a valuable alternative to sufentanil in clinical practice.

Trial Registration

Chinese Clinical Trial Registry, ChiCTR2300072104, Date of registration: June 2, 2023.

Key Summary Points

Why carry out this study?

Labor pain can be severe. One way to manage it is epidural analgesia—a small tube placed in the lower back delivers pain medicine directly to the nerves.

The medicine usually includes ropivacaine (numbs the area) plus an opioid painkiller. Two common opioids are sufentanil and alfentanil.

We wanted to know: Does alfentanil work faster than sufentanil? Is it just as safe?

What was learned from the study?

Faster relief: Alfentanil worked in 8 min; sufentanil took 10 min (2 min faster).

Equal pain control: Both groups had good pain relief and similar satisfaction.

Both medicines are safe and effective. Alfentanil may be better when faster pain relief matters. Women can discuss both options with their doctors.

Introduction

Epidural analgesia is widely recognized as the gold standard for labor pain relief, providing reliable analgesic efficacy and high maternal–fetal safety, while also offering satisfactory anesthesia for instrumental delivery and emergency cesarean section when required [1]. Patient-controlled epidural analgesia (PCEA) is an effective method with high maternal satisfaction and a low incidence of adverse effects [2]. In recent years, programmed intermittent epidural bolus (PIEB) has been introduced as a novel technique for labor analgesia. Compared with conventional continuous epidural infusion, PIEB reduces the total anesthetic consumption, improves maternal satisfaction, and lowers the incidence of motor block [3–5]. Currently, a combined regimen of PIEB and PCEA is commonly employed, which minimizes local anesthetic dosage, exerts minimal influence on labor progression, and achieves superior analgesic outcomes [6].

The combination of low-concentration local anesthetics with opioids has become widely accepted in obstetric analgesia [7]. Ropivacaine, a long-acting amide local anesthetic, is particularly favored for labor analgesia due to its ability to provide sensory blockade with relative sparing of motor function at low concentrations [8]. It is frequently combined with small doses of opioids such as sufentanil or fentanyl [9, 10]. Numerous studies have demonstrated satisfactory analgesia with sufentanil; however, a recent meta-analysis revealed that sufentanil is associated with a substantial risk of pruritus, nausea, and vomiting, with incidence rates as high as 82% [11]. These adverse effects remain major limitations in achieving ideal labor analgesia.

Alfentanil, a synthetic derivative of fentanyl acting on the μ-opioid receptor, is characterized by rapid onset, short duration of action, and fast metabolism. Compared with fentanyl and sufentanil, alfentanil has lower potency but offers a favorable pharmacokinetic profile, making it suitable for labor analgesia by providing prompt and effective pain relief [12, 13].

Based on these considerations, we hypothesized that epidural analgesia with 0.075% ropivacaine combined with equipotent alfentanil would achieve a faster onset than ropivacaine combined with sufentanil.

Methods

Study Design

This was a prospective, randomized, controlled, single-blind trial with two parallel groups, conducted at four tertiary hospitals in China. Six hospitals were registered, but only four completed the study. The study protocol was approved by the Ethics Committee of the General Hospital of the Northern Theater Command of the Chinese People’s Liberation Army (Approval No. Y [2023] 069). All participating sites accepted the central approval. The clinical trial registration number was ChiCTR2300072104, and the period of the study was from June 2023 to June 2024. The study protocol was conducted in accordance with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Written informed consent was obtained from all participants prior to enrollment. This study complies with the ICMJE recommendations on clinical trial registration and transparency of results reporting [14].

Before initiation, all investigators from the participating centers received standardized training from the principal investigator. The training covered clinical procedures, outcome assessment, and data collection to ensure consistency and objectivity across sites.

Participants

Eligible parturients were nulliparous women with full-term singleton pregnancies (37–42 weeks) in vertex presentation. They were required to be 20–35 years of age, with an American Society of Anesthesiologists (ASA) physical status of II, height between 150 and 170 cm, and body mass index (BMI) between 20 and 35 kg/m². Enrollment occurred when cervical dilation reached 2–3 cm with regular uterine contractions, and suitability for vaginal delivery was confirmed by the attending obstetrician and midwife.

Women were excluded if they had contraindications to neuraxial anesthesia, including coagulopathy, infection at the puncture site, uncorrected hypovolemia or hypotension, elevated intracranial pressure, or severe spinal deformities. Pregnancies complicated by gestational diabetes, preeclampsia, or placenta previa, as well as significant maternal cardiac, neurologic, hepatic, or renal disease, were also excluded. Fetuses with intrauterine growth restriction or congenital malformations were not eligible.

Additional exclusion criteria included inability to cooperate with epidural placement or pain scoring, a baseline visual analogue scale (VAS) score < 6 before analgesia, allergy to local anesthetics or opioids, or prior opioid administration. Participants were withdrawn if epidural catheterization failed or accidental dural puncture occurred, if severe adverse events developed such as profound hypotension, local anesthetic systemic toxicity, or total spinal anesthesia, if conversion to cesarean section became necessary, if informed consent was withdrawn, or if rapid cervical dilation (≥ 5 cm within 45 min of epidural initiation) was observed.

Group Allocation

Participants were randomly assigned in a 1:1 ratio to either the sufentanil group (group S) or the alfentanil group (group A) using a computer-generated random number table. Allocation was concealed until the initiation of epidural analgesia, and parturients were blinded to group assignment.

The choice of study doses was based on prior pharmacological evidence. Under the PIEB regimen with 0.075% ropivacaine, the 90% effective concentration (EC90) of alfentanil was reported as 3.85 μg/ml (95% CI, 3.65–4.28 μg/ml) [12]. Considering the analgesic potency ratio of alfentanil to morphine (40–50:1) and sufentanil to morphine (approximately 1000:1), the equipotency ratio between alfentanil and sufentanil was estimated to be 20–25:1.

Based on these calculations, the final study solutions were defined as 0.075% ropivacaine combined with 0.2 μg/ml sufentanil in group S and 0.075% ropivacaine combined with 4 μg/ml alfentanil in group A.

Randomization and Blinding

A center-stratified block randomization scheme with randomly varying block sizes (4 or 6) was employed to ensure balance within each center. An independent statistician generated the allocation sequence with SAS 9.4. “Center” served as the stratification factor (four strata).

Within each stratum, participants were randomly assigned to either group S or group A in a 1:1 ratio using permuted blocks of length 4 or 6. The 442 unique randomization numbers (ID 001–ID 442) were pre-distributed across centers according to anticipated recruitment.

The sequence was uploaded to a central web-based randomization system (IWRS) that was inaccessible to investigators before randomization. After confirming eligibility, the investigator logged into the system, entered the participant’s details, and immediately received the next randomization number and corresponding group assignment, thereby maintaining allocation concealment. Because the trial was single-blind, only participants were blinded to group allocation; investigators were aware of the assigned treatment and responsible for its administration and follow-up. The statistician who performed the primary analyses remained blinded to group membership until the database was locked. This was a single-blind trial: only the participants were blinded to group assignment, whereas drug preparation, dispensing, monitoring, and all clinical management were conducted by an unblinded study team.

Epidural Analgesia Procedure

Upon admission to the labor ward at 2–3-cm cervical dilation, routine monitoring was established, including electrocardiogram, noninvasive blood pressure, heart rate, saturation of peripheral oxygen, uterine contractions, and fetal heart rate. An intravenous line was secured, and lactated Ringer’s solution was administered.

With the patient in the left lateral position, epidural puncture was performed at the L2–3 or L3–4 interspace (preferably L2–3). The epidural catheter was advanced 4 cm cephalad. After confirming the absence of cerebrospinal fluid or blood aspiration, a test dose of 3 ml 1% lidocaine was injected. Upon negative test results, the catheter was fixed in place. Patients with dural puncture or failed catheterization were excluded.

The catheter was connected to an electronic analgesia pump programmed for PIEB combined with PCEA. The regimen was: PIEB bolus dose 10 ml, interval 50 min, background infusion 3 ml/h; PCEA bolus 8 ml, lockout time 20 min. Effective analgesia was defined as VAS score ≤ 3 within 30 min after epidural initiation.

A VAS score above 3 at 30 min after epidural labor analgesia was considered inadequate analgesia. In cases of incomplete analgesia, the possible causes were considered and appropriate measures were taken according to the manifestations of incomplete analgesia. For example, if the analgesic plane was adequate (T10-S4) but the analgesic intensity was insufficient, the concentration of analgesic could be increased. For bilateral blocks and insufficient analgesic planes, a large volume (5–15 ml) of low-concentration local anesthetic was used for planar diffusion.

Outcomes

The selection of outcome measures was guided by the Core Outcome Measures in Effectiveness Trials (COMET) Initiative recommendations for developing core outcome sets [15]. The primary outcome of this study was the onset of analgesia, defined as the median time from drug administration to the first recording of a VAS score ≤ 3 within 30 min. The VAS score was evaluated every 2 min within 30 min of epidural analgesia.

Secondary outcomes encompassed several maternal parameters, including hemodynamic variables (blood pressure, heart rate, and oxygen saturation), intrauterine pressure, temperature and fetal heart rate, which were recorded at baseline, 15, 30, and 45 min after initiation of epidural analgesia, and again at full cervical dilation. Pain intensity was assessed using the VAS, while motor block was evaluated with the Bromage scale. The highest level of sensory block and maternal body temperature were also documented.

Additional indicators included the duration of analgesia, length of labor, mode of delivery, oxytocin requirement, and total anesthetic consumption (total volume of PIEB solutions and total doses of opioids used). Neonatal condition was assessed by Apgar scores at 1 and 5 min after birth. Maternal satisfaction was rated on a 0–10 scale, and adverse events such as pruritus, nausea, vomiting, hypotension, urinary retention, and lower limb numbness were systematically recorded. Secondary outcomes that were not pre-specified in the trial registry were analyzed post hoc, including intrauterine pressure, maternal temperature, maternal satisfaction scores, neonatal Apgar scores, and oxytocin requirement. However, all data were routinely captured in pre-specified case report form (CRF) fields as part of standard obstetric monitoring and required no additional measurements or retrospective data extraction.

Sample Size Calculation

Based on pilot data, the mean onset time was 8.1 ± 1.6 min with 0.2 μg/ml sufentanil + 0.075% ropivacaine and 6.6 ± 1.4 min with 4 μg/ml alfentanil + 0.075% ropivacaine. With α = 0.05 and β = 0.10 (power = 90%), a sample size of 201 participants per group was required. Assuming a 10% dropout rate, 221 parturients were planned per group, yielding a total of 442 participants.

Statistical Analysis

The primary analysis was conducted on the per-protocol (PP) population, including only those participants who completed the intervention as assigned without major protocol violations, to assess the consistency of the findings. Data were analyzed using SPSS version 27.0. Continuous variables with normal distribution were expressed as mean ± standard deviation (SD) and compared using independent-samples t tests. Non-normally distributed data were expressed as median (interquartile range, IQR) and compared with the Mann–Whitney U test. Median differences (and 95% CIs) were calculated with Hodges–Lehmann estimators. Categorical data were expressed as counts (percentages) and compared using chi-square tests. Repeated measurements across time points were analyzed using generalized estimating equations (GEE), including time-by-group interactions. A two-sided P < 0.05 was considered statistically significant.

Results

Patient Population

Between June 2023 and June 2024, a total of 546 parturients were screened, of whom 464 met eligibility criteria. Ultimately, 442 women were randomized to receive either alfentanil (n = 221) or sufentanil (n = 221) in combination with ropivacaine. In the alfentanil group, 13 women and in the sufentanil group, 14 women were converted to cesarean delivery due to intrauterine infection, fetal distress, or poor labor progression. Rapid cervical dilation within 45 min of epidural initiation occurred in three women in each group. Additional attrition included one case lost to follow-up and one treatment failure in each group. Thus, 405 participants (203 in the alfentanil group and 202 in the sufentanil group) were included in the final analysis (Fig. 1). Baseline characteristics, including maternal age, height, weight, BMI, and gestational age were comparable between the two groups (Table 1).

Fig. 1.

Flowchart of participant enrollment and trial progression (two additional sites (n = 0) were activated but never began recruitment because of personnel and drug/equipment shortages; therefore they do not appear in the participant flow)

Table 1.

Baseline demographic and clinical characteristics by treatment group and recruiting sites

Variables	Site 1			Site 2			Site 3			Site 4			Total		P
	Overall	Group S	Group A	Overall	Group S	Group A	Overall	Group S	Group A	Overall	Group S	Group A	Group A	Group S
n	150	75	75	128	64	64	75	37	38	52	26	26	203	202
Age (years)	30.4 ± 2.1	30.5 ± 2.5	30.3 ± 1.5	30.3 ± 1.7	30.6 ± 1.6	30.0 ± 1.7	30.4 ± 1.7	30.2 ± 1.5	30.5 ± 1.9	30.3 ± 1.6	30.1 ± 1.7	30.5 ± 1.6	30.3 ± 1.7	30.4 ± 2.0	0.38
Height (cm)	163.1 ± 3.8	164.1 ± 3.3	162.2 ± 4.1	162.9 ± 3.9	162.2 ± 3.9	163.5 ± 3.7	163.2 ± 4.2	163.1 ± 4.3	163.3 ± 4.2	162.7 ± 3.8	163.3 ± 3.7	162.1 ± 3.8	162.8 ± 3.9	163.2 ± 3.8	0.39
Weight (kg)	71.0 ± 4.8	72.1 ± 4.0	69.8 ± 5.3	70.6 ± 4.9	69.6 ± 5.1	71.5 ± 4.6	70.5 ± 5.71	70.1 ± 5.2	71.0 ± 6.1	70.1 ± 4.3	70.1 ± 3.9	70.1 ± 4.7	70.6 ± 5.2	70.7 ± 4.7	0.91
BMI (kg/m2)	26.1 ± 1.5	26.3 ± 1.3	26.0 ± 1.8	26.1 ± 1.6	26.0 ± 1.6	26.2 ± 1.5	25.9 ± 1.7	25.8 ± 1.7	26.1 ± 1.6	25.9 ± 1.3	25.8 ± 1.2	26.1 ± 1.4	26.1 ± 1.6	26.1 ± 1.5	0.73
Gestational age (weeks)	39.0 ± 0.8	39.0 ± 0.9	39.0 ± 0.7	38.9 ± 1.0	39.1 ± 0.8	38.7 ± 1.1	39.2 ± 0.7	39.3 ± 0.6	39.1 ± 0.8	39.2 ± 0.9	39.2 ± 0.7	39.2 ± 1.1	39.0 ± 0.9	39.1 ± 0.8	0.15

BMI body mass index

Site 1, General Hospital of Northern Theater Command; Site 2, Dalian Women and Children’s Medical Group; Site 3, Chaoyang Second Hospital; Site 4, Benxi Central Hospital

Data are presented as mean ± standard deviation (SD)

Primary Outcome

The onset time of analgesia was significantly shorter in the alfentanil group than in the sufentanil group (8.0 min vs. 10.0 min, P < 0.001; Table 2).

Table 2.

Comparison of onset time of analgesia between the two groups

Onset time of analgesia (min)	Group S (n = 202)	Group A (n = 203)	Difference in median (95% CI)	P
Analgesia onset time (min)	10.0 (6.0, 12.0)	8.0 (4.0, 10.0)	– 2.0 (– 3.0 to – 2.0)	< 0.001

Data are presented as median (interquartile range)

Secondary Outcomes

Maternal hemodynamic variables, uterine activity, fetal heart rate, VAS pain scores, sensory block level, and body temperature were recorded at baseline (P0), 15 min (P1), 30 min (P2), 45 min (P3), and full cervical dilation (P4) (Table 3). No significant between-group differences were observed at any time point (all P > 0.05). Compared with baseline, both groups showed significant decreases in systolic and diastolic blood pressure and heart rate at P1–P3, as well as significant reductions in VAS pain scores at P1–P4 (all P < 0.05). Maternal body temperature increased progressively throughout labor, reaching significance at P1–P4. Uterine pressure increased significantly at P4 in both groups. Additional group-specific findings included a rise in SpO₂ at P2 and P4 in the alfentanil group, and a decrease in fetal heart rate at P2 followed by an increase at P4 in the sufentanil group (all P < 0.05). Importantly, no motor block was observed in either group, and all Bromage scores remained 0. These indicators are represented in the figure (Fig. 2) as trends over time.

Table 3.

Perinatal data at different time points in the two groups

Maternal and fetal data	Group	P0	P1			P2	P3	P4
Systolic BP (mmHg)	S	121.4 ± 10.3	116.8 ± 9.7*			115.9 ± 9.3*	116.3 ± 8.4*	121.0 ± 8.7
	A	120.4 ± 10.6	116.0 ± 10.5*			115.8 ± 11.3*	115.7 ± 9.7*	120.2 ± 9.4
Diastolic BP (mmHg)	S	75.8 ± 7.6	72.4 ± 7.7*			71.5 ± 7.1*	72.0 ± 6.9*	75.6 ± 6.9
	A	75.9 ± 7.7	72.3 ± 7.4*			71.5 ± 7.3*	71.5 ± 7.6*	75.1 ± 7.1
HR (bpm)	S	81.0 ± 10.5	78.4 ± 8.7*			77.7 ± 8.6*	77.7 ± 7.6*	81.0 ± 8.3
	A	82.7 ± 11.2	78.9 ± 8.3*			79.3 ± 9.2*	78.9 ± 9.0*	81.9 ± 8.7
SpO2 (%)	S	98.2 ± 0.9	98.2 ± 1.0			98.2 ± 1.0	98.2 ± 1.0	98.2 ± 0.9
	A	98.2 ± 1.0	98.2 ± 1.0			98.3 ± 1.0*	98.3 ± 1.0	98.3 ± 1.0*
aIntrauterine pressure (mmHg)	S	61.4 ± 13.2	62.0 ± 13.7			61.5 ± 15.9	63.0 ± 13.7	73.5 ± 8.5*
	A	63.2 ± 13.8	64.7 ± 15.0			64.3 ± 14.7	63.7 ± 15.1	73.8 ± 9.7*
Fetal HR (bpm)	S	143.0 ± 8.3	141.8 ± 7.7*			143.2 ± 8.2	142.2 ± 8.4	145.0 ± 8.0*
	A	143.0 ± 8.6	142.3 ± 8.4			142.7 ± 8.2	142.6 ± 8.1	144.5 ± 8.0
aTemperature (°C)	S	36.5 ± 0.2	36.5 ± 0.2*			36.5 ± 0.2*	36.6 ± 0.2*	36.7 ± 0.2*
	A	36.5 ± 0.2	36.5 ± 0.2*			36.5 ± 0.2*	36.6 ± 0.2*	36.6 ± 0.2*
VAS pain score	S	8 (8, 9)	3 (3,3)*			3 (2, 3)*	3 (3, 3)*	5 (5, 6)*
	A	8 (7, 9)	3 (3,3)*			3 (2, 3)*	3 (3, 3)*	5 (5, 6)*
Highest sensory block level	S	–	T10 (8, 10)*			T10 (9, 10)*	T10 (9, 10)*	T12 (11, 12)*
	A	–	T10 (9, 10)*			T10 (9, 10)*	T10 (9, 10)*	T12 (11, 12)*
Bromage score	S	0 (0)	0 (0)			0 (0)	0 (0)	0 (0)
	A	0 (0)	0 (0)			0 (0)	0 (0)	0 (0)

BP blood pressure, HR heart rate, SpO₂ saturation of peripheral oxygen, VAS Visual Analogue Scale

P0, before epidural analgesia; P1, 15 min after analgesia; P2, 30 min after analgesia; P3, 45 min after analgesia; P4, at full cervical dilation. ^*p < 0.05 vs. P0

^aNot pre-specified in the trial registry; exploratory (post hoc) analysis

Data are expressed as mean ± SD or median (interquartile range)

Fig. 2.

Time-course changes in maternal systolic blood pressure, diastolic blood pressure HR, SpO₂, VAS pain score, highest sensory block level, intrauterine pressure, fetal HR, and temperature following epidural alfentanil versus sufentanil for labor analgesia

Other clinical outcomes, including total analgesia duration, length of labor, mode of delivery, oxytocin consumption, total drug usage, total volume of PIEB solutions, total doses of opioid used and maternal satisfaction scores, were not significantly different between groups (Table 4). All neonates achieved Apgar scores of 10 at both 1 and 5 min after birth.

Table 4.

Comparison of analgesic use, duration of labor, and delivery outcomes between the two groups

Indicator	Group S (n = 202)	Group A (n = 203)	P
Duration of analgesia (min)	381.1 ± 244.5	364.4 ± 186.4	0.96
Duration of first stage (min)	451.5 ± 188.0	448.6 ± 173.7	0.80
Duration of second stage (min)	67.1 ± 30.4	71.4 ± 26.1	0.14
Duration of third stage (min)	10.9 ± 21.8	9.7 ± 9.2	0.48
Total duration of labor (min)	529.6 ± 200.9	529.6 ± 183.0	0.56
Episiotomy, n (%)	98 (49)	90 (44)	0.38
aOxytocin dose (U)	1.7 ± 1.2	1.6 ± 1.2	0.49
Volume of analgesic solution (ml)	78.5 (52.0, 105.0)	80.0 (56.0, 110.0)	0.80
Total volume of PIEB solutions (ml)	77.0 (50.2, 116.8)	76.5 (51.6, 112.7)	0.96
Total doses of opioid used (μg)	15.7 (10.4, 21.0)	16.0 (11.2, 22.0)*	0.80
a1-min Apgar score	10 (10,10)	10 (10, 10)	NAb
a5-min Apgar score	10 (10, 10)	10 (10, 10)	NAb
aMaternal satisfaction score	9.0 (8.0, 9.0)	9.0 (8.0, 9.0)	0.80

^*Doses were converted to sufentanil-equivalent micrograms using a potency ratio of alfentanil: sufentanil = 20: 1

^aNot pre-specified in the trial registry; exploratory (post hoc) analysis

^bAll neonates achieved 1-min Apgar score and 5-min Apgar score Apgar score of 10; statistical comparison was not applicable

Adverse Events

Adverse events are summarized in Table 5. The incidence of lower limb numbness, pruritus, nausea or vomiting, and urinary retention was slightly higher in the sufentanil group than in the alfentanil group, but the differences did not reach statistical significance (all P > 0.05).

Table 5.

Comparison of adverse reactions between the two groups

Adverse reaction	Group S (n = 202)	Group A (n = 203)	P
Lower limb numbness	86(43)	79(39)	0.45
Itching	5(3)	2(1)	0.44
Nausea and vomiting	12(6)	7(3)	0.24
Urinary retention	5(3)	4(2)	0.99
Total	108(53)	92(45)	0.12

Data are expressed as number of cases (percentage)

Discussion

0.075% ropivacaine combined with alfentanil achieved faster onset of epidural analgesia than that with sufentanil, while demonstrating comparable overall efficacy and no increase in adverse events. The faster onset observed with alfentanil is likely attributable to its pharmacological characteristics. Alfentanil has a smaller molecular weight, a lower pKa (6.5), and exists predominantly in a non-ionized form at physiologic pH, facilitating rapid penetration across the blood–brain barrier and rapid equilibration between plasma and effect sites [16]. Previous studies have also shown that alfentanil diffuses more rapidly within the epidural space, giving it an advantage in producing prompt analgesia [17]. Although earlier work suggested that a shorter onset may translate into superior long-term analgesic profiles, our results did not show significant differences in VAS scores between groups at later time points [18]. Both regimens provided adequate analgesia throughout labor.

A study observed the analgesic and side effects of different epidural doses of fentanyl (30 and 100 μg), alfentanil (300 and 1000 μg), and sufentanil (3 and 10 μg) administered to healthy volunteers[19]. Low plasma opioid concentrations measured after small epidural opioid doses suggested a spinal mechanism for analgesia. At the dosages used in that study, the analgesic effects of epidural fentanyl and alfentanil were superior to sufentanil at 2, 55, and 95 min after administration. However, our study observed that the combination of 0.075% ropivacaine and alfentanil had a faster onset of action than sufentanil, indicating that alfentanil had better analgesic effects in the early stages of administration. The two studies were consistent. However, at other observation time points, there was no significant difference in the analgesic effect between the two groups in our study, which may be due to the much lower doses of alfentanil and sufentanil used in the epidural space per unit time compared to the above study, or it may be related to the low concentration of ropivacaine used in combination. Another study compared the analgesic effects and adverse reactions of alfentanil versus fentanyl when used in combination with bupivacaine for epidural labor analgesia[20]. The results indicated that when used in a continuous epidural infusion with low-dose bupivacaine, alfentanil provided superior pain relief during both stage I and II of labor with no significant maternal or neonatal side effects. Our study only observed the rapid onset of alfentanil in the early stage of epidural administration, and there was no significant difference in the analgesic effect between the two groups in the following period. This may be related to the selection and evaluation methods of the main observation indicators, as well as the different infusion modes of the analgesic pump.

We noted that VAS scores increased at full cervical dilation, with a small number of women reporting severe breakthrough pain that was not relieved by PCEA. This phenomenon may be explained by the transition from visceral to somatic pain in the second stage of labor, which may not be fully suppressed by low-dose ropivacaine. Some studies have proposed increasing ropivacaine concentration or adding lidocaine during this stage, but optimal protocols for managing breakthrough pain remain uncertain.

Hemodynamic stability was preserved in both groups. Decreases in blood pressure and heart rate after initiation likely reflected relief of labor pain. No motor block occurred, consistent with the known separation of sensory and motor blockade at low ropivacaine concentrations. Sensory block regressed with labor progression, yet remained adequate for labor analgesia. Neither drug prolonged labor or affected uterine activity. Prior studies have suggested conflicting effects of sufentanil on labor duration [21, 22], while others reported that opioid adjuvants may be associated with longer labor times [23, 24]. In our study, however, no significant differences were observed in the first, second, or third stages of labor, consistent with reports showing minimal impact of opioid supplementation. Similarly, previous work has indicated that opioids such as fentanyl and morphine may alter myometrial contractility, whereas sufentanil does not suppress uterine contractions [25]. In the present trial, uterine pressure and oxytocin requirements were comparable, suggesting that neither alfentanil nor sufentanil adversely affected uterine activity or labor progression.

With respect to adverse effects, the incidence of pruritus, nausea, vomiting, and urinary retention was low in both groups and substantially lower than reported in prior studies and meta-analyses [11, 26, 27]. This likely reflects the relatively low opioid concentrations used. While the sufentanil group exhibited a slightly higher frequency of minor side effects, differences were not statistically significant. Lower limb numbness occurred in both groups but was mild and transient, and was more plausibly related to maternal positioning or local anesthetic exposure than to the choice of opioid. Importantly, no neonatal compromise was observed, and all Apgar scores were normal. In both groups, maternal temperature gradually increased during labor, and a few women developed intrapartum fever at full cervical dilation. This finding is consistent with previous reports suggesting that epidural-related fever may involve altered maternal thermoregulation or inflammatory responses [28, 29]. Importantly, neonatal outcomes were unaffected, and no cases of fetal bradycardia or respiratory depression were observed.

This study has several limitations. First, the trial was restricted to nulliparous women with singleton, term pregnancies, which may limit generalizability to multiparous women or those with high-risk pregnancies. Second, attrition occurred due to cesarean conversions or rapid cervical dilation, and these cases were excluded from analysis. Third, only one PIEB + PCEA regimen was evaluated; alternative dosing strategies or pump settings may yield different results. Future studies should explore optimal drug concentrations and administration parameters for breakthrough pain in the second stage of labor. Finally, this study has the following protocol deviations: two centers never started; some secondary outcomes were added post hoc. All deviations were reported to the ethics committee. They did not influence the direction of the primary results.

Conclusions

In summary, epidural labor analgesia using 0.075% ropivacaine combined with either 4 μg/ml alfentanil or 0.2 μg/ml sufentanil provided reliable and equivalent pain relief with low rates of adverse effects. Both regimens were safe for mothers and neonates, and represented effective options for clinical practice. Alfentanil demonstrated a faster onset of action than sufentanil, offering an advantage in achieving rapid analgesia.

Author Contributions

Conceptualization: Yufang Xiu, Huijuan Cao and Yugang Diao. Design: Xiao Jiang, Yufang Xiu, Chang Jia, Yingjie Sun, Bo Han, Jianyu Zu, Huijuan Cao and Yugang Diao. Data analysis: Xiao Jiang and Yufang Xiu. Data acquisition and interpretation: Xiao Jiang, Yufang Xiu, Chang Jia, Huijuan Cao, Shanni Zhang, Nana Han, Lingling Pan, Huixuan Sun, Jing Li, Yingjian Wang, Kean Wang, Yufei Man, Wenchao Liu, Zhenzhou Guan, Fang Yao, Ning Jin, Zhiqiang Xue, Wenhua Yuan, Peng Li, Yuyue Gong, Qi Wang, Sijin Lu, and Huijun Wang. Drafting: Xiao Jiang, Yufang Xiu and Huijuan Cao. All authors reviewed and approved the final manuscript.

Funding

This work and the journal’s Rapid Service Fee were both supported by the Shenyang Science and Technology Plan (2023).

Data Availability

The data used to support the findings of this study are available from the corresponding authors upon request.

Declarations

Conflict of Interest

Xiao Jiang, Yufang Xiu, Chang Jia, Bo Han, Jianyu Zu, Shanni Zhang, Nanna Han, Lingling Pan, Huixuan Sun, Jing Li, Yingjian Wang, Kean Wang, Yufei Man, Wenchao Liu, Zhenzhou Guan, Fang Yao, Ning Jin, Zhiqiang Xue, Wenhua Yuan, Peng Li, Yuyue Gong, Qi Wang, Sijin Lu, Huijun Wang, Yingjie Sun, Yugang Diao, and Huijuan Cao have nothing to disclose.

Ethical Approval

The study protocol was approved by the Ethics Committee of the General Hospital of the Northern Theater Command of the Chinese People’s Liberation Army (Approval No. Y [2023] 069). All participating sites accepted the central approval. The clinical trial registration number was ChiCTR2300072104, and the period of the study was from June 2023 to June 2024. The study protocol was conducted in accordance with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Written informed consent was obtained from all participants prior to enrollment.