Effects of butorphanol combined with ropivacaine on plasma adrenocorticotropic hormone and cortisol levels and postpartum depression in labor analgesia

Abstract

BACKGROUND

Labor pain triggers robust hypothalamic-pituitary-adrenal-axis activation, releasing adrenocorticotropic hormone (ACTH)/cortisol that fuels systemic inflammation and predicts postpartum depression (PPD). Although epidural ropivacaine is standard in China, adding the κ-agonist butorphanol may synergistically block pain and restrain this neuroendocrine stress response, offering a novel strategy to protect maternal mental health.

AIM

To investigate the effects of the combined use of butorphanol and ropivacaine on the plasma levels of ACTH and cortisol in patients undergoing labor analgesia as well as the incidence of PPD. We also compared the incidence of adverse reactions between the two groups. This study aimed to evaluate the regulatory effects of drug combinations and their side effects on the stress response of pregnant women, providing a basis for clinical intervention.

METHODS

Between June 2020 and June 2023, 114 pregnant women were randomly divided into study and control groups, with 57 participants in each group. The research group received a combination therapy of butorphanol and ropivacaine, whereas the control group received a combination therapy of sufentanil and ropivacaine. All participants received combined spinal epidural anesthesia to alleviate delivery pain. The Visual Analog Scale was used to assess the pain levels at different timepoints. We compared the incidence of adverse reactions and evaluated the incidence of PPD in the delivery room at 2 hours, 1 day, and 7 days postpartum using the Edinburgh Postnatal Depression Scale. Venous blood samples were collected using a fully automated chemiluminescence analyzer to measure ACTH and cortisol.

RESULTS

The Visual Analog Scale scores of the study group were significantly lower than those of the control group at all timepoints (P < 0.05). In addition, the Edinburgh Postnatal Depression Scale scores of the study group on days 1 and 7 postpartum were significantly lower than those of the control group (P < 0.05), indicating a lower risk of PPD in the study group. There was no significant difference in 24-hour neonatal behavioral neurological assessment, 1-minute Apgar score, and total treatment cost between the two groups of newborns (P > 0.05), and no respiratory depression was observed. The incidence rates of adverse reactions were 5.26% and 17.54% in the study and control groups, respectively. Two hours after delivery, both groups showed a decreasing trend in ACTH and cortisol; however, the levels in the study group were significantly lower than those in the control group (P < 0.05).

CONCLUSION

The combination of butorphanol and ropivacaine for labor analgesia can significantly reduce pain scores in women and lower the risk of postpartum pain. Additionally, it reduces the incidence of adverse reactions without compromising the safety of both the mother and newborn. This effect may be attributed to the synergistic analgesic effects of the drugs, neuroendocrine regulation, and the improved psychological and physiological conditions of the mother.

Key Words: Butorphanol; Ropivacaine; Labor analgesia; Adrenocorticotropic hormone; Cortisol; Postpartum depression

Core Tip: This study demonstrates that a combination of butorphanol and ropivacaine for labor analgesia significantly reduces pain scores, stress hormone levels (adrenocorticotropic hormone and cortisol), and the incidence of postpartum depression compared to sufentanil-ropivacaine. The combination provides a faster onset of analgesia, fewer adverse reactions, and better neuroendocrine regulation, making it a safer and more effective option for maternal care.

INTRODUCTION

As one of the most severe forms of physical pain in humans, the World Health Organization has clearly stated that effectively alleviating labor pain is a crucial part of maternal healthcare. Labor not only activates the hypothalamic-pituitary-adrenal (HPA) axis, leading to the excitation of the sympathetic nervous system and the release of stress hormones, such as adrenocorticotropic hormone (ACTH) and cortisol, but also imposes significant physical and psychological stress on women[1]. This stress-induced neuroendocrine response is particularly significant given the established link between mental stress and systemic inflammation, which can contribute to various pathological conditions, including cardiovascular events[2]. However, it can increase the risk of postpartum depression (PPD), anxiety, and stress disorders[3], leading to mental health problems in mothers[4]. Labor pain can be regarded as a potential independent predictor of PPD[5]. This is further supported by recent evidence that stressors during the third trimester of pregnancy, specifically the frequency and intensity of daily stressful life events, are significantly associated with heightened symptoms of postpartum anxiety and depression, highlighting a critical window for intervention[6]. Therefore, optimizing the labor analgesia strategy while effectively controlling pain and regulating the excessive neuroendocrine stress response has a dual strategic significance for ensuring the physical and mental health of mothers and infants.

Presently, epidural analgesia is considered the most widely used and effective method of labor analgesia in China[7]. Innovations in drug compatibility is crucial for enhancing the effectiveness of pain management. Ropivacaine, known for its excellent sensorimotor nerve block and relatively safe cardiovascular performance, is commonly used for labor analgesia. However, relying solely on local anesthesia can still result in an incomplete blockade and sudden pain when managing severe and dynamic labor pain. Studies indicate that the overuse of ropivacaine during labor may harm the health of both the mother and baby, while an insufficient dosage can lead to inadequate pain relief[8]. Therefore, it is often used in combination with other analgesics in clinical practice to enhance its analgesic effects. Butorphanol is an opioid with κ-receptor agonist and partial μ-receptor agonist/antagonist effects, and has a “cap effect”[9]. The risk for respiratory depression is relatively low. It also has potential sedative and anxiolytic effects, showing unique advantages in obstetric pain management[10]. Butorphanol offers significant advantages in terms of pain control and hemodynamic stabilization during surgery with fewer side effects and improved safety. When used in conjunction with ropivacaine, it can achieve multi-target synergistic analgesia and neuroendocrine regulation: Ropivacaine blocks pain signals by acting on sodium channels in peripheral nerve axons and butorphanol produces a strong analgesic effect through κ receptors at the spinal cord and above, while activating these receptors has been shown to directly inhibit the activity of the HPA axis, reducing the release of ACTH and corticotropin-releasing hormone (CRH). This coordinated model of peripheral block and central regulation is expected to provide more comprehensive analgesic effects and reduce the excessive impact of childbirth on the body’s stress response system.

PPD is a common complication in the perinatal period, and its onset and progression may be related to perinatal pain[11]. Typical symptoms include persistent depression, a lack of pleasure, and mood disorders. These symptoms not only damage the patient’s mental health but also destroy the intimate relationship between mother and child and may even threaten the stability of the family[12]. Providing adequate pain relief during the perinatal period is an effective strategy for reducing the frequency of PPD. However, the relationship between epidural anesthesia and the risk of PPD requires further validation through large-scale studies. To address these issues, this study aimed to explore an innovative approach using butorphanol and ropivacaine in a rigorous randomized controlled trial. This study assessed the dynamic effects of this combination on the plasma levels of ACTH and cortisol in women receiving labor analgesia and investigated its potential association with the risk of PPD, providing a basis for clinical interventions.

MATERIALS AND METHODS

Data

Between June 2020 and June 2023, 114 pregnant women were randomly divided into control and study groups, with 57 participants in each group. The study was approved by the No. 1 People’s Hospital of Liangshan Yi Autonomous Prefecture Ethics Committee, No. 2025-013 and all pregnant women and their families provided written informed consent. To randomize participants, we generated a completely random sequence of numbers from 1 to 114 using SPSS Statistics 27.0 (IBM, Armonk, NY, United States) and arranged them in ascending order. Participants with odd numbers were assigned to the study group, whereas those with even numbers were assigned to the control group. Group information (“study” or “control”), based on the random sequence, were placed into individual sealed envelopes. After a subject completed enrollment and signed the informed consent form, the researchers opened the next envelope in the order of envelope number and assigned the subject based on group information. Specialized personnel who were not involved in the intervention process completed the outcome evaluations. The evaluator was not exposed to the group information and was instructed to not inquire or speculate about the patient’s grouping situation. None of the data collection forms used for the evaluation included group identification. In the data analysis stage, the data administrator encoded the grouping information into “group A” and “group B” and the analyst conducted statistical analysis without knowing what these labels meant. The coding meaning was not revealed until all analyses were completed. Throughout the entire research process, we explicitly requested researchers who were aware of the grouping to avoid discussing any information related to the grouping with the outcome assessors and data analysis, including incomplete maternal data, patients who were lost to follow-up after delivery, and those with neuropathy, spinal anesthesia contraindications, pain medication avoidance, or allergies to the study drugs before enrollment. Prenatal metabolic screening and depression index assessments were performed, and patients with abnormal results, severe heart and lung diseases, or systemic infections were excluded. When grouping, the information for each group was organized and recorded by designated personnel. The other researchers involved in the study were unaware of the drugs used and their group assignments. The equipment used in this study included an automatic optical transmission immunosensing analyzer, automatic luminescence monitor, uterine shock pump, and fetal multiparameter monitor. The drugs used in this study were normal saline, lidocaine, sufentanil, ropivacaine, and butorphanol[10].

Anesthesia treatment

Upper-limb venous access was established, and 500 mL of sodium lactate Ringer’s solution was administered. A fetal heart rate (HR) monitor was connected to monitor uterine contractions and fetal HR. A routine electrocardiogram monitor recorded the mother’s baseline blood pressure, oxygen saturation, HR, respiratory rate, and electrocardiogram. Low-flow oxygen was administered through a nasal cannula. When the mother entered regular uterine contractions and requested labor analgesia, the anesthesiologist assessed whether she met the inclusion criteria. All mothers were placed in the left lateral position. All patients underwent the combined spinal-epidural anesthesia technique with puncture at the L2-3 or L3-4 intervertebral space. If necessary, obese mothers were positioned under ultrasound guidance. All epidural punctures were performed by the same anesthesia team, consisting of three senior attending physicians with ≥ 8 years of clinical experience. According to the Chinese Expert Consensus on Neuraxial Labor Analgesia[13], all team members received standardized training and perform approximately 200 procedures annually. The puncture technique, ultrasound-assisted indications, and criteria for catheter placement depth were based on the same standard operating procedure. Therefore, it is reasonable to assume that technical variability had a minimal impact on primary outcomes. After routine skin disinfection, 1% lidocaine was used for local infiltration anesthesia and a 16-G epidural needle was inserted along the midline of the spine into the epidural space. After successful puncture and confirmation of the absence of fluid reflux, an epidural catheter was placed 3-4 cm from the head and securely fixed. The patient was instructed to lie supine and 3 mL of 1% lidocaine was injected into the epidural space as a single trial dose to confirm the absence of subarachnoid block and full spinal anesthesia. The epidural catheter was connected to a patient-controlled epidural analgesia pump. The study group received butorphanol and ropivacaine, whereas the control group received fentanyl and ropivacaine, which were administered using a combination of 1% ropivacaine and buprenorphine diluted in normal saline to 125 mL. The solution for the pump in the study group was 10 mL of 1% ropivacaine, 4 mg of butorphanol, and 11.3 mL of 0.9% sodium chloride. For the control group, the solution was 10 mL of 1% ropivacaine, 50 μg of sufentanil, and 114 mL of 0.9% sodium chloride. The parameters were set based on the milliliters of drugs: (1) Loading dose: 5 mL; (2) Total patient-controlled epidural analgesia dose: 125 mL; (3) Background infusion rate: 2 mL/hour; (4) Pulse pump analgesia dose: 8 mL per dose; (5) Lockout time: 25 minutes; and (6) Analgesic duration: 4-16 hours.

Observation indicators

General data for the two groups, including age, gestational weeks, weight, and height, were collected and compared (Table 1). In terms of analgesia, onset time, first patient-controlled analgesia (PCA) administration time, total PCA dosage, and ropivacaine dose were compared between the two groups. Visual Analog Scale (VAS) scores at T0 (before anesthesia), T1 (10 minutes after administration), T2 (cervical dilation to 3 cm), T3 (complete cervical dilation), T4 (fetal delivery), and T5 (2 hours postpartum) were recorded and compared between groups. The VAS score ranges from 0 to 10, with 0 indicating no pain and 10 indicating severe pain. Higher scores indicate more severe pain. Ramsay scores were also collected at each timepoint and scored as follows: 1 point, restlessness; 2 points, clear cooperation; 3 points, drowsy but responsive to commands; 4 points, mild sleep (can be awakened); 5 points, deep sleep (slow response); and 6 points, deep sleep (no response) (Table 2). ACTH and cortisol levels were measured before anesthesia and 2 hours after delivery. Three milliliters of maternal venous blood were collected before anesthesia. After delivery, the sample was centrifuged at 3000 × g rpm and enzyme-linked immunosorbent assay was performed using an automatic chemiluminescence analyzer. Neonatal safety was assessed using neonatal behavioral neurological assessment, Apgar, and respiratory depression scores. The total medication cost was compared between the two groups in a cost-benefit analysis. The Edinburgh Postnatal Depression Scale (EPDS) was also used to assess the incidence of PPD at 2 hours, 1 day, and 7 days after delivery. If the EPDS score was greater than or equal to 10, the patient was considered to have PPD[14].

Table 1 Comparison of general data between the two groups, mean ± SD.

Clinical data categories	Research group	Control group	P value
Age (years)	29.06 ± 3.99	30.27 ± 3.95	0.718
Fetal age (weeks)	39.46 ± 0.96	38.74 ± 5.45	0.829
Weight (kg)	67.57 ± 8.62	66.81 ± 8.06	0.759
Altitude (cm)	160.00 ± 4.00	157.00 ± 4.00	0.327

Table 2 Visual Analog Scale scores.

VAS score clinical manifestations
Level 0-3 is classified as mild pain, and patients are more likely to experience it. Acceptance, able to sleep	0	Analgesia
	1	Painless when lying flat, pain on the side
	2	Deep breathing is painless, coughing is painful
Pain of 4 to 6 is classified as moderate pain, and patients sleep, dyssomnia	3	I feel pain when I take a deep breath and cough
	4	Slight pain when lying flat
	5	Pain is persistent when lying flat
Pain on a scale of 7 to 10 is classified as severe and patients are unable to sleep	6	The pain gets worse when lying down
	7	More severe pain
	8	Pain is persistent, unbearable and severe
	9	Unbearable pain
	10	The pain was unbearable

Statistical analysis

SPSS 26.0 (IBM, Armonk, NY, United States) was used for data analysis. The independent sample t-test and paired sample t-test were used within groups, and the normal distribution of measurement data is expressed as mean ± SD. The χ² test was used to analyze the count data. Statistical significance was established at P < 0.05.

RESULTS

A total of 143 patients were screened, of whom 114 were ultimately included in the study and divided equally between the experimental (57 cases) and control groups (57 cases). The exclusion criteria (n = 29) were loss to follow-up, incomplete maternal data, or hospital referral. There were no significant differences between the two groups in maternal age, weight, height, or gestational age (P > 0.05), indicating that the two groups were comparable.

Pain relief was significantly faster in the study group than in the control group (P < 0.05). There were no significant differences between the two groups in duration of initial PCA, total amount of PCA drugs, or ropivacaine dose (P > 0.05; Table 3). The VAS scores of the study group were significantly lower than those of the control group from T1 to T4 (P < 0.05; Table 4). There were no significant differences in Ramsay scores between the two groups at any timepoint (P > 0.05; Table 5). There were no significant differences in neonatal behavioral neurological assessment levels, Apgar scores, or total treatment costs between the two groups of newborns (P > 0.05), and no respiratory depression was observed (Table 6). Two hours after delivery, both groups had significantly lower ACTH and cortisol levels than the pre-anesthesia levels (P < 0.05), and the study group had significantly lower ACTH and cortisol levels than the control group (P < 0.05; Table 7).

Table 3 Comparison of analgesic effect indexes and ropivacaine dosage in two groups of parturients, mean ± SD.

Group	Case load	Time to onset of analgesics (minutes)	First PCA time (minutes)	Total PCA drug volume (mL)
Control group	57	5.1 ± 1.8	88.0 (57.5-102.5)	36.9 (15.0-47.2)
Research Group	57	4.3 ± 1.9	85.0 (55.0-98.0)	38.2 (18.0-48.0)
t		2.308
P value		0.023	0.226	0.734

PCA: Patient-controlled analgesia.

Table 4 Comparison of Visual Analog Scale scores between the two groups at different time points, mean ± SD.

Group	T0	T1	T2	T3	T4	T5
Control group	8.20 ± 0.61	3.02 ± 0.38	4.68 ± 0.31	5.04 ± 0.37	3.61 ± 0.29	2.69 ± 0.18
Research group	8.12 ± 0.56	2.03 ± 0.35	4.31 ± 0.28	4.57 ± 0.33	3.26 ± 0.19	2.41 ± 0.21
t	0.483	9.581	4.428	4.740	4.67	4.9
P value	0.581	0.000	0.000	0.000	0.002	0.089

Table 5 Comparison of Ramsay scores at different time points, mean ± SD.

Group	Case load	T0	T1	T2	T3	T4	T5
Control group	57	1.0 ± 0.2	2.2 ± 0.4	2.1 ± 0.3	2.2 ± 0.5	1.6 ± 0.7	2.1 ± 0.3
Research group	57	1.0 ± 0.1	2.3 ± 0.5	2.2 ± 0.5	2.2 ± 0.5	1.6 ± 0.7	2.1 ± 0.3
t		0.000	1.179	1.295	0.000	0.000	0.000
P value		1.000	0.241	0.198	1.000	1.000	1.000

Table 6 Comparison of neonatal behavioral neurological assessment score, Apgar score, respiratory depression, and total cost between two groups, mean ± SD.

Group	Case load	24 hours NABA	1 minute Apgar	Total cost (yuan)	Respiratory depression
Control group	57	38.89 ± 1.00	9.77 ± 0.72	575.68 ± 33.75	0
Research group	57	38.74 ± 0.87	9.63 ± 0.58	568.82 ± 30.43	0
t		0.854	1.143	1.140	0.000
P value		0.395	0.255	0.257	1.000

NABA: Neonatal behavioral neurological assessment.

Table 7 Comparison of adrenocorticotropic hormone and cortisol levels between the two groups, mean ± SD.

Group	ACTH (pg/mL)		t	P value	Cortisol (μg/dL)		t	P value
	Preanesthesia	Two hours after delivery			Preanesthesia	Two hours after delivery
Control group (n = 57)	25.46 ± 3.10	15.88 ± 5.33	3.684	0.007	45.27 ± 9.47	40.87 ± 9.05	2.934	0.019
Research group (n = 57)	26.05 ± 3.14	10.20 ± 4.26	4.529	0.014	39.38 ± 10.36	35.24 ± 6.08	5.587	0.028
t	0.147	5.397			0.314	3.136
P value	0.792	0.000			0.665	0.000

ACTH: Adrenocorticotropic hormone.

Compared to the control group, the study group had lower EPDS scores on days 1 and 7 postpartum (P < 0.05). The incidence of PPD was lower in the study group than in the control group; however, the difference was not significant (P > 0.05; Table 8). Table 8 compares the EPDS scores and PPD incidence between the two groups at different timepoints. One patient in the study group developed itching, nausea/vomiting, and urinary retention but no respiratory depression. In the control group, three patients had nausea/vomiting, two patients had itching, and five patients had urinary retention. The incidence of adverse reactions in the study group was 5.26%, which was significantly lower than that in the control group (17.54%; P < 0.05). Respiratory depression was not observed in either group of newborns

Table 8 Comparison of Edinburgh Postnatal Depression Scale scores and predicts postpartum depression occurrence between two groups, mean ± SD.

Group	EPDS scores				PPD incidence, n (%)
	Delivery room	Two hours after delivery	1 day after delivery	Seven days after delivery
Control group (n = 57)	3.98 ± 1.20	2.87 ± 1.23	3.69 ± 1.42	1.64 ± 0.65	3 (5.26)
Research group (n = 57)	4.02 ± 1.87	2.90 ± 1.32	3.05 ± 1.28	0.92 ± 0.40	0 (0.00)
t/χ2	0.136	0.126	2.528	7.122	1.369
P value	0.892	0.900	0.013	< 0.001	0.242

EPDS: Edinburgh Postnatal Depression Scale; PPD: Predicts postpartum depression.

DISCUSSION

Childbirth is a significant physiological challenge for women and is often accompanied by severe pain. Effective anesthesia should quickly alleviate pain while avoiding respiratory depression. In the present study, the analgesic response in the study group was significantly faster than that in the control group, and the T1-T4 VAS scores were notably lower. This suggests that the combination of butorphanol and ropivacaine can significantly shorten the onset time of analgesia and provide a rapid and significant analgesic effect surpassing that of sufentanil and ropivacaine. The reasons for this are as follows. Butorphanol has high lipophilicity, allowing it to quickly penetrate the dura mater and spread to the subarachnoid space, where it activates κ receptors in the dorsal horn of the spinal cord, producing an analgesic effect[15]. It can inhibit the production of inflammatory mediators and inflammatory responses during labor[16]. As a pure μ-receptor agonist, sufentanil provides significant analgesic effects, but it takes longer to take effect and requires diffusion through the cerebrospinal fluid to reach a wider range of μ receptors. Butorphanol enhances the sodium channel-blocking effect of ropivacaine by activating κ receptors: When κ receptors are activated, the G protein-coupled potassium channels in spinal neurons open, leading to cell hyperpolarization and enhancing the analgesic effects of local anesthetics[17]. It reduces the release of neurotransmitters from nerve endings and blocks pain transmission[18]. In conjunction with the sodium channel-blocking effect, ropivacaine inhibits neuronal excitability, thereby accelerating the sensory block to the T10 level. The core of labor pain lies in the regulation of visceral pain associated with uterine contractions. Butorphanol produces a mild analgesic effect by selectively activating κ receptors, thus alleviating visceral pain[19]. Subtilin mainly acts on μ receptors to relieve somatic pain and has a weak inhibitory effect on the release of substance P in the visceral pain conduction pathway. When its blood concentration is too high, it can cause adverse reactions such as respiratory depression and fetal bradycardia[20]. Thus, at the same dose, butorphanol can alleviate labor pain more quickly and thoroughly. Moreover, the peak effect of butorphanol in the epidural space occurs significantly earlier than that of sufentanil. Owing to its small molecular weight and low protein-binding rate, butorphanol can be released into the target tissue and take effect more rapidly.

This study evaluated the inhibitory effect of labor analgesia on stress responses by measuring ACTH and cortisol levels before and 2 hours after delivery. Labor pain, a strong stressor, activates the HPA axis, leading to increased ACTH release from the adrenal glands. These two indicators directly reflect body stress. In this study, baseline values were set before anesthesia and re-measurement 2 hours after delivery was used to assess changes in stress under analgesic intervention. If ACTH/cortisol levels significantly decreased, this would indicate that the analgesic effectively blocked the pain-stress pathway. The study found no significant differences in Ramsay scores between the two groups at different timepoints, suggesting that the sedative effects of the different anesthesia protocols were comparable. Additionally, 2 hours after delivery, the ACTH and cortisol levels in the study group were significantly lower than those before anesthesia; however, compared to the control group, the ACTH and cortisol levels in the study group showed that the combined use of butorphanol and ropivacaine was significantly more effective than the combination of sufentanil and ropivacaine in reducing ACTH and cortisol levels. This may be due to butorphanol, a highly selective κ-receptor agonist, effectively inhibiting visceral pain conduction in the dorsal spinal cord. Sufentanil acts on μ receptors, which tends to suppress somatic pain. Compared with sufentanil, butorphanol is more effective in inhibiting the release of pain-related neuropeptides, thereby reducing the activation of the HPA axis by signals from the pain source. Additionally, butorphanol directly inhibits the activity of CRH neurons, thereby reducing the release of cortisol.

The EPDS was initially developed in 1987. Its psychometric properties have been rigorously validated as a tool for assessing perinatal mood disorders. To enhance cultural adaptability, a Chinese research team localized the scale in 2007, creating a revised version that aligned with Chinese cultural characteristics. This revised version has become a standard tool in China for detecting PPD. The academic community generally agrees that a score of 9-10 on the EPDS is the diagnostic threshold, and other studies have confirmed that an EPDS score of 9.5 or higher indicates depressive symptoms[21]. Based on this, we set a postpartum EPDS score of 10 or higher as the threshold for PPD. Significant changes occur in the neuroendocrine system during the perinatal period. The decline in reproductive hormones (such as estrogen and progesterone), a sharp decrease in neuroregulatory substances (such as norepinephrine and cortisol), and an imbalance in the metabolism of monoamine neurotransmitters (particularly serotonin) form the pathological basis of PPD. Multidimensional neurochemical disorders may impair emotional regulation by altering synaptic plasticity and signal transmission efficiency.

This study found that compared with the control group, the study group had significantly lower EPDS scores on days 1 and 7 postpartum. The incidence of postpartum pain in the study group was lower than that in the control group, suggesting that the combination of butorphanol and ropivacaine for labor analgesia can reduce the risk of postpartum pain. The mechanisms underlying this effect include the following. First, butorphanol, acting as a κ-receptor agonist and μ-receptor antagonist, takes effect rapidly at the spinal level and reduces side effects such as respiratory depression. Ropivacaine, a long-acting local anesthetic, blocks nerve conduction of pain signals and extends the duration of analgesia. When used together, these two drugs significantly reduced the VAS pain score, alleviated stress responses caused by severe pain, and increased cortisol levels. Butorphanol enhances the analgesic effect of ropivacaine, reduces its concentration, and has no effect on the respiratory and circulatory systems, thereby preventing symptoms such as skin itching, nausea, and vomiting[22]. Ropivacaine can improve motor nerve blockade[23] and does not affect the daily activities of postpartum women. These benefits help reduce negative emotions associated with drug side effects, indirectly lowering the incidence of postpartum pain. Second, butorphanol and ropivacaine regulate neurotransmitters and endocrine functions. Butorphanol activates κ receptors, promoting the release of endogenous opioid peptides, which helps regulate the HPA axis and reduces the interference of pain stress on the endocrine system. Ropivacaine inhibits the transmission of pain signals to the central nervous system by stabilizing the membrane potential of nerve cells and reducing abnormal discharge, thus further alleviating neuroendocrine disorders. Additionally, effective pain relief can reduce the overactivation of the hypothalamus by pain stimuli, maintaining the balance of mood-related neurotransmitters, such as dopamine and serotonin, thereby improving the emotional state of pregnant women. Third, butorphanol and ropivacaine help improve the psychological and physiological condition of postpartum women. Excellent pain relief enables postpartum women to get out of bed sooner, accelerates uterine recovery, and reduces anxiety and depression caused by prolonged bed rest. Pain control also improves sleep quality and alleviates emotional issues caused by insomnia. Furthermore, clinical practice has shown that the combined use of butorphanol and ropivacaine can reduce the incidence of complications such as urinary retention and postpartum bleeding, which are independent risk factors for PPD. Finally, childbirth stress can cause sudden increases in ACTH and cortisol levels by activating the HPA axis. Long-term or excessive activation of the HPA axis can damage hippocampal neurons and increase the risk of depression by affecting the reuptake of serotonin and norepinephrine. In this study, the levels of ACTH and cortisol in the study group were significantly lower than those in the control group at 2 hours after delivery, suggesting that butorphanol may reduce the damage caused by stress hormones to emotion-related brain areas by inhibiting excessive activation of the HPA axis. The κ opioid receptor is widely distributed in the central nervous system (including the paraventricular nucleus and locus coeruleus). After butorphanol activates the kappa receptor, it can inhibit the excitability of hypothalamic CRH neurons, suppress CRH secretion, and reduce ACTH and cortisol levels, thus alleviating the physiological stress load in postpartum women and maintaining early emotional stability[24,25]. Thus, the butorphanol-mediated suppression of HPA axis overactivation and the subsequent reduction in stress hormones may partly explain the observed decrease in mean EPDS scores. Nevertheless, the present study only found a reduction in EPDS values on postpartum days 1 and 7, whereas the incidence of PPD (EPDS ≥ 10) remained statistically similar between groups. This pattern is in line with two recent meta-analyses[26,27] that enrolled 2469 and 3276 parturients, respectively: Neuraxial labour analgesia lowered the mean EPDS score by approximately 0.4 points, but the pooled risk ratio for PPD incidence still crossed unity. Both studies estimated that 1000-1200 additional participants would be required to detect a 20% reduction in incidence. Consequently, the single-center design (n = 114) of the current trial was under-powered for “event” differences, rather than the analgesic regimen being inherently ineffective. The butorphanol dose (4 mg) used in our epidural regimen was selected according to the “Expert Consensus on Analgesia with Butorphanol Tartrate”[28]. However, no dose-finding component was incorporated into the present randomized controlled trial. Future prospective cohorts or dose-response studies are therefore warranted to determine whether lower (or higher) incremental doses might further optimize maternal analgesia and stress-hormone suppression without increasing side-effects.

There are some limitations of this study. First, the failure to estimate the sample size before the start of the experiment may have resulted in insufficient validation. Future research should be based on pre-experiments or existing data with prior sample size estimations to ensure that the results have sufficient statistical validity. Second, this study was conducted at a single center with a limited sample size. Despite the use of randomization, there may still be unmeasured confounding factors, such as the prenatal psychological status of the mother, the level of social support, and other interventions during delivery, which may affect stress hormone levels and postpartum emotions.

CONCLUSION

This study demonstrated that the combination of butorphanol and ropivacaine for labor analgesia offers significant advantages over the combination of sufentanil and ropivacaine. Advantages include faster pain relief, better stress response suppression, and improved safety. Butorphanol, due to its high lipophilicity, can quickly penetrate the spinal barrier, preferentially activate κ receptors, inhibit visceral pain transmission, and work synergistically with ropivacaine to accelerate nerve block and shorten the onset time. Additionally, butorphanol activates hypothalamic κ receptors, directly inhibiting the ACTH-melanocyte-stimulating hormone axis, which significantly reduces perinatal stress damage compared to the control group. Butorphanol also reduces the risk of respiratory depression without increasing the risk of adverse reactions, such as nausea and itching. However, this was a single-center, small-sample study, which may limit the generalizability of the results. Moreover, long-term follow-up was conducted on maternal psychological outcomes (such as the recurrence rate of PPD within 6 months) and neonatal neurodevelopment. Therefore, multicenter follow-up studies are warranted. Therefore, future multicenter follow-up studies are essential. A large-scale randomized controlled trial involving high-risk pregnant populations (e.g., those with gestational hypertension or diabetes) is required to confirm the generalizability of this analgesic regimen.