Introduction

The effective management of postpartum pain is crucial in obstetric anaesthesia, as inadequate pain control directly impacts maternal physiological recovery, sleep quality, breastfeeding success rates and even contributes to a higher incidence of postpartum depression. Therefore, optimising analgesia strategies after caesarean section plays a pivotal role in promoting rapid recovery and providing comfortable medical care.

Neuraxial morphine is considered the gold standard for postpartum analgesia, offering effective and prolonged pain relief for a duration of 14–36 hours,1 2 which should be carefully conducted in accordance with the recommendations provided by the American Society of Anesthesiologists (ASA) and the American Society of Regional Anesthesiology and Pain Medicine (ASRA). The guidelines recommend close monitoring of ventilation, oxygenation and level of consciousness in patients who received a single dose of morphine, which should be conducted continuously for a minimum duration of 20 min postadministration, followed by hourly assessments until 2 hours after dosing. The frequency of monitoring can be adjusted based on the patient’s overall clinical condition and concurrent medication usage. The patients who receive other forms of analgesia, such as intravenous or epidural pumps, should be monitored on an hourly basis during the first 12 hours, every 2 hours from 12 to 24 hours, and at least every 4 hours thereafter. Special attention must be given to patients with an increased risk of respiratory depression.3 However, considering the minimal risk of respiratory depression associated with contemporary strategies for administering neuraxial morphine, studies have demonstrated the safety of clinically relevant doses of neuraxial morphine following caesarean section. The highest and lowest rates of clinically significant respiratory depression were found to be 1.63/10 000 (95% CI 0.62 to 8.77) and 1.08/10 000 (95% CI 0.24 to 7.22), respectively.4 The Society for Obstetric Anesthesia and Perinatology (SOAP) also suggests that the frequency and intensity of such monitoring may be excessive for healthy women without specific comorbidities. SOAP recommends using an ultra-low dose of morphine (intrathecal ≤50 ug, epidural ≤1 mg) for neuraxial analgesia, which does not require additional respiratory monitoring in the absence of other risk factors affecting respiration. For low-dose morphine (intrathecal: 50–150 μg, epidural: 1–3 mg), respiratory and sedation assessments should be conducted every 2 hours during a postoperative period lasting 12 hours. High doses of morphine (intrathecal >150 μg, epidural >3 mg) should be monitored according to ASA/ASRA standards.5 In cases where low-dose morphine is administrated to low-risk women, excessive vigilance in monitoring for respiratory depression may impact the allocation of medical resource and increase nursing workload. However, for high-risk patients with comorbidities or risk factors that predispose them to respiratory depression, it is essential to proactively identify and adjust the monitoring approach beforehand. Additionally, the monitoring of respiratory function may also disrupt sleep patterns of mothers, interfere with lactation processes, impede the provision of neonatal care, and thus compromise the quality of patient-centred care following a caesarean section without providing ant additional safety benefits.

The ASA/ASRA guidelines inadvertently reduce the utilisation of neuraxial morphine, despite research and long-term clinical use demonstrating the safety of low doses of intrathecal or epidural morphine for postpartum pain management. Over the past few decades, millions of women in the USA who underwent caesarean section have safely received neuraxial morphine, which offers superior analgesic effect compared with systemic opioid administration and should be prioritised for postpartum pain relief. The combination of low-dose neuraxial morphine administration with various analgesics (eg, non-steroidal anti-inflammatory drugs, acetaminophen) effectively mitigates postoperative pain following caesarean section, while concurrently reducing the incidence of side effects such as pruritus, nausea and vomiting, and potential respiratory depression by 30%.6 Alternatively, in the absence of these drugs, regional nerve block such as transversus abdominis plane block (TAPB) and quadratus lumborum block (QLB) may be considered.6 However, recent studies suggest that while TAPB and QLB provide effective postoperative pain relief compared with control groups, their additional benefits when combined with neuraxial morphine administration are limited.7 The guidelines issued by the European Regional Association of Anesthesia and Analgesia and the European Association of Obstetric Anesthesia recommend the administration of intrathecal morphine (50–100 μg) or diacetylmorphine (300 μg) during caesarean section or morphine (2–3 mg) or diacetylmorphine (2–3 mg) through an epidural catheter as an alternative.8 Both options yield similar analgesic effects and side effects.9 Furthermore, it is important to note that there is a ceiling effect associated with neuraxial administration of morphine, which means higher doses (intrathecal >150 μg; epidural >4 mg) may not provide better analgesia but can increase the incidence of side effects such as nausea, vomiting and pruritus.2 10

In light of the prevailing practice in our institution, where a majority of caesarean sections are performed under combined spinal and epidural anaesthesia, followed by postoperative patient-controlled intravenous analgesia (PCIA) along with regional nerve block (such as TAPB), this research aims to enhance the multimodal postpartum analgesia programme and investigate the optimal dosage of epidural morphine for healthy women. The objective is to alleviate moderate and severe postoperative pain after caesarean section while minimising opioid usage and associated complications. Additionally, it seeks to reduce unnecessary respiratory monitoring resources, save medical costs, promote patient-centred enhanced recovery after caesarean (ERAC) and improve maternal and infant outcomes.

Methods and analysisStudy design and patient enrolment

This study is planned to enrol parturients who are scheduled for elective caesarean section under combined spinal and epidural anaesthesia at our institution between March 2024 and September 2024. Eligible participants will be randomly assigned in a proportional manner to receive varying doses of epidural morphine or placebo. Based on the preliminary experiment conducted in our institution, it was observed that the prevalence of moderate to severe pain (Numerical Rating Scale (NRS) pain scores ≥4) within 24 hours after caesarean section under combined spinal-epidural anaesthesia with conventional analgesia was found to be 38.9%. We assume that the occurrence of moderate and severe pain within 24 hours after epidural administration of different doses of morphine (1 mg, 2 mg, 3 mg and 4 mg), respectively, decreases to 35%, 30%, 25% and 25% with one-sided α level of significance set at 2.5% and a power of analysis set at 90%. The minimum required sample size for this study has been determined to be 245 cases. Considering an anticipated dropout rate and loss to follow-up of approximately 20%, we intend to enrol a total of 310 parturients, with each group consisting of 62 parturients. The power calculations were performed using Power Analysis and Sample Size software 2019. The recruitment process has not yet commenced at the time of submission, and the study is expected to conclude with the last follow-up of the final enrolled parturient in September 2024. The article follows the Standard Protocol Items: Recommendations for Interventional Trials reporting guidelines11 and this trial has been registered with Chinese Clinical Trial Registry.

Patient and public involvement

Patients or the public were not involved in the design, or conduct, or reporting, or dissemination plans of our research.

Eligibility criteria

Parturients meeting the inclusion criteria during screening and not possessing any of the exclusion criteria (box 1) are eligible for enrolment. Additionally, they have the option to withdraw from the trial at any time if they revoke their informed consent, change the anaesthesia method during surgery, experience loss to follow-up or encounter a perioerative situation where the sensory block level exceeds T4 without intervention.

Box 1 Inclusion and exclusion criteriaInclusion criteria

American Society of Anesthesiologists classification I–II healthy pregnant women, aged ≥18 years old.

Elective caesarean section performed under combined spinal and epidural anaesthesia.

Signed informed consent for trial participation.

Exclusion criteria

Contraindications for neuraxial anaesthesia, including abnormal coagulation function, anticoagulant therapy, severe hypovolaemia, or haemodynamic instability.

Emergency or any unforeseen caesarean sections.

Body mass index ≥40 kg/m2.

Previous neurological diseases; (cerebral haemorrhage, cerebral infarction or transient ischaemic attack, etc).

Past or existing cardiovascular diseases (such as congenital heart disease, coronary heart disease, severe arrhythmias).

Severe obstetric complications, such as pre-eclampsia and eclampsia, pregnancy-induced hypertension, placenta previa, or placental abruption.

Diagnosed or suspected obstructive sleep apnoea syndrome.

Long-term use of opioids or psychotropic drugs.

Refusal to participate in the experiment, difficulties with language expression or failure to cooperate with the interviewer.

Assessment of outcomes

The primary outcome is the incidence of postoperative NRS pain score ≥4 points within 24 hours, primarily assessed through bedside follow-up conducted by investigators and patient self-assessment at 2, 4, 6, 8, 12 and 24 hours postoperatively. The secondary outcomes include the following:

Incidence of postoperative NRS score ≥4 within 48 hours.

Incidence of pulse oxygen saturation (SpO2) <90% (air inhalation)/SpO2<95% (nasal cannula oxygen inhalation) or RR <10 breaths/min.

Ramsay sedation score.

The total amount and times of additional press of PCIA pump and use of other rescue analgesics.

Time to first flatus and food intake.

Maternal and neonatal urinary morphine concentrations.

Occurrence of other adverse reactions and neonatal complications.

Randomisation and blinding

Randomisation is performed using a computer-generated randomisation list and the treatment notes are folded in opaque sealed envelopes in equal proportions. On the arrival of parturients who meet the inclusion criteria and provide informed consent to the operating room, a separate attending anaesthesiologist, uninvolved in the study or postoperative follow-up, randomly selected one envelope and followed the provided instructions for intervention. The assignment of groups remains blinded for surgeons, nurses, follow-up staff members, patients and data analysts.

Statistical analysis

The analysis includes all enrolled parturients, excluding those who withdraw from the trial prematurely or undergo a switch to general anaesthesia or experience a sensory block plane above T4 without pharmacological intervention. Additionally, subgroup analysis is conducted based on the actual treatment received. NRS pain scores are collected at 2, 4, 6, 8, 12, 24 and 48 hours after surgery. Mean values of NRS at each time point are reported for each group. A linear regression model is used with time as the independent variable and the parturient’s corresponding NRS scores as dependent variables to compare differences and determine the corresponding CIs among all groups. The measurement data are expressed as mean±SD, while the normality is assessed using the Shapiro-Wilk test. The analysis of variance is used to assess significant differences among data that follow a normal distribution, whereas the Kruskal-Wallis rank sum test is used for non-normally distributed data. χ2 test or Fisher’s exact method is used for count data rates. Statistical significance is defined as p<0.05 on both sides. The Kaplan-Meier method is employed to determine the median time of the first postoperative request for rescue analgesia, and comparisons between groups are made using logarithmic rank tests and proportional risk regression with specific time intervals and 95% CIs.

Date collection

One day prior to the operation, parturients who meet the screening criteria through the operation scheduling system undergo informed consent signing and receive education regarding the trial, including the NRS scoring standard and utilisation of an analgesic pump. The patients’ general information is documented in accordance with the case report form (CRF), which encompasses their name, age, gender, hospitalisation number, height, weight, occupation, educational level, contact details, diagnosis, medical history, complications (if any), special pharmaceuticals and drug allergies. The caesarean sections are performed through a transverse incision in the lower segment of the uterus and combined spinal-epidural anaesthesia is administered. The administration of intraoperative drugs (including local anaesthetics, intravenous drugs, obstetric drugs, postoperative analgesics, etc), duration of anaesthesia and surgery, as well as fluid intake and output volume are also documented.

All the participants are followed up at 2, 4, 6, 8, 12, 24 and 48 hours postoperatively. The outcomes include NRS pain scores, sedation level, RR and SpO2, administration of rescue analgesics if necessary, frequency and total amount of PCIA pump usage, time to first flatus and food intake, urinary morphine concentrations in parturients and infants, as well as any adverse reactions such as nausea, vomiting, pruritus or urinary retention and neonatal depression. Additionally documented on discharge are the overall hospitalisation cost, the duration of postoperative hospital stay and the incidence of complications during this period.

Intervention

The study outline is presented in figure 1. Intraoperative interventions: On the parturient’s arrival in the operating room, standard ECG and non-invasive blood pressure monitoring and establishment of venous access should be performed. The parturient should be positioned in left lateral decubitus for combined spinal and epidural anaesthesia at either L3–L4 or L2–L3 intervertebral space. Following strict adherence to aseptic principles, a 16-gauge Tuohy needle is used to puncture the ligamentum flavum, followed by insertion of a 25-gauge needle through the dura mater. After confirming unobstructed cerebrospinal fluid outflow, 0.5% bupivacaine (2.5–2.7 mL) is then administered into the subarachnoid space, followed by placement of an epidural catheter approximately 3–4 cm cephalad from the initial puncture site. Subsequently, the parturient’s position should be changed to supine with a leftward tilt of the operating bed while blood pressure monitoring occurs at 1 min intervals. The administration of phenylephrine at a rate of 0.5 μg/kg/min is employed concurrently to maintain blood pressure fluctuations within±20% prior to surgery, with adjustments being made accordingly based on specific circumstances. The morphine injection (1 mL:10 mg) is diluted with 0.5% glucose and sodium chloride infusion solution to achieve a concentration of 1 mg/mL, and subsequently administered through the epidural catheter 5 min prior to the end of the surgical procedure. Following the injection, an additional 2–4 mL of 0.5% glucose and sodium chloride infusion solution is delivered via the epidural catheter to ensure a total volume of 5 mL. The control group is administrated an epidural injection of 5 mL of a solution containing 0.5% glucose and sodium chloride infusion solution. (The sensory block level is evaluated before and after administration, with discontinuation of any medication or saline infusion if the sensory block level surpasses T4.) The intravenous analgesia pump uses a mixture of butorphanol tartrate (12 mg) and 150 mL of 0.9% sodium chloride solution, with a background dose set at 2 mL, single doses at 2 mL and a lockout time of 30 min. It is connected to the parturient’s vein channel and initiated at the start of suturing the skin. Intravenous administration of dexamethasone (5 mg) and metoclopramide (10 mg) is routinely used for proactive management of postpartum nausea and vomiting in all patients.

Figure 1

Study outline. NRS, Numerical Rating Scale; PCIA, patient-controlled intravenous analgesia; RR, respiratory rate.

Postoperative management: All participants are admitted to the postanaesthesia care unit. An experienced anaesthesiologist performs bilateral sterilisation and administers a unilateral injection of 15 mL 0.25% ropivacaine containing dexamethasone 2.5 mg into the transversus abdominis plane under ultrasound guidance for all parturients. They are transferred to the ward approximately 20 min later, without any exceptional circumstances. During the initial 24-hour postoperative period, all parturients should undergo ECG monitoring and receive inhaled oxygen at a rate of 2 L/min through a nasal catheter while maintaining urinary catheters. Subsequently, blood pressure and oxygen saturation levels are monitored every 6 hours, along with pneumatic therapy implemented for venous thrombosis prevention. The researchers not involved in the grouping and intervention process conduct bedside assessments of enrolments at 2, 4, 6, 8, 12, 24 and 48 hours postsurgery. All endpoints are accurately documented in CRF format according to respective time points.

Pain intensity is evaluated using the Numeric Rating Scale (NRS), an 11-point scale, with 0 indicating no pain and 10 representing the most severe pain (table 1). If the NRS scores fall between 4 and 6, parturients are instructed to either press the automatic administration button on the PCIA pump as preoperative education or request an intramuscular injection of pethidine (50–100 mg) and chlorpromazine hydrochloride (25 mg) from ward nurses. In cases where NRS score exceeded 6, direct intramuscular injections of pethidine (50–100 mg) and chlorpromazine hydrochloride injection (25 mg) may be administered in addition to activating the PCIA pump for pain relief. The goal for effective pain management is to achieve NRS score ≤3.

Table 1

Description of Numeric Rating Scale (NRS)

The sedation level of the parturients is assessed using Ramsay sedation scoring system (table 2), with satisfactory sedation falling within scores 2–4, while excessive sedation is indicated by scores 5 and 6.12 If the SpO2 level drops below 90% during air inhalation or below 95% while receiving oxygen through nasal cannula, accompanied by RR less than 10 breaths per minute as indicated on monitoring equipment, it is imperative for the patient’s family members or caregivers to promptly notify the attending physician by activating the alarm bell. Moreover, if necessary, naloxone should be administered within a dosage range of 0.2–0.4 mg. In cases of severe respiratory depression, immediate respiratory support such as tracheal intubation or laryngeal mask is essential. Patients experiencing severe itching may be administrated propofol (10 mg) or naloxone, along with the addition of granisetron 3 mg if they also present with severe nausea and vomiting.

Table 2

Description of Ramsay Sedation Scale11

Study quality control and requirement

The investigators use standardised operating procedures (SOPs) to ensure the quality of clinical trial forms. All data are guaranteed to be accurate and reliable, with regular supervision and verification by the principal investigator. All conclusions are derived from the original data. Researchers responsible for patient data collection and postoperative follow-up should promptly complete the CRFs after each interview, which will be submitted for storage after being signed by the principal investigator. Centralised management and analysis of all data are conducted, employing standardised statistical methods to summarise and analyse the results, with involvement from personnel well versed in biostatistics. On completion of the study, a termination notice will be submitted to the hospital’s ethics committee following established procedures by the principal.

Ethical considerations, amendments and dissemination

The present clinical trial adheres to the Declaration of Helsinki by the World Medical Assembly, as well as the Ethical Review Measures for Biomedical Research involving Human Subjects set forth by the National Health and Family Planning Commission of the People’s Republic of China, in conjunction with other relevant regulations. The principles and requirements pertaining to informed consent, privacy protection, cost-free research participation and compensation, risk management, safeguarding vulnerable populations, as well as indemnification for research-related damages shall be duly implemented. Before enrolling each participant, it is the responsibility of the investigator to provide a comprehensive and meticulous orientation regarding the purpose, procedures and potential risks of the study to both the subjects and their legal representative. Furthermore, it is crucial for investigators to ensure that a written informed consent form is properly executed, thereby guaranteeing participants’ understanding of their voluntary participation in the clinical study and their right to refuse or withdraw from involvement at any stage without facing discrimination or retaliation. Informed consent should be maintained as an essential document for future reference in clinical research.

Trial status

The study protocol was approved by the Ethics Committee of West China Second University Hospital of Sichuan University on 7 March 2023 and registered on www.chictr.org.cn on 27 January 2024. The recruitment process is anticipated to commence in March 2024.

Discussion

The management of postpartum pain has consistently been a primary concern in the field of obstetric anaesthesia due to its direct impact on adverse reactions with the rate of caesarean sections remaining persistently high, particularly among elderly and high-risk pregnant women. Adequate postoperative analgesia is crucial for mitigating perioperative stress response and minimising acute and chronic complications associated with pain.13 Therefore, optimising the analgesia strategy following caesarean section plays a pivotal role in promoting rapid recovery and providing comfortable medical care.

The opioid analgesic morphine is indicated for the treatment of acute and chronic moderate to severe pain. It exerts its effects primarily by agonising μ-opioid receptors, resulting in analgesia and sedation.14 The metabolism of oral or intramuscular injected morphine results in the formation of morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G),15 which are primarily eliminated through renal excretion, with a minor portion being excreted into breast milk. Epidural administration of morphine specifically targets opioid receptors located in the posterior horn of the spinal cord, thereby exerting its effects along spinal nerves. Meanwhile, a portion of the drug is absorbed into circulation and acts on opioid receptors within the central nervous system. Previous study suggests that urine concentrations of morphine and its metabolites are highly correlated to those of serum.16 Considering the feasibility of specimen acquisition, we collect maternal urine samples at 3 hours and 6 hours post partum, as well as infant samples at 3 hours after neonatal sucking. (Breast feeding is initiated within 2 hours after delivery.) All samples are put in tubes without additives and stored at a temperature of −70℃ before being analysed at the Department of Medical Laboratory, West China Second University Hospital. The urine samples yield a positive result once the concentration reached 300 ng/mL.17

In recent years, there has been a growing emphasis on multimodal analgesia in research, aiming to optimise perioperative pain management, prevent central sensitisation and mitigate the adverse effects of opioid misuse. Since 2012, the National Institute for Health and Care Excellence guidelines from the UK have advocated for the implementation of enhanced recovery after surgery (ERAS) protocols in obstetric units.18 The ERAS society has issued three distinct guidelines specifically addressing the postoperative needs of women undergoing caesarean sections, encompassing prenatal care, intraoperative care, postnatal care and perinatal care.19–21 The ERAC protocol recommends the utilisation of neuraxial morphine, which is the most commonly applied analgesic method, in combination with intravenous non-opioid analgesics in the operation room or oral acetaminophen before or after delivery. In institutions where neuraxial morphine is unavailable, TAPB or QLB can be used.6 The administration of neuraxial morphine for analgesia necessitates comprehensive monitoring of parturients’ respiratory system, oxygenation and level of consciousness due to its potential effects. This requires a significant allocation of medical resources including monitoring equipment and personnel, which limits the application of neuraxial morphine for postpartum analgesia. Despite suboptimal management of postpartum pain, as evidenced by a preliminary investigation conducted at our institution that typically involves a combination of TAPB and PCIA. We propose that an optimal dosage of neuraxial morphine, the primary focus of this trial, in conjunction with multimodal analgesia such as a PCIA pump and TAPB for pain management, could not only mitigate the adverse effects associated with opioid utilisation and alleviate monitoring burdens but also yield superior analgesic efficacy.

This trial has been meticulously designed; however, certain limitations still persist. First, the concentration gradient of morphine in insufficient groups is inadequate. A dose of 1 mL:10 mg morphine diluted to 1 mg/mL aligns with clinical practice and there is no evidence that a lower dosage range can produce clinically differences. To ensure valid administration, we perform a flush of the tube with 2–4 mL 0.5% glucose and sodium chloride injection for the experimental group and 5 mL for the control group. Second, a thorough investigation into the optimal analgesic dose of morphine may be lacking. Although the maximum single dose of epidural morphine for analgesia is 5 mg,22 there seems to be a ceiling effect observed with epidural morphine administration, where doses exceeding 4 mg do not necessarily result in improved analgesic effects but rather increase the likelihood of side effects such as nausea, vomiting and pruritus.2 10 Therefore, for this trial, we set the maximum dosage at 4 mg. Additionally, in order to enhance clinical practicability, we refrain from imposing restrictions on the dosage of neuraxial local anaesthetics, incision length, operation duration or the qualifications of surgeons and anaesthesiologists. It is important to acknowledge that there may be additional confounding factors that could potentially impact the accuracy of our results. The aforementioned indicators can be incorporated into subsequent analyses to evaluate correlations and control for confounding bias. Most importantly, the primary outcome is a subjective rating scale, which may be influenced by cognitive bias and patients’ preconceived notion of pain, potentially leading to inaccurate assessment of the analgesic effect and introducing subjective bias. To address this concern, prior to trial initiation, researchers should undergo systematic training on relevant scales, implement SOPs and receive education on trial-related content including NRS scoring criteria and the use of PCIA pump for enrolled parturients. Additionally, objective indicators such as the incidence of rescue analgesia and PCIA pump usage are also evaluated in order to comprehensively assess the analgesic effect.

The trial is expected to contribute to the improvement of safety, efficacy and widespread utilisation of epidural morphine in clinical practice, ultimately facilitating ERAC.