Efficacy and Safety of Intrathecal Morphine for Postoperative Pain Management Following Planned Caesarean Section

Phase 4

Not yet recruiting

• Conditions: Caesarean section, acute postoperative pain

• Registration Number: 2024-518678-16-00
• Lead Sponsor: Anne Juul Wikkelsø

Brief Summary

The aim of this trial is to evaluate analgesic efficacy and safety (patients and neonates) associated with addition of low-dose (80 µg) intrathecal morphine versus placebo to standard multimodal postoperative pain management in patients undergoing elective caesarean section.

Detailed Description

RATIONALE: Caesarean section is surgical procedure associated with moderate to severe postoperative pain, which can negatively affect recovery, mother-child bonding and the initiation of breastfeeding. Intrathecal morphine may offer pain relief for up to 24 hours, and is widely implemented and recommended as part of multimodal postoperative pain management. Despite the widespread use, there is limited evidence for the balance between benefits and harms of low-dose intrathecal morphine in patients undergoing caesarean section.

OBJECTIVE: To evaluate analgesic efficacy as well as maternal and neonatal safety associated with addition of low-dose (80 µg) intrathecal morphine versus placebo to standard multimodal postoperative pain management in patients undergoing planned caesarean section.

MAIN TRIAL ENDPOINTS: Two co-primary outcomes will be assessed, reflecting analgesic efficacy and safety:

1. Level of pain (NRS 0-10) when mobilising from supine to sitting position within 24 hours.

2. Maternal and neonatal serious adverse events: a binary composite outcome consisting of maternal or neonatal death within 7 days, maternal respiratory depression within 24 hours, neonatal admission to intensive care unit within 24 hours, maternal or neonatal hospitalisation within 7 days after discharge and maternal severe vomiting or nausea within 24 hours.

SECONDARY TRIAL ENDPOINTS: Opioid consumption within 24 hours, morphine associated adverse effects within 24 hours (binary composite outcome: vomiting, nausea, dizziness, pruritus and urinary retention), obstetric quality of recovery score at 24 hours, participants satisfaction with postoperative pain-treatment during the first 24 hours and established breastfeeding within 30 days.

TRIAL DESIGN: Superiority, investigator-initiated, pragmatic, randomised, blinded, placebo-controlled multicentre trial.

TRIAL POPULATION:

Inclusion criteria: Patients 18 years or older, with singleton pregnancy, scheduled for elective caesarean section under spinal anaesthesia who provide written informed consent.

Exclusion criteria: Allergy to or contraindications towards the trial medication, planned combined spinal-epidural anaesthesia or postoperative epidural, inability to understand or read Danish and previous inclusion in the trial.

INTERVENTION: Participants will be randomised 1:1 to receive either 80 µg (0.2 ml) preservative-free morphine or placebo (0.2 ml isotonic sodium chloride) added to a single-shot spinal anaesthesia consisting of 11.5 mg hyperbaric bupivacaine and 10 μg fentanyl.

TRIAL SIZE: A total of 1,312 participants is required to show/reject a 35% relative increase in the composite co-primary safety outcome, with an estimated baseline incidence of 21% without intrathecal morphine and a power of 80%. We adjust statistically for having two primary outcomes by using an alpha of 2.5%. We reach a power of 99.9% for the co-primary outcome of pain score with an estimated mean Numeric Rating Scale (0-10) of 4.88, standard deviation of 2.0 and relevant mean difference of 1.0.

ETHICAL CONSIDERATIONS: Intrathecal morphine for caesarean delivery represents a common medical practice which is not supported by robust evidence. High-quality data on efficacy and safety of the treatment will enable clinicians to tailor postoperative pain treatment to each patient, thus improving care for future patients. Choosing low-dose morphine minimises the risk of adverse effects, and all trial participants will receive standard multimodal pain treatment. There is no evidence of any harmful neonatal effects. All trial participants will give informed consent, and the trial will adhere to the Declaration of Helsinki as well as national and international standards of good clinical practice.

PLANNED SUBSTUDIES:

* Incidence of desaturation and bradypnea during the first 24 hours following surgery, assessed using continuous wireless respiratory monitoring in a subpopulation of 100 patients at 3 trial sites.

* Efficacy and safety of intrathecal morphine in participant subgroups: The influence of different pre-existing factors on the primary outcomes

Study Timeline

• Study First Submitted: 2025-01-17
• Study First Submitted QC: 2025-01-28
• Study First Posted: 2025-01-29
• Status Verified: 2025-07
• Last Update Submitted: 2025-07-02
• Last Update Posted: 2025-07-09
• Study Start: 2025-07-15
• Primary Completion: 2027-05-31
• Study Completion: 2027-06-30

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: Female
• Target Recruitment: 1312

Inclusion Criteria

Patients ≥ 18 years

Singleton pregnancy

Scheduled for elective caesarean section performed under spinal anaesthesia

Written informed consent

Exclusion Criteria

Allergy to or contraindications towards trial medication

Patients planned for postoperative epidural due to expected difficult postoperative pain management

Patients planned for combined spinal-epidural as primary anaesthesia

Inability to understand and read Danish

Previous inclusion in the trial

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Primary Outcome Measures

Name	Time	Method
Level of pain when mobilising from supine to sitting position within 24 hours: Level of pain when mobilising from supine to sitting position within 24 hours		Level of pain when mobilising from supine to sitting position within 24 hours: Level of pain when mobilising from supine to sitting position within 24 hours
Maternal and neonatal safety: Binary composite outcome consisting of 1) participants with respiratory depression 2) participants with severe nausea/vomiting within 24 hours 3) neonatal admission within 48 hours 4) hospitalisation of participant or neonate within 7 days after discharge and 5) death of either participant or neonate within 7 days		Maternal and neonatal safety: Binary composite outcome consisting of 1) participants with respiratory depression 2) participants with severe nausea/vomiting within 24 hours 3) neonatal admission within 48 hours 4) hospitalisation of participant or neonate within 7 days after discharge and 5) death of either participant or neonate within 7 days

Secondary Outcome Measures

Name	Time	Method
Opioid consumption within 24 hours		Opioid consumption within 24 hours
Morphine associated adverse events within 24 hours: Vomiting, nausea, dizziness, pruritus and urinary retention		Morphine associated adverse events within 24 hours: Vomiting, nausea, dizziness, pruritus and urinary retention
Obstetric quality of recovery score at 24 hours		Obstetric quality of recovery score at 24 hours
Participants satisfaction with postoperative pain-treatment during the first 24 hours		Participants satisfaction with postoperative pain-treatment during the first 24 hours
Established breastfeeding at 30 days		Established breastfeeding at 30 days

Trial Locations

Locations (6)

Rigshospitalet; 🇩🇰 Copenhagen Oe, Denmark

Lillebaelt Hospital; 🇩🇰 Kolding, Denmark

Odense University Hospital; 🇩🇰 Odense C, Denmark

Region Sjaelland; 🇩🇰 Roskilde, Denmark

Region Hovedstaden; 🇩🇰 Hvidovre, Denmark

Aarhus University Hospital; 🇩🇰 Aarhus N, Denmark

Rigshospitalet

🇩🇰Copenhagen Oe, Denmark

Kim Ekelund

Site contact

+4535450563

kim.ekelund@regionh.dk