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

MOTHER Trial: Efficacy and Safety of Low-dose Intrathecal Morphine Following Planned Caesarean Section - a Randomised, Blinded, Clinical, Controlled, Multicentre Trial.

The goal of this clinical trial is to learn if morphine added to the spinal anaesthesia can improve postoperative pain treatment for patients undergoing caesarean section, without increasing the risk of serious adverse events in mother and baby.

The main questions it aims to answer are:

• Is the treatment effective in preventing postoperative pain?
• Is the treatment safe for both mother and baby?

Participants will be given a normal spinal anaesthesia with addition of either morphine or sodium chloride (inactive substance). All participants will receive standard postoperative pain treatment, including morphine tablets as needed. Researchers will collect data from the electronic medical record and ask the participants to fill out questionnaires about pain levels and possible side effects.

Study Overview

• Status: Recruiting
• Conditions: Postoperative Pain; Caesarean Section
• Intervention / Treatment: Drug: Intrathecal Morphine; Drug: Placebo (Sodium Chloride Injection, 0.9%)

Detailed Description

BACKGROUND AND OBJECTIVE:

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.

The objective of the trial is 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.

The trial is a superiority, investigator-initiated, pragmatic, randomised, blinded, placebo-controlled multicentre trial.

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 Type: Interventional
• Enrollment (Estimated): 1312
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Anneline B Seegert, MD; Phone Number: +4547326397; Email: ansee@regionsjaelland.dk
• Study Contact Backup: Name: Anne J Wikkelsø, MD, PhD; Phone Number: +4547325046; Email: awik@regionsjaelland.dk

Study Locations

• Denmark
  • Aarhus, Denmark, 8200
    • Recruiting
    • Aarhus University Hospital
    • Contact: Deepti Jain, MD; Phone Number: +4530911052; Email: deepjain@rm.dk
  • Copenhagen, Denmark, 2100
    • Not yet recruiting
    • Copenhagen University Hospital - Rigshospitalet
    • Contact: Kim Ekelund, MD, PhD; Phone Number: +4535450563; Email: kim.ekelund@regionh.dk
    • Contact: Kim Lindelof, MD, PhD; Email: kim.lindelof@regionh.dk
  • Herlev, Denmark, 2730
    • Not yet recruiting
    • Copenhagen University Hospital - Herlev and Gentofte, Herlev
    • Contact: Kim Wildgaard, MD, PhD; Phone Number: +4538682170; Email: Kim.Wildgaard@regionh.dk
  • Hillerød, Denmark, 3400
    • Not yet recruiting
    • Copenhagen University Hospital - North Zealand, Hillerød
    • Contact: Patricia Duch, MD; Phone Number: +4548292504; Email: patricia.duch@regionh.dk
  • Hvidovre, Denmark, 2650
    • Recruiting
    • Copenhagen University Hospital - Amager and Hvidovre, Hvidovre
    • Contact: Maria E Kromann, MD, PhD; Phone Number: +4538620694; Email: Maria.Egede.Kromann@regionh.dk
  • Kolding, Denmark, 6000
    • Recruiting
    • University Hospital of Southern Denmark - Lillebælt Hospital, Kolding
    • Contact: Helene K Nedergaard, MD, PhD; Phone Number: +4553272244; Email: helene.korvenius.nedergaard@rsyd.dk
  • Odense C, Denmark, 5000
    • Recruiting
    • University Hospital of Southern Denmark - Odense University Hospital
    • Contact: Mette L Andersson; Phone Number: +4565414937; Email: mf_andersson@me.com
  • Roskilde, Denmark, 4000
    • Recruiting
    • Zealand University Hospital
    • Contact: Anne J Wikkelsø, MD, PhD; Phone Number: +4547325046; Email: awik@regionsjaelland.dk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients ≥ 18 years
• Singleton pregnancy
• Scheduled for planned 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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo (Sodium Chloride Injection, 0.9%); 0.2 ml of isotonic sodium chloride added to a single-shot spinal anaesthesia consisting of 11.5 mg hyperbaric bupivacaine and 10 μg fentanyl.
Experimental: Intrathecal morphine	Drug: Intrathecal Morphine; 80 μg preservative-free morphine (0.2 ml) added to a single-shot spinal anaesthesia consisting of 11.5 mg hyperbaric bupivacaine and 10 μg fentanyl

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Level of pain when mobilising from supine to sitting position within 24 hours	Longitudinal measurements of NRS (0-10) at 6, 12, 18 and 24 hours with most focus on the 24-hour pain level	6, 12, 18 and 24 hours following spinal anaesthesia
Maternal and neonatal serious adverse events	Binary composite outcome: Death of either participant or neonate within 7 days; Participants with clinically significant respiratory depression within 24 hours, defined as respiratory depression documented in the electronic medical record, e.g. need for airway management or pharmacological intervention (subjective assessment by treating clinician, validated by 2 investigators); Neonates needing admission to neonatal intensive care unit within 48 hours; Hospitalisation of either participant or neonate within 7 days after discharge; Participants with severe vomiting or nausea within 24 hours, defined as ≥5 points on the 'Simplified postoperative nausea and vomiting impact scale'63 at any time point (6, 12, 18 and 24 hours)	Within 7 days from discharge

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Opioid consumption within 24 hours	Mg oral morphine equivalents	Within 24 hours following spinal anaesthesia
Morphine associated adverse effects within 24 hours	Binary composite outcome: participants experiencing either: Vomiting (patient reported, yes/no); Nausea; Dizziness; Pruritus Nausea, dizziness, and pruritus is assessed as "none", "little", "moderate", or "severe" with patients reporting "moderate" or "severe" categorised as having a positive outcome; Urinary retention, defined as need for re-catheterisation within 24 hours	Within 24 hours following spinal anaesthesia
Obstetric quality of recovery score at 24 hours	Obs-QoR-10 (0-100)	Within 24 hours following spinal anaesthesia
Participants satisfaction with postoperative pain-treatment during the first 24 hours	NRS 0-10	Within 24 hours following spinal anaesthesia
Established breastfeeding at 30 days	Proportion of neonates being exclusively breastfed at 30 days	30 days from surgery

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Serious adverse events, pain at 24 hours and opioid consumption, compared using Win Ratio	A composite outcome analysed using Win Ratio, consisting of; Maternal and neonatal serious adverse events (as defined in the primary outcome); Level of pain when mobilising from supine to sitting position at 24 hours (NRS 0-10); Opioid consumption within 24 hours (mg oral morphine equivalents)	Within 7 days from discharge
Overall severity of pruritus within 24 hours	NRS 0-10	Within 24 hours following spinal anaesthesia
Pharmacological treatment for opioid-related adverse effects within 24 hours	Dexametasone, dosage (mg) 5-HT3 receptor antagonists, type, dosage (mg) Dopamine receptor antagonists, type, dosage (mg) Droperidol, dosage (mg) Antihistamines, type, dosage (mg) Pethidine, dosage (mg) Naloxone, dosage (mg) Clonidine, dosage (mg)	Within 24 hours following spinal anaesthesia
Ability to mobilise independently	Proportion of participants able to mobilise independently at 6, 12, 18 and 24 hours	6, 12, 18 and 24 hours following spinal anaesthesia
Level of pain at rest within 48 hours	Longitudinal measurements of NRS (0-10) at 6, 12, 18, 24 and 48 hours	6, 12, 18, 24 and 48 hours following spinal anaesthesia
Opioid consumption within 48 hours	Mg oral morphine equivalents	Within 48 hours following spinal anaesthesia
"Rescue" supplemental pain treatment with truncal nerve block or epidural within 24 hours	Binary composite outcome: participants receiving either an unplanned postoperative truncal nerve block or epidural analgesia within 24 hours	Within 24 hours following spinal anaesthesia
Level of pain when mobilising from supine to sitting position at 48 hours	NRS 0-10	Within 48 hours following spinal anaesthesia
Total consumption of non-opioid analgesic medication (paracetamol, NSAIDs) within 24 hours and 48 hours	Paracetamol, dosage (mg) NSAIDs, type, dosage (mg)	Within 24 and 48 hours following spinal anaesthesia
Intraoperative nausea, vomiting and pruritus	Binary composite outcome: participants experiencing either; Intraoperative nausea; Intraoperative vomiting; Intraoperative pruritus Nausea and pruritus are assessed as "none", "little", "moderate", or "severe" with patients reporting "moderate" or "severe" categorised as having a positive outcome. Vomiting is assessed as yes/no. Intraoperative is defined as from administration of spinal anaesthesia until the patient is leaving the operating room	During surgery
Overall severity of pain within 24 hours (ObsQoR-10)	NRS 0-10	Within 24 hours following spinal anaesthesia
Overall severity of nausea/vomiting within 24 hours (ObsQoR-10)	NRS 0-10	Within 24 hours following spinal anaesthesia
Overall severity of dizziness within 24 hours (ObsQoR-10)	NRS 0-10	Within 24 hours following spinal anaesthesia
Overall severity of shivering within 24 hours (ObsQoR-10)	NRS 0-10	Within 24 hours following spinal anaesthesia
Overall feeling of being comfortable within 24 hours (ObsQoR-10)	NRS 0-10	Within 24 hours following spinal anaesthesia
Overall ability to mobilise independently within 24 hours (ObsQoR-10)	NRS 0-10	Within 24 hours following spinal anaesthesia
Overall ability to independently hold infant within 24 hours (ObsQoR-10)	NRS 0-10	Within 24 hours following spinal anaesthesia
Overall ability to nurse/feed infant independently within 24 hours (ObsQoR-10)	NRS 0-10	Within 24 hours following spinal anaesthesia
Overall ability to handle personal hygiene within 24 hours (ObsQoR-10)	NRS 0-10	Within 24 hours following spinal anaesthesia
Overall feeling of being in control within 24 hours (ObsQoR-10)	NRS 0-10	Within 24 hours following spinal anaesthesia
Length of hospital stay	Total length of primary hospital stay (hours)	Within 7 days from discharge
Readmission or unplanned hospital re-attendance within 7 days	Binary composite outcome: participants needing either: Hospital readmission within 7 days; Re-attendance (unplanned hospital out-patient consultation) within 7 days	Within 7 days following surgery
Failed or insufficient spinal anaesthesia	Binary composite outcome: participants needing either: Conversion to general anaesthesia; Repeated neuraxial procedure; Supplemental intraoperative pain treatment	Within 24 hours following spinal anaesthesia
Hospital-free days within 7 days	Number of days out of hospital for both participant and neonate within 7 days	Within 7 days following surgery
Ogilvie's syndrome/ileus within 7 days	Proportion of participants with Ogilvie's syndrome/ileus that requires surgery or treatment with neostigmine within 7 days	Within 7 days following surgery
Apgar score at 5 minutes following birth	0-10	5 minutes following birth
Apgar score <7 at 5 minutes following birth	Proportion of neonates with Apgar score <7 at 5 minutes following birth	5 minutes following birth
Neonatal need for respiratory support within 48 hours	Proportion of neonates needing respiratory support within 48 hours, defined as either: Continuous positive airway pressure treatment; Positive pressure ventilation; HNF (high nasal flow); Intubation; Oxygen therapy	Within 48 hours following birth
Neonatal sedation resulting in failed breast-/bottle feeding within 48 hours	Proportion of neonates not being breastfed or bottle fed due to neonatal sedation, corresponding to L=0 (too sleepy or reluctant, no sustained latch or suck achieved) on the LATCH scoring system	24 and 48 hours following birth
Neonatal hospitalisation within 24 hours after discharge	Proportion of neonates hospitalised within 24 hours after discharge of participant	24 hours after discharge

Collaborators and Investigators

• Sponsor: Anne Juul Wikkelsø

Study record dates

Study Major Dates

• Study Start (Actual): July 15, 2025
• Primary Completion (Estimated): May 31, 2027
• Study Completion (Estimated): June 30, 2027

Study Registration Dates

• First Submitted: January 17, 2025
• First Submitted That Met QC Criteria: January 28, 2025
• First Posted (Actual): January 29, 2025

Study Record Updates

• Last Update Posted (Actual): December 19, 2025
• Last Update Submitted That Met QC Criteria: December 18, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Keywords: Caesarean section; Cesarean section; Spinal morphine; Intrathecal morphine; Postoperative pain; Cesarean delivery; Caesarean delivery; elective caesarean
• Additional Relevant MeSH Terms: Pain; Neurologic Manifestations; Postoperative Complications; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Pain, Postoperative; Inorganic Chemicals; Chlorine Compounds; Sodium Compounds; Chlorides; Hydrochloric Acid; Sodium Chloride
• Other Study ID Numbers: 2024-518678-16-00 (Ctis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Data supporting the findings of this study are available from the corresponding author in accordance with Danish law and upon reasonable request.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No