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

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

• Intrathecal Morphine (Drug): 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
• Placebo (Sodium Chloride Injection, 0.9%) (Drug): 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.

Primary outcomes

• Level of pain when mobilising from supine to sitting position within 24 hours [6, 12, 18 and 24 hours following spinal anaesthesia]: Longitudinal measurements of NRS (0-10) at 6, 12, 18 and 24 hours with most focus on the 24-hour pain level
• Maternal and neonatal serious adverse events [Within 7 days from discharge]: Binary composite outcome: 1. Death of either participant or neonate within 7 days 2. 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) 3. Neonates needing admission to neonatal intensive care unit within 48 hours 4. Hospitalisation of either participant or neonate within 7 days after discharge 5. 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)

Secondary outcomes

• Opioid consumption within 24 hours [Within 24 hours following spinal anaesthesia]: Mg oral morphine equivalents
• Morphine associated adverse effects within 24 hours [Within 24 hours following spinal anaesthesia]: Binary composite outcome: participants experiencing either: 1. Vomiting (patient reported, yes/no) 2. Nausea 3. Dizziness 4. 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 5. Urinary retention, defined as need for re-catheterisation within 24 hours
• Obstetric quality of recovery score at 24 hours [Within 24 hours following spinal anaesthesia]: Obs-QoR-10 (0-100)
• Participants satisfaction with postoperative pain-treatment during the first 24 hours [Within 24 hours following spinal anaesthesia]: NRS 0-10
• Established breastfeeding at 30 days [30 days from surgery]: Proportion of neonates being exclusively breastfed at 30 days

Other outcomes

• Serious adverse events, pain at 24 hours and opioid consumption, compared using Win Ratio [Within 7 days from discharge]: A composite outcome analysed using Win Ratio, consisting of 1. Maternal and neonatal serious adverse events (as defined in the primary outcome) 2. Level of pain when mobilising from supine to sitting position at 24 hours (NRS 0-10) 3. Opioid consumption within 24 hours (mg oral morphine equivalents)
• Overall severity of pruritus within 24 hours [Within 24 hours following spinal anaesthesia]: NRS 0-10
• Pharmacological treatment for opioid-related adverse effects within 24 hours [Within 24 hours following spinal anaesthesia]: 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)
• Ability to mobilise independently [6, 12, 18 and 24 hours following spinal anaesthesia]: Proportion of participants able to mobilise independently at 6, 12, 18 and 24 hours
• Level of pain at rest within 48 hours [6, 12, 18, 24 and 48 hours following spinal anaesthesia]: Longitudinal measurements of NRS (0-10) at 6, 12, 18, 24 and 48 hours
• Opioid consumption within 48 hours [Within 48 hours following spinal anaesthesia]: Mg oral morphine equivalents
• "Rescue" supplemental pain treatment with truncal nerve block or epidural within 24 hours [Within 24 hours following spinal anaesthesia]: Binary composite outcome: participants receiving either an unplanned postoperative truncal nerve block or epidural analgesia within 24 hours
• Level of pain when mobilising from supine to sitting position at 48 hours [Within 48 hours following spinal anaesthesia]: NRS 0-10
• Total consumption of non-opioid analgesic medication (paracetamol, NSAIDs) within 24 hours and 48 hours [Within 24 and 48 hours following spinal anaesthesia]: Paracetamol, dosage (mg) NSAIDs, type, dosage (mg)
• Intraoperative nausea, vomiting and pruritus [During surgery]: Binary composite outcome: participants experiencing either 1. Intraoperative nausea 2. Intraoperative vomiting 3. 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
• Overall severity of pain within 24 hours (ObsQoR-10) [Within 24 hours following spinal anaesthesia]: NRS 0-10
• Overall severity of nausea/vomiting within 24 hours (ObsQoR-10) [Within 24 hours following spinal anaesthesia]: NRS 0-10
• Overall severity of dizziness within 24 hours (ObsQoR-10) [Within 24 hours following spinal anaesthesia]: NRS 0-10
• Overall severity of shivering within 24 hours (ObsQoR-10) [Within 24 hours following spinal anaesthesia]: NRS 0-10
• Overall feeling of being comfortable within 24 hours (ObsQoR-10) [Within 24 hours following spinal anaesthesia]: NRS 0-10
• Overall ability to mobilise independently within 24 hours (ObsQoR-10) [Within 24 hours following spinal anaesthesia]: NRS 0-10
• Overall ability to independently hold infant within 24 hours (ObsQoR-10) [Within 24 hours following spinal anaesthesia]: NRS 0-10
• Overall ability to nurse/feed infant independently within 24 hours (ObsQoR-10) [Within 24 hours following spinal anaesthesia]: NRS 0-10
• Overall ability to handle personal hygiene within 24 hours (ObsQoR-10) [Within 24 hours following spinal anaesthesia]: NRS 0-10
• Overall feeling of being in control within 24 hours (ObsQoR-10) [Within 24 hours following spinal anaesthesia]: NRS 0-10
• Length of hospital stay [Within 7 days from discharge]: Total length of primary hospital stay (hours)
• Readmission or unplanned hospital re-attendance within 7 days [Within 7 days following surgery]: Binary composite outcome: participants needing either: 1. Hospital readmission within 7 days 2. Re-attendance (unplanned hospital out-patient consultation) within 7 days
• Failed or insufficient spinal anaesthesia [Within 24 hours following spinal anaesthesia]: Binary composite outcome: participants needing either: 1. Conversion to general anaesthesia 2. Repeated neuraxial procedure 3. Supplemental intraoperative pain treatment
• Hospital-free days within 7 days [Within 7 days following surgery]: Number of days out of hospital for both participant and neonate within 7 days
• Ogilvie's syndrome/ileus within 7 days [Within 7 days following surgery]: Proportion of participants with Ogilvie's syndrome/ileus that requires surgery or treatment with neostigmine within 7 days
• Apgar score at 5 minutes following birth [5 minutes following birth]: 0-10
• Apgar score <7 at 5 minutes following birth [5 minutes following birth]: Proportion of neonates with Apgar score <7 at 5 minutes following birth
• Neonatal need for respiratory support within 48 hours [Within 48 hours following birth]: Proportion of neonates needing respiratory support within 48 hours, defined as either: 1. Continuous positive airway pressure treatment 2. Positive pressure ventilation 3. HNF (high nasal flow) 4. Intubation 5. Oxygen therapy
• Neonatal sedation resulting in failed breast-/bottle feeding within 48 hours [24 and 48 hours following birth]: 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
• Neonatal hospitalisation within 24 hours after discharge [24 hours after discharge]: Proportion of neonates hospitalised within 24 hours after discharge of participant

Sex: Female, ages: 18 Years to any

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