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Procedural pain in premature infants (POPPI): a blinded randomized placebo-controlled trial of oral morphine

Presented at the Neonatal Society 2018 Autumn Meeting (programme).

Moultrie F1, Hartley C1, Hoskin A1, Green G1, Monk V2, Bell JL2, Juszczak E2, Norman JE3, Rogers R4, Patel C4, Adams E4, Slater R1

1 Dept of Paediatrics, University of Oxford
2 National Perinatal Epidemiology Unit, University of Oxford
3 MRC Centre for Reproductive Health, The Queen’s Medical Research Institute, Edinburgh
4 Oxford University Hospitals NHS Foundation Trust

Background: Premature infants must repeatedly undergo painful and destabilising procedures such as screening examinations for retinopathy of prematurity (ROP). Pain in these infants however remains undertreated due to a lack of evidence-based analgesics. Morphine is often used for sedation and comfort during ventilation but evidence of its analgesic efficacy is inconclusive in premature infants. We hypothesised that oral morphine could provide effective and safe analgesia in non-ventilated premature infants for acute procedures.

Methods: Infants were randomised to blindly receive 100μg/kg of oral morphine sulphate or placebo 1 hour before a clinically-required heel lance and ROP exam, on a single occasion. Infants were born at <32 weeks’ gestation or weighing <1501g, and were 34-42 weeks at study. Co-primary outcomes were the Premature Infant Pain Profile-Revised (PIPP-R) score after ROP exam and the magnitude of noxious-evoked brain activity after heel lancing. Physiological stability and safety were secondary outcomes. The trial was registered (ECT: 2014- 003237-25) and approved by MHRA and Northampton REC (15/EM/0310). The planned sample size was 156.

Results: 15 infants were randomised to receive morphine and 16 placebo. One infant allocated to receive placebo was withdrawn prior to study. In November 2017, the Data Monitoring Committee identified that the pre-defined stopping boundary had been breached; 3/15 (20%) infants who received morphine experienced apnoeas requiring resuscitation with non-invasive positive pressure ventilation in the 24-hours post-administration, compared to 0/15 in the placebo group. Trial recruitment was thereafter stopped following data review, which revealed evidence of profound respiratory adverse effects of morphine without suggestion of analgesic efficacy. Neither of the primary outcomes assessing analgesic efficacy were significantly different between the groups (PIPP-R following ROP screening: morphine: PIPP-R mean±SD =11.1±3.2; placebo: PIPP-R=10.5±3.4; mean difference 0.5, 95% CI:-2.0-3.0, p=0.66; noxious-evoked brain activity following heel lancing: morphine: median (IQR) 0.99 (0.40-1.56); placebo: 0.75 (0.33-1.22); median difference 0.25, 95% CI:-0.16-0.80, p=0.25).

Conclusion: Oral morphine (100μg/kg) administered to non-ventilated premature infants has the potential to cause significant cardiorespiratory adverse effects without suggestion of benefit. We cannot recommend its use for ROP screening and advise caution if considering its use for other acute painful procedures in this population.

Corresponding author:

Acknowledgements: The trial was funded by the Wellcome Trust and National Institute for Health Research. Miranda Buckle, Marianne van der Vaart, Deniz Gursul and Sezgi Goksan assisted with data collection.

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