Analgesic efficacy and safety of morphine in the Procedural Pain in Premature Infants (Poppi) study: randomised placebo-controlled trial

Abstract

Background: Infant pain has immediate and long-term effects but is undertreated because of a paucity of evidence-based analgesics. Although morphine is often used to sedate ventilated infants, its analgesic efficacy is unclear. We aimed to establish whether oral morphine could provide effective and safe analgesia in non-ventilated premature infants for acute procedural pain.

Methods: In this single-centre masked trial, 31 infants at the John Radcliffe Hospital, Oxford, UK, were randomly allocated using a web-based facility with a minimisation algorithm to either 100 μg/kg oral morphine sulphate or placebo 1 h before a clinically required heel lance and retinopathy of prematurity screening examination, on the same occasion. Eligible infants were born prematurely at less than 32 weeks' gestation or with a birthweight lower than 1501 g and had a gestational age of 34-42 weeks at the time of the study. The co-primary outcome measures were the Premature Infant Pain Profile-Revised (PIPP-R) score after retinopathy of prematurity screening and the magnitude of noxious-evoked brain activity after heel lancing. Secondary outcome measures assessed physiological stability and safety. This trial is registered with the European Clinical Trials Database (number 2014-003237-25).

Findings: Between Oct 30, 2016, and Nov 17, 2017, 15 infants were randomly allocated to morphine and 16 to placebo; one infant assigned placebo was withdrawn from the study before monitoring began. The predefined stopping boundary was crossed, and trial recruitment stopped because of profound respiratory adverse effects of morphine without suggestion of analgesic efficacy. None of the co-primary outcome measures differed significantly between groups. PIPP-R score after retinopathy of prematurity screening was mean 11·1 (SD 3·2) with morphine and 10·5 (3·4) with placebo (mean difference 0·5, 95% CI -2·0 to 3·0; p=0·66). Noxious-evoked brain activity after heel lancing was median 0·99 (IQR 0·40-1·56) with morphine and 0·75 (0·33-1·22) with placebo (median difference 0·25, 95% CI -0·16 to 0·80; p=0·25).

Interpretation: Administration of oral morphine (100 μg/kg) to non-ventilated premature infants has the potential for harm without analgesic efficacy. We do not recommend oral morphine for retinopathy of prematurity screening and strongly advise caution if considering its use for other acute painful procedures in non-ventilated premature infants.

Funding: Wellcome Trust and National Institute for Health Research.

Figure 1

Trial profile EEG=electroencephalography. EMG=electromyography. PIPP-R=Premature Infant Pain Profile–Revised. ROP=retinopathy of prematurity. *One excluded because of artifact.

Figure 2

Example of data recorded in an infant assigned morphine 48 h records of heart rate, oxygen saturation, and mean blood pressure every 6 h are shown for the 24 h periods before and after the clinical procedure. Episodes of tachycardia, bradycardia, oxygen desaturation, and apnoea are identified (red vertical lines). The reflex withdrawal activity, EEG activity, and change in heart rate and oxygen saturation are shown in the 10 s before and after the heel lance. The noxious-evoked brain activity template is projected onto the EEG trace (overlaid in red). The time of drug administration is indicated by the green vertical line (approximately 1 h before the clinical procedure). This infant was chosen as a representative example because he had all clinical stability events (tachycardia, bradycardia, oxygen desaturation, and apnoea) and had clear changes in reflex withdrawal, brain activity, and physiology to the heel lance. Traces of noxious-evoked brain activity to the heel lance and 48 h physiological traces for all individual infants are in the appendix. bpm=beats per min. EEG=electroencephalogram.

Figure 3

Co-primary and secondary outcome measures of analgesic efficacy Co-primary outcomes are shown in (A) and (B). (A) Mean (SE) PIPP-R scores after ROP screening. (B) Median (SE) magnitude of noxious-evoked brain activity after heel lance. The (Woody) filtered EEG is shown overlaid with the template of noxious-evoked brain activity (in red). Secondary outcomes are shown in (C) and (D). (C) Mean (SE) PIPP-R score after heel lance. (D) Median (SE) magnitude of reflex withdrawal activity after heel lance. Magnitude is quantified using RMS in 250 ms windows. EEG=electroencephalogram. EMG=electromyography. PIPP-R=Premature Infant Pain Profile-Revised. RMS=root-mean-square. ROP=retinopathy of prematurity.

Figure 4

Assessments of physiological stability (A) Median (SE) of the standardised difference in number of episodes of desaturation in the 6 h period after the clinical procedure compared with the 6 h period before. (B) Median (SE) of the standardised difference in number of episodes of desaturation in the 24 h period after the clinical procedure compared with the 24 h period before. (C) Median (SE) of the standardised difference in number of episodes of bradycardia in the 6 h period after the clinical procedure compared with the 6 h period before. (D) Median (SE) of the standardised difference in number of episodes of bradycardia in the 24 h period after the clinical procedure compared with the 24 h period before. (E) Mean (SE) heart rate during the 48 h monitoring period. (F) Mean (SE) respiratory rate during the 48 h monitoring period. (G) Mean (SE) oxygen saturation during the 48 h monitoring period. (E–G) Individual infant traces are baseline-corrected to the average baseline across all infants. Time zero is the point of the clinical procedure. Black vertical dashed line indicates the time of administration of morphine or placebo. Grey boxes indicate periods during which the treatment groups differed significantly. *p=0·0007. †p=0·019.