Use of morphine before retinopathy of prematurity examinations
Authors: Marsha Campbell-Yeo, Britney Benoit
Journal: The Lancet (2018)

Understanding optimum ways to reduce pain and stress associated with medical procedures in paediatric populations reflects health-care providers' inherent mandate to do no harm. This is especially urgent in vulnerable preterm populations who undergo an average of 12 painful procedures daily while receiving neonatal care,1Cruz MD Fernandes AM Oliveira CR Epidemiology of painful procedures performed in neonates: a systematic review of observational studies.Eur J Pain. 2016; 20: 489-498Crossref PubMed Scopus (181) Google Scholar given our increasing understanding of the adverse effects of early pain exposure on later neurodevelopment and behaviour.2Grunau RE Holsti L Peters JWB Long-term consequences of pain in human neonates.Semin Fetal Neonatal Med. 2006; 11: 268-275Summary Full Text Full Text PDF PubMed Scopus (325) Google Scholar Several interventions—such as breastfeeding,3Benoit B Martin-Misener R Latimer M Campbell-Yeo M Breast-feeding analgesia in infants.J Perinat Neonatal Nurs. 2017; 31: 145-159Crossref PubMed Scopus (56) Google Scholar parent–infant skin-to-skin contact,4Johnston C Campbell-Yeo M Disher T et al.Skin-to-skin care for procedural pain in neonates.Cochrane Database Syst Rev. 2017; 2 (CD008435.)PubMed Google Scholar and sweet-tasting solutions5Stevens B Yamada J Ohlsson A Haliburton S Shorkey A Sucrose for analgesia in newborn infants undergoing painful procedures.Cochrane Database Syst Rev. 2016; 7 (CD001069.)PubMed Google Scholar—have been shown to reduce biobehavioural pain response associated with needle-related procedures. However, similar intervention efficacy to reduce the moderate-to-severe pain associated with commonly performed eye examinations to diagnose retinopathy of prematurity has not been reported.6Disher T Cameron C Mitra S Cathcart K Campbell-Yeo M Pain-relieving interventions for retinopathy of prematurity: a meta-analysis.Pediatrics. 2018; 142: e20180401Crossref PubMed Scopus (30) Google Scholar Considering this gap in neonatal pain care, Caroline Hartley and colleagues report in The Lancet the findings of their single-centre, masked, randomised, placebo-controlled clinical trial,7Hartley C Moultrie F Hoskin A et al.Analgesic efficacy and safety of morphine in the Procedural Pain in Premature Infants (Poppi) study: randomised placebo-controlled trial.Lancet. 2018; (published online Nov 30.)http://dx.doi.org/10.1016/S0140-6736(18)31813-0Summary Full Text Full Text PDF Scopus (54) Google Scholar in which they examined the analgesic effectiveness of 100 μg/kg of oral morphine sulfate compared with placebo in non-ventilated, stable, preterm neonates (born <32 weeks' gestation or with a birthweight of <1501 g) to reduce acute procedural pain after heel lance and consecutive retinopathy of prematurity eye examination. The trial is particularly novel in that the authors measured multimodal pain responses, including biobehavioural pain scores, noxious-evoked brain activity, and reflex withdrawal. Episodes of oxygen desaturation, bradycardia, tachycardia, apnoea, and requirement for increased respiratory support during the 6 h and 24 h after the procedure were also monitored. Hartley and colleagues required a sample size of 132 neonates to detect a clinically meaningful reduction in the coprimary outcomes of Premature Infant Pain Profile-Revised (PIPP-R) score (2 point difference on the scale) after retinopathy of prematurity screening and 40% reduction in noxious-evoked brain activity after heel lancing. A final sample of 156 infants was proposed to allow for multiple births and 10% loss to follow-up. As per the a priori stopping boundary, the Data Monitoring Committee recommended that the trial be stopped after enrolment of 31 neonates. An appreciable increase was noted in the number of apnoea episodes, and a significant increase was seen in required respiratory support at 6 h and 24 h after morphine exposure. The authors reported no difference between groups in PIPP-R scores after retinopathy of prematurity eye examination (with morphine, mean 11·1 [SD 3·2]; with placebo, 10·5 [3·4]; mean difference 0·5, 95% CI −2·0 to 3·0; p=0·66). The magnitude of noxious-evoked brain activity after heel lancing also did not differ between groups (with morphine, 0·99 [IQR 0·40–1·56]; with placebo, 0·75 [0·33 to 1·22]; median difference 0·25, 95% CI −0·16 to 0·80; p=0·25). This Article has several strengths. Most notably, the study aim addresses a highly relevant clinical concern, and the findings are consistent with previous work reporting that retinopathy of prematurity eye examinations are associated with moderate-to-severe pain responses in preterm neonates.6Disher T Cameron C Mitra S Cathcart K Campbell-Yeo M Pain-relieving interventions for retinopathy of prematurity: a meta-analysis.Pediatrics. 2018; 142: e20180401Crossref PubMed Scopus (30) Google Scholar While not novel, safety concerns and recommendations for cautious administration and close monitoring are consistent with previous work using morphine for procedural pain treatment in non-ventilated preterm neonates8Taddio A Crosdale B Hogan ME et al.Safety of morphine in nonintubated infants in the neonatal intensive care unit.Clin J Pain. 2009; 25: 418-422Crossref PubMed Scopus (16) Google Scholar and practice guidelines.9American Academy of Pediatrics Committee on Fetus and Newborn and Section on Anesthesiology and Pain MedicinePrevention and management of procedural pain in the neonate: an update.Pediatrics. 2016; 137: e20154271Crossref PubMed Scopus (86) Google Scholar The study also has methodological limitations that should be noted. Although Hartley and colleagues acknowledge their study was significantly underpowered because of early cessation, they interpret a trend towards greater noxious-evoked brain activity in morphine-treated neonates, compared with those who received placebo, as a suggestion of no analgesic effect—a finding that is more likely attributable to type II error in view of the small sample size. In an underpowered trial, this trend and suggestion should not be interpreted as analgesic ineffectiveness. Despite these concerns, Hartley and colleagues are not the first to question the analgesic adequacy of morphine for procedural pain in preterm neonates, with previous work10Carbajal R Lenclen R Jugie M Paupe A Barton BA Anand KJ Morphine does not provide adequate analgesia for acute procedural pain among preterm neonates.Pediatrics. 2005; 115: 1494-1500Crossref PubMed Scopus (203) Google Scholar reporting no difference in biobehavioural pain scores after heel lance in ventilated preterm neonates receiving a 100 μg/kg intravenous loading dose of morphine compared with placebo. Several clinical considerations should also be noted when interpreting the results of this study. It is unusual in a clinical neonatal setting for painful procedures to be clustered so closely together, as was done in Hartley and colleagues' study, in view of previous findings11Holsti L Grunau RE Oberlander TF Whitfield MF Prior pain induces heightened motor responses during clustered care in preterm infants in the NICU.Early Hum Dev. 2005; 81: 293-302Crossref PubMed Scopus (90) Google Scholar showing previous pain increased biobehavioural reactivity (physiological and facial pain responses, and body movements) in preterm infants during subsequent tactile procedures. Additionally, neonates who received placebo in this study received only swaddling during the heel lance as non-pharmacological pain management. However, recommendations for the ethical conduct of studies examining needle-related pain advise that all neonates should receive an optimum pain-relieving intervention,12Bellieni CV Johnston CC Analgesia, nil or placebo to babies, in trials that test new analgesic treatments for procedural pain.Acta Paediatr. 2016; 105: 129-136Crossref PubMed Scopus (26) Google Scholar, 13Campbell-Yeo M “First, do no harm”: the use of analgesia or placebo as control for babies in painful clinical trials.Acta Paediatr. 2016; 105: 119-120Crossref PubMed Scopus (6) Google Scholar such as breastfeeding,3Benoit B Martin-Misener R Latimer M Campbell-Yeo M Breast-feeding analgesia in infants.J Perinat Neonatal Nurs. 2017; 31: 145-159Crossref PubMed Scopus (56) Google Scholar skin-to-skin contact,4Johnston C Campbell-Yeo M Disher T et al.Skin-to-skin care for procedural pain in neonates.Cochrane Database Syst Rev. 2017; 2 (CD008435.)PubMed Google Scholar or sweet-tasting solutions5Stevens B Yamada J Ohlsson A Haliburton S Shorkey A Sucrose for analgesia in newborn infants undergoing painful procedures.Cochrane Database Syst Rev. 2016; 7 (CD001069.)PubMed Google Scholar to reduce potential for associated adverse effects of untreated pain. Undoubtedly, Hartley and colleagues' work highlights the urgent need to identify optimum ways to reduce pain associated with retinopathy of prematurity examinations in highly vulnerable preterm neonates and supports existing knowledge regarding the need for close surveillance while receiving oral morphine. Further, it prompts investigation into the efficacy and dosing of morphine and other pharmacological and non-pharmacological treatments for procedure-related pain in this population. We declare no competing interests. Analgesic efficacy and safety of morphine in the Procedural Pain in Premature Infants (Poppi) study: randomised placebo-controlled trialAdministration 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. Full-Text PDF Open AccessA universal right to pain relief: balancing the risks in a vulnerable patient populationWorldwide, 15 million premature infants are born every year, according to a WHO report . With mortality risks reduced, neonatal research is focusing on improving quality of life and preventing long-term adverse outcomes in surviving preterm infants. Most of these infants require frequent essential painful procedures, and there is often an unspoken acceptance that this iatrogenic pain is unavoidable. Perhaps the discomfort of painful procedures is assumed to be fleeting and inconsequential; after all, many adults are familiar with the momentary pain of blood tests, and for most of us these events do not affect our wellbeing. Full-Text PDF