Impaired Neurodevelopmental Outcomes in Very Preterm Infants: Much Too Easy to Blame It Just on Morphine!

Abstract

See related article, p 81Very preterm infants are very sensitive to the deleterious effects of pain and stress to which they are frequently exposed during their stay in the neonatal intensive care unit (NICU).1Carbajal R. Rousset A. Danan C. Coquery S. Nolent P. Ducrocq S. et al.Epidemiology and treatment of painful procedures in neonates in intensive care units.JAMA. 2008; 300: 60-70Crossref PubMed Scopus (662) Google Scholar, 2Roofthooft D.W. Simons S.H. Anand K.S. Tibboel D. van Dijk M. Eight years later, are we still hurting newborn infants?.Neonatology. 2014; 105: 218-226Crossref PubMed Scopus (154) Google Scholar Appropriate pain assessment with validated behavioral instruments and optimal pain relief are therefore important goals to achieve in every neonate admitted to a NICU. The ultimate goal is to reach, with the least amount of pharmacotherapy, a situation where the newborn infant is receiving optimal comfort and pain control in the safest way possible. Zwicker et al in this issue of The Journal recommend a search for alternatives for opioids for pain relief in very preterm infants based on their findings.3Zwicker J.G. Miller S.P. Grunau R.E. Chau V. Brant R. Studholme C. et al.Smaller cerebellar growth and poorer neurodevelopmental outcomes in very preterm infants exposed to neonatal morphine.J Pediatr. 2016; 172: 81-87Google Scholar The authors performed serial magnetic resonance imaging near birth and at the term-equivalent age to measure the volume of the cerebellum and cerebrum in 136 out of a cohort of 188 infants born between 24 and 32 weeks of gestation. They found that the volume of the cerebellum correlated with the amount of morphine administered to these infants even after adjusting for many other covariates such as disease severity and exposure to other medications. See related article, p 81 During their stay in the NICU, preterm infants are exposed to 5-15 procedures a day that are painful and/or stressful.1Carbajal R. Rousset A. Danan C. Coquery S. Nolent P. Ducrocq S. et al.Epidemiology and treatment of painful procedures in neonates in intensive care units.JAMA. 2008; 300: 60-70Crossref PubMed Scopus (662) Google Scholar, 2Roofthooft D.W. Simons S.H. Anand K.S. Tibboel D. van Dijk M. Eight years later, are we still hurting newborn infants?.Neonatology. 2014; 105: 218-226Crossref PubMed Scopus (154) Google Scholar These painful and/or stressful exposures are suggested to be associated with cerebral alterations such as smaller frontal and parietal brain widths associated with reduced white matter volume and subcortical gray matter maturation, and abnormal behavior at term equivalent age.4Steinhorn R. McPherson C. Anderson P.J. Neil J. Doyle L.W. Inder T. Neonatal morphine exposure in very preterm infants-cerebral development and outcomes.J Pediatr. 2015; 166: 1200-1207Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar To reduce the consequences of these procedures on brain development, the use of morphine or fentanyl has become common practice in the NICU.5Carbajal R. Eriksson M. Courtois E. Boyle E. Avila-Alvarez A. Andersen R.D. et al.Sedation and analgesia practices in neonatal intensive care units (EUROPAIN): results from a prospective cohort study.Lancet Respir Med. 2015; 3: 796-812Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar However, to complicate matters, the use of these opioids in animals causes changes in both brain structure and behavior.6Seatriz J.V. Hammer Jr., R.P. Effects of opiates on neuronal development in the rat cerebral cortex.Brain Res Bull. 1991; 30: 523-527Crossref Scopus (86) Google Scholar, 7Boasen J.F. McPherson R.J. Hays S.L. Juul S.E. Gleason C.A. Neonatal stress or morphine treatment alters adult mouse conditioned place preference.Neonatology. 2009; 95: 230-239Crossref PubMed Scopus (58) Google Scholar An important question that still remains is if findings primarily in mice and rats can be translated to the preterm human. In a very recent report, data gaps in mouse pharmacokinetics underscore the systematic lack of discussion regarding the rationale behind the dose selection of drugs used in preclinical animal studies.8Kleiman R.J. Ehlers M.D. Data gaps limit the translational potential of preclinical research.Sci Transl Med. 2016; 8: 320-321Crossref Scopus (18) Google Scholar This lack of a drug exposure–response relationship in a specific target organ such as the brain casts doubt on mechanistic interpretations. Furthermore, any changes in the route of administration, species, age or strain of animal, time points under investigation, duration of dosing, or organ targeted for intervention can alter the relation between dose, exposure, and the response.8Kleiman R.J. Ehlers M.D. Data gaps limit the translational potential of preclinical research.Sci Transl Med. 2016; 8: 320-321Crossref Scopus (18) Google Scholar The need for a central repository of information about brain penetration, protein binding, and pharmacokinetic profiles of drugs and pharmacologic tools in rodents to effectively support translational research, together with a much closer collaboration between pharmaceutical industry and academic medical centers was highlighted.9Vallance P. Williams P. Dollery C. The future is much closer collaboration between the pharmaceutical industry and academic medical centers.Clin Pharmacol Ther. 2010; 87: 525-527Crossref PubMed Scopus (21) Google Scholar What about the human neonate? Until now, reports on the neurologic consequences of opioid exposure in the very preterm neonate have been inconclusive. Two large clinical trials investigating continuous morphine administration in preterm infants did not result in short-term neurodevelopmental benefits.10Anand K.J. Hall R.W. Desai N. Shephard B. Bergqvist L.L. Young T.E. et al.Effects of morphine analgesia in ventilated preterm neonates: primary outcomes from the NEOPAIN randomized trial.Lancet. 2004; 363: 1673-1682Abstract Full Text Full Text PDF PubMed Scopus (415) Google Scholar, 11Simons S.H. van Dijk M. van Lingen R.A. Roofthooft D.W. Duivenvoorden H.J. Jongeneel N. et al.Routine morphine infusion in preterm newborns who received ventilator support.JAMA. 2003; 290: 2419-2427Crossref PubMed Scopus (227) Google Scholar At age 5-7 years, the children who were morphine-exposed during their NICU stay had smaller head circumferences and body size, poorer performance on tests of short-term memory, and a higher likelihood of social problems. Major differences in morphine exposure might be blamed for these findings, taking into consideration the fact that dosing in this trial was high and children with the worst outcomes had been exposed to substantially more morphine. Very recently, a large-scale study in very preterm infants exposed to low-dose morphine did not show long-term negative neurobehavioral outcomes.3Zwicker J.G. Miller S.P. Grunau R.E. Chau V. Brant R. Studholme C. et al.Smaller cerebellar growth and poorer neurodevelopmental outcomes in very preterm infants exposed to neonatal morphine.J Pediatr. 2016; 172: 81-87Google Scholar The authors concluded that the greater severity of illness in the newborns who were exposed to morphine rather than the impact of morphine itself could explain their findings. In contrast, the paper of Zwicker et al3Zwicker J.G. Miller S.P. Grunau R.E. Chau V. Brant R. Studholme C. et al.Smaller cerebellar growth and poorer neurodevelopmental outcomes in very preterm infants exposed to neonatal morphine.J Pediatr. 2016; 172: 81-87Google Scholar concluded that exposure to morphine was independently associated with impaired cerebellar growth and poorer neurodevelopmental outcomes in early childhood. Perhaps it is too easy to blame these findings on morphine use alone. The authors indicated limitations of their study such as lack of information on why morphine was administered,3Zwicker J.G. Miller S.P. Grunau R.E. Chau V. Brant R. Studholme C. et al.Smaller cerebellar growth and poorer neurodevelopmental outcomes in very preterm infants exposed to neonatal morphine.J Pediatr. 2016; 172: 81-87Google Scholar a quite crucial piece of information because the use of morphine in preterm infants in the presence of pain is probably a good thing, whereas using morphine in the absence of pain is probably not. However, more important is the possible confounding by indication. It is clear in Table I that in the infants exposed to more than 1.905 mg/kg morphine there was also the use of dexamethasone, hydrocortisone, and midazolam, whereas in the infants exposed to less than 1.905 mg/kg, these medications were not co-administered. The higher dose group of infants also had a lower gestational age, lower birth weight, higher Score for Neonatal Acute Physiology, version II, more painful procedures including minor and major surgeries, more hypotension, and a 10-fold increase in days on the ventilator. The patients exposed to more than 1.905 mg/kg were completely different from the patients who were exposed to less than 1.905 mg/kg. It seems at least premature to link impaired neurodevelopmental outcome of these very preterm infants solely to the use of morphine. More sick infants will receive more morphine on clinical grounds and these infants will also, due to their underlying amount of illness, have an increased risk of having an impaired neurodevelopmental outcome. Taken together, it seems that translation of findings in mice and rats to the human preterm infant is fraught with unsurpassable problems. Lack of pharmacokinetics in small rodents, lack of mechanistic understanding, and lack of ability to translate knowledge from rodent to human are a few of the reasons why we are still struggling with finding the optimal management of pain in preterm infants. It seems that low-dose morphine use in the NICU is not associated with any long-term negative effects if used in a situation where pain relief is indicated. To blame adverse neurodevelopmental outcomes in preterm infants solely on morphine is not appropriate based on the existing animal and human literature. Crucial is and will be the link between the patient and his or her need to receive adequate treatment to relief pain and stress in the safest way possible. We need to continue to search for the most effective and safe analgesic to use in preterm infants, taking into consideration optimal efficacy with minimal toxicity. Several studies are currently being conducted and hopefully will provide us with a safer and more effective way to treat our preterm infants well. Smaller Cerebellar Growth and Poorer Neurodevelopmental Outcomes in Very Preterm Infants Exposed to Neonatal MorphineThe Journal of PediatricsVol. 172PreviewTo examine the relationship between morphine exposure and growth of the cerebellum and cerebrum in very preterm neonates from early in life to term-equivalent age, as well as to examine morphine exposure and brain volumes in relation to neurodevelopmental outcomes at 18 months corrected age (CA). Full-Text PDF