http://informahealthcare.com/jmf ISSN: 1476-7058 (print), 1476-4954 (electronic) J Matern Fetal Neonatal Med, 2015; 28(2): 222–228 ! 2014 Informa UK Ltd. DOI: 10.3109/14767058.2014.908178
REVIEW ARTICLE
Neonatal morphine in extremely and very preterm neonates: its effect on the developing brain – a review Juliette Schuurmans, Manon Benders, Petra Lemmers, and Frank van Bel J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by Mcgill University on 02/07/15 For personal use only.
Department of Neonatology, University Medical Center, Utrecht, The Netherlands
Abstract
Keywords
Objective: Preterm infants requiring intensive care experience a large number of stressful and painful procedures. Management of stress and pain is therefore an important issue. This review provides an overview of the research on the use of morphine and its neurodevelopmental effects on this vulnerable group of neonates. Methods: A structural literature search of both experimental and clinical data has been done using an electronic database (PubMed), but also relevant reference lists and related articles were used. Results: A total of 39 sources were considered relevant for this review to elucidate the effects of morphine on the developing brain. The results showed that both animal experimental and clinical data displayed conflicting results on the effects of neonatal morphine on neurodevelopmental outcome. However, in contrast to specific short-term neurological outcomes long-term neurodevelopmental outcome does not seem to be adversely affected by morphine. Conclusion: After a careful review of the literature, no definite conclusions concerning the effects of neonatal morphine on the long-term neurodevelopmental outcome in extremely premature neonates can be drawn. More prospectively designed trials should be conducted using reliable and validated pain assessment scores to evaluate effects of morphine on long-term neurodevelopmental outcome to demonstrate a beneficial or adverse effect of morphine in preterm infants.
Extremely and very preterm neonates, long-term neurodevelopmental outcome, morphine
Introduction Preterm neonates have a functioning system to react to stress and pain, and mount an endocrine, behavioral [1] and cortical response [2]. The stress response can be reduced by administration of opioid analgesics [3], from which morphine is used most. Infants admitted to the neonatal intensive care unit (NICU) will often experience stress, which is supported by the notion that they also mount a hormonal and physiological stress response that can be reduced by morphine [4]. However, even though preterm infants are able to perceive pain, their response to pain is still immature and diffuse and less localized than in adults [5]. Untreated neonatal stress or pain has many adverse effects, such as impaired brain development [6], altered pain perception at later age [7], and poorer cognition and motor function as compared to infants born full-term [8]. Infants admitted at the NICU experience many painful procedures per day (one study reporting a mean of 10 per day [9]). Mechanically ventilated Address for correspondence: Frank van Bel, MD, PhD, Department of Neonatology, University Medical Center/Wilhelmina Children’s Hospital, KE 04.123.1, Lundlaan 6, 3584 EA, Utrecht, The Netherlands. Tel: +31887554545. Fax: +3188755321. E-mail: [email protected]
History Received 10 December 2013 Revised 25 February 2014 Accepted 21 March 2014 Published online 29 April 2014
preterm infants are experiencing stress and often fight against the ventilator leading to asynchronous ventilation resulting in suboptimal oxygenation. Therefore, continuous infusion of morphine to maintain ventilated infants in a sedative state is a common clinical practice in most NICUs [10]. As evaluated in several randomized controlled trials, information about the effectiveness and short- and longterm safety of morphine in neonates remains scarce. It has been suggested that morphine use in the human neonate has lasting neurodevelopmental adverse effects. Because preterm neonates have an immature brain, they are thought to be more vulnerable to morphine treatment, which may potentially affect their neurodevelopmental outcome [10]. Moreover, some studies performed in rodents have reported that morphine can play a modifying role in neurodevelopmental processes such as maturation and proliferation of important regions in the brain [11–14], which could result in long-term sequelae [15]. This review provides an overview of the research on the use of morphine and its neurodevelopmental effects in preterm neonates admitted to the NICU, with a special focus on very and extremely preterm infants. Both experimental and clinical data will be reviewed. Also, the effects on short- and long-term neurodevelopmental outcome of morphine treatment will be discussed followed by an
DOI: 10.3109/14767058.2014.908178
evaluation of the effectiveness of morphine to reduce stress or pain.
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Methods A literature search was performed in electronic databases such as Pubmed for keywords including ‘‘extremely premature neonate’’, ‘‘morphine’’, ‘‘continuous morphine infusion’’, ‘‘NICU’’ and ‘‘neurodevelopmental outcome’’. We limited the search for papers published until December 2013. Publications concerning the effects of morphine in neonates after maternal use were excluded. Relevant manuscripts were selected through the search as well as from reference lists from the relevant publications. Manuscripts concerning both experimental and clinical data on the long- and short-term neurological outcome were included. A total of 39 sources were selected for this review to elucidate the effects of neonatal morphine on neurodevelopment. The effects of morphine on the brain Morphine is the most well-known opioid analgesic. There are three opioid receptors, m, d and k. The m-opioid receptor is thought to be responsible for most of the analgesic effects. Morphine acts as a pure agonist of the m-opioid receptor. This receptor is distributed throughout the brain, dorsal root ganglia and in the peripheral nervous system. In the adult brain, m-opioid receptors are predominantly located in the peri-aquaductal gray area, hypothalamus, nucleus raphe magnus and in the limbic system where activation produces euphoria [16]. The molecular mechanism of morphine consists of the activation of a G-protein coupled receptor (GPCR) that signals through cyclic AMP (cAMP). cAMP levels decrease when morphine binds to the m-receptor. Upon activation of the GPCR by morphine, calcium influx decreases resulting in a lower pre-synaptic neurotransmitter release. Furthermore, due to promotion of potassium efflux, post-synaptic neurons are hyperpolarized leading to a decrease in transmission of neurotransmitters. In this manner, ascending neuronal pain pathways are inhibited and the perception and response to pain is changed [16]. Morphine is mainly metabolized by glucuronidation in the liver producing two active metabolites. These metabolites are morphine-3-glucuronide, which has antagonistic m-opioid activity, and morphine-6-glucuronide, which has a more potent agonistic analgesic activity than morphine itself. Apart from its analgesic ability, morphine produces adverse effects such as sedation, respiratory depression, nausea, vomiting and constipation. Besides these specific side effects, morphine can lead to development of tolerance, dependence and withdrawal [16]. It has been suggested that in premature neonates, due to different pharmacokinetics, tolerance develops more quickly than in babies born term. Both adequate weaning, environmental factors such as a reduction in noise at the NICU, and pharmacotherapeutic options (including clonidine) can be used to prevent opioid withdrawal symptoms [17]. The pharmacokinetic properties of morphine are different in preterm babies compared to full-term infants or adults. Both glucuronidation of morphine and morphine clearance are significantly related to gestational age and birth weight [18].
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Pharmacokinetic and pharmacodynamics modeling is important in clinical practice in order to establish the correct doses and dose adjustments for individual patients [19]. Clearance rates for morphine in preterm neonates can be predicted by several models [19]. In the next section, we will focus on the effects of morphine on the immature brain. The effects of morphine on the immature brain Experimental evidence of effects of morphine on the immature brain As mentioned before, opioids play a significant role in important neurodevelopmental processes [11,12]. In rodents, the brain spurt takes place from the second to fourth postnatal weeks. This makes it a convenient experimental model to study early neurodevelopment. Special protocols for rodents have been developed which simulate the stressful experiences that preterm infants encounter when admitted to a neonatal intensive care unit [15]. In a mouse model that studies the effect of morphine and stress on adult learning, both factors can affect neurodevelopment in such a way that adult place preference learning was impaired. However, when the two effects of neonatal morphine and stress are combined they can balance out into what seems to be normal learning. Neonatal treatment with morphine did not seem to disrupt adult behavior or anxiety [15]. In a similar model in rats, however, early treatment with morphine seemed to change the stress response in adults in such a way that learning was impaired regardless of the presence or absence of neonatal stress. Several specific effects of morphine on neurogenesis have been studied in various brain areas in rodents. For normal synaptogenesis and differentiation to occur during the brain growth spurt, neuronal activity is important. Since morphine interferes with neurotransmitter release as was mentioned above, this could potentially affect the developing brain. A mechanism that has been proposed to account for neuronal damage by general anesthetic agents is the blockage of excitatory NMDA receptors and activation of inhibitory GABA receptors in the immature brain [20]. The role of morphine on excitatory/inhibitory neurotoxicity in the developing brain is not entirely clear. To elucidate whether morphine also predisposes to neurotoxicity, a study by Massa et al. [11], investigated the effect of morphine during the brain growth spurt in the rat cerebral cortex at PD7-15 and PD15-20. Their results indicated that morphine did neither lead to changes in dendritic arborization, spinogenesis of dendrites in the rat, nor result in apoptosis in a specific area in the pre-frontal cortex [11]. However, in a neonatal rodent model of chronic morphine exposure associated with morphine dependence and anti-nociceptive tolerance, it was demonstrated that repeated injections of morphine on PD 1–7, so representing earlier stages of development, were able to induce apoptosis in the cortex and amygdala, but not in other areas. The proposed mechanism of morphine-induced apoptosis is not yet clear [14]. Furthermore, a combination of severe pain or mild repetitive pain and pre-emptive morphine in rat pups showed a protective effect of morphine on neuro-degeneration in terms of apoptosis only at specific times of
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neurodevelopment. Morphine reduced the number of apoptotic cells in rats experiencing severe pain and in rats experiencing repetitive mild pain, but at three and five days, respectively, after start of the experiments [21]. On molecular level, hippocampal gene expression is influenced by both stress and morphine treatment in rodents [22]. In the absence of pain or stress, morphine has adverse neurodevelopmental effects on the rat brain by delaying maturation of the hippocampus [12]. In mice, stress, depending on the severity, changes gene expression involved in the stress response and immune reaction. Morphine was able to reduce these effects for some genes, but not for others. The effect of both stress and morphine on hippocampal gene expression; and therefore, neurodevelopmental outcome can be hard to predict [22]. Thus, even though it is very clear that early stress results in adverse neurodevelopmental effects and that morphine can affect brain development, the effects of morphine treatment in stressful situations simulating neonatal intensive care, in (rodent) animal models show interesting, but variable results. Moreover, extrapolation from animal to human data is not straight forward. Short-term clinical effects of morphine in preterm infants Although several short-term adverse effects of morphine are well-known in the adult, such as respiratory depression, hypotension, constipation and tolerance, dependence and withdrawal, this is less clear in preterm neonates. Routine continuous morphine administration in ventilated preterm newborns is not recommended by the authors of a systematic review and meta-analysis in 2010 because not enough scientific evidence could be found for a beneficial effect of morphine treatment [10]. However, given its common clinical use, the question still remains to be answered whether morphine treatment leads to adverse events and worsen clinical outcome in case its use is clinically needed. Short-term neurological outcome has been investigated by assessing the incidence of peri-intraventricular hemorrhage (PIVH), periventricular leucomalacia (PVL) and neonatal death (death within 28 days) as a composite outcome in neonates born extremely and very preterm (532 weeks) [20,23–25]. The large NEOPAIN trial, which included 893 children, showed no significant overall differences in composite outcome between placebo and morphine-treated infants of very preterm age [24], nor did a study performed by Simons et al. [25], which included children born at all gestational ages. However, an adverse outcome was reported in the NEOPAIN trial in preterm infants of 27-to-29 weeks, who were treated with a high dose of morphine (loading dose of 100 mg/kg, followed by continuous infusion with 20 mg/kg/h) [24]. Additionally, neonates in the placebo group who received open label morphine showed a significant increase in neonatal mortality, severe PIVH and PVL. The incidence of PIVH after morphine treatment has been found to be lower in the study by Simons et al. [25] as compared to the non-morphine-treated counterparts. In this randomized controlled trial, lower dosing regimens were used (infusions of 10 mg/kg for all age groups), as well as a shorter duration of the treatment period of only seven days. This lower
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incidence of PIVH was also reported in a pilot study by Anand et al. [23]. It has been hypothesized that morphine-related hypotension might influence the incidence of PIVH [23]. In preterm neonates, morphine administration does not lead clinically to hemodynamic instability indicated by arterial blood pressure and determination of blood pressure variability [23,26]. Both continuous morphine administration [23,26] as well as bolus administration of morphine [26] have been associated with brief periods of hypotension in previously normotensive neonates. These periods of hypotension, however, did not appear to be clinically relevant. If hypotension was already present before onset of the study medication, morphine treatment has been shown to lead to adverse neurological outcome [24]. It seems, therefore, that the results concerning the incidence of PIVH’s are in disagreement. Furthermore, continuous morphine administration appeared to have neither adverse nor beneficial effect on short-term neurological outcome if used in a low dose. Additional research should be performed to study the effect of bolus administration on short-term neurological outcome, since an increase in adverse neurological events has been reported [24]. Anand et al. [23], assessed short-term neurodevelopmental outcome by means of the Neurobehavioural Assessment of the Premature Infant (NAPI) [27] score, which is used to observe the developmental progress of preterm infants between 32 weeks of gestational age and term. However, no difference could be found between morphine- and placebotreated patients [23]. Both the NEOPAIN study, as well as the study performed by Simons et al., assessed the effect of morphine to reduce neonatal pain measured by various pain scores. Overall reduction of pain by the Premature Infant Pain Profile in a meta-analysis did not show any significant difference between morphine and placebo [10], although PIPP showed a significant reduction in pain during endotracheal tube suctioning at 24 h of morphine infusion, in the NEOPAIN study [24]. Simons et al. [25] assessed neonatal pain with the NIPS [28] and PIPP [29], and these scores did not reduce when morphine was used. Open label morphine was needed in both studies to reduce pain on the basis of clinical judgment. Given the above-mentioned conflicting results when using different pain assessment scores, further research seems warranted in order to provide a method to detect whether or not the preterm neonate suffers from pain and, if so, to provide adequate analgesia. To achieve this goal the use of near infrared spectroscopy (NIRS) may be of help here. It has been shown that neonates are able to perceive pain at a cortical level using this technique [2]. NIRS can provide additional value in combination with other brain monitoring devices in relation to neurological outcome in infants [30]. A well designed study with this bedside technique may help us to achieve appropriate pain management in this vulnerable patient group. Several other existing methods that are routinely used at the NICU to relieve procedural stress and/ or pain in neonates admitted to the NICU is the use of oral glucose or sucrose, developmental support care, breastfeeding and skin-to-skin care. These measures have been investigated in systematic reviews and meta-analyses [31–33]. It was shown that both sucrose and breast milk are effective at
DOI: 10.3109/14767058.2014.908178
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reducing several parameters of pain (such as duration of crying time, heart rate) during single painful events such as heel lances. However, more research is needed in extremely premature neonates who are mechanically ventilated since there are only very few data of the effects in this patient group as well as on the long-term neurodevelopmental effects. A non-pharmacological method that has been specifically investigated low birth weight infants admitted to the NICU is developmental care, which includes a range of (environmental) factors to reduce stress in the NICU. Overall, based on the meta-analysis, limited benefit was shown of developmental care on clinical outcome of these infants. However, more research is needed in this area with consistent results before definite conclusions can be drawn [33]. Long-term effects of morphine on neurodevelopmental outcome Only limited research has been performed on the long-term neurodevelopmental outcome of extremely and very prematurely-born infants who were treated with morphine, while being ventilated mechanically. No prospective randomized controlled trials have been conducted specifically aiming to investigate long-term neurodevelopmental outcome. Similar to the short-term studies, the available information on the long-term effects of morphine generally do not show any definite effects on neurodevelopmental outcome. Although prematurely born children have a higher chance of death and disability as well as cognitive, behavioral and attention problems than children born at term [34], morphine treatment in this vulnerable patient group does not seem to be related to overall IQ and motor function at later age [8,35–38]. Still, some specific issues deserve attention: MacGregor et al. [36], showed no significant differences in intelligence score, motor assessment or behavior at 5 years of age, but all three measurements showed a trend towards a better neurodevelopmental outcome in the group of children treated with morphine compared to children treated with pancuronium or a 5% dextrose solution. However, no information has been presented on morphine use after the original study period of maximum 14 days of treatment, which makes it difficult to interpret these study results. In contrast to the above-mentioned study by MacGregor et al. [36], results concerning the long-term effects of morphine use over the first 28 days of life have been recently published by de Graaf et al. [35]. This follow-up study at five years of age included, apart from intelligence, behavior and motor abilities, a checklist for chronic pain and health-related quality of life which was completed by the parents. The authors report a trend towards a more negative outcome in the morphine-treated patients. Only a specific part of the intelligence test, the visual analysis, displayed a significantly worse outcome after morphine treatment after correction with a propensity score. Also open label morphine use has been taken into account in this study. It appeared that intelligence, motor and behavioral scores were not associated with morphine treatment in the neonatal period after adjustment with a propensity score accounting for clinically relevant confounding variables [35]. Recently, the latest follow-up
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results of this trial have been published [38]. Children were tested at the age of eight or nine years on general functioning (IQ, visual motor integration, behavior) and executive functions. The authors conclude that at this age there are no significant adverse consequences of neonatal morphine treatment in terms of intelligence, visual motor integration behavior or executive functions. On the contrary, a positive effect of morphine on daily life executive functions was found [38]. Another study to be mentioned is the French EPIPAGE study. This is a prospective cohort study consisting of children born very prematurely (22–32 weeks of gestation) which evaluated long-term neurodevelopmental outcome at 5 years of age in nine regions in France [37]. These children were treated according to clinical protocols and not on the basis of randomization. The cohort includes a large number of children: one-third of all births in France in 1997. The results showed no association between prolonged sedation/analgesia and disability or death after five years when adjusted with a propensity score. An important shortcoming of the study, however, is that there is no differentiation in medications. Therefore, no specific effect of morphine can be elucidated from these results. Furthermore, the power of this study to predict neurodevelopmental outcome was very low, since sedation/analgesia appeared to be a rare event in this cohort [37]. A small number of children (morphine: n ¼ 14; placebo: n ¼ 5) who participated in the NEOPAIN trial were examined for long-term neurodevelopmental outcome and assessed for behavior, intelligence and operant tests at five to seven years of age [39]. No significant differences in IQ score or in behavior assessment were found, although it seemed that more children from the morphine-treated group experienced social problems. Overall, the study results indicate no beneficial or adverse effect of morphine in general, but the small size of the study precludes that definitive conclusions can be drawn here. Finally, Grunau et al. [8] found that morphine exposure was related to poorer motor function at eight months of corrected chronological age, but not to cognitive development. Considering all above-mentioned results together, it can be concluded that morphine does not seem to have a negative effect on neurodevelopmental outcome. None of these studies were prospectively designed to investigate the long-term neurodevelopmental outcome, thus, the power of these studies to show a more specific effect of morphine on neurodevelopment was too low. Also, selection bias and loss to follow up could play a key role in the evaluation of the results, since most studies used a smaller subset from the original population. Furthermore, since the original trials used different protocols in terms of dosing regimens of morphine as well as in duration of treatment, it is difficult to compare the longterm outcome results. Also, the tools to assess cognitive, motor function and behavior at later age are not always comparable. Table 1 provides schematically the details of the studies discussed above. In summary, there is a need for a more standardized approach to study long-term neurological outcome after morphine treatment in the neonatal period. More prospectively designed randomized controlled trials, which include
87
1572
137
90
19
89
MacGregor et al. [36]
Roze et al. [37]
Grunau et al. [8]
de Graaf et al. [35]
Ferguson et al. [39]
de Graaf et al. [38]
N
Morphine: 31 [28–32] Control: 30 [29–32]
28 [27–29]
30 [27–31]
29.1 ± 2.6
Exposed: 27 [26–29] Non-exposed: 30 [27–31]
29 [27–31]
GA (wk) Median [range] Or Mean ± SD
Retrospective analysis of small subset NEOPAIN Retrospective analysis
14 days
Cumulative first 28 days of life
Loading dose: 100 mg/kg followed by: 23–26 wks: 10 mg/kg/h 27–29 wks: 20 mg/kg/h 30–32 wks: 30 mg/kg/h Loading dose: 100 mg/kg followed by 10 mg/kg/h
Retrospective analysis
Cumulative first 28 days of life
Loading dose: 100 mg/kg followed by 10 mg/kg/h
Prospective birth cohort
Observational
47 days Variable
Retrospective analysis
Type of study
5 days
Duration of study
Daily average mg/kg mean ± SD: 2.7 ± 6.8
No specification of analgesics/sedatives
50–100 mg/kg/h or 25 mg/kg/h
Morphine dosing
Table 1. Long-term neurodevelopmental outcome after neonatal morphine (negative effect ; positive effect +; no effect ±).
8/9 years
5–7 years
5 years
8 and 18 months CCA
5 years
5–6 years
Age at evaluation
Long-term neurodevelopmental outcome
Intelligence ± Visual motor integration ± Behavior ±
Intelligence: ± Motor: ± Behavior: ± Intelligence: ± Motor: ± Behavior: ± 8 months: Motor: Cognitive: ± 18 months: Motor: ± Cognitive: ± Intelligence: ± Visual motor integration: ± Behavior: ± Visual score: Intelligence: ± Motor: ± Behavior: ±
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Executive functions (rated by parents or teachers): + Executive function skills ±
Choice resp. latency task: Social problems: Head circumference:
Pain questionnaire: ± Health Utility Index: ±
Specific effects
226 J. Schuurmans et al. J Matern Fetal Neonatal Med, 2015; 28(2): 222–228
Morphine and the developing brain
DOI: 10.3109/14767058.2014.908178
enough infants to achieve a high enough power to detect small differences in long-term neurodevelopmental outcome are needed in order to be able to safely recommend routine morphine infusion in mechanically ventilated premature neonates.
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Conclusion As was mentioned in the ‘‘Introduction’’ section, pain at neonatal age can have serious consequences in later life [6–8]. Preterm infants who are mechanically ventilated experience stress clinically while struggling against the ventilator. Current clinical practice uses continuous morphine infusion as sedative and analgesic relief for the premature infant; however, routine infusion of morphine is not recommended based on a systematic review and meta-analysis [5]. Especially children born extremely and very prematurely are at risk since they are in an important period of rapid neurodevelopment. Infants admitted at a NICU undergo many painful/stressful procedures during their stay. Since it is also known that these infants are able to perceive this pain, it is important to relieve pain and stress to prevent long-term adverse neurodevelopmental outcome. The relevant articles selected by the literature search show that morphine is known to modulate brain development in experimental animal studies. Conflicting results were reported on morphine as neurotoxic agent during neurodevelopment in rodents [11,14]. A rodent model simulating neonatal intensive care showed that morphine could sometimes balance out long-term effects of pain or stress [15]. Also, hippocampal gene expression was affected differently by morphine in the presence or absence of stress [22]. Studies which looked at the short-term neurological effects of neonatal morphine showed conflicting results. In general, no adverse effect of morphine could be established, but in case of bolus administration, high dosage regimes and in previously present hypotension, incidence of neonatal morbidity/mortality increased. Subsequently, when using a lower dosing scheme, lower incidence of neurological morbidity was found [23–26]. Studies which described the long-term effects of morphine on the neurodevelopment showed no overall adverse or beneficial effects of neonatal morphine administration on motor, cognitive and behavioral measurements at various ages [35–39]. Therefore, also a protective effect of morphine when administered during stress cannot be excluded, because up to nine years of age, these children do not seem to be adversely affected. Still, these results need to be looked at carefully, considering that none of these studies were powered to look at long-term outcome. Furthermore, different pain assessment scores used in the different studies show conflicting results regarding the effectiveness of morphine to reduce stress/pain. In order to be able to evaluate the long-term effects, as well as the effectiveness of morphine in this group of patients, future research should look at validation of reliable pain assessment scores for chronic stress in preterm infants. This could be done by means of techniques such as NIRS, which is a technique used to monitor cerebral oxygen saturation. NIRS can provide additional value in combination
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with other brain monitoring devices in relation to neurological outcome in infants [30]. Furthermore, non-pharmacological treatment options which are known to sometimes relieve short-term procedural stress, such as sucrose could be evaluated for their effectiveness in ventilated premature infants perceiving chronic stress [31]. Ultimately, more prospectively designed trials should be designed to evaluate the effects of morphine on long-term neurodevelopmental outcome in order to demonstrate a definitive beneficial or adverse effect of morphine treatment in premature infants before any safe clinical recommendations can be provided.
Declaration of interest The authors report no declaration of interest.
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30. van Bel F, Lemmers P, Naulaers G. Monitoring neonatal regional cerebral oxygen saturation in clinical practice: value and pitfalls. Neonatology 2008;94:237–44. 31. Stevens B, Yamada J, Lee GY, Ohlsson A. Sucrose for analgesia in newborn infants undergoing painful procedures. Cochrane Database Syst Rev 2013;1:CD001069. 32. Shah PS, Aliwalas L, Shah V. Breastfeeding or breastmilk to alleviate procedural pain in neonates: a systematic review. Breastfeed Med 2007;2:74–82. 33. Symington A, Pinelli J. Developmental care for promoting development and preventing morbidity in preterm infants. Cochrane Database Syst Rev 2006;2:CD001814. 34. Aarnoudse-Moens CS, Weisglas-Kuperus N, van Goudoever JB, Oosterlaan J. Meta-analysis of neurobehavioral outcomes in very preterm and/or very low birth weight children. Pediatrics 2009;124: 717–28. 35. de Graaf J, van Lingen RA, Simons SH, et al. Long-term effects of routine morphine infusion in mechanically ventilated neonates on children’s functioning: five-year follow-up of a randomized controlled trial. Pain 2011;152:1391–7. 36. MacGregor R, Evans D, Sugden D, et al. Outcome at 5–6 years of prematurely born children who received morphine as neonates. Arch Dis Child Fetal Neonatal Ed 1998;79:F40–3. 37. Roze J, Denizot S, Carbajal R, et al. Prolonged sedation and/or analgesia and 5-year. Neurodevelopment outcome in very preterm infants. Arch Pediatr Adolesc Med 2008;162:728–30. 38. de Graaf J, van Lingen RA, Valkenburg AJ, et al. Does neonatal morphine use affect neuropsychological outcomes at 8 to 9 years of age? Pain 2013;154:449–58. 39. Ferguson SA, Ward WL, Paule MG, et al. A pilot study of preemptive morphine analgesia in preterm neonates: effects on head circumference, social behavior, and response latencies in early childhood. Neurotoxicol Teratol 2012;34:47–55.
REVIEW ARTICLE
Neonatal morphine in extremely and very preterm neonates: its effect on the developing brain – a review Juliette Schuurmans, Manon Benders, Petra Lemmers, and Frank van Bel J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by Mcgill University on 02/07/15 For personal use only.
Department of Neonatology, University Medical Center, Utrecht, The Netherlands
Abstract
Keywords
Objective: Preterm infants requiring intensive care experience a large number of stressful and painful procedures. Management of stress and pain is therefore an important issue. This review provides an overview of the research on the use of morphine and its neurodevelopmental effects on this vulnerable group of neonates. Methods: A structural literature search of both experimental and clinical data has been done using an electronic database (PubMed), but also relevant reference lists and related articles were used. Results: A total of 39 sources were considered relevant for this review to elucidate the effects of morphine on the developing brain. The results showed that both animal experimental and clinical data displayed conflicting results on the effects of neonatal morphine on neurodevelopmental outcome. However, in contrast to specific short-term neurological outcomes long-term neurodevelopmental outcome does not seem to be adversely affected by morphine. Conclusion: After a careful review of the literature, no definite conclusions concerning the effects of neonatal morphine on the long-term neurodevelopmental outcome in extremely premature neonates can be drawn. More prospectively designed trials should be conducted using reliable and validated pain assessment scores to evaluate effects of morphine on long-term neurodevelopmental outcome to demonstrate a beneficial or adverse effect of morphine in preterm infants.
Extremely and very preterm neonates, long-term neurodevelopmental outcome, morphine
Introduction Preterm neonates have a functioning system to react to stress and pain, and mount an endocrine, behavioral [1] and cortical response [2]. The stress response can be reduced by administration of opioid analgesics [3], from which morphine is used most. Infants admitted to the neonatal intensive care unit (NICU) will often experience stress, which is supported by the notion that they also mount a hormonal and physiological stress response that can be reduced by morphine [4]. However, even though preterm infants are able to perceive pain, their response to pain is still immature and diffuse and less localized than in adults [5]. Untreated neonatal stress or pain has many adverse effects, such as impaired brain development [6], altered pain perception at later age [7], and poorer cognition and motor function as compared to infants born full-term [8]. Infants admitted at the NICU experience many painful procedures per day (one study reporting a mean of 10 per day [9]). Mechanically ventilated Address for correspondence: Frank van Bel, MD, PhD, Department of Neonatology, University Medical Center/Wilhelmina Children’s Hospital, KE 04.123.1, Lundlaan 6, 3584 EA, Utrecht, The Netherlands. Tel: +31887554545. Fax: +3188755321. E-mail: [email protected]
History Received 10 December 2013 Revised 25 February 2014 Accepted 21 March 2014 Published online 29 April 2014
preterm infants are experiencing stress and often fight against the ventilator leading to asynchronous ventilation resulting in suboptimal oxygenation. Therefore, continuous infusion of morphine to maintain ventilated infants in a sedative state is a common clinical practice in most NICUs [10]. As evaluated in several randomized controlled trials, information about the effectiveness and short- and longterm safety of morphine in neonates remains scarce. It has been suggested that morphine use in the human neonate has lasting neurodevelopmental adverse effects. Because preterm neonates have an immature brain, they are thought to be more vulnerable to morphine treatment, which may potentially affect their neurodevelopmental outcome [10]. Moreover, some studies performed in rodents have reported that morphine can play a modifying role in neurodevelopmental processes such as maturation and proliferation of important regions in the brain [11–14], which could result in long-term sequelae [15]. This review provides an overview of the research on the use of morphine and its neurodevelopmental effects in preterm neonates admitted to the NICU, with a special focus on very and extremely preterm infants. Both experimental and clinical data will be reviewed. Also, the effects on short- and long-term neurodevelopmental outcome of morphine treatment will be discussed followed by an
DOI: 10.3109/14767058.2014.908178
evaluation of the effectiveness of morphine to reduce stress or pain.
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Methods A literature search was performed in electronic databases such as Pubmed for keywords including ‘‘extremely premature neonate’’, ‘‘morphine’’, ‘‘continuous morphine infusion’’, ‘‘NICU’’ and ‘‘neurodevelopmental outcome’’. We limited the search for papers published until December 2013. Publications concerning the effects of morphine in neonates after maternal use were excluded. Relevant manuscripts were selected through the search as well as from reference lists from the relevant publications. Manuscripts concerning both experimental and clinical data on the long- and short-term neurological outcome were included. A total of 39 sources were selected for this review to elucidate the effects of neonatal morphine on neurodevelopment. The effects of morphine on the brain Morphine is the most well-known opioid analgesic. There are three opioid receptors, m, d and k. The m-opioid receptor is thought to be responsible for most of the analgesic effects. Morphine acts as a pure agonist of the m-opioid receptor. This receptor is distributed throughout the brain, dorsal root ganglia and in the peripheral nervous system. In the adult brain, m-opioid receptors are predominantly located in the peri-aquaductal gray area, hypothalamus, nucleus raphe magnus and in the limbic system where activation produces euphoria [16]. The molecular mechanism of morphine consists of the activation of a G-protein coupled receptor (GPCR) that signals through cyclic AMP (cAMP). cAMP levels decrease when morphine binds to the m-receptor. Upon activation of the GPCR by morphine, calcium influx decreases resulting in a lower pre-synaptic neurotransmitter release. Furthermore, due to promotion of potassium efflux, post-synaptic neurons are hyperpolarized leading to a decrease in transmission of neurotransmitters. In this manner, ascending neuronal pain pathways are inhibited and the perception and response to pain is changed [16]. Morphine is mainly metabolized by glucuronidation in the liver producing two active metabolites. These metabolites are morphine-3-glucuronide, which has antagonistic m-opioid activity, and morphine-6-glucuronide, which has a more potent agonistic analgesic activity than morphine itself. Apart from its analgesic ability, morphine produces adverse effects such as sedation, respiratory depression, nausea, vomiting and constipation. Besides these specific side effects, morphine can lead to development of tolerance, dependence and withdrawal [16]. It has been suggested that in premature neonates, due to different pharmacokinetics, tolerance develops more quickly than in babies born term. Both adequate weaning, environmental factors such as a reduction in noise at the NICU, and pharmacotherapeutic options (including clonidine) can be used to prevent opioid withdrawal symptoms [17]. The pharmacokinetic properties of morphine are different in preterm babies compared to full-term infants or adults. Both glucuronidation of morphine and morphine clearance are significantly related to gestational age and birth weight [18].
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Pharmacokinetic and pharmacodynamics modeling is important in clinical practice in order to establish the correct doses and dose adjustments for individual patients [19]. Clearance rates for morphine in preterm neonates can be predicted by several models [19]. In the next section, we will focus on the effects of morphine on the immature brain. The effects of morphine on the immature brain Experimental evidence of effects of morphine on the immature brain As mentioned before, opioids play a significant role in important neurodevelopmental processes [11,12]. In rodents, the brain spurt takes place from the second to fourth postnatal weeks. This makes it a convenient experimental model to study early neurodevelopment. Special protocols for rodents have been developed which simulate the stressful experiences that preterm infants encounter when admitted to a neonatal intensive care unit [15]. In a mouse model that studies the effect of morphine and stress on adult learning, both factors can affect neurodevelopment in such a way that adult place preference learning was impaired. However, when the two effects of neonatal morphine and stress are combined they can balance out into what seems to be normal learning. Neonatal treatment with morphine did not seem to disrupt adult behavior or anxiety [15]. In a similar model in rats, however, early treatment with morphine seemed to change the stress response in adults in such a way that learning was impaired regardless of the presence or absence of neonatal stress. Several specific effects of morphine on neurogenesis have been studied in various brain areas in rodents. For normal synaptogenesis and differentiation to occur during the brain growth spurt, neuronal activity is important. Since morphine interferes with neurotransmitter release as was mentioned above, this could potentially affect the developing brain. A mechanism that has been proposed to account for neuronal damage by general anesthetic agents is the blockage of excitatory NMDA receptors and activation of inhibitory GABA receptors in the immature brain [20]. The role of morphine on excitatory/inhibitory neurotoxicity in the developing brain is not entirely clear. To elucidate whether morphine also predisposes to neurotoxicity, a study by Massa et al. [11], investigated the effect of morphine during the brain growth spurt in the rat cerebral cortex at PD7-15 and PD15-20. Their results indicated that morphine did neither lead to changes in dendritic arborization, spinogenesis of dendrites in the rat, nor result in apoptosis in a specific area in the pre-frontal cortex [11]. However, in a neonatal rodent model of chronic morphine exposure associated with morphine dependence and anti-nociceptive tolerance, it was demonstrated that repeated injections of morphine on PD 1–7, so representing earlier stages of development, were able to induce apoptosis in the cortex and amygdala, but not in other areas. The proposed mechanism of morphine-induced apoptosis is not yet clear [14]. Furthermore, a combination of severe pain or mild repetitive pain and pre-emptive morphine in rat pups showed a protective effect of morphine on neuro-degeneration in terms of apoptosis only at specific times of
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neurodevelopment. Morphine reduced the number of apoptotic cells in rats experiencing severe pain and in rats experiencing repetitive mild pain, but at three and five days, respectively, after start of the experiments [21]. On molecular level, hippocampal gene expression is influenced by both stress and morphine treatment in rodents [22]. In the absence of pain or stress, morphine has adverse neurodevelopmental effects on the rat brain by delaying maturation of the hippocampus [12]. In mice, stress, depending on the severity, changes gene expression involved in the stress response and immune reaction. Morphine was able to reduce these effects for some genes, but not for others. The effect of both stress and morphine on hippocampal gene expression; and therefore, neurodevelopmental outcome can be hard to predict [22]. Thus, even though it is very clear that early stress results in adverse neurodevelopmental effects and that morphine can affect brain development, the effects of morphine treatment in stressful situations simulating neonatal intensive care, in (rodent) animal models show interesting, but variable results. Moreover, extrapolation from animal to human data is not straight forward. Short-term clinical effects of morphine in preterm infants Although several short-term adverse effects of morphine are well-known in the adult, such as respiratory depression, hypotension, constipation and tolerance, dependence and withdrawal, this is less clear in preterm neonates. Routine continuous morphine administration in ventilated preterm newborns is not recommended by the authors of a systematic review and meta-analysis in 2010 because not enough scientific evidence could be found for a beneficial effect of morphine treatment [10]. However, given its common clinical use, the question still remains to be answered whether morphine treatment leads to adverse events and worsen clinical outcome in case its use is clinically needed. Short-term neurological outcome has been investigated by assessing the incidence of peri-intraventricular hemorrhage (PIVH), periventricular leucomalacia (PVL) and neonatal death (death within 28 days) as a composite outcome in neonates born extremely and very preterm (532 weeks) [20,23–25]. The large NEOPAIN trial, which included 893 children, showed no significant overall differences in composite outcome between placebo and morphine-treated infants of very preterm age [24], nor did a study performed by Simons et al. [25], which included children born at all gestational ages. However, an adverse outcome was reported in the NEOPAIN trial in preterm infants of 27-to-29 weeks, who were treated with a high dose of morphine (loading dose of 100 mg/kg, followed by continuous infusion with 20 mg/kg/h) [24]. Additionally, neonates in the placebo group who received open label morphine showed a significant increase in neonatal mortality, severe PIVH and PVL. The incidence of PIVH after morphine treatment has been found to be lower in the study by Simons et al. [25] as compared to the non-morphine-treated counterparts. In this randomized controlled trial, lower dosing regimens were used (infusions of 10 mg/kg for all age groups), as well as a shorter duration of the treatment period of only seven days. This lower
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incidence of PIVH was also reported in a pilot study by Anand et al. [23]. It has been hypothesized that morphine-related hypotension might influence the incidence of PIVH [23]. In preterm neonates, morphine administration does not lead clinically to hemodynamic instability indicated by arterial blood pressure and determination of blood pressure variability [23,26]. Both continuous morphine administration [23,26] as well as bolus administration of morphine [26] have been associated with brief periods of hypotension in previously normotensive neonates. These periods of hypotension, however, did not appear to be clinically relevant. If hypotension was already present before onset of the study medication, morphine treatment has been shown to lead to adverse neurological outcome [24]. It seems, therefore, that the results concerning the incidence of PIVH’s are in disagreement. Furthermore, continuous morphine administration appeared to have neither adverse nor beneficial effect on short-term neurological outcome if used in a low dose. Additional research should be performed to study the effect of bolus administration on short-term neurological outcome, since an increase in adverse neurological events has been reported [24]. Anand et al. [23], assessed short-term neurodevelopmental outcome by means of the Neurobehavioural Assessment of the Premature Infant (NAPI) [27] score, which is used to observe the developmental progress of preterm infants between 32 weeks of gestational age and term. However, no difference could be found between morphine- and placebotreated patients [23]. Both the NEOPAIN study, as well as the study performed by Simons et al., assessed the effect of morphine to reduce neonatal pain measured by various pain scores. Overall reduction of pain by the Premature Infant Pain Profile in a meta-analysis did not show any significant difference between morphine and placebo [10], although PIPP showed a significant reduction in pain during endotracheal tube suctioning at 24 h of morphine infusion, in the NEOPAIN study [24]. Simons et al. [25] assessed neonatal pain with the NIPS [28] and PIPP [29], and these scores did not reduce when morphine was used. Open label morphine was needed in both studies to reduce pain on the basis of clinical judgment. Given the above-mentioned conflicting results when using different pain assessment scores, further research seems warranted in order to provide a method to detect whether or not the preterm neonate suffers from pain and, if so, to provide adequate analgesia. To achieve this goal the use of near infrared spectroscopy (NIRS) may be of help here. It has been shown that neonates are able to perceive pain at a cortical level using this technique [2]. NIRS can provide additional value in combination with other brain monitoring devices in relation to neurological outcome in infants [30]. A well designed study with this bedside technique may help us to achieve appropriate pain management in this vulnerable patient group. Several other existing methods that are routinely used at the NICU to relieve procedural stress and/ or pain in neonates admitted to the NICU is the use of oral glucose or sucrose, developmental support care, breastfeeding and skin-to-skin care. These measures have been investigated in systematic reviews and meta-analyses [31–33]. It was shown that both sucrose and breast milk are effective at
DOI: 10.3109/14767058.2014.908178
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reducing several parameters of pain (such as duration of crying time, heart rate) during single painful events such as heel lances. However, more research is needed in extremely premature neonates who are mechanically ventilated since there are only very few data of the effects in this patient group as well as on the long-term neurodevelopmental effects. A non-pharmacological method that has been specifically investigated low birth weight infants admitted to the NICU is developmental care, which includes a range of (environmental) factors to reduce stress in the NICU. Overall, based on the meta-analysis, limited benefit was shown of developmental care on clinical outcome of these infants. However, more research is needed in this area with consistent results before definite conclusions can be drawn [33]. Long-term effects of morphine on neurodevelopmental outcome Only limited research has been performed on the long-term neurodevelopmental outcome of extremely and very prematurely-born infants who were treated with morphine, while being ventilated mechanically. No prospective randomized controlled trials have been conducted specifically aiming to investigate long-term neurodevelopmental outcome. Similar to the short-term studies, the available information on the long-term effects of morphine generally do not show any definite effects on neurodevelopmental outcome. Although prematurely born children have a higher chance of death and disability as well as cognitive, behavioral and attention problems than children born at term [34], morphine treatment in this vulnerable patient group does not seem to be related to overall IQ and motor function at later age [8,35–38]. Still, some specific issues deserve attention: MacGregor et al. [36], showed no significant differences in intelligence score, motor assessment or behavior at 5 years of age, but all three measurements showed a trend towards a better neurodevelopmental outcome in the group of children treated with morphine compared to children treated with pancuronium or a 5% dextrose solution. However, no information has been presented on morphine use after the original study period of maximum 14 days of treatment, which makes it difficult to interpret these study results. In contrast to the above-mentioned study by MacGregor et al. [36], results concerning the long-term effects of morphine use over the first 28 days of life have been recently published by de Graaf et al. [35]. This follow-up study at five years of age included, apart from intelligence, behavior and motor abilities, a checklist for chronic pain and health-related quality of life which was completed by the parents. The authors report a trend towards a more negative outcome in the morphine-treated patients. Only a specific part of the intelligence test, the visual analysis, displayed a significantly worse outcome after morphine treatment after correction with a propensity score. Also open label morphine use has been taken into account in this study. It appeared that intelligence, motor and behavioral scores were not associated with morphine treatment in the neonatal period after adjustment with a propensity score accounting for clinically relevant confounding variables [35]. Recently, the latest follow-up
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results of this trial have been published [38]. Children were tested at the age of eight or nine years on general functioning (IQ, visual motor integration, behavior) and executive functions. The authors conclude that at this age there are no significant adverse consequences of neonatal morphine treatment in terms of intelligence, visual motor integration behavior or executive functions. On the contrary, a positive effect of morphine on daily life executive functions was found [38]. Another study to be mentioned is the French EPIPAGE study. This is a prospective cohort study consisting of children born very prematurely (22–32 weeks of gestation) which evaluated long-term neurodevelopmental outcome at 5 years of age in nine regions in France [37]. These children were treated according to clinical protocols and not on the basis of randomization. The cohort includes a large number of children: one-third of all births in France in 1997. The results showed no association between prolonged sedation/analgesia and disability or death after five years when adjusted with a propensity score. An important shortcoming of the study, however, is that there is no differentiation in medications. Therefore, no specific effect of morphine can be elucidated from these results. Furthermore, the power of this study to predict neurodevelopmental outcome was very low, since sedation/analgesia appeared to be a rare event in this cohort [37]. A small number of children (morphine: n ¼ 14; placebo: n ¼ 5) who participated in the NEOPAIN trial were examined for long-term neurodevelopmental outcome and assessed for behavior, intelligence and operant tests at five to seven years of age [39]. No significant differences in IQ score or in behavior assessment were found, although it seemed that more children from the morphine-treated group experienced social problems. Overall, the study results indicate no beneficial or adverse effect of morphine in general, but the small size of the study precludes that definitive conclusions can be drawn here. Finally, Grunau et al. [8] found that morphine exposure was related to poorer motor function at eight months of corrected chronological age, but not to cognitive development. Considering all above-mentioned results together, it can be concluded that morphine does not seem to have a negative effect on neurodevelopmental outcome. None of these studies were prospectively designed to investigate the long-term neurodevelopmental outcome, thus, the power of these studies to show a more specific effect of morphine on neurodevelopment was too low. Also, selection bias and loss to follow up could play a key role in the evaluation of the results, since most studies used a smaller subset from the original population. Furthermore, since the original trials used different protocols in terms of dosing regimens of morphine as well as in duration of treatment, it is difficult to compare the longterm outcome results. Also, the tools to assess cognitive, motor function and behavior at later age are not always comparable. Table 1 provides schematically the details of the studies discussed above. In summary, there is a need for a more standardized approach to study long-term neurological outcome after morphine treatment in the neonatal period. More prospectively designed randomized controlled trials, which include
87
1572
137
90
19
89
MacGregor et al. [36]
Roze et al. [37]
Grunau et al. [8]
de Graaf et al. [35]
Ferguson et al. [39]
de Graaf et al. [38]
N
Morphine: 31 [28–32] Control: 30 [29–32]
28 [27–29]
30 [27–31]
29.1 ± 2.6
Exposed: 27 [26–29] Non-exposed: 30 [27–31]
29 [27–31]
GA (wk) Median [range] Or Mean ± SD
Retrospective analysis of small subset NEOPAIN Retrospective analysis
14 days
Cumulative first 28 days of life
Loading dose: 100 mg/kg followed by: 23–26 wks: 10 mg/kg/h 27–29 wks: 20 mg/kg/h 30–32 wks: 30 mg/kg/h Loading dose: 100 mg/kg followed by 10 mg/kg/h
Retrospective analysis
Cumulative first 28 days of life
Loading dose: 100 mg/kg followed by 10 mg/kg/h
Prospective birth cohort
Observational
47 days Variable
Retrospective analysis
Type of study
5 days
Duration of study
Daily average mg/kg mean ± SD: 2.7 ± 6.8
No specification of analgesics/sedatives
50–100 mg/kg/h or 25 mg/kg/h
Morphine dosing
Table 1. Long-term neurodevelopmental outcome after neonatal morphine (negative effect ; positive effect +; no effect ±).
8/9 years
5–7 years
5 years
8 and 18 months CCA
5 years
5–6 years
Age at evaluation
Long-term neurodevelopmental outcome
Intelligence ± Visual motor integration ± Behavior ±
Intelligence: ± Motor: ± Behavior: ± Intelligence: ± Motor: ± Behavior: ± 8 months: Motor: Cognitive: ± 18 months: Motor: ± Cognitive: ± Intelligence: ± Visual motor integration: ± Behavior: ± Visual score: Intelligence: ± Motor: ± Behavior: ±
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Executive functions (rated by parents or teachers): + Executive function skills ±
Choice resp. latency task: Social problems: Head circumference:
Pain questionnaire: ± Health Utility Index: ±
Specific effects
226 J. Schuurmans et al. J Matern Fetal Neonatal Med, 2015; 28(2): 222–228
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enough infants to achieve a high enough power to detect small differences in long-term neurodevelopmental outcome are needed in order to be able to safely recommend routine morphine infusion in mechanically ventilated premature neonates.
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Conclusion As was mentioned in the ‘‘Introduction’’ section, pain at neonatal age can have serious consequences in later life [6–8]. Preterm infants who are mechanically ventilated experience stress clinically while struggling against the ventilator. Current clinical practice uses continuous morphine infusion as sedative and analgesic relief for the premature infant; however, routine infusion of morphine is not recommended based on a systematic review and meta-analysis [5]. Especially children born extremely and very prematurely are at risk since they are in an important period of rapid neurodevelopment. Infants admitted at a NICU undergo many painful/stressful procedures during their stay. Since it is also known that these infants are able to perceive this pain, it is important to relieve pain and stress to prevent long-term adverse neurodevelopmental outcome. The relevant articles selected by the literature search show that morphine is known to modulate brain development in experimental animal studies. Conflicting results were reported on morphine as neurotoxic agent during neurodevelopment in rodents [11,14]. A rodent model simulating neonatal intensive care showed that morphine could sometimes balance out long-term effects of pain or stress [15]. Also, hippocampal gene expression was affected differently by morphine in the presence or absence of stress [22]. Studies which looked at the short-term neurological effects of neonatal morphine showed conflicting results. In general, no adverse effect of morphine could be established, but in case of bolus administration, high dosage regimes and in previously present hypotension, incidence of neonatal morbidity/mortality increased. Subsequently, when using a lower dosing scheme, lower incidence of neurological morbidity was found [23–26]. Studies which described the long-term effects of morphine on the neurodevelopment showed no overall adverse or beneficial effects of neonatal morphine administration on motor, cognitive and behavioral measurements at various ages [35–39]. Therefore, also a protective effect of morphine when administered during stress cannot be excluded, because up to nine years of age, these children do not seem to be adversely affected. Still, these results need to be looked at carefully, considering that none of these studies were powered to look at long-term outcome. Furthermore, different pain assessment scores used in the different studies show conflicting results regarding the effectiveness of morphine to reduce stress/pain. In order to be able to evaluate the long-term effects, as well as the effectiveness of morphine in this group of patients, future research should look at validation of reliable pain assessment scores for chronic stress in preterm infants. This could be done by means of techniques such as NIRS, which is a technique used to monitor cerebral oxygen saturation. NIRS can provide additional value in combination
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with other brain monitoring devices in relation to neurological outcome in infants [30]. Furthermore, non-pharmacological treatment options which are known to sometimes relieve short-term procedural stress, such as sucrose could be evaluated for their effectiveness in ventilated premature infants perceiving chronic stress [31]. Ultimately, more prospectively designed trials should be designed to evaluate the effects of morphine on long-term neurodevelopmental outcome in order to demonstrate a definitive beneficial or adverse effect of morphine treatment in premature infants before any safe clinical recommendations can be provided.
Declaration of interest The authors report no declaration of interest.
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