Analgosedation with low‐dose morphine for preterm infants with CPAP: risks and benefits

Enders, J.; Gebauer, Corinna; Pulzer, F.; Robel-Tillig, E.; Knüpfer, M.

doi:10.1111/j.1651-2227.2008.00815.x

Cited by 18 publications

(11 citation statements)

References 15 publications

(24 reference statements)

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“…Although an intravenous morphine dose of 10–30 μg/kg provided effective analgesia in infants receiving continuous positive airway pressure in a previous study, 24 severe apnoeic episodes requiring substantial intervention were reported in 9% of participants (who were very premature), and consistent with the findings of our study, a reduction in heart rate and respiratory rate was suggested. Similarly, a dose of 100 μg/kg of intravenous morphine in ventilated premature infants provided effective pain relief for central line placement in a previous study, 25 but with significantly increased ventilation requirements compared with infants who received tetracaine.…”

Section: Discussionsupporting

confidence: 90%

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

et al. 2018

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SummaryBackgroundInfant 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.MethodsIn 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).FindingsBetween 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).InterpretationAdministration 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.FundingWellcome Trust and National Institute for Health Research.

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Section: Discussionsupporting

confidence: 90%

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

et al. 2018

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“…Based on in vitro and animal parameters a PD model was developed, which was confirmed using human literature data. In the current model it appears that the PK-PD relationship is different in neonates compared to older children and adults, as the effect size for neonates reported by Enders et al [35] was largely underpredicted. In contrast, the pain score-time profiles matched with observations in older individuals using the same binding-effect relationship for morphine [35].…”

Section: Plos Computational Biologymentioning

confidence: 60%

“…In the current model it appears that the PK-PD relationship is different in neonates compared to older children and adults, as the effect size for neonates reported by Enders et al [35] was largely underpredicted. In contrast, the pain score-time profiles matched with observations in older individuals using the same binding-effect relationship for morphine [35]. Neonates therefore appear more sensitive to morphine compared to older age groups, although more clinical PD data is required to confirm this finding [19].…”

Section: Plos Computational Biologymentioning

confidence: 60%

Physiologically based pharmacokinetic/pharmacodynamic model for the prediction of morphine brain disposition and analgesia in adults and children

Verscheijden

Litjens²,

Koenderink

et al. 2021

PLoS Comput Biol

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Morphine is a widely used opioid analgesic, which shows large differences in clinical response in children, even when aiming for equivalent plasma drug concentrations. Age-dependent brain disposition of morphine could contribute to this variability, as developmental increase in blood-brain barrier (BBB) P-glycoprotein (Pgp) expression has been reported. In addition, age-related pharmacodynamics might also explain the variability in effect. To assess the influence of these processes on morphine effectiveness, a multi-compartment brain physiologically based pharmacokinetic/pharmacodynamic (PB-PK/PD) model was developed in R (Version 3.6.2). Active Pgp-mediated morphine transport was measured in MDCKII-Pgp cells grown on transwell filters and translated by an in vitro-in vivo extrapolation approach, which included developmental Pgp expression. Passive BBB permeability of morphine and its active metabolite morphine-6-glucuronide (M6G) and their pharmacodynamic parameters were derived from experiments reported in literature. Model simulations after single dose morphine were compared with measured and published concentrations of morphine and M6G in plasma, brain extracellular fluid (ECF) and cerebrospinal fluid (CSF), as well as published drug responses in children (1 day– 16 years) and adults. Visual predictive checks indicated acceptable overlays between simulated and measured morphine and M6G concentration-time profiles and prediction errors were between 1 and -1. Incorporation of active Pgp-mediated BBB transport into the PB-PK/PD model resulted in a 1.3-fold reduced brain exposure in adults, indicating only a modest contribution on brain disposition. Analgesic effect-time profiles could be described reasonably well for older children and adults, but were largely underpredicted for neonates. In summary, an age-appropriate morphine PB-PK/PD model was developed for the prediction of brain pharmacokinetics and analgesic effects. In the neonatal population, pharmacodynamic characteristics, but not brain drug disposition, appear to be altered compared to adults and older children, which may explain the reported differences in analgesic effect.

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“…31 According to our results, pharmacological and nonpharmacological analgesia will be frequently required during application of nCPAP; on the other hand, fewer infants receiving HHHFNC will require non-pharmacological interventions only. Enders et al 32 has advocated the use of low-dose morphine (single intravenous dose of 0.01 mg kg − 1 ) for analgosedation in preterm infants receiving nCPAP, however, 9.3% of infants receiving low-dose morphine in their study developed considerable delayed apnea. Controversy exists regarding the safety and long-term impact of opioids analgesia in mechanically ventilated neonates.…”

Section: Discussionmentioning

confidence: 97%

Assessment of pain during application of nasal-continuous positive airway pressure and heated, humidified high-flow nasal cannulae in preterm infants

2014

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Analgosedation with low‐dose morphine for preterm infants with CPAP: risks and benefits

Abstract: Morphine in dosage less than half of recommended dosage has a high analgetic and sedative potential. The danger of delayed severe apnea has to be taken into consideration in the clinical situation, especially in patients<28 weeks.

Cited by 18 publications

References 15 publications

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

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

Physiologically based pharmacokinetic/pharmacodynamic model for the prediction of morphine brain disposition and analgesia in adults and children

Assessment of pain during application of nasal-continuous positive airway pressure and heated, humidified high-flow nasal cannulae in preterm infants

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