Pharmacokinetics of a single dose of morphine in preterm infants during the first week of life

Bhat, Rama; Chari, Gopal; Gulati, Anil; Aldana, O.; Velamati, Ramakrishna; Bhargava, Hemendra N.

doi:10.1016/s0022-3476(05)81102-3

Cited by 112 publications

(55 citation statements)

References 8 publications

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“…There was considerable inter-individual variation in both clearance and indices of glucuronidation (M3G and M6G to morphine ratios). This is consistent with previous studies of the pharmacokinetics of morphine in preterm infants (Bhat et al, 1990). Owing to the small number of patients in this study we are unable to comment on differences in clearance and glucuronidation between neonates and infants and further studies are required to document any changes in glucuronidation through infancy.…”

Section: Discussionsupporting

confidence: 87%

“…The mean plasma clearance of morphine in the fullterm neonates in this study was 20.1 ml min-' kg-' and this is higher than that previously reported in preterm infants (4.7 ml min-' kg-' , 3.4-15.5 ml min-' kg-' (Bhat et al, 1990), and 3.6 ml min-' kg-' (Barrett et al, 1991)). The study by Bhat and co-workers reported increasing clearance with increasing gestational age (3.4 ml min-' kg-' in infants under 30 weeks gestation, 9.6 ml min-' kg-' in infants of 31-37 weeks gestation, and a value of 15.5 ml min-' kg-' in the 3 fullterm infants studied).…”

Section: Discussioncontrasting

confidence: 61%

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Morphine metabolism in neonates and infants.

Choonara

Lawrence

Michalkiewicz

et al. 1992

Brit J Clinical Pharma

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The metabolism of morphine was studied in seven fullterm neonates and five infants receiving a continuous infusion of morphine. All the patients had detectable plasma concentrations of morphine 3‐glucuronide (M3G) and 10 had detectable concentrations of morphine 6‐glucuronide (M6G). The mean plasma clearance of morphine was 20.1 ml min‐1 kg‐1 in neonates and 23.4 ml min‐1 kg‐1 in the group as a whole. The M3G/morphine ratio (7.3) was higher than that previously reported for preterm neonates (5.0) but lower than that reported for children (23.9).

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Section: Discussionsupporting

confidence: 87%

Section: Discussioncontrasting

confidence: 61%

Morphine metabolism in neonates and infants.

Choonara

Lawrence

Michalkiewicz

et al. 1992

Brit J Clinical Pharma

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“…Our findings that opioid receptor antagonism increased levels of big ET-1 while decreasing levels of ET-1 again lend evidence to the existence of opioid receptors with influence upon ECE activity. The dose of morphine used in the present study was based on pharmacokinetic studies using single morphine doses of 0.1 mg/kg in preterm infants (23) and loading doses of 0.1 mg/kg/h for 2 h, followed by infusion doses (24), which demonstrated serum levels of 100 ng/mL or greater. One limitation of the study is that we did not measure the levels of morphine or its metabolites in the media.…”

Section: Discussionmentioning

confidence: 99%

Influence of Morphine and Naloxone on Endothelin and its Receptors in Newborn Piglet Brain Vascular Endothelial Cells: Clinical Implications in Neonatal Care

et al. 2004

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The present study examines the hypothesis that morphine exposure alters newborn brain vascular endothelial cell production of endothelin (ET)-1, as well as the mRNA expression of its receptors. Newborn piglet vascular endothelial cells were treated with morphine (100 ng/mL media), naloxone (100 ng/mL media), or drug-free media (control) for 6, 24, 48, and 96 h. Media was analyzed for ET-1 and big ET-1 levels and the cells were assessed for ET A and ET B receptor mRNA expression. Morphine exposure progressively increased ET-1 production from 6 to 96 h with concurrent reductions in big ET-1 levels starting at 24 h to almost undetectable levels by 96 h. Whereas ET A receptor mRNA expression increased 2-fold at 6 h and 4-fold at 96 h, ET B receptor mRNA expression remained unchanged. Naloxone exposure caused significant decreases in ET-1 levels, whereas an opposite effect was noted in big ET-1 levels, which increased from 6 through 96 h. Naloxone caused a progressive decrease in ET A receptor mRNA expression at 6 h through 96 h and a 2-fold increase in ET B receptor mRNA expression at 48 and 96 h. Intermittent and/or continuous infusions of morphine are often used for analgesia and sedation of infants in the neonatal intensive care unit. In the newborn piglet, continuous infusion of morphine results in increased systemic and sagittal sinus vein ET-1 levels (1). In vitro, ET-1 is involved in cerebral pial artery vasoconstriction, and therefore may be involved in the regulation of cerebral blood flow (2). ET-1 is a potent vasoconstrictive peptide that binds with high affinity to the endothelin receptor ET A , which mediates vasoconstriction by activating the phospholipase C/protein kinase C cascade (3), by decreasing smooth muscle sensitivity to NO (4), and possibly by increasing cytosolic free calcium levels (5) and superoxide anion production (6). The endothelin receptor ET B has a lower affinity for ET-1 and mediates vascular relaxation through a mechanism coupled to endothelial production of nitric oxide (7), although some vasoconstrictor activity of ET B has also been shown (8, 9). "Big ET" is a precursor to endothelin with almost no vasoconstrictor activity (10); ET-1 is formed when big ET-1 is cleaved by ECE (11). Published data have shown poor correlation between systemic ET levels and tissue levels of its production (12).We have previously shown that morphine infusion in newborn piglets increases ET-1 levels, up-regulates ET A mRNA expression, and down-regulates ET B mRNA expression as measured in systemic and sagittal sinus venous blood and ABSTRACT147

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“…O início de ação varia de três a cinco minutos com T 1/2 Ke0 (meia vida de equilíbrio entre o plasma e o local de ação -cérebro) de 30 minutos 20 . Estudos de farmacocinética após doses em bolus mostraram que em recém-nascidos prematuros, menores e maiores de 30 semanas de gestação, observa-se meia-vida de eliminação maior e depuração diminuída nos pacientes mais prematuros, apesar de variações individuais importantes terem sido notadas nos dois grupos 21 . Avaliando-se a meia-vida de eliminação, a depuração e o metabolismo da morfina em recém-nascidos de 24 a 40 semanas, de idade gestacional do primeiro ao sexagésimo dia de vida, notou-se um espectro amplo de variação nos parâmetros farmacocinéticos, e a meia-vida tende a diminuir e a depuração a aumentar com o aumento da idade gestacional 21,22 .…”

Section: Morfinaunclassified

“…It has an onset of action of 3 to 5 minutes and T 1/2 Ke0 (equilibrium half-life between the plasma and its site of actionbrain) of 30 minutes 20 . Pharmacokinetics studies after a bolus dose showed that, in premature neonates, younger than and older than 30 weeks of gestation, the elimination half-life is greater and more premature patients have reduced depuration, although both groups presented important individual variations 21 . Evaluating the elimination half-life, depuration, and metabolism of morphine in newborns with 24 to 40 weeks, from the first to the 60 th day of life, a wide variation in pharmacokinetic parameters was noted, but the half-life tends to decrease and depuration to increase with increased gestational age 21,22 .…”

Section: Morphinementioning

confidence: 99%

Sedação e analgesia em neonatologia

Silva¹,

Gomez²,

Máximo³

et al. 2007

Rev. Bras. Anestesiol.

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JUSTIFICATIVA E OBJETIVOS:A importância do estudo da dor em Neonatologia se deve ao fato de que a sensação de dor e estresse significa sofrimento e desconforto para os recém-nascidos e, apesar desse conhecimento, pouco tem sido feito para minimizá-los. Nessa revisão foram discutidas: a prevenção da dor, as medidas não-farmacológicas e farmacológicas para o seu tratamento e a sedação em recém-nascidos. CONTEÚDO:Várias são as medidas não-farmacológicas que podem ser tomadas com intuito de prevenir a dor nas Unidades de Terapia Intensiva Neonatal e também para tornar o ambiente mais humanizado e menos estressante para os pacientes e seus familiares. O tratamento da dor no recém-nascido consiste em medidas não-farmacológicas (sucção não-nutritiva, glicose) e farmacológicas (analgésicos não-opióides, opióides e anestésicos locais). A sedação em recém-nascidos é produzida por fármacos que agem diminuindo a atividade, a ansiedade e a agitação do paciente, podendo levar à amnésia de eventos dolorosos ou não-dolorosos. A sedação pode ser feita pela administração de hidrato de cloral, barbitúricos, propofol e benzodiazepínicos. CONCLUSÕES:A prevenção da dor e a indicação de analgesia devem ser individualizadas e sempre consideradas em todos os recém-nascidos portadores de doenças potencialmente dolorosas e/ ou submetidos a procedimentos invasivos, cirúrgicos ou não.

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Pharmacokinetics of a single dose of morphine in preterm infants during the first week of life

Cited by 112 publications

References 8 publications

Morphine metabolism in neonates and infants.

Morphine metabolism in neonates and infants.

Influence of Morphine and Naloxone on Endothelin and its Receptors in Newborn Piglet Brain Vascular Endothelial Cells: Clinical Implications in Neonatal Care

Sedação e analgesia em neonatologia

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