Morphine metabolism in neonates and infants.

Choonara, Imti; Lawrence, Andrew J.; Michalkiewicz, A.; Bowhay, A.; Ratcliffe, J.

doi:10.1111/j.1365-2125.1992.tb05652.x

Cited by 63 publications

(29 citation statements)

References 20 publications

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“…This ratio, however, is very low, even in the neonatal period, indicating that the contribution of sulfation to the metabolism of morphine is minimal. In another study, Choonara et al 9 demonstrated that full-term neonates and older infants have a well-developed mechanism for the glucuronidation of morphine at both position 3 and position 6. In all cases, the plasma concentrations of morphine-3-glucuronide were higher than those of morphine and the plasma concentrations of morphine-6-glucuronide were higher than those of morphine in 7 of the 10 infants in whom morphine-6-glucuronide was detectable.…”

Section: Resultsmentioning

confidence: 99%

“…As noted above, in premature infants who were given morphine intravenously, only morphine-3-glucuronide was detected in the plasma 2 hours after dosing, whereas morphine-6-glucuronide was detected in the plasma 24 hours after dosing. The plasma concentration ratios of morphine-3-glucuronide to morphine and morphine-6-glucuronide to morphine increased significantly with increasing birth weight 9. Morphine-6-glucuronide is a potent opioid agonist, whereas morphine-3-glucuronide functionally antagonizes several of the effects of both morphine and morphine-6-glucuronide 9.…”

Section: Discussionmentioning

confidence: 97%

“…As observed in Table 1, nine of the selected articles reported on metabolic aspects of morphine processing in neonates 8-16. The most important information to be gathered from these papers is as follows: (a) sulfation is a minor component of morphine transformation 8,11; (b) glucuronidation is an essential metabolic step, converting morphine either to morphine-3-glucuronide or to morphine-6-glucuronide 9,10,12-14; (c) the relatively inactive morphine-3-glucuronide is produced as early as day 1 of life in preterm and term neonates, whereas the highly active morphine-6-glucuronide only appears on day 2 12,13; and (d) there is no obvious correlation of dose with analgesic/sedative effects during the first days of life, especially in preterm neonates.…”

Section: Discussionmentioning

confidence: 99%

“…The plasma concentration ratios of morphine-3-glucuronide to morphine and morphine-6-glucuronide to morphine increased significantly with increasing birth weight 9. Morphine-6-glucuronide is a potent opioid agonist, whereas morphine-3-glucuronide functionally antagonizes several of the effects of both morphine and morphine-6-glucuronide 9. Considering these opposing properties, the proportions of the two metabolites formed are clearly relevant.…”

Section: Discussionmentioning

confidence: 99%

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Metabolism and pharmacokinetics of morphine in neonates: A review

Pacifici¹

2016

Clinics

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Morphine is an agonist of the µ and k receptors, whose activation results in analgesia. Morphine-like agonists act through the µ opioid receptors to cause pain relief, sedation, euphoria and respiratory depression. Morphine is glucuronidated and sulfated at positions 3 and 6; the plasma concentration ratios correlate positively with birth weight, which probably reflects increased liver weight with increasing birth weight. Moreover, morphine clearance correlates positively with gestational age and birth weight. Steady-state morphine plasma concentrations are achieved after 24-48 hours of infusion, but the glucuronide metabolite plasma concentrations do not reach steady state before 60 hours. The morphine-3-glucuronide metabolite has lower clearance, a shorter half-life and a smaller distribution volume compared with the morphine-6 metabolite, which is the most active morphine-like agonist. Ordinary doses cause constipation, urinary retention and respiratory depression. Neonatal pain relief may require a blood level of approximately 120 ng/ml, whereas lower levels (20-40 ng/ml) seem adequate for children. A bibliographic search was performed using the PubMed database and the keywords “morphine metabolism neonate” and “morphine pharmacokinetics neonate”. The initial and final cutoff points were January 1990 and September 2015, respectively. The results indicate that morphine is extensively glucuronidated and sulfated at positions 3 and 6, and that the glucuronidation rate is lower in younger neonates compared with older infants. Although much is known about morphine in neonates, further research will be required to ensure that recommended therapeutic doses for analgesia in neonates are evidence based.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Metabolism and pharmacokinetics of morphine in neonates: A review

Pacifici¹

2016

Clinics

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“…Evaluation of the predictive performance of the maturation model of Anand et al [8] Method I In order to evaluate the predictive performance of Equation 1, the clearance values of morphine for individual children (n = 147) were obtained from the literature [10][11][12][13][14][15][16][17][18][19]. The clearance data included pre-term (gestational age = 24-36 weeks, n = 75), term (gestational age = 37-41 weeks, n = 33), infants (1 week to 2 months, n = 12), younger children (>2 to 10 months, n = 15), and older children (3.1 to 5 years, n = 12).In these studies, clearance was estimated by non-compartmental as well was by compartmental analysis.…”

Section: Anand Et Al's Methodsmentioning

confidence: 99%

Evaluation of a morphine maturation model for the prediction of morphine clearance in children: how accurate is the predictive performance of the model?

Mahmood

2010

Brit J Clinical Pharma

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The pharmacokinetics of morphine are well known in pre-term and term neonates, infants, younger and older children, as well as in adults. There are circumstances when a pharmacokinetic study may not be possible in children (especially neonates and infants), and as a result one would like to predict drug clearance in children. Several methods, such as allometric scaling and prediction based on incorporation of physiological parameters, have been suggested. Recently a morphine maturation model has been proposed to predict morphine clearance in the paediatric population. WHAT THIS STUDY ADDSThe current study evaluates the predictive performance of the morphine maturation model for the prediction of morphine clearance in pre-term, term, infants and children up to 5 years of age. The results of the study highlight the shortcomings of the model to predict morphine clearance in children in aforementioned age groups. AIMSRecently, a maturation model that incorporates a sigmoidal Emax type model has been proposed for the estimation of morphine clearance in paediatric patients. The primary objective of this report is to evaluate the predictive performance of the morphine maturation model for the prediction of morphine clearance in children of different ages. The secondary objective of this report is to evaluate the predictive performance of exponent 0.75 on bodyweight in the absence of the sigmoidal part of the morphine maturation model. METHODSIn order to evaluate the predictive performance of the morphine maturation model, the clearance values of morphine for individual children (preterm neonates to 5-year-old children; n = 147) were obtained from the literature. The predicted clearance of morphine in an individual child, obtained from the maturation model as well as from the fixed exponent 0.75 was compared with the observed clearance in that individual child. RESULTSThe morphine maturation model's predictive power in neonates, infants and younger children is poor and the inclusion of the sigmoidal part in the model only helps in reducing the substantial error introduced in the prediction due to the application of exponent 0.75 on bodyweight. Furthermore, the real benefit of the sigmoidal Emax part of the model disappears by 1 year of age. CONCLUSIONSThe morphine maturation model has a poor predictive power of morphine clearance in preterm and term neonates, infants and very young children and may not be of any practical value for the prediction of morphine clearance in this age group.

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Developmental Hepatic Pharmacology in Pediatrics

Behm

2013

Pediatric Drug Development

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Morphine metabolism in neonates and infants.

Cited by 63 publications

References 20 publications

Metabolism and pharmacokinetics of morphine in neonates: A review

Metabolism and pharmacokinetics of morphine in neonates: A review

Evaluation of a morphine maturation model for the prediction of morphine clearance in children: how accurate is the predictive performance of the model?

Developmental Hepatic Pharmacology in Pediatrics

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