Pharmacokinetic-pharmacodynamic relationships of morphine in neonates

Chay, Paul C W; Duffy, B. J.; Walker, Judith S.

doi:10.1038/clpt.1992.30

Cited by 130 publications

(83 citation statements)

References 8 publications

(10 reference statements)

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“…In a study of 10 premature neonates (26-34 weeks gestation) within the first 24 hr of life, Hartley et al (1993) found plasma concentrations in the range of 94-422 ng/ml, and similar values have been found in infants at term (Chay et al 1992). This contrasts with a study involving older children of mean age 11 years, where a mean plasma concentration of only 12 ng/ml was needed to maintain postoperative analgesia (Lynn et al 1984).…”

Section: Morphinementioning

confidence: 86%

“…Some glucuronidation of morphine MiniReview has been found even in the very premature neonate of 24-25 weeks gestational age (Choonara et al 1989). In three studies in premature neonates of gestational age 25-36 weeks, mean clearance ranged from 2.2-2.8 ml/min./kg (Chay et al 1992;Hartley et al 1993;Mikkelsen et al 1994). In contrast, rates of morphine clearance in neonates born at term are generally greater, i.e.…”

Section: Morphinementioning

confidence: 99%

“…It has been suggested that mean morphine plasma concentrations required to produce a therapeutic effect are higher in the neonate than in older children and adults, due to the slower rates of metabolism to the strong agonist morphine-6-glucuronide (Chay et al 1992). In a study of 10 premature neonates (26-34 weeks gestation) within the first 24 hr of life, Hartley et al (1993) found plasma concentrations in the range of 94-422 ng/ml, and similar values have been found in infants at term (Chay et al 1992).…”

Section: Morphinementioning

confidence: 99%

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Neonatal Hepatic Drug Elimination

Gow

Ghabrial

Smallwood

et al. 2001

Pharmacology & Toxicology

104

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After the transition from in utero to newborn life, the neonate becomes solely reliant upon its own drug clearance processes to metabolise xenobiotics. Whilst most studies of neonatal hepatic drug elimination have focussed upon in vitro expression and activities of drug-metabolising enzymes, the rapid physiological changes in the early neonatal period of life also need to be considered. There are dramatic changes in neonatal liver blood flow and hepatic oxygenation due to the loss of the umbilical blood supply, the increasing portal vein blood flow, and the gradual closure of the ductus venosus shunt during the first week of life. These changes which may well affect the capacity of neonatal hepatic drug metabolism. The hepatic expression of cytochromes P450 1A2, 2C, 2D6, 2E1 and 3A4 develop at different rates in the postnatal period, whilst 3A7 expression diminishes. Hepatic glucuronidation in the human neonate is relatively immature at birth, which contrasts with the considerably more mature neonatal hepatic sulfation activity. Limited in vivo studies show that the human neonate can significantly metabolise xenobiotics but clearance is considerably less compared with the older infant and adult. The neonatal population included in pharmacological studies is highly heterogeneous with respect to age, body weight, ductus venosus closure and disease processes, making it difficult to interpret data arising from human neonatal studies. Studies in the perfused foetal and neonatal sheep liver have demonstrated how the oxidative and conjugative hepatic elimination of drugs by the intact organ is significantly increased during the first week of life, highlighting that future studies will need to consider the profound physiological changes that may influence neonatal hepatic drug elimination shortly after birth.The development of clinical pharmacology has resulted in a more rational approach to drug therapy, as well as a deeper understanding of the factors capable of influencing drug disposition, and hence drug effects. Of these factors, age is of great importance. However, substantial differences in drug disposition not only exist between neonates and adults, but also among premature neonates, term neonates, infants and children.During the last two decades drug disposition in the neonatal period has been studied extensively. A major impetus for these studies seems to have been a series of incidents involving illness or death following the administration of drugs at ratios of dose/body weight innocuous in an adult (Craft et al. 1974;Gershanik et al. 1982). These studies have shown that the transition from neonate to childhood is characterised by the ontogeny of all of the processes of drug absorption, distribution, hepatic metabolism and renal excretion, with the development of hepatic drug metabolism being particularly important.The extent to which the neonatal drug-metabolising en-

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Section: Morphinementioning

confidence: 86%

Section: Morphinementioning

confidence: 99%

Section: Morphinementioning

confidence: 99%

See 1 more Smart Citation

Neonatal Hepatic Drug Elimination

Gow

Ghabrial

Smallwood

et al. 2001

Pharmacology & Toxicology

104

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“…Firstly, it has been observed that premature infants are more tolerant of high doses of opioids than adults. For example, plasma concentrations of morphine approaching 300 ng ml-' are not associated with significant adverse effects in premature infants [3], whereas similar concentrations in the adult may cause nausea, vomiting and severe respiratory depression. The second explanation relates to the pharmacological action of buprenorphine as a partial agonist at the opioid receptor.…”

Section: Discussionmentioning

confidence: 99%

“…Recent work has shown the benefit of administering morphine or diamorphine to the neonate to provide effective and safe analgesia or sedation [3,4]. In addition to pain relief, the use of a continuous infusion of an opioid in mechanically ventilated newborn infants has been shown to improve the synchronisation between the infants' own breathing and the ventilator.…”

Section: Introductionmentioning

confidence: 99%

The pharmacokinetics and physiological effects of buprenorphine infusion in premature neonates.

Simpson

Rutter

Kurihara-Bergstrom

et al. 1993

Brit J Clinical Pharma

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1. The pharmacokinetics and physiological effects of buprenorphine were studied in 12 newborn premature neonates (27 to 32 weeks gestational age) who were given a loading dose of 3.0 micrograms kg‐1 of buprenorphine followed by an intravenous infusion of 0.72 micrograms kg‐ 1 h‐1 of buprenorphine. Plasma concentrations of buprenorphine were measured during the infusion, at steady‐state and for 24 h after the cessation of the buprenorphine infusion. 2. The mean steady‐state plasma buprenorphine concentration (+/‐ s.d.) for an infusion rate of 0.72 micrograms kg‐1 h‐1 was 4.3 +/‐ 2.6 ng ml‐1. 3. Buprenorphine clearance was 0.23 +/‐ 0.07 l h‐1 kg‐1, the elimination half‐life was 20 +/‐ 8 h and the volume of distribution was 6.2 +/‐ 2.11 l kg‐1. 4. Small but significant falls were noted in systolic blood pressure at 6 h and heart rate at 1, 6 and 12 h after the administration of buprenorphine, but these did not appear to cause any clinical deterioration. 5. Four of the 12 subjects studied required an increase in the infusion rate of buprenorphine to achieve adequate sedation. 6. The results suggest that this dosing regimen of buprenorphine is safe but may not be as effective as other opioids in producing sedation and analgesia in premature newborns.

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Analgesia and Sedation in Preterm Neonates Who Require Ventilatory Support

Anand

McIntosh²,

Lagercrantz³

et al. 1999

Arch Pediatr Adolesc Med

377

128

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Background: Preterm neonates are exposed to multiple painful procedures after birth and exhibit acute physiological responses to pain. Occurrence of early intraventricular hemorrhage within 24 to 72 hours after birth suggests a role of pain and stress in the multifactorial causation of severe intraventricular hemorrhage and periventricular leukomalacia. We proposed that such neurologic outcomes in preterm neonates who require ventilatory support may be reduced by morphine analgesia or midazolam sedation compared with a placebo. Objectives: To define the incidence of clinical outcomes in the target study population, to estimate the effect size and adverse effects associated with analgesia and sedation, and to calculate the sample size for a definitive test of this hypothesis. Methods: Sixty-seven preterm neonates were randomized in a pilot clinical trial from 9 centers. Neonates of 24 to 32 weeks' gestation were eligible if they had been intubated and required ventilatory support for less than 8 hours and if they were enrolled within 72 hours after birth. Exclusion criteria included major congenital anomalies, severe intrapartum asphyxia, and participation in other research studies. Severity of illness was assessed by the Clinical Risk Index for Babies, and neonates were randomized to receive continuous infusions of morphine sulfate, midazolam hydrochloride, or 10% dextrose (placebo). Masked study medications were continued as long as clinically necessary, then weaned and stopped according to predefined criteria. Levels of sedation (COMFORT scores) and responses to pain (Premature Infant Pain Profile scores) were measured before , during, and 12 hours after discontinuation of drug infusion. Cranial ultrasound examinations were performed as part of routine practice, and poor neurologic outcomes were defined as neonatal death, severe intraventricular hemorrhage (grade III or IV), or periventricular leukomalacia. Results: No significant differences occurred in the demographic, clinical, and socioeconomic variables related to mothers and neonates in the 3 groups or in the severity of illness at birth as measured by Clinical Risk Index for Babies scores. Two neonates in the placebo group and 1 neonate in the midazolam group died; no deaths occurred in the morphine group. Poor neurologic outcomes occurred in 24% of neonates in the placebo group, 32% in the midazolam group, and 4% in the morphine group (likelihood ratio 2 = 7.04, P = .03). Secondary clinical outcomes and neurobehavioral outcomes at 36 weeks' postconceptional age were similar in the 3 groups. Responses elicited by endotracheal tube suction (Premature Infant Pain Profile scores) were significantly reduced during the morphine (PϽ.001) and midazolam (P = .002) infusions compared with the placebo group. Conclusions: This pilot trial suggests that preemptive analgesia given by continuous low-dose morphine infusion may reduce the incidence of poor neurologic outcomes in preterm neonates who require ventilatory support. Limitations in the sample size of this pil...

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Pharmacokinetic-pharmacodynamic relationships of morphine in neonates

Cited by 130 publications

References 8 publications

Neonatal Hepatic Drug Elimination

Neonatal Hepatic Drug Elimination

The pharmacokinetics and physiological effects of buprenorphine infusion in premature neonates.

Analgesia and Sedation in Preterm Neonates Who Require Ventilatory Support

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