Morphine kinetics after diamorphine infusion in premature neonates.

Abstract

1 The pharmacokinetics of morphine were studied in 26 newborn premature neonates (26-38 weeks gestational age) who were given a loading dose of 50 pLg kg-' of diamorphine followed by an intravenous infusion of 15 ,ug kg-' h-1 of diamorphine.Plasma concentrations of morphine were measured during the infusion at steady-state and for 24 h after the cessation of the diamorphine infusion. 2 The mean steady-state plasma morphine concentration (± s.d.) for a diamorphine infusion rate of 15 ,ug kg-' h-1 was 62.5 ± 22.8 ng ml-'.3 Morphine clearance was 3.6 ± 0.9 ml min-' kg-1, the elimination half-life was 8.93.3 h and the volume of distribution was 2.7 ± 1.0 1 kg-'. 4 Morphine elimination kinetics were described by a mono-exponential function. 5There was a direct relationship between the gestational age of the patients and the clearance (r2 = 0.31, P = 0.003) and half-life (r2 = 0.35, P = 0.01) of morphine, but no relationship was found between gestational age and volume of distribution. 6 The results suggest that the currently used dosing regimen of diamorphine achieves a safe and effective morphine concentration in the premature newborn but that the loading dose could be modified to achieve a more rapid onset of analgesia.Keywords diamorphine morphine pharmacokinetics premature newborn intravenous infusion dose regimen

Recommended use of morphine in neonates, infants and children based on a literature review: Part 1—Pharmacokinetics

“…Thus the longer effect only a part of the neonates producing M3G; possibly due to the sensitivity of the assay (12,17). Only Bhat of a single dose of morphine seen in neonates can most probably be ascribed to the lower metabolic pharmacokinetic values (17,24,26) and even a triexponential model has been suggested (27). capacity and thereby the lower elimination rate of morphine in neonates.…”

Development of Morphine Glucuronidation in Premature Neonates

“…Clearly, from the data presented above, M3G/morphine plasma concentration ratios increase significantly from neonatal values to those found in older children, consistent with increasing plasma clearance of morphine (3.6, 3.4-9.6 and 4.7 ml/min/kg in preterm neo nates [7,8,10]; 15.5 and 20.1 ml/min/kg in fullterm neonates [8,21]; 25.7 ml/min/kg in children [10]). Developmental changes in the pharmacokinetics of morphine in premature and fullterm neonates have been reported [7,8,11], but these studies provided no indica tion of changes in the relative amounts of morphine, M3G and M6G in plasma during maturation of the metabolic and excretory mechanisms.…”

“…Preterm infants can me tabolise morphine by glucuronidation, but their metabolic capacity is reduced in com parison with children aged 1-16 years [10]. Developmental changes in the half-life [7,8,11] and plasma clearance of morphine [7,8] in premature neonates support this view, but provide no indication of changes in the rela tive plasma levels of M3G and M6G during maturation of the metabolic and excretory mechanisms. A recent study by Bhat et al [9] noted marked variability in the presence of either metabolite in plasma or urine from pre term newborns who received a single intrave nous dose of morphine.…”

“…Developmental changes in the pharmacokinetics of morphine in premature and fullterm neonates have been reported [7,8,11], but these studies provided no indica tion of changes in the relative amounts of morphine, M3G and M6G in plasma during maturation of the metabolic and excretory mechanisms. Using M3G/morphine and M6G/morphine plasma concentration ratios as indices of metabolic and/or excretory func tion, we have investigated the development of the glucuronidation pathway in preterm neo nates.…”

“…The metabolism and pharma cokinetics of morphine have been widely studied in adults [3,4] and, to a lesser degree, in children [5,6], but data from premature neonates is limited [7][8][9][10][11], Morphine is me tabolised, predominantly by the liver (also the intestine and kidney), to glucuronides which are subsequently excreted by the kidney [3], This biotransformation is facilitated by mor phine uridinediphosphate glucuronosyltransferases (morphine-UDPGTs) which transfer the glucuronic acid group from UDP-glucuronic acid to acceptor groups on the sub strate (3-phenolic and 6-alcoholic hydroxyl groups). Both glucuronide metabolites thus formed (morphine-3-glucuronide, M3G, and morphine-6-glucuronide, M6G) are pharma cologically active.…”