Morphine, morphine‐6‐glucuronide and morphine‐3‐glucuronide pharmacokinetics in newborn infants receiving diamorphine infusions

Abstract

1 The pharmacokinetics of morphine, morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G) were studied in 19 ventilated newborn infants ( 24-41 weeks gestation) who were given a loading dose of 50 mg kg−1 or 200 mg kg−1 of diamorphine followed by an intravenous infusion of 15 mg kg−1 h−1 of diamorphine. Plasma concentrations of morphine, M3G and M6G were measured during the accrual to steady-state and at steady state of the diamorphine infusion. 2 Following both the 50 mg kg−1 or 200 mg kg−1 loading doses the mean steadystate plasma concentration (±s.d.) of morphine, M3G and M6G were 86±52 ng ml−1, 703±400 ng ml−1 and 48±28 ng ml−1 respectively and morphine clearance was found to be 4.6±3.2 ml min−1 kg−1. 3 M3G formation clearance was estimated to be 2.5±1.8 ml min−1 kg−1, and the formation clearance of M6G was estimated to be 0.46±0.32 ml min−1 kg−1. 4 M3G metabolite clearance was 0.46±0.60 ml min−1 kg−1, the elimination half-life was 11.1±11.3 h and the volume of distribution was 0.55±1.13 l kg−1. M6G metabolite clearance was 0.71±0.36 ml min−1 kg−1, the elimination half-life was 18.2±13.6 h and the volume of distribution was 1.03±0.88 l kg−1. 5 No significant effect of the loading dose (50 mg kg−1 or 200 mg kg−1) on the plasma morphine or metabolite concentrations or their derived pharmacokinetic parameters was found. 6 We were unable to identify correlations between gestational age of the infants and any of the determined pharmacokinetic parameters. 7 M3G5morphine and M6G5morphine steady-state plasma concentration ratios were 11.0±10.8 and 0.8±0.8, respectively. 8 The metabolism of morphine in neonates, in terms of the respective contributions of each glucuronide pathway, was similar to that in adults.

Metabolism and pharmacokinetics of morphine in neonates: A review

“…The distribution volume in preterm neonates was 190 l/70 kg and did not change with age. Barret et al 24 studied the pharmacokinetics of morphine, morphine-6-glucuronide and morphine-3-glucuronide in 19 ventilated preterm and term newborn infants. Kinetic parameters are displayed in Table 2.…”

Morphine Administration and Short-term Pulmonary Outcomes Among Ventilated Preterm Infants

“…These doses were based on morphine pharmacokinetic data available at the time of protocol development. [9][10][11][12][13][14] Increases in the study drug infusion were permitted only if the infant grew to a higher GA stratum, not to provide additional analgesia (AA). The study drug therapy was weaned and stopped (1) if extubation was expected within 24 hours, (2) if no spontaneous respiration occurred at Paco 2 values of 5.3 to 6.7 kPa, (3) if the patient's clinical condition was deteriorating rapidly, or (4) if study drug administration had continued for 14 days.…”

Morphine, Hypotension, and Adverse Outcomes Among Preterm Neonates: Who’s to Blame? Secondary Results From the NEOPAIN Trial

“…These doses were based on morphine pharmacokinetic data available at the time of protocol development. 21,22 Neonates randomized to placebo received a similar-volume loading dose, infusion rate, and weaning protocol. Because of ethical concerns, 23 both randomized groups received additional bolus doses of open-label morphine, on the basis of clinical judgment and specific protocol criteria.…”