morphine-3-glucuronide and Birth-Weight

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.

Topics: Age Factors; Analgesics, Opioid; Birth Weight; Central Nervous System Stimulants; Extracorporeal Membrane Oxygenation; Gestational Age; Humans; Infant, Newborn; Morphine; Morphine Derivatives; Respiration, Artificial; Time Factors

We sought to provide a rational basis for morphine administration in preterm infants in the immediate postnatal period by determining the clearance and evaluating the efficacy and adverse effects of a continuous infusion.. Morphine was infused for 2 to 4 days (140 microg/kg over 1 hour followed by 20 microg/kg/h) to 31 ventilator-treated newborn infants (gestational age, 24 to 41 weeks; birth weight, 765 to 4,015 g). Morphine, morphine-3-glucuronide, and morphine-6-glucuronide concentrations in serum were determined from arterial blood obtained at 2, 12, 24, 48, and 60 hours after the start of morphine infusion at a median postnatal age of 10 hours.. The mean +/- SD steady-state morphine concentration, 167 +/- 77 ng/mL, was achieved between 24 and 48 hours of infusion, and morphine-6-glucuronide and morphine-3-glucuronide concentrations did not reach steady state within 60 hours. Morphine clearance (range, 0.8 to 6.5 mL/min/kg) correlated significantly with gestational age (r = 0.60; P < .01) and birth weight (r = 0.55; P < .01). Pain relief did not correlate with the steady-state morphine concentration. However, significantly higher morphine concentrations were found in infants with decreased gastrointestinal motility (187 +/- 82 ng/mL) compared with those without (128 +/- 51 ng/mL; P < .05).. Morphine should be used with caution in prematurely born infants because of its low clearance, which correlates with gestational age.

Topics: Birth Weight; Gestational Age; Humans; Infant, Newborn; Metabolic Clearance Rate; Morphine; Morphine Derivatives; Narcotics

In premature neonates (25-34 weeks gestation) who were given morphine intravenously during the first 24 h of life, only morphine, and morphine-3-glucuronide (M3G) were detected in plasma obtained after a 2-hour loading infusion, but morphine-6-glucuronide (M6G) could also be quantified following 24 h of continuous infusion. M3G/morphine and M6G/morphine plasma concentration ratios increased significantly with increasing birth weight. However, the M6G/M3G plasma concentration ratio decreased with increasing birth weight (and gestational age), thus providing the first indication in vivo of the differential development of uridinediphosphate glucuronosyltransferases in humans.

Topics: Birth Weight; Female; Gestational Age; Humans; Infant, Newborn; Infant, Premature; Kinetics; Male; Morphine; Morphine Derivatives

The glucuronidation of morphine was investigated in 10 premature neonates (postnatal age < 24 h at initiation of treatment) following 24 h of therapy (2 h loading infusion, followed by a constant rate infusion). Morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) were measured in plasma obtained at 24 h in all babies. Plasma concentrations of M3G and M6G correlated significantly with morphine concentration (P < 0.01 in both cases), and with each other (P < 0.001), suggesting that the capacity for morphine glucuronidation in premature neonates is not saturated at the infusion rates used in this study. M3G/morphine and M6G/morphine plasma concentration ratios were independent of morphine infusion rates (P > 0.05) and morphine plasma concentrations (P > 0.05), providing further evidence of linear kinetics. However, M3G/morphine and M6G/morphine plasma concentration ratios increased significantly with increasing birth weight (P < 0.05 in both cases). This probably reflects increase in liver weight with increasing birth weight. Although morphine glucuronidation is deficient in premature neonates, significant concentrations of the respiratory stimulant M3G are achieved rapidly (20% of morphine plasma concentrations at 2 h). At this time, the respiratory depressant M6G could not be detected.

Topics: Birth Weight; Female; Humans; Infant, Newborn; Infant, Premature; Male; Morphine; Morphine Derivatives