Newborns admitted to neonatal intensive care units (NICUs) undergo a variety of painful procedures and stressful events. Because the effect of continuous morphine infusion in preterm neonates has not ...been investigated systematically, there is confusion regarding whether morphine should be used routinely in this setting.
To evaluate the effects of continuous intravenous morphine infusion on pain responses, incidence of intraventricular hemorrhage (IVH), and poor neurologic outcome (severe IVH, periventricular leukomalacia, or death).
A randomized, double-blind, placebo-controlled trial conducted between December 2000 and October 2002 in 2 level III NICUs in the Netherlands of 150 newborns who had received ventilatory support (inclusion criteria: postnatal age younger than 3 days and ventilation for less than 8 hours; exclusion criteria: severe asphyxia, severe IVH, major congenital malformations, and administration of neuromuscular blockers).
Intravenous morphine (100 microg/kg and 10 microg/kg per hour) or placebo infusion was given for 7 days (or less because of clinical necessity in several cases).
The analgesic effect of morphine, as assessed using validated scales; the effect of morphine on the incidence of IVH; and poor neurologic outcome.
The analgesic effect did not differ between the morphine and placebo groups, judging from the following median (interquartile range) pain scores: Premature Infant Pain Profile, 10.1 (8.2-11.6) vs 10.0 (8.2-12.0) (P =.94); Neonatal Infant Pain Scale, 4.8 (3.7-6.0) vs 4.8 (3.2-6.0) (P =.58); and visual analog scale, 2.8 (2.0-3.9) vs 2.6 (1.8-4.3) (P =.14), respectively. Routine morphine infusion decreased the incidence of IVH (23% vs 40%, P =.04) but did not influence poor neurologic outcome (10% vs 16%, P =.66). In addition, analyses were adjusted for the use of additional open-label morphine (27% of morphine group vs 40% of placebo group, P =.10).
Lack of a measurable analgesic effect and absence of a beneficial effect on poor neurologic outcome do not support the routine use of morphine infusions as a standard of care in preterm newborns who have received ventilatory support. Follow-up is needed to evaluate the long-term effects of morphine infusions on the neurobehavioral outcomes of prematurity.
Data on contributors to between-individual variability in overall tramadol clearance and O-demethyl tramadol (M1) formation in preterm neonates and young infants are limited.
A population ...pharmacokinetic analysis of tramadol and M1 was undertaken using non-linear mixed effects model. Covariate analysis included weight, postmenstrual age (PMA), postnatal age (PNA), creatinaemia, (cardiac) surgery, cardiac defect, and cytochrome (CYP)2D6 polymorphisms, classified by CYP2D6 activity score.
In 57 patients (25–54 weeks PMA), 593 observations were collected. Tramadol clearance was described using a two-compartment, zero-order input, first-order elimination linear model. An additional compartment was used to characterize M1. Tramadol clearance at term age was 17.1 litre h−1 (70 kg)−1 (CV, 37.2%). Size (37.8%) and PMA (27.3%) contribute to this variability. M1 formation clearance (CL2M1, i.e. the contribution of M1 synthesis to M clearance) was 4.11 litre h−1 (70 kg)−1 (CV, 110.9%) at term age. Size and PMA were the major contributors to the variability (52.7%); the CYP2D6 activity score contributes 6.4% to this variability.
Overall tramadol clearance estimates confirm earlier reports while CL2M1 variability is explained by size, PMA, and CYP2D6 polymorphisms. The CL2M1 is very low in preterm neonates, irrespective of the CYP2D6 polymorphism with subsequent rapid maturation. The slope of this increase depends on the CYP2D6 activity score. The current pharmacokinetic observations suggest a limited μ-opioid receptor-mediated analgesic effect of M1 in preterm neonates and a potential CYP2D6 polymorphism-dependent effect beyond term age.
Tramadol is potentially a very useful pain relief medication in neonates and infants. It is primarily metabolized into O-demethyl tramadol (M1) by CYP2D6. Data concerning tramadol disposition and ...CYP2D6 activity in young infants are not available.
A population pharmacokinetic analysis of tramadol and M1 time–concentration profiles was undertaken using non-linear mixed-effects models (NONMEM), based on newly collected data on tramadol and M1 time–concentration profiles in neonates and young infants (n=20) and published studies on intravenous tramadol in children and adults. M1 formation served as a surrogate for CYP2D6 activity.
Tramadol clearance was described using a two-compartment linear model with zero-order input and first-order elimination. Clearance increased from 25 weeks post-conception age (PCA) (5.52 litre h−1 70 kg−1) to reach 84% of the mature value by 44 weeks PCA (standardized to a 70 kg adult using allometric ‘1/4 power’ models). The central volume of distribution decreased from 25 weeks PCA (256 litre 70 kg−1) to reach 120% of its mature value by 87 weeks PCA. Formation clearance to M1 contributed 43% of tramadol clearance, but had no relationship with PCA. There was a weak non-linear relationship between PCA and M1 metabolite clearance.
Maturational clearance of tramadol is almost complete by 44 weeks PCA. A target concentration of 300 µg litre−1 is achieved after a bolus of tramadol hydrochloride 1 mg kg−1 and can be maintained by infusion of tramadol hydrochloride 0.09 mg kg−1 h−1 at 25 weeks PCA, 0.14 mg kg−1 h−1 at 30 weeks PCA, 0.17 mg kg−1 h−1 at 35 weeks PCA, 0.18 mg kg−1 h−1 at 40 weeks, 0.19 mg kg−1 h−1 at 50 weeks PCA to 1 yr, 0.18 mg kg−1 h−1 at 3 yr and 0.12 mg kg−1 h−1 in adulthood. CYP2D6 activity was observed as early as 25 weeks PCA, but the impact of CYP2D6 polymorphism on the variability in pharmacokinetics, metabolism and pharmacodynamics of tramadol remains to be established.
During human development impressive changes in drug disposition occur. An important determinant of drug clearance is metabolism, something that is not only determined by ontogenic regulation but also ...by genetic processes which add to the variability of drug metabolism during different stages of childhood. Therefore, an understanding of the developmental regulation of different metabolic pathways, together with information on the genetic determinants of drug metabolism, will increase the knowledge of inter- and intraindividual variability in drug disposition during childhood. Conjugation has historically received less attention than cytochrome P450 metabolism. An important group of conjugation reactions are catalysed by the uridine 5'-diphosphate (UDP)-glucuronosyltransferases (UGTs); to date at least 10 different UGT isoforms have been identified. The UGTs are not only involved in the metabolism of many drugs e.g. morphine, paracetamol (acetaminophen) but also capable of the biotransformation of important endogenous substrates (e.g. bilirubin, ethinylestradiol) and several xenobiotics. Isoform specificity for these substrates has, however, not been fully characterised. Serious adverse events associated with chloramphenicol toxicity in the neonate have highlighted the importance of developmental changes in UGT activity. However, isoform-specific differences preclude the generalisation of a simple developmental pattern for UGT activity. UGT2B7 is the only UGT isoform for which ontogeny has been characterised both in vitro and in vivo, using morphine as the probe drug. However, no general developmental pattern for the individual UGT isoforms which might be of value for the clinician is currently available. Genetic polymorphisms have been identified for the UGT family. Not only for the UGT1A gene, which reduces bilirubin glucuronidation, leading to genetic hyperbilirubinaemia (the Crigler-Najjar and Gilbert's syndromes), but also for 3 other UGT isoforms. However, the impact of these genetic differences on drug metabolism remains to be established because of overlapping isoform specificity of the drugs studied, as well as a lack of specific probe substrates to test the activity of individual UGT isoforms in relation to these gene mutations. Clearly, an information gap exists regarding the developmental and genetic aspects of UGT regulation and its potential impact on therapy. More research is needed on the pharmacogenetics and ontogeny of the UGTs for effective translation of scientific information into clinically applicable knowledge.
To investigate age-related differences in morphine requirements and metabolism in full-term neonates.
Randomized double-blind study in the pediatric surgical intensive care unit.
Sixty-eight neonates ...(52 aged under 7 days, 16 aged 7 day or older) following major surgery.
After surgery patients were randomly assigned to continuous morphine (10 micro g/kg per hour) or intermittent morphine (30 micro g/kg per 3 hours). Additional morphine was administered on guidance of pain scores.
Pain was measured by the Comfort behavioral scale and visual analogue scale. Morphine and morphine-6-glucuronide (M6G) plasma concentrations were determined before and 0, 6, 12, and 24 h after surgery. The younger neonates differed significantly from the older neonates in morphine requirement (median 10 vs. 10.8 micro g/kg per hour), morphine plasma concentration 23.0 vs. 15.3 ng/ml), and M6G/morphine ratio (0.6 vs. 1.5). Pain scores did not differ between age groups or morphine treatment groups. Neonates who were mechanically ventilated longer than 24 h had significantly higher morphine plasma concentrations than the spontaneously breathing neonates 12 and 24 h after surgery (29.1 vs. 13.1 ng/ml and 26.9 vs. 12.0 ng/ml, respectively). Morphine plasma concentrations were not correlated with analgesia or respiratory depression. Five neonates (intermittent morphine) showed respiratory insufficiency; however, the difference between the groups was not significant.
Neonates aged 7 days or younger require significantly less morphine postoperatively than older neonates. The two morphine regimens (continuous, intermittent) were equally effective and safe. Mechanical ventilation decreases morphine metabolism and clearance.
To investigate clinical variables such as gestational age, sex, weight, the therapeutic regimens used and mechanical ventilation that might affect morphine requirements and plasma concentrations of ...morphine and its metabolites.
In a double-blind study, neonates and infants stratified for age group I 0–4 weeks (neonates), group II ≥4–26 weeks, group III ≥26–52 weeks, group IV ≥1–3 yr admitted to the paediatric intensive care unit after abdominal or thoracic surgery received morphine 100 µg kg−1 after surgery, and were randomly assigned to either continuous morphine 10 µg kg−1 h−1 or intermittent morphine boluses 30 µg kg−1every 3 h. Pain was measured using the COMFORT behavioural scale and a visual analogue scale. Additional morphine was administered on guidance of the pain scores. Morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) plasma concentrations were measured before, directly after, and at 6, 12 and 24 h after surgery.
Multiple regression analysis of different variables revealed that age was the most important factor affecting morphine requirements and plasma morphine concentrations. Significantly fewer neonates required additional morphine doses compared with all other age groups (P<0.001). Method of morphine administration (intermittent vs continuous) had no significant influence on morphine requirements. Neonates had significantly higher plasma concentrations of morphine, M3G and M6G (all P<0.001), and significantly lower M6G/morphine ratio (P<0.03) than the older children. The M6G/M3G ratio was similar in all age groups.
Neonates have a narrower therapeutic window for postoperative morphine analgesia than older age groups, with no difference in the safety or effectiveness of intermittent doses compared with continuous infusions in any of these age groups. In infants >1 month of age, analgesia is achieved after morphine infusions ranging from 10.9 to 12.3 µg kg−1 h−1 at plasma concentrations of <15 ng ml−1.
Br J Anaesth 2003; 90: 642–52
Adolescents infected with human immunodeficiency virus (HIV) represent a heterogeneous group of pubertal children and young adults. Antiretroviral therapy (ART) in adolescents is complex and depends ...on multiple factors. The continued use of higher (weight‐ or surface‐based) pediatric doses can result in potentially toxic drug exposure, whereas early introduction of lower adult doses can lead to the development of drug resistance and virologic failure. The physiological and psychosocial changes during puberty create strong grounds for an individualized therapeutic approach in HIV‐infected adolescents.
Clinical Pharmacology & Therapeutics (2008); 84, 6, 734–740 doi:10.1038/clpt.2008.187
Paracetamol (acetaminophen) is the most widely used drug to treat pain or fever in pregnant women or neonates, but its pharmacokinetics (PK) and pharmacodynamics (PD) warrant a focused analysis. ...During pregnancy, there is an important increase in paracetamol clearance. Consequently, it is reasonable to anticipate that the analgesic effect of paracetamol will decrease faster, whereas higher doses may result in even higher oxidative toxic metabolites. Therefore, most peripartal PD data relate to multimodal analgesia strategies. In neonates, weight/size is the most relevant covariate of paracetamol PK. This resulted in proposed dosing regimens containing higher doses than currently prescribed in the label for term neonates. Using adequate dosing, paracetamol is a poor procedural analgesic, is effective for mild-to-moderate pain, and has morphine-sparing effects. Short-term safety has been well documented, and there is active research investigating the potential association between paracetamol exposure and atopy, fertility, and neurobehavior.
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