ArticlePaediatric anaesthesia2014
The pharmacokinetics of methadone and its metabolites in neonates, infants, and children.
Article in Paediatric anaesthesia, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to 3 registered trials, which are not on this map. Cited by 33 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
A Randomized, Double-blind, Controlled, Multi-site Study of the Pharmacokinetics and Pharmacodynamics of Methadone vs. Morphine During Mechanical Ventilation Following Cardiac Surgery in Neonates, Infants and Children
The Effect of Methadone vs. Fentanyl Administration on Postoperative Pain Control in Pediatric Patients Undergoing Cardiac Surgery: A Randomized, Double-Blinded Controlled Trial
Methadone for Emergence Delirium in Children Undergoing Outpatient Strabismus Surgery
Who cites it
33 citing papers in PubMed, 83 citations in OpenAlex.
- Trial
- Comparison of Safety and Efficacy of Methadone vs Morphine for Treatment of Neonatal Abstinence Syndrome: A Randomized Clinical Trial.JAMA pediatrics · 2018Trial
- Pharmacokinetics and analgesic effects of methadone in children and adults with sickle cell disease.Pediatric blood & cancer · 2016Trial
- Pharmacokinetics of Oral Methadone in the Treatment of Neonatal Abstinence Syndrome: A Pilot Study.The Journal of pediatrics · 2015Trial
- Methadone versus morphine for treatment of neonatal abstinence syndrome: a prospective randomized clinical trial.Journal of perinatology : official journal of the California Perinatal Association · 2015Trial
- Application of Pharmacometric Modelling Towards Precise Dosing in Neonates, Infants and Toddlers: A Scoping Review.Clinical pharmacokinetics · 2026Review
- A Scoping Review of Non-Opioid Therapeutics for Opioid Withdrawal: Translational Relevance to Neonatal Opioid Withdrawal Syndrome (NOWS) Research.Clinical and translational science · 2026Article
- Article
- Visceral Pain in Preterm Infants with Necrotizing Enterocolitis: Underlying Mechanisms and Implications for Treatment.Paediatric drugs · 2025Review
- Accidental Methadone Toxicity in a 3-Year-Old Leading to Severe Cerebellitis and Death: A Case Report.Case reports in pediatrics · 2025Article
- What we know and what we don't know about the perioperative use of methadone in children and adolescents.Paediatric anaesthesia · 2023Review
- Potential problems and solutions of opioid-based treatment in neonatal opioid withdrawal syndrome (NOWS): a scoping review protocol.BMJ open · 2023Article
- Use of physiologically-based pharmacokinetic modeling to inform dosing of the opioid analgesics fentanyl and methadone in children with obesity.CPT: pharmacometrics & systems pharmacology · 2022Article
- Pharmacokinetic Pharmacodynamic Modelling Contributions to Improve Paediatric Anaesthesia Practice.Journal of clinical medicine · 2022Review
- Pharmacokinetic modeling of R and S-Methadone and their metabolites to study the effects of various covariates in post-operative children.CPT: pharmacometrics & systems pharmacology · 2021Article
- Clinical pharmacology and dosing regimen optimization of neonatal opioid withdrawal syndrome treatments.Clinical and translational science · 2021Review
- Stereoselective Analysis of Methadone and EDDP in Laboring Women and Neonates in Plasma and Dried Blood Spots and Association with Neonatal Abstinence Syndrome.American journal of perinatology · 2021Article
- Towards Evidence-Based Weaning: a Mechanism-Based Pharmacometric Model to Characterize Iatrogenic Withdrawal Syndrome in Critically Ill Children.The AAPS journal · 2021Article
- Methadone effectively attenuates acute and long-term consequences of neonatal repetitive procedural pain in a rat model.Pediatric research · 2021Article
- Methadone: applications in pediatric anesthesiology and critical care medicine.Journal of anesthesia · 2021Review
Corrections and comments
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Authors and funding
9 authors at 4 institutions in 2 countries.
Funding
Abstract
backgroundThe lack of methadone pharmacokinetic data in children and neonates restrains dosing to achieve the target concentration in these populations. A minimum effective analgesic concentration of methadone in opioid naïve adults is 0.058 mg·l(-1) , while no withdrawal symptoms were observed in neonates suffering opioid withdrawal if plasma concentrations of methadone were above 0.06 mg·l(-1) . The racemate of methadone which is commonly used in pediatric and anesthetic care is metabolized to 2-ethylidine-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) and 2-ethyl-5-methyl-3,3-diphenylpyrroline (EMDP).
methodsData from four studies (age 33-week PMA-15 years) were pooled (n = 56) for compartment analysis using nonlinear mixed effects modeling. Parameter estimates were standardized to a 70-kg person using an allometric model approach. Investigation was made of the racemate and metabolite (EDDP and EMDP) dispositions. In addition, neonatal data (n = 7) allowed further study of R- and S-enantiomer pharmacokinetics.
resultsA three-compartment linear disposition model best described the observed time-concentration profiles with additional compartments for metabolites. Population parameter estimates (between-subject variability) were central volume (V1) 21.5 (29%) l.70 kg(-1) , peripheral volumes of distribution V2 75.1 (23%) l.70 kg(-1) and V3 484 (8%) l.70 kg(-1) , clearance (CL) 9.45 (11%) l·h(-1) .70 kg(-1) , and intercompartment clearances Q2 325 (21%) l·h(-1) .70 kg(-1) and Q3 136 (14%) l·h(-1) .70 kg(-1) . EDDP formation clearance was 9.1 (11%) l·h(-1) .70 kg(-1) , formation clearance of EMDP from EDDP 7.4 (63%) l·h(-1) .70 kg(-1) , elimination clearance of EDDP was 40.9 (26%) l·h(-1) .70 kg(-1) and the rate constant for intermediate compartments 2.17 (43%) h(-1) .
conclusionsCurrent pharmacokinetic parameter estimates in children and neonates are similar to those reported in adults. There was no clearance maturation with age. Neonatal enantiomer clearances were similar to those described in adults. A regimen of 0.2 mg·kg(-1) per 8 h in neonates achieves a target concentration of 0.06 mg·l(-1) within 36 h. Infusion, rather than intermittent dosing, should be considered if this target is to be achieved in older children after cardiac surgery.
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What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.