The Use of Methadone in Newborn Infants (Methadone)

Optimizing the Use of Methadone in Newborn Infants

This proposed investigation will test the following hypotheses: 1) Enzymatic activity of CYP2B6 characterized by the formation clearance of methadone to EDDP (CLf,EDDP), is directly related to both gestational and postnatal age; 2) variations in the CYP2B6 gene (SNPs) are associated with variable activity of the CYP2B6 enzyme (as measured by the formation clearance, CLf,EDDP), and 3) the elimination rate of methadone and its major metabolite EDDP in neonates is dependent on the glomerular filtration rate and therefore on the stage of development (defined by both gestational and postnatal age). The investigators propose to develop a PK model for methadone dosing in neonates that takes into account both developmental stage and genetic variability. The long-term goal of the proposed investigations is to improve dosing of methadone in neonates exposed to opioids in utero or post-natally, leading to improved control of their withdrawal syndrome and decreased adverse drug reactions associated with the current use of methadone in these vulnerable patients. More immediately, the investigators will develop a PK model for methadone dosing based on relevant developmental and genetic characteristics. The acquired knowledge based on the proposed study will lead to a more efficacious treatment of pain or opiate withdrawal syndrome in newborn infants with a decreased chance of adverse drug reactions.

Study Overview

• Status: Completed
• Conditions: Premature Birth of Newborn; Critically Ill
• Intervention / Treatment: Drug: Methadone

Detailed Description

The investigators will identify and recruit from the NICU of CNMC 60 preterm neonates uniformly distributed with respect to gestational age and encompassing GA's of from 22 to less than 43 weeks.

• Stratified Selection by Gestational Age (GA): The study neonates will be selected to achieve balance in the following GA strata: (22-24 wks, 25-26 wks, 27-28 wks, 29-30 wks, 31-32 wks, 33-37 wks; 38-43 wks). Stratification will be done to ensure broad representation by GA. As described below, analyses will treat GA as a continuous variable.
• Randomization will assign a newborn infant to group 1 (n=30) or group 2 (n=30).
• Study medications: Methadone and inulin administration Blood and urine will be collected for the purposes of this research project. Blood will be drawn from the indwelling arterial catheter that already is in place for clinical purposes. The amount of blood obtained for all study related determinations will be minimized and kept at less than 3 mL/kg of blood per 48 hour period. The study will last 60 hours for group 1 and 72 hours for group.
• DNA study 0.3ml whole blood will be collected from each subject
• PK study Blood samples (0.2 mL per sample) will be taken in 30 newborn infants at t=0, 1, 4, 12, 36, 60 h (group 1) after the administration of one dose of methadone, and in 30 newborn infants at t=0, 2, 8, 24, 48, 72 hr (group 2) after the administration of methadone. A total of 1.5 ml of blood will be collected from each subject
• Urine Collection Urine samples will be collected from each infant's diaper (wood pulp based study diapers) every 3-4 hours over the first 24 hour period or alternatively, from an indwelling urinary catheter placed based on clinical indications unrelated to the study protocol.

• Study Type: Interventional
• Enrollment (Actual): 60
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Childrens Research Institute
    • Washington, District of Columbia, United States, 20010
      • Childrens's Research Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 5 months to 9 months (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Newborn infants of both genders and all races who have:

  • a postnatal age of less than 3 months
  • an indwelling (peripheral or umbilical) arterial line, and
  • already treated with an opioid (morphine or fentanyl) for clinical reasons

Exclusion Criteria:

• Neonates with severe asphyxia grade III or IV intraventricular hemorrhage,
• Neonates with major congenital malformations or facial malformations (e.g., cleft lip and palate), neurological disorders

• Neonates receiving continuous or intermittent neuromuscular blockers neonates will be excluded who have:

  • clinical or biochemical evidence of hepatic and renal failure (including systemic hypoperfusion
  • received drugs that are CYP2B6 substrates
  • been exposed in utero to methadone, despite the fact that they indeed receive a CYP2B6 substrate through their mother, will not be excluded but will be analyzed as a subgroup

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group 1; Gestational age less than 29 weeks We will substitute for one study dose 0.1 mg morphine with 0.1 mg methadone, whereas if the infant has been treated with fentanyl substitute for that one study dose 1 μg fentanyl with 0.1 mg methadone. Administration of inulin: Inulin will be administered as a glucose 10%-inulin solution containing 25 gr. inulin/L, at an infusion rate of 0.6 mL/kg/h. After 24 h, the inulin clearance will be calculated.	Drug: Methadone; If the infant has been treated with morphine than substitute for that one study dose 0.1 mg morphine with 0.1 mg methadone, whereas if the infant has been treated with fentanyl substitute for that one study dose 1 μg fentanyl with 0.1 mg methadone. Administration of inulin: Inulin will be administered as a glucose 10%-inulin solution containing 25 gr. inulin/L, at an infusion rate of 0.6 mL/kg/h. After 24 h, the inulin clearance will be calculated.; Other Names: inulin (Sinistrin)
Experimental: Group 2; Gestational age greater then 29 weeks We will substitute for that one study dose 0.1 mg morphine with 0.1 mg methadone, whereas if the infant has been treated with fentanyl substitute for that one study dose 1 μg fentanyl with 0.1 mg methadone. Administration of inulin: Inulin will be administered as a glucose 10%-inulin solution containing 25 gr. inulin/L, at an infusion rate of 0.6 mL/kg/h. After 24 h, the inulin clearance will be calculated.	Drug: Methadone; If the infant has been treated with morphine than substitute for that one study dose 0.1 mg morphine with 0.1 mg methadone, whereas if the infant has been treated with fentanyl substitute for that one study dose 1 μg fentanyl with 0.1 mg methadone. Administration of inulin: Inulin will be administered as a glucose 10%-inulin solution containing 25 gr. inulin/L, at an infusion rate of 0.6 mL/kg/h. After 24 h, the inulin clearance will be calculated.; Other Names: inulin (Sinistrin)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Methadone PK and EDDP	Primary outcome: Plasma and urine levels of methadone and EDDP (2-ethylidene- 1,5-dimethyl-3,3-diphenylpyrrolidine, the main metabolite of methadone). Secondary endpoints: CYP2DB6 genetic variability.	36 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
DNA	Secondary endpoints: CYP2DB6 genetic variability.	36 months

Collaborators and Investigators

• Sponsor: John van den Anker

Publications and helpful links

General Publications

• van Donge T, Samiee-Zafarghandy S, Pfister M, Koch G, Kalani M, Bordbar A, van den Anker J. Methadone dosing strategies in preterm neonates can be simplified. Br J Clin Pharmacol. 2019 Jun;85(6):1348-1356. doi: 10.1111/bcp.13906. Epub 2019 Apr 10.

Study record dates

Study Major Dates

• Study Start: December 1, 2010
• Primary Completion (Actual): December 1, 2017
• Study Completion (Actual): December 1, 2017

Study Registration Dates

• First Submitted: March 30, 2011
• First Submitted That Met QC Criteria: March 31, 2011
• First Posted (Estimate): April 1, 2011

Study Record Updates

• Last Update Posted (Actual): July 26, 2018
• Last Update Submitted That Met QC Criteria: July 25, 2018
• Last Verified: July 1, 2018

More Information

Terms related to this study

• Keywords: Methadone; neonates; NICU
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Pregnancy Complications; Obstetric Labor Complications; Obstetric Labor, Premature; Premature Birth; Critical Illness; Physiological Effects of Drugs; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Opioid; Narcotics; Respiratory System Agents; Antitussive Agents; Methadone
• Other Study ID Numbers: 4781 (Other Grant/Funding Number: OPD Grant); IV Methadone (Other Grant/Funding Number: KDA027992A)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No