The Pharmacokinetics of Oral Methadone in the Treatment of Neonatal Abstinence Syndrome

The Utility and Pharmacokinetics of Oral Methadone in the Treatment of Neonatal Abstinence Syndrome in Neonates

The chronic use of opiate medications during pregnancy is a major public health challenge. Prolonged exposure to opiates in utero may result in withdrawal symptoms in infants commonly referred to as neonatal abstinence syndrome (NAS). Signs of NAS may include irritability, high-pitched crying, muscle tightness, seizures, diarrhea, vomiting, poor feeding, and unstable body temperature. Many infants may be treated by supportive (non-pharmacological) therapy by minimizing stimulation, cuddling, responding promptly to hunger cues, and other comfort care. However, some infants continue to show severe symptoms of withdrawal despite these interventions. In these cases, infants may be treated with medications (pharmacological therapy). Although it has been several decades since the first descriptions of NAS, there still remains limited information with regards to the most effective treatment. We hypothesize that medical treatment protocols of NAS with methadone can be optimized by better understanding what the body does to the drug (the population-based pharmacokinetics of methadone).

Study Overview

• Status: Completed
• Conditions: Neonatal Abstinence Syndrome
• Intervention / Treatment: Drug: Methadone

• Study Type: Observational
• Enrollment (Actual): 20

Contacts and Locations

Study Locations

• United States
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • The University Hospital
    • Cincinnati, Ohio, United States, 45255
      • Mercy Hospital Anderson

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 1 month (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Infants diagnosed with Neonatal Abstinence Syndrome and are treated with oral methadone.

Description

Inclusion Criteria:

1. Chronic in utero exposure to opiates
2. Term infant, greater than or equal to 37 weeks gestation
3. Failure of non-pharmacologic treatment of NAS
4. Infant meets criteria for pharmacologic treatment of NAS as determined by physical findings consistent with drug withdrawal and Finnegan scoring system
5. The attending neonatologist chooses to treat the qualifying infant with oral methadone.

Exclusion Criteria:

1. Prematurity
2. Congenital Abnormalities
3. Acutely ill neonates
4. Confounding medical illness necessitating therapy with opiates other than for NAS
5. Neonates whose only exposure to opiates were narcotics administered during labor
6. Infants who are wards of the state

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Intervention / Treatment

Methadone; All infants requiring pharmacological treatment of their NAS symptoms are treated with a standardized protocol utilizing oral methadone. This treatment protocol has been the standard of care for infants with NAS at our institution for many years. Infants enrolled in this study will have blood samples drawn at predetermined times in order to obtain information regarding the pharmacokinetics of oral methadone in this population.

Drug: Methadone; The starting dose of the protocol is 0.05mg/kg by mouth given every 6 hours and gradually decreased in a stepwise, standardized fashion.; Other Names: methadone hydrochloride

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Methadone and EDDP (2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine) blood concentration	Timed blood samples will be collected to estimate pharmacokinetic parameters of oral methadone and its major metabolite EDDP using population pharmacokinetic methods.	Participants will be followed for the duration of the hospital stay (an expected average of 4 weeks).

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Failed Protocol Wean	Blood specimens for the analysis of methadone and EDDP concentrations will be obtained from infants who do not tolerate the standard methadone dosing taper to investigate its utility in identifying rapid metabolizers of methadone.	Participants will be followed for the duration of the hospital stay (an expected average of 4 weeks).
Number of participants requiring adjunctive pharmacological treatment	This endpoint will look at the number of patients who require supplemental phenobarbital in the treatment of NAS symptoms.	Participants will be followed for the duration of the hospital stay (an expected average of 4 weeks).
Length of hospitalization	This endpoint will describe the number of days infants were hospitalized for treatment of NAS.	Participants will be followed for the duration of the hospital stay (an expected average of 4 weeks).
Readmission to the hospital	This endpoint will describe the number of infants treated for NAS who later developed withdrawal symptoms after discharge that required readmission to the hospital.	Participants will be followed for the duration of the hospital stay (an expected average of 4 weeks) and will complete a follow-up survey up to 2 weeks after hospital discharge.
Clinical resolution of NAS symptoms	The length of medical therapy with oral methadone (in days) required to result in the clinical resolution of NAS symptoms will be measured.	Participants will be followed for the duration of the hospital stay (an expected average of 4 weeks) and will complete a follow-up survey up to 2 weeks after hospital discharge.

Collaborators and Investigators

• Sponsor: Children's Hospital Medical Center, Cincinnati
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Investigators: Principal Investigator: Jason R Wiles, MD, Children's Hospital Medical Center, Cincinnati; Principal Investigator: Henry Akinbi, MD, Children's Hospital Medical Center, Cincinnati; Principal Investigator: Alexander Vinks, PharmD, PhD, Children's Hospital Medical Center, Cincinnati

Publications and helpful links

General Publications

• Wiles JR, Isemann B, Mizuno T, Tabangin ME, Ward LP, Akinbi H, Vinks AA. Pharmacokinetics of Oral Methadone in the Treatment of Neonatal Abstinence Syndrome: A Pilot Study. J Pediatr. 2015 Dec;167(6):1214-20.e3. doi: 10.1016/j.jpeds.2015.08.032. Epub 2015 Sep 11.

Study record dates

Study Major Dates

• Study Start: December 1, 2012
• Primary Completion (Actual): December 1, 2013
• Study Completion (Actual): December 1, 2013

Study Registration Dates

• First Submitted: December 14, 2012
• First Submitted That Met QC Criteria: December 18, 2012
• First Posted (Estimate): December 21, 2012

Study Record Updates

• Last Update Posted (Estimate): June 13, 2014
• Last Update Submitted That Met QC Criteria: June 12, 2014
• Last Verified: June 1, 2014

More Information

Terms related to this study

• Keywords: Pharmacokinetics; Methadone; Newborn; Neonate; Neonatal Abstinence Syndrome
• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Pathologic Processes; Substance-Related Disorders; Disease; Infant, Newborn, Diseases; Syndrome; Neonatal Abstinence Syndrome; 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: CCHMC-PK-1; 5T32HD069054 (U.S. NIH Grant/Contract)