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

• ClinicalTrials.gov Identifier: NCT01754324
• Recruitment Status: Completed
• First Posted: December 21, 2012
• Last Update Posted: June 13, 2014
• Sponsor: Children's Hospital Medical Center, Cincinnati
• Collaborator: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Information provided by (Responsible Party): Jason Wiles, MD, Children's Hospital Medical Center, Cincinnati

Study Description

Brief Summary:

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).

Condition or disease	Intervention/treatment
Neonatal Abstinence Syndrome	Drug: Methadone

Study Design

• Study Type: Observational
• Actual Enrollment: 20 participants
• Observational Model: Cohort
• Time Perspective: Prospective
• Official Title: The Utility and Pharmacokinetics of Oral Methadone in the Treatment of Neonatal Abstinence Syndrome in Neonates
• Study Start Date: December 2012
• Actual Primary Completion Date: December 2013
• Actual Study Completion Date: December 2013

Groups and Cohorts

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 Name: methadone hydrochloride

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

1. Failed Protocol Wean [ Time Frame: Participants will be followed for the duration of the hospital stay (an expected average of 4 weeks). ]
   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.
2. Number of participants requiring adjunctive pharmacological treatment [ Time Frame: Participants will be followed for the duration of the hospital stay (an expected average of 4 weeks). ]
   This endpoint will look at the number of patients who require supplemental phenobarbital in the treatment of NAS symptoms.
3. Length of hospitalization [ Time Frame: Participants will be followed for the duration of the hospital stay (an expected average of 4 weeks). ]
   This endpoint will describe the number of days infants were hospitalized for treatment of NAS.
4. Readmission to the hospital [ Time Frame: 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. ]
   This endpoint will describe the number of infants treated for NAS who later developed withdrawal symptoms after discharge that required readmission to the hospital.
5. Clinical resolution of NAS symptoms [ Time Frame: 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. ]
   The length of medical therapy with oral methadone (in days) required to result in the clinical resolution of NAS symptoms will be measured.

Eligibility Criteria

• Ages Eligible for Study: up to 1 Month (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No
• Sampling Method: Non-Probability Sample

Study Population

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

Criteria

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

Contacts and Locations

Locations

United States, Ohio

The University Hospital

Cincinnati, Ohio, United States, 45229

Mercy Hospital Anderson

Cincinnati, Ohio, United States, 45255

Sponsors and Collaborators

Children's Hospital Medical Center, Cincinnati

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

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Jason Wiles, MD, Neonatology Fellow, Children's Hospital Medical Center, Cincinnati
• ClinicalTrials.gov Identifier: NCT01754324
• Other Study ID Numbers: CCHMC-PK-1; 5T32HD069054 ( U.S. NIH Grant/Contract )
• First Posted: December 21, 2012
• Last Update Posted: June 13, 2014
• Last Verified: June 2014

Keywords provided by Jason Wiles, MD, Children's Hospital Medical Center, Cincinnati:

Neonatal Abstinence Syndrome; Pharmacokinetics; Methadone; Neonate; Newborn

Additional relevant MeSH terms:

Neonatal Abstinence Syndrome; Syndrome; Disease; Pathologic Processes; Infant, Newborn, Diseases; Substance-Related Disorders; Chemically-Induced Disorders; Mental Disorders; Methadone; Analgesics, Opioid; Narcotics; Central Nervous System Depressants; Physiological Effects of Drugs; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Antitussive Agents; Respiratory System Agents