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

Study Overview
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Brief Summary
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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).

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

Conditions
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Neonatal Abstinence Syndrome

Intervention / Treatment
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* Drug: Methadone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Chronic in utero exposure to opiates Term infant, greater than or equal to 37 weeks gestation Failure of non-pharmacologic treatment of NAS Infant meets criteria for pharmacologic treatment of NAS as determined by physical findings consistent with drug withdrawal and Finnegan scoring system The attending neonatologist chooses to treat the qualifying infant with oral methadone. Exclusion Criteria: Prematurity Congenital Abnormalities Acutely ill neonates Confounding medical illness necessitating therapy with opiates other than for NAS Neonates whose only exposure to opiates were narcotics administered during labor Infants who are wards of the state

Ages Eligible for Study
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Maximum Age: 1 Month

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Methadone<br>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<br>* The starting dose of the protocol is 0.05mg/kg by mouth given every 6 hours and gradually decreased in a stepwise, standardized fashion.<br>* Other names: methadone hydrochloride;|

What is the study measuring?
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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. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Neonatal Abstinence Syndrome, Pharmacokinetics, Methadone, Neonate, Newborn