Randomized Control Trial of Buprenorphine vs. Morphine for the Treatment of Neonatal Opioid Withdrawal Syndrome (NOWS)

Study Overview
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Brief Summary
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This randomized control trial will compare buprenorphine and morphine, two currently used medications for the treatment of neonatal opioid withdrawal syndrome (NOWS), in newborns to determine which medication will reduce the number of days of pharmacological treatment.

Detailed Description
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This randomized control trial will compare buprenorphine to morphine, two currently used medications for the treatment of NOWS, to determine whether the use of buprenorphine for NOWS treatment will reduce the number of days of pharmacological treatment. After an infant is born they will be monitored for signs of NOWS. Once an infant reaches treatment thresholds, they will be randomized using a double dummy design to either the buprenorphine or morphine treatment arm. After randomization infants will receive a syringe with either morphine or placebo every 4 hours and every 8 hours infant will receive 1 sublingual application of buprenorphine or placebo. To maintain the blind infants enrolled in the study will receive both interventions. During the study medication doses will be weaned by 10% of the stabilization dose. Study intervention will continue until 20 percent of the maximal dose has been reached. Use of a second line drug will be permissible after randomization and after an infant has had 2 consecutive escalations. Second line drug will be phenobarbital, in addition to the study drug. Infants in both groups will be evaluated and scored for NOWS symptoms to determine if weaning study medication is permissible each day. NOWS scores that do not reach the threshold for escalation will wean in accordance with standard clinical practice. If NOWS symptoms increase during treatment, infants will have the dose of the study drug increased by 10% to the previous day's dose. When stable for 24 hours, the weaning process will continue. The NICU Network Neurobehavioral Scale (NNNS) will be administered prior to starting study medication and once off study medication but prior to discharge to examine proportion of infants in each medication arm for the abnormal NNNS profiles which has been associated with atypical early childhood outcomes including behavior problems and low IQ scores. Development at 18 months of age will also be assessed to examine any differences in both arms of the study.

Official Title
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Prospective Randomized Blinded Trial to Shorten Pharmacologic Treatment of Newborns With Neonatal Opioid Withdrawal Syndrome (NOWS)

Conditions
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Neonatal Opioid Withdrawal Syndrome

Intervention / Treatment
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* Drug: Buprenorphine or Placebo
* Drug: Morphine or Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Infant gestational age greater than or equal 36 weeks Mother receiving either methadone from a drug treatment program, buprenorphine from a licensed physician, or an opioid prescription for a documented medical need Mother had at least 2 prenatal appointments. Infant toleration of oral medication administration Infant is considered medically stable by the attending physician Singleton Pregnancy English Speaking Exclusion Criteria: Within 30 days of birth the mother has actively used illicit drugs (excluding THC) or obtaining oral opioids, methadone, or buprenorphine from a non-licensed physician or drug treatment program The mother has had less than 2 prenatal care visits The mother reports excessive alcohol use during pregnancy Mother is less than 18 years of age or is not capable of signing consent The infant has a gestational age less than or equal to 35 weeks and 6 days The infant has dysmorphic features including evidence of aneuploidy The infant is not able to tolerate oral medication administration Multiple gestation pregnancy Hypoxic-ischemic encephalopathy Seizures from etiologies other than NOWS Non-English Speaking Infant started on NOWS standard care medication prior to study consent

Ages Eligible for Study
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Minimum Age: 18 Years

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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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Infants will be randomly assigned to treatment arms of either morphine or buprenorphine
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Morphine<br>Infants randomized to the morphine arm will start at a dose of 0.06 mg/kg/dose every 4 hours. A buprenorphine placebo will also be given at the same frequency as a faux drug. | Drug: Buprenorphine or Placebo<br>* The double blind, double dummy design necessitates that both drugs be on an identical schedule. The 4-hour dosing allows for this pairing. If a patient is randomized to the buprenorphine arm, medication administration will follow an every 8-hour dosing but medication will be substituted with placebo during the intermediary time point.<br>Drug: Morphine or Placebo<br>* If a patient is randomized to the morphine arm, morphine will be given every 4 hours. Placebo will also be given at the same frequency as a faux drug.<br>|
| Experimental: Buprenorphine<br>Infants randomized to the buprenorphine arm will be started on a dose of 10 mg/kg/dose every 8 hours. A morphine placebo will also be given at the same frequency as a faux drug. Patients can only be randomized to only one arm. | Drug: Buprenorphine or Placebo<br>* The double blind, double dummy design necessitates that both drugs be on an identical schedule. The 4-hour dosing allows for this pairing. If a patient is randomized to the buprenorphine arm, medication administration will follow an every 8-hour dosing but medication will be substituted with placebo during the intermediary time point.<br>Drug: Morphine or Placebo<br>* If a patient is randomized to the morphine arm, morphine will be given every 4 hours. Placebo will also be given at the same frequency as a faux drug.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total amount of opioid medication for treatment of NOWS | Total amount of opioid medication given to infant for the duration of their hospitalization | Duration of pharmacological treatment with opioid medication while admitted to the hospital up to 30 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Length of total stay | Length of hospital stay due to NOWS | During hospitalization for NOWS up to 30 days | 
| Length of stay secondary to NOWS | Total length of hospital stay secondary to NOWS | During hospitalization for NOWS up to 30 days | 
| Neurobehavioral Profile | Neurobehavior will be assessed with Neonatal Intensive Care Unit (NICU) Network Neurobehavioral Scale (NNNS). The NNNS is a comprehensive evaluation of neurologic and behavioral functioning as well as signs of stress. Profile 5 is the most atypical, and is characterized by exaggerated scores for arousal, excitability, hypertonicity, quality of movement, and stress abstinence. The atypical profile as been associated with atypical early childhood outcomes, including more behavior problems and lower IQ scores. Researchers will compare the proportion of atypical neurobehavioral profiles for infants in each intervention arm. | At birth before randomization to NOWS treatment arm around 18-24 hours of life and prior to hospital discharge up to 30 days of life | 
| Cognitive, Language, and Motor Development From 18 Month Old Bayley Neurodevelopmental Assessment | The Bayley Scales of Infant and Toddler Development (BSID-III) assesses the development of infants and children (1-42 months) through a series of developmental play tasks, identifying children with developmental delay. Raw scores of completed items are summarized within three distinct scale scores (Cognitive Scale, Language Scale, Motor Scale). Scale scores are each converted to composite scores to determine the child's performance compared with scores of age-matched children of typical development (percentile rank). A higher composite score indicates more ideal developmental outcome (range 40-160). At 18 month follow-up visit, participants were assessed using the BSID-III for composite score outcomes. | 18 months old | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Neonatal Opioid Withdrawal Syndrome, Neonatal Abstinence Syndrome