Blinded Trial of Buprenorphine or Morphine in the Treatment of the Neonatal Abstinence Syndrome

Study Overview
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Brief Summary
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The opioid neonatal abstinence syndrome (NAS) is a condition of withdrawal symptoms after utero exposure to opioids. In an open label Phase 1 trial sublingual buprenorphine was associated with a  30% reduction length of treatment compared to standard of care morphine. Due to the subjective nature of the scoring instrument, efficacy in a blinded trial is needed to unequivocally establish the superiority of buprenorphine over morphine. The primary objective of the trial is to compare length of treatment using sublingual buprenorphine or oral morphine solution in the pharmacologic treatment of the NAS.

Detailed Description
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This was a single-site, randomized, double-blind, double-dummy, parallel-group clinical trial. Potential patients were identified in the pre-natal period by staff of the Thomas Jefferson University Family center. Mothers who provided consent were contacted upon admission to TJUH. Inclusion and exclusion criteria were reassessed during the peri-partum period and study details reviewed again with the mother, and where possible, the father of the child. Women admitted to TJUH with in utero exposure to opioids who are not in the Family Center present were screened and approached for consent during their inpatient stay. Infants at risk for NAS had abstinence assessed using the MOTHER scoring instrument, which is based upon Finnegan Score and will hereafter be called the NAS score. This is the standard instrument used at TJUH. A need for initiation of treatment was defined as any consecutive 3 scores adding up to ≥ 24 or any single score ≥12, and the clinical decision of the attending physician that the infant requires pharmacologic therapy. Randomization took place following reaching of the threshold for initiation of treatment and a re-review of inclusion and exclusion criteria. Patients were randomized to treatment groups of 1) oral morphine/sublingual placebo for buprenorphine or 2) oral placebo for morphine/sublingual buprenorphine. Randomization was stratified according to in utero exposure to methadone or buprenorphine. Oral morphine or placebo for morphine was administered by mouth every 4 hours, while buprenorphine or placebo for buprenorphine was administered every 8 hours. NAS scores were obtained every 4 hours. Dose assessment took place on a daily basis. If the three previous NAS scores are greater than 24, a dose advancement took place (at the discretion of the neonatologist). Morphine/placebo will be increased by 20% and buprenorphine/placebo will be increased by 25%. NNNS scoring took place for all infants who provide consent at day 2-3 of life, or earlier if pharmacologic treatment is required before this time, on day 10 of life, and in the post therapy period (but no later than corrected post gestational age of 46 weeks).

Official Title
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A Randomized, Active-Control, Double-Blind, Double-Dummy Clinical Trial Comparing Sublingual Buprenorphine And Morphine Solution For The Treatment Of Neonatal Opioid Abstinence Syndrome

Conditions
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Neonatal Abstinence Syndrome

Intervention / Treatment
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* Drug: sublingual buprenorphine
* Drug: oral morphine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ≥ 37 weeks gestation Exposure to opiates in utero Demonstration of signs and symptoms of neonatal abstinence syndrome requiring treatment Exclusion Criteria: Major congenital malformations and/or intrauterine growth retardation Medical illness requiring intensification of medical therapy. This includes, but is not limited to suspected sepsis requiring antibiotic therapy. Hypoglycemia requiring treatment with intravenous dextrose. Bilirubin >20 mg/dL (The need for phototherapy is not exclusionary) Concomitant benzodiazepine or severe alcohol abuse , self-report of regular use of alcohol or of benzodiazepines use in the past 30 days, and/or receipt of benzodiazepines by prescription (as determined by self-report or intake urine) by the mother 30 days prior to birth, Concomitant use of Cytrochrom (CYP) 3A inhibitors (erythromycin, clarithromycin, ketoconazole, itraconazole, HIV protease inhibitors) or inducers (rifampin, carbamazepine, phenobarbital) prior to initiation of NAS treatment Seizure activity or other neurologic abnormality Breast feeding Inability of mother to give informed consent due to co-morbid psychiatric diagnosis
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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: sublingual buprenorphine<br>This is the group that received active sublingual buprenorphine and placebo for oral morphine | Drug: sublingual buprenorphine<br>* Initial daily dose: 15.9 mcg/kg/day; Initial unit dose: 5.3 mcg/kg q8 hours; Maximum daily dose: 60 mcg/kg/day; Up-titration rate: 25%; Weaning rate: 10%; Cessation Dose: Within 10 or 20% of starting dose<br>* Other names: Buprenex;|
| Active Comparator: oral morphine<br>This is the group that received active oral morphine and placebo for sublingual buprenorphine | Drug: oral morphine<br>* Initial daily dose: 0.4 mg/kg/day; Initial unit dose: 0.07 mg/kg q 4 hours; Maximum daily dose: 1.25 mg/kg/day; Up-titration rate: 20%; Weaning rate: 10%; Cessation Dose: 0.025 mg/kg q 4 hours<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Length of Treatment | This endpoint will compare length of treatment (in days) using sublingual buprenorphine or oral morphine solution. | Patients will be followed for the duration of hospital stay, an expected average of 5 weeks. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Length of Hospitalization | This endpoint will compare length of stay in the hospital (in days) using sublingual buprenorphine or morphine solution. | Duration of hospital stay is an expected average of 5 weeks. | 
| Number of Patients Requiring Supplemental Phenobarbital Treatment. | This endpoint will compare requirement number of patients who require use of supplemental phenobarbital. | Patients will be followed for the duration of hospital stay, an expected average of 5 weeks. | 
| Number of Participants With Adverse Events as a Measure of Safety and Tolerability | Adverse events will be collected, graded by severity, and assessed for causality referent to study drug. | Patients will be followed for the duration of hospital stay, an expected average of 5 weeks. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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buprenorphine, neonatal abstinence syndrome, morphine, pharmacokinetics