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

Phase 3

Completed

Conditions: Neonatal Abstinence Syndrome

Interventions: Drug: oral morphine
Drug: sublingual buprenorphine

Registration Number: NCT01452789

Lead Sponsor: Thomas Jefferson University

Brief Summary: 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: 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).

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 63

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
oral morphine	oral morphine	This is the group that received active oral morphine and placebo for sublingual buprenorphine
sublingual buprenorphine	sublingual buprenorphine	This is the group that received active sublingual buprenorphine and placebo for oral morphine

Primary Outcome Measures

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

Secondary Outcome Measures

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