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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01452789
Recruitment Status : Completed
First Posted : October 17, 2011
Results First Posted : March 24, 2020
Last Update Posted : March 24, 2020
National Institute on Drug Abuse (NIDA)
Information provided by (Responsible Party):
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.

Condition or disease Intervention/treatment Phase
Neonatal Abstinence Syndrome Drug: sublingual buprenorphine Drug: oral morphine Phase 3

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).

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 63 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Randomized, Active-Control, Double-Blind, Double-Dummy Clinical Trial Comparing Sublingual Buprenorphine And Morphine Solution For The Treatment Of Neonatal Opioid Abstinence Syndrome
Study Start Date : November 2011
Actual Primary Completion Date : June 2016
Actual Study Completion Date : June 2016

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: sublingual buprenorphine
This is the group that received active sublingual buprenorphine and placebo for oral morphine
Drug: sublingual buprenorphine
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
Other Name: Buprenex

Active Comparator: oral morphine
This is the group that received active oral morphine and placebo for sublingual buprenorphine
Drug: oral morphine
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

Primary Outcome Measures :
  1. Length of Treatment [ Time Frame: 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 :
  1. Length of Hospitalization [ Time Frame: 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.

  2. Number of Patients Requiring Supplemental Phenobarbital Treatment. [ Time Frame: 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.

  3. Number of Participants With Adverse Events as a Measure of Safety and Tolerability [ Time Frame: 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.

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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01452789

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United States, Pennsylvania
Thomas Jefferson University Hosptial
Philadelphia, Pennsylvania, United States, 19107
Sponsors and Collaborators
Thomas Jefferson University
National Institute on Drug Abuse (NIDA)
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Principal Investigator: Walter K Kraft, MD Thomas Jeffeson University
Publications automatically indexed to this study by Identifier (NCT Number):
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Responsible Party: Thomas Jefferson University Identifier: NCT01452789    
Other Study ID Numbers: 11F.193
R01DA029076-01A1 ( U.S. NIH Grant/Contract )
First Posted: October 17, 2011    Key Record Dates
Results First Posted: March 24, 2020
Last Update Posted: March 24, 2020
Last Verified: March 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Interested investigators should contact the PI listed on Study protocol, statistical action plan and informed consent are available in the public domain as a supplement to the publication
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Time Frame: Available after Jan. 1, 2020
Access Criteria: PI and co-investigators will have discretion to share data with potential collaborators.
Keywords provided by Thomas Jefferson University:
neonatal abstinence syndrome
Additional relevant MeSH terms:
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Neonatal Abstinence Syndrome
Pathologic Processes
Infant, Newborn, Diseases
Substance-Related Disorders
Chemically-Induced Disorders
Mental Disorders
Analgesics, Opioid
Central Nervous System Depressants
Physiological Effects of Drugs
Sensory System Agents
Peripheral Nervous System Agents
Narcotic Antagonists