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

Overview

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.

Full Title of Study: “Prospective Randomized Blinded Trial to Shorten Pharmacologic Treatment of Newborns With Neonatal Opioid Withdrawal Syndrome (NOWS)”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
  • Study Primary Completion Date: May 17, 2021

Detailed Description

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.

Interventions

  • Drug: Buprenorphine or Placebo
    • 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.
  • Drug: Morphine or Placebo
    • 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.

Arms, Groups and Cohorts

  • Active Comparator: Morphine
    • 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.
  • Experimental: Buprenorphine
    • 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.

Clinical Trial Outcome Measures

Primary Measures

  • Total amount of opioid medication for treatment of NOWS
    • Time Frame: Duration of pharmacological treatment with opioid medication while admitted to the hospital up to 30 days
    • Total amount of opioid medication given to infant for the duration of their hospitalization

Secondary Measures

  • Length of total stay
    • Time Frame: During hospitalization for NOWS up to 30 days
    • Length of hospital stay due to NOWS
  • Length of stay secondary to NOWS
    • Time Frame: During hospitalization for NOWS up to 30 days
    • Total length of hospital stay secondary to NOWS
  • Neurobehavioral Profile
    • Time Frame: 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
    • 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.
  • Cognitive, Language, and Motor Development From 18 Month Old Bayley Neurodevelopmental Assessment
    • Time Frame: 18 months old
    • 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.

Participating in This Clinical Trial

Inclusion Criteria

1. Infant gestational age greater than or equal 36 weeks 2. Mother receiving either methadone from a drug treatment program, buprenorphine from a licensed physician, or an opioid prescription for a documented medical need 3. Mother had at least 2 prenatal appointments. 4. Infant toleration of oral medication administration 5. Infant is considered medically stable by the attending physician 6. Singleton Pregnancy 7. English Speaking Exclusion Criteria:

1. 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 2. The mother has had less than 2 prenatal care visits 3. The mother reports excessive alcohol use during pregnancy 4. Mother is less than 18 years of age or is not capable of signing consent 5. The infant has a gestational age less than or equal to 35 weeks and 6 days 6. The infant has dysmorphic features including evidence of aneuploidy 7. The infant is not able to tolerate oral medication administration 8. Multiple gestation pregnancy 9. Hypoxic-ischemic encephalopathy 10. Seizures from etiologies other than NOWS 11. Non-English Speaking 12. Infant started on NOWS standard care medication prior to study consent

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Women and Infants Hospital of Rhode Island
  • Collaborator
    • National Institute of General Medical Sciences (NIGMS)
  • Provider of Information About this Clinical Study
    • Principal Investigator: James Padbury, Principal Investigator – Women and Infants Hospital of Rhode Island
  • Overall Official(s)
    • Adam J Czynski, DO, Principal Investigator, Women and Infants Hospital

References

Lester BM, Tronick EZ, Brazelton TB. The Neonatal Intensive Care Unit Network Neurobehavioral Scale procedures. Pediatrics. 2004 Mar;113(3 Pt 2):641-67.

Davis JM, Shenberger J, Terrin N, Breeze JL, Hudak M, Wachman EM, Marro P, Oliveira EL, Harvey-Wilkes K, Czynski A, Engelhardt B, D'Apolito K, Bogen D, Lester B. Comparison of Safety and Efficacy of Methadone vs Morphine for Treatment of Neonatal Abstinence Syndrome: A Randomized Clinical Trial. JAMA Pediatr. 2018 Aug 1;172(8):741-748. doi: 10.1001/jamapediatrics.2018.1307.

Kraft WK, Adeniyi-Jones SC, Ehrlich ME. Buprenorphine for the Neonatal Abstinence Syndrome. N Engl J Med. 2017 Sep 7;377(10):997-998. doi: 10.1056/NEJMc1709121. No abstract available.

Brown MS, Hayes MJ, Thornton LM. Methadone versus morphine for treatment of neonatal abstinence syndrome: a prospective randomized clinical trial. J Perinatol. 2015 Apr;35(4):278-83. doi: 10.1038/jp.2014.194. Epub 2014 Oct 30.

Asti L, Magers JS, Keels E, Wispe J, McClead RE Jr. A quality improvement project to reduce length of stay for neonatal abstinence syndrome. Pediatrics. 2015 Jun;135(6):e1494-500. doi: 10.1542/peds.2014-1269. Epub 2015 May 4.

Devlin LA, Lau T, Radmacher PG. Decreasing Total Medication Exposure and Length of Stay While Completing Withdrawal for Neonatal Abstinence Syndrome during the Neonatal Hospital Stay. Front Pediatr. 2017 Oct 10;5:216. doi: 10.3389/fped.2017.00216. eCollection 2017.

Kraft WK, Dysart K, Greenspan JS, Gibson E, Kaltenbach K, Ehrlich ME. Revised dose schema of sublingual buprenorphine in the treatment of the neonatal opioid abstinence syndrome. Addiction. 2011 Mar;106(3):574-80. doi: 10.1111/j.1360-0443.2010.03170.x. Epub 2010 Oct 6.

Hall ES, Rice WR, Folger AT, Wexelblatt SL. Comparison of Neonatal Abstinence Syndrome Treatment with Sublingual Buprenorphine versus Conventional Opioids. Am J Perinatol. 2018 Mar;35(4):405-412. doi: 10.1055/s-0037-1608634. Epub 2017 Nov 7.

Moore JN, Gastonguay MR, Ng CM, Adeniyi-Jones SC, Moody DE, Fang WB, Ehrlich ME, Kraft WK. The Pharmacokinetics and Pharmacodynamics of Buprenorphine in Neonatal Abstinence Syndrome. Clin Pharmacol Ther. 2018 Jun;103(6):1029-1037. doi: 10.1002/cpt.1064. Epub 2018 Apr 28.

Anagnostis EA, Sadaka RE, Sailor LA, Moody DE, Dysart KC, Kraft WK. Formulation of buprenorphine for sublingual use in neonates. J Pediatr Pharmacol Ther. 2011 Oct;16(4):281-4. doi: 10.5863/1551-6776-16.4.281.

Clinical trials entries are delivered from the US National Institutes of Health and are not reviewed separately by this site. Please see the identifier information above for retrieving further details from the government database.

At TrialBulletin.com, we keep tabs on over 200,000 clinical trials in the US and abroad, using medical data supplied directly by the US National Institutes of Health. Please see the About and Contact page for details.