Based on the planned interim analysis results at 50% recruitment, after IRB reviewed the results, further enrollment was stopped.

The study plans to compare the use of Clonidine versus Phenobarbital as an additional medication to neonatal morphine sulfate for treatment of newborn infants undergoing drug withdrawal symptoms due to mother's use of opioid drug use. The investigators hypothesis is that use of Clonidine will lead to shorter duration of treatment, hospital stay and thereby early discharge home.

Introduction: Neonatal abstinence syndrome (NAS) is a symptom complex experienced by 55 to 94% of neonates who are exposed to intrauterine opioids. Recent studies have shown that combination therapies are superior to monotherapy with neonatal morphine sulfate (NMS). Phenobarbital has been shown to reduce the length of hospitalization, decrease severity of withdrawal, as well as decrease hospital costs and care giver demands. Similarly, clonidine, an α2-adrenergic receptor agonist, has also been shown to be safe, effective and reduces length of treatment.

Phenobarbital as an antiepileptic acts on the GABA (A) receptors and has been shown in animal models to inhibit neuronal cell proliferation, survival and neurogenesis. In human infants long term treatment with phenobarbital may result in neuro-developmental compromise. Due to these potentially harmful effects of Phenobarbital (P) alternative therapies should be explored more thoroughly including clonidine (C).

Our primary aim is to compare the length of NAS treatment with NMS in the two study groups - NMS/C versus NMS/P. Our secondary aims are to compare the total dosage of NMS, total length of hospital stay for NAS treatment, treatment failures and adverse effect profiles for the two study groups. We hypothesize that clonidine when compared to phenobarbital as an adjunct therapy, will have shorter length of stay, with fewer treatment failures and side effects.

Study design/Methods: This study will be a prospective, randomized, non-blinded clinical trial of NMS/C versus NMS/P for treatment of infants with NAS. Infants will be recruited from the Baystate Children's Hospital Neonatal Intensive Care Unit (NICU) and Neonatal Continuing Care Nursery (NCCN), a level III unit, over a 2 year study period. After randomization, infants will adhere to strict treatment initiation and withdrawal protocols. Maternal and infant descriptive data will be collected along with specific data regarding vital signs, drug dosages, length of treatment, treatment failures and adverse effects.

The primary outcome will be length of treatment with NMS in the two study arms. The secondary outcomes will be - a) total length of hospital stay for NAS treatment, b) mean total treatment dose and mean daily dose of NMS, c) total number of treatment failures,d) adverse effects such as bradycardia, hypotension, hypertension e) Total outpatient therapy days with Phenobarbital

Significance: This comparison study is potentially of great significance. If clonidine is proven to be equally effective in treatment of NAS many of the detrimental effects of phenobarbital therapy may be avoided for infants on long term pharmacotherapy for treatment of withdrawal with shorter length of hospital stay.

Inclusion Criteria:

• 0 to 15 days of age
• Prenatal exposure to opioids with development of moderate to severe NAS (2 consecutive abstinence scores of ≥ 8)
• Medically stable

Exclusion Criteria:

• Gestational age < 35 weeks
• Intrauterine growth retardation (birth weight below the 5th percentile)
• Congenital heart disease
• Congenital anomalies
• Medically unstable

Exposure to Benzodiazepines prenatally

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During the hospital stay

In the phenobarbital group, 3 infants (8.8%), manifested over sedation signs (poor feeds, and mild respiratory depression). This prompted serum phenobarbital measurements which were noted to be supra-therapeutic (>40 mg/dL) and required dosage adjustment.

One of the major limitations to our study was the inability to blind the two groups for the study medications.