Neonatal Abstinence Syndrome
Conditions
Brief summary
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.
Detailed description
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.
Interventions
DRUGClonidine
This group of infants undergoing NAS will be treated with neonatal morphine sulfate and Clonidine as an adjunct medication to control the symptoms. Once stable Finnegan scores \<8 for 24h, NMS will be weaned by 10% daily till off, then Clonidine will be weaned off in a stepwise manner. Infant will not go home on any medication for NAS. NMS will be dosed as mg/kd/day divided q3h and Clonidine will be dosed as microgm/kg/day divided q6h based upon the initial Finnegan scores.
DRUGPhenobarbital
Infants in this arm will be treated as current standard practice with NMS and Phenobarbital. NMS will be weaned by 10% daily to completely off during the hospital stay. Infants will be discharged home on Phenobarbital. NMS will be dosed as mg/kg/day divided q3h and Phenobarbital will be dosed as mg/kg/day divided q8h based on the Finnegan scores.
Sponsors
Baystate Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 15 Days
Healthy volunteers
No
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 \-
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Length of Treatment With Neonatal Morphine Sulfate | subjects were followed for the duration of treatment, up to 3 months |
Secondary
| Measure | Time frame |
|---|---|
| Total Dose of NMS Used | For the duration of treatment, upto 3 months |
Countries
United States
Participant flow
Recruitment details
The study was conducted at Baystate Children's Hospital Davis Neonatal Intensive Care Unit (NICU), a level III, regional perinatal referral center, for Western Massachusetts, from June 2010 to June 2012
Pre-assignment details
Overall 82 infants were consented for the study but 14 were excluded either because they did not have continued high modified Finnegan Scores (n=13), or had Unstable clinical status (n=1)
Participants by arm
| Arm | Count |
|---|---|
| NMS/Clonidine | 34 |
| NMS/Phenobarbital | 34 |
| Total | 68 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 2 | 0 |
Baseline characteristics
| Characteristic | Total | NMS/Clonidine | NMS/Phenobarbital |
|---|---|---|---|
| Age Continuous | 2.05 days STANDARD_DEVIATION 1.32 | 1.8 days STANDARD_DEVIATION 0.9 | 2.26 days STANDARD_DEVIATION 1.6 |
| Sex: Female, Male Female | 35 Participants | 19 Participants | 16 Participants |
| Sex: Female, Male Male | 33 Participants | 15 Participants | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 34 | 3 / 34 |
| serious Total, serious adverse events | 0 / 34 | 0 / 34 |
Outcome results
Primary
Length of Treatment With Neonatal Morphine Sulfate
Time frame: subjects were followed for the duration of treatment, up to 3 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| NMS/Clonidine | Length of Treatment With Neonatal Morphine Sulfate | 18.2 days |
| NMS/Phenobarbital | Length of Treatment With Neonatal Morphine Sulfate | 13.6 days |
Secondary
Total Dose of NMS Used
Time frame: For the duration of treatment, upto 3 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| NMS/Clonidine | Total Dose of NMS Used | 5.7 mg/kg |
| NMS/Phenobarbital | Total Dose of NMS Used | 4.6 mg/kg |