Sedatives for opiate withdrawal in newborn infants.
BACKGROUND
Neonatal abstinence syndrome (NAS) due to opiate withdrawal may result in disruption of the mother-infant relationship, sleep-wake abnormalities, feeding difficulties, weight loss and seizures. Treatments used to ameliorate symptoms and reduce morbidity include opiates, sedatives and non-pharmacological treatments.


OBJECTIVE
To assess the effectiveness and safety of using a sedative compared to a non-opiate control for NAS due to withdrawal from opiates, and to determine which type of sedative is most effective and safe.


METHODS
The standard search strategy of the Neonatal Review Group was used. This update included searches of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1, 2005), MEDLINE 1966-March 2005 and abstracts of conference proceedings.


METHODS
Trials enrolling infants with NAS born to mothers with an opiate dependence, with > 80% follow up and using random or quasi-random allocation to sedative or control. Control could include another sedative or non-pharmacological treatment.


METHODS
Each author assessed study quality and extracted data independently. Primary outcomes included treatment failure (failure to achieve symptom control or use of additional drug treatment), seizure occurrence, mortality and neurodevelopment. Treatment effect was expressed using (RR), risk difference (RD), mean difference (MD) and weighted mean difference (WMD). Meta-analysis was performed using a fixed effect model.


RESULTS
Six studies enrolling a total of 305 patients met inclusion criteria (Coyle 2002; Finnegan 1984; Kahn 1969; Kaltenbach 1986; Khoo 1995; Madden 1977); however, two (Finnegan 1984; Kaltenbach 1986) may be sequential reports that include some identical patients. Methodological concerns included the use of quasi-random allocation methods in four studies, and sizeable, largely unexplained differences in reported numbers allocated to each group in three studies. Phenobarbitone compared to supportive care alone has not been shown to reduce treatment failure or time to regain birthweight (one study). However, the duration of supportive care given to infants was significantly reduced (MD -162.1 mins/day, 95% CI -249.2, -75.1). Comparing phenobarbitone to diazepam, meta-analysis of two studies found phenobarbitone produced a significant reduction in treatment failure (typical RR 0.39, 95% CI 0.24, 0.62). There was no significant difference in duration of treatment or hospital stay. Comparing phenobarbitone with chlorpromazine, one study found no significant difference in treatment failure rate. No data for neurodevelopment reported by treatment group of allocation were available. No trials were eligible that assessed clonidine for NAS. In infants treated with an opiate, a small quasi-random study reported a reduced severity of withdrawal. Infants were weaned from an opiate more quickly which allowed earlier hospital discharge and reduced hospital costs. These findings may reflect the low dose of opiate used for initial treatment and the policy of discharging infants home on phenobarbitone but not morphine.


CONCLUSIONS
In newborn infants with NAS, there is no evidence that phenobarbitone compared with supportive care alone reduces treatment failure; however, phenobarbitone may reduce the daily duration of supportive care needed. Phenobarbitone, compared to diazepam, reduces treatment failure. In infants treated with an opiate, the addition of phenobarbitone may reduce withdrawal severity. Further trials are required to determine if this finding is applicable when a higher initial dose of opiate is used, and determine the effects of phenobabritone on infant development. There is insufficient evidence to support the use of chlorpromazine or clonidine in newborn infants with NAS. Clonidine and chlorpromazine should only be used in the context of a randomised clinical trial. This review should be taken in conjunction with the review "Opiate treatment for opiate withdrawal in newborn infants" (Osborn 2002a) which indicates that an opiate is the preferred initial therapy for NAS.
Osborn
D A
DA
RPA Newborn Care, Royal Prince Alfred Hospital, Missenden Road, Camperdown, NSW, Australia, 2050. david.osborn@email.cs.nsw.gov.au
Jeffery
H E
HE
Cole
M J
MJ
D002746:Chlorpromazine / Q000627:therapeutic use; D003000:Clonidine / Q000627:therapeutic use; D003975:Diazepam / Q000627:therapeutic use; D006801:Humans; D006993:Hypnotics and Sedatives / Q000627:therapeutic use*; D007231:Infant, Newborn; D009357:Neonatal Abstinence Syndrome / Q000188:drug therapy*; D009293:Opioid-Related Disorders / Q000188:drug therapy*; D010634:Phenobarbital / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic
D006993:Hypnotics and Sedatives; D003000:Clonidine; D003975:Diazepam; D002746:Chlorpromazine; D010634:Phenobarbital