Sedatives for opiate withdrawal in newborn infants

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.

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.

The standard search strategy of the Neonatal Review Group was used. This included searches of the Cochrane Controlled Trials Register (The Cochrane Library, Issue 1, 2002) and MEDLINE 1966-2002.

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.

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.

Five studies enrolling a total of 285 patients met inclusion criteria (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 rather than random patient allocation methods in three studies, and sizeable, largely unexplained differences in reported numbers allocated to each group in three studies. Phenobarbital 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 required to be given to infants each day was significantly reduced (MD -162.1 minutes/day, 95% CI -249.2, -75.1). Comparing phenobarbital to diazepam, meta-analysis of two studies found that phenobarbital 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 duration of hospital stay. Comparing phenobarbital with chlorpromazine, one study found no significant difference in treatment failure rate. No data for neurodevelopment were available, reported by treatment group as allocated. No trials were eligible that assessed clonidine for NAS.

In newborn infants with NAS, there is no evidence that phenobarbital, compared with supportive care alone, reduces treatment failure; however, phenobarbital may reduce the daily duration of supportive care needed. Phenobarbital, compared to diazepam, reduces treatment failure. 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. The results of this review, taken in conjunction with the related review, Opiate treatment for opiate withdrawal in newborn infants (Osborn 2002), indicate that treatment with opiates is the preferred initial therapy for NAS. It is hypothesised that this is particularly true for infants whose mothers have used only opiates during pregnancy. If a sedative is used, phenobarbital is preferred to diazepam. The results of an ongoing trial of the addition of phenobarbital to an opiate are awaited.