Sedatives for opioid withdrawal in newborn infants

Review question

To determine the effectiveness and safety of using a sedative (sleep-inducing medicine) compared to a non-opioid or a non-medicine control for the treatment of neonatal abstinence syndrome (NAS) due to withdrawal from opioids.

Background

Use of opioids (prescribed or illicit) by pregnant women may result in their newborn infant experiencing withdrawal symptoms collectively referred to as NAS, which may result in disruption of the mother–infant relationship, sleeping and feeding difficulties, weight loss and seizures (fits). Treatments for newborn infants used to ameliorate NAS and reduce complications include supportive treatments such as a dummy (pacifier); swaddling or close wrapping; small frequent feeds; close skin contact by carrying in sling and other methods; and prescription of opioids or sedatives, or both.

Study characteristics

The search was up-to-date to September 2020.

Key results

We included 10 trials, enrolling 581 infants with NAS caused by maternal opioid use in pregnancy, in the review. There were multiple comparisons of different sedatives and regimens. The addition of phenobarbital to supportive care increased duration of hospitalisation and treatment, but reduced duration supportive care each day compared to supportive care alone. Phenobarbital reduced treatment failure compared to both diazepam and chlorpromazine. Clonidine and opioid compared to phenobarbital and opioid increased in days of hospitalisation and days of treatment. There were insufficient data to determine the safety and incidence of side effects for infants treated with combinations of opioids and sedatives including phenobarbital and clonidine. Side effects reported in infants treated with an opioid included oversedation from the addition of phenobarbital, and low blood pressure from the addition of clonidine with rebound high blood pressure and NAS reported after stopping clonidine. We found one ongoing study of clonidine plus morphine for NAS.

Certainty of the evidence

This was low to very low for all results.

Authors' conclusions: 

There is very low-certainty evidence that phenobarbital increases duration of hospitalisation and treatment, but reduces days to regain birthweight and duration of supportive care each day compared to supportive care alone. There is low-certainty evidence that phenobarbital reduces treatment failure compared to diazepam and very low-certainty evidence that  phenobarbital reduces treatment failure compared to chlorpromazine. There is low-certainty evidence of an increase in days' hospitalisation and days' treatment with clonidine and opioid compared to phenobarbital and opioid. There are insufficient data to determine the safety and incidence of adverse events for infants treated with combinations of opioids and sedatives including phenobarbital and clonidine.

Read the full abstract...
Background: 

Neonatal abstinence syndrome (NAS) due to opioid withdrawal may result in disruption of the mother–infant relationship, sleep–wake abnormalities, feeding difficulties, weight loss, seizures and neurodevelopmental problems.

Objectives: 

To assess the effectiveness and safety of using a sedative versus control (placebo, usual treatment or non-pharmacological treatment) for NAS due to withdrawal from opioids and determine which type of sedative is most effective and safe for NAS due to withdrawal from opioids.

Search strategy: 

We ran an updated search on 17 September 2020 in CENTRAL via CRS Web and MEDLINE via Ovid. We searched clinical trials databases, conference proceedings and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials.

Selection criteria: 

We included trials enrolling infants with NAS born to mothers with an opioid dependence with more than 80% follow-up and using randomised, quasi-randomised and cluster-randomised allocation to sedative or control.

Data collection and analysis: 

Three review authors assessed trial eligibility and risk of bias, and independently extracted data. We used the GRADE approach to assess the certainty of the evidence.

Main results: 

We included 10 trials (581 infants) with NAS secondary to maternal opioid use in pregnancy. There were multiple comparisons of different sedatives and regimens. There were limited data available for use in sensitivity analysis of studies at low risk of bias.

Phenobarbital versus supportive care: one study reported there may be little or no difference in treatment failure with phenobarbital and supportive care versus supportive care alone (risk ratio (RR) 2.73, 95% confidence interval (CI) 0.94 to 7.94; 62 participants; very low-certainty evidence). No infant had a clinical seizure. The study did not report mortality, neurodevelopmental disability and adverse events. There may be an increase in days' hospitalisation and treatment from use of phenobarbital (hospitalisation: mean difference (MD) 20.80, 95% CI 13.64 to 27.96; treatment: MD 17.90, 95% CI 11.98 to 23.82; both 62 participants; very low-certainty evidence).

Phenobarbital versus diazepam: there may be a reduction in treatment failure with phenobarbital versus diazepam (RR 0.39, 95% CI 0.24 to 0.62; 139 participants; 2 studies; low-certainty evidence). The studies did not report mortality, neurodevelopmental disability and adverse events. One study reported there may be little or no difference in days' hospitalisation and treatment (hospitalisation: MD 3.89, 95% CI –1.20 to 8.98; 32 participants; treatment: MD 4.30, 95% CI –0.73 to 9.33; 31 participants; both low-certainty evidence).

Phenobarbital versus chlorpromazine: there may be a reduction in treatment failure with phenobarbital versus chlorpromazine (RR 0.55, 95% CI 0.33 to 0.92; 138 participants; 2 studies; very low-certainty evidence), and no infant had a seizure. The studies did not report mortality and neurodevelopmental disability. One study reported there may be little or no difference in days' hospitalisation (MD 7.00, 95% CI –3.51 to 17.51; 87 participants; low-certainty evidence) and 0/100 infants had an adverse event.

Phenobarbital and opioid versus opioid alone: one study reported no infants with treatment failure and no clinical seizures in either group (low-certainty evidence). The study did not report mortality, neurodevelopmental disability and adverse events. One study reported there may be a reduction in days' hospitalisation for infants treated with phenobarbital and opioid (MD –43.50, 95% CI –59.18 to –27.82; 20 participants; low-certainty evidence).

Clonidine and opioid versus opioid alone: one study reported there may be little or no difference in treatment failure with clonidine and dilute tincture of opium (DTO) versus DTO alone (RR 0.09, 95% CI 0.01 to 1.59; 80 participants; very low-certainty evidence). All five infants with treatment failure were in the DTO group. There may be little or no difference in seizures (RR 0.14, 95% CI 0.01 to 2.68; 80 participants; very low-certainty evidence). All three infants with seizures were in the DTO group. There may be little or no difference in mortality after discharge (RR 7.00, 95% CI 0.37 to 131.28; 80 participants; very low-certainty evidence). All three deaths were in the clonidine and DTO group. The study did not report neurodevelopmental disability. There may be little or no difference in days' treatment (MD –4.00, 95% CI –8.33 to 0.33; 80 participants; very low-certainty evidence). One adverse event occurred in the clonidine and DTO group. There may be little or no difference in rebound NAS after stopping treatment, although all seven cases were in the clonidine and DTO group.

Clonidine and opioid versus phenobarbital and opioid: there may be little or no difference in treatment failure (RR 2.27, 95% CI 0.98 to 5.25; 2 studies, 93 participants; very low-certainty evidence). One study reported one infant in the clonidine and morphine group had a seizure, and there were no infant mortalities. The studies did not report neurodevelopmental disability. There may be an increase in days' hospitalisation and days' treatment with clonidine and opioid versus phenobarbital and opioid(hospitalisation: MD 7.13, 95% CI 6.38 to 7.88; treatment: MD 7.57, 95% CI 3.97 to 11.17; both 2 studies, 91 participants; low-certainty evidence). There may be little or no difference in adverse events (RR 1.55, 95% CI 0.44 to 5.40; 2 studies, 93 participants; very low-certainty evidence). However, there was oversedation only in the phenobarbital and morphine group; and hypotension, rebound hypertension and rebound NAS only in the clonidine and morphine group.