Sedatives for opiate withdrawal in newborn infants

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Authors

David A Osborn1, Heather E Jeffery2, Michael J Cole3

Background - Methods - Results - Characteristics of Included Studies - References - Data Tables & Graphs


1Department of Mothers and Babies NICU, Royal Prince Alfred Hospital, Camperdown, Australia [top]
2RPA Newborn Care, RPA Women and Babies, Royal Prince Alfred Hospital and University of Sydney, School of Public Health, Sydney, Australia [top]
3Dept. of Neonatology, Westmead Hospital, Westmead, Australia [top]

Citation example: Osborn DA, Jeffery HE, Cole MJ. Sedatives for opiate withdrawal in newborn infants. Cochrane Database of Systematic Reviews 2010, Issue 10. Art. No.: CD002053. DOI: 10.1002/14651858.CD002053.pub3.

Contact person

David A Osborn

Department of Mothers and Babies NICU
Royal Prince Alfred Hospital
John Hopkins Drive
Camperdown
NSW
2005
Australia

E-mail: david.osborn@email.cs.nsw.gov.au

Dates

Assessed as Up-to-date: 05 April 2010
Date of Search: 31 March 2010
Next Stage Expected: 31 March 2012
Protocol First Published: Issue 2, 2000
Review First Published: Issue 3, 2002
Last Citation Issue: Issue 10, 2010

What's new

Date / Event Description
28 April 2010
Updated

This updates the review "Sedatives for opiate withdrawal in newborn infants" published in Issue 3, 2005 of the Cochrane Database of Systematic Reviews (Osborn 2005).

Search updated in March 2010.

One new trial added (Agthe 2009). New outcomes included.

28 April 2010
New citation: conclusions changed

Conclusions updated.

History

Date / Event Description
16 October 2008
Amended

Converted to new review format.

31 March 2005
New citation: conclusions not changed

Substantive amendment

31 March 2005
Updated

This is an update of the existing review "Sedatives for opiate withdrawal in newborn infants" published in The Cochrane Library, Issue 3, 2002 (Osborn 2002b).

One additional study included, which compared phenobarbitone versus placebo in infants treated with dilute tincture of opium for neonatal abstinence syndrome.

Abstract

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.

Objectives

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.

Search methods

This update included searches of the Cochrane Central Register of Controlled Trials (Issue 1, 2010), MEDLINE 1966 to April 2010 and abstracts of conference proceedings.

Selection criteria

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.

Data collection and analysis

Each author assessed study quality and extracted data independently.

Results

Seven studies enrolling 385 patients were included. There were substantial methodological concerns for most studies including the use of quasi-random allocation methods and sizeable, largely unexplained differences in reported numbers allocated to each group.

One study reported phenobarbitone compared to supportive care alone did not reduce treatment failure or time to regain birthweight, but resulted in a significant reduction in duration of supportive care (MD -162.1 min/day, 95% CI -249.2, -75.1). Comparing phenobarbitone to diazepam, meta-analysis of two studies found phenobarbitone resulted in a significant reduction in treatment failure (typical RR 0.39, 95% CI 0.24, 0.62). Comparing phenobarbitone with chlorpromazine, one study reported no significant difference in treatment failure.

In infants treated with an opiate, one study reported addition of clonidine resulted in no significant difference in treatment failure, seizures or mortality. In infants treated with an opiate, one study reported addition of phenobarbitone significantly reduced the proportion of time infants had a high abstinence severity score, duration of hospitalisation and maximal daily dose of opiate.

Authors' conclusions

Infants with NAS due to opiate withdrawal should receive initial treatment with an opiate. Where a sedative is used, phenobarbitone should be used in preference to diazepam. In infants treated with an opiate, the addition of phenobarbitone or clonidine may reduce withdrawal severity. Further studies are needed to determine the role of sedatives in infants with NAS due to opiate withdrawal and the safety and efficacy of adding phenobarbitone or clonidine in infants treated with an opiate for NAS.

Plain language summary

Sedatives for opiate withdrawal in newborn infants

When a sedative is needed to ameliorate symptoms in newborn infants with opiate withdrawal due to maternal opiate use in pregnancy, phenobarbitone is preferred. Use of opiates (commonly prescribed methadone or illicit heroin) by pregnant women may result in a withdrawal syndrome in their newborn infants. This may result in disruption of the mother-infant relationship, sleeping and feeding difficulties, weight loss and seizures. Treatments for newborn infants used to ameliorate these symptoms and reduce complications include opiates, sedatives (phenobarbitone or diazepam) and supportive treatments (swaddling, settling, massage, relaxation baths, pacifiers or waterbeds). Trials of sedatives have generally been of poor quality. Individual studies have reported that use of phenobarbitone compared to supportive care alone reduces the amount time an infant needs supportive care, is better than diazepam at preventing treatment failure and reduces the severity of withdrawal in infants treated with a opiate. In infants treated with an opiate, the addition of a sedative (phenobarbitone or clonidine) may reduce withdrawal severity, although safety and efficacy need confirming. The long term effects of use of phenobarbitone on an infant's development have not been determined.

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Background

Opiate use in pregnancy and neonatal abstinence syndrome (NAS) due to opiate withdrawal is currently a significant clinical and social problem. The US 1999 National Household Survey on Drug Abuse (NHSDA 1999) estimated that 39.7% of individuals over 12 years had ever used an illicit drug, with heroin use reported by 1.4%. Current illicit drug use (within last month) was reported by 6.7% (14.8 million people) and heroin by 0.1% (200, 000 people). Rates of illicit drug use were almost half during pregnancy, with 3.4% of pregnant women reporting use of an illicit drug in the past month. This represents an estimated 3, 000 pregnant women who are current users of heroin in the US. These figures are similar to Australian data (NDSHS 1998).

Between 48% and 94% of infants exposed to opiates in utero develop clinical signs of withdrawal, with signs of withdrawal from methadone more common than from heroin (Alroomi 1988; Doberczak 1991; Fricker 1978; Lam 1992; Maas 1990; Madden 1977; Olofsson 1983; Ostrea 1976). There is some evidence to correlate methadone dose and severity of withdrawal (Doberczak 1991; Harper 1977; Ostrea 1976). Clinically significant manifestations of withdrawal are uncommon if the methadone dose is below 20 mg/day (Strauss 1976). The onset of features of withdrawal from heroin tends to begin within 24 hours and clinical manifestations are usually mild (Alroomi 1988; Bell 1995), whereas withdrawal from methadone usually begins between two and seven days after birth (Doberczak 1991) and may be delayed up to a month (Kandall 1974). Clinical features of neonatal opiate abstinence syndrome include neurological excitability, gastrointestinal dysfunction and autonomic signs (AAP 1998). There may be poor feeding, sleep-wake abnormalities (O'Brien 2002), vomiting, dehydration, poor weight gain and seizures. In addition, infants of mothers using illicit drugs may be at increased risk of neonatal mortality (Hulse 1998), sudden infant death syndrome (Kandall 1993), and abnormal neurodevelopmental outcomes (de Cubas 1993; Ornoy 1996).

Seizures occur in 2% to 11% of infants withdrawing from opiates (Herzlinger 1977; Kandall 1977; Doberczak 1991) and may be more common with methadone than heroin withdrawal (Herzlinger 1977). Although there is evidence in animals that withdrawal from opiates and opiate antagonists is eleptogenic (Olson 1997), there is little evidence that this is the case in humans. Case series of infants with neonatal opiate withdrawal in whom seizures have been reported (Herzlinger 1977; Kandall 1974) have not systematically controlled for maternal use of other drugs throughout pregnancy or reported seizures in infants exposed only to opiates in utero.

The American Academy of Pediatrics (AAP 1998) recommends that for infants with confirmed drug exposure the indications for drug therapy should be seizures, poor feeding, diarrhoea and vomiting resulting in excessive weight loss and dehydration, inability to sleep and fever unrelated to infection. An abstinence score such as the Lipsitz tool (Lipsitz 1975), Neonatal Abstinence Scoring System (Finnegan 1975a) and Neonatal Withdrawal Inventory (Zahorodny 1998) may document significant manifestations of withdrawal. Although the validity of these scoring systems is not proven, they may provide more objective criteria for assessing infants and deciding on treatment. When pharmacological treatment is chosen, the AAP recommends that for opiate withdrawal tincture of opium is the preferred drug. For sedative-hypnotic withdrawal, phenobarbitone is the agent of choice.

Sedatives used for opiate withdrawal have included clonidine (an alpha2 presynaptic blocker), chlorpromazine, phenobarbitone and diazepam (Theis 1997; AAP 1998). It may be that, by using a sedative, many infants will avoid further opiate exposure and duration of treatment will be reduced to the period of acute withdrawal.

The questions to be addressed by this review are: 1) what is the evidence, from randomised and quasi-randomised controlled trials, that a sedative is better than control in the treatment of clinically significant NAS due to opiate withdrawal (control may be placebo, the usual management of the newborn infant or any form of non-pharmacological treatment designed to settle infant and mother, establish feeding and facilitate mother-infant interaction); and 2) what is the evidence for use of a specific sedative from trials comparing different types of sedatives. The goals of treatment should be to provide comfort to the mother and infant in relieving symptoms, and improve feeding, weight gain, prevent seizures, reduce unnecessary hospitalisation, improve mother-infant interaction and reduce the incidence of infant mortality and abnormal neurodevelopment. This is an update of a previous review (Osborn 2002b; Osborn 2005b). A separate review (Osborn 2002a; Osborn 2005; Osborn 2010) examines the evidence for the use of opiates in infants with NAS due to opiate withdrawal.

Objectives

  1. 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 opiates.
  2. To determine which type of sedative is most effective and safe for NAS due to withdrawal from opiates.

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Methods

Criteria for considering studies for this review

Types of studies

Trials using random or quasi-random patient allocation.

Types of participants

Infants in the neonatal period with NAS born to mothers with an opiate dependence. Withdrawal may be determined by the presence of signs consistent with NAS or the use of a standardised score of NAS.

Types of interventions

Trials comparing the following were eligible:

  1. sedative (e.g. clonidine, a benzodiazepine, barbiturate or neuroleptic agent) versus non-opiate control (either placebo, usual management of the newborn infant or non-pharmacological treatment designed to settle infant and mother, establish feeding and facilitate mother-infant interaction).
  2. sedative versus other sedative.

Types of outcome measures

Primary outcomes
  1. Treatment failure: including failure to achieve control defined as a failure to reduce a standardised score of NAS from a clinically significant level to a clinically 'safe' level defined by author of trial, or the use of additional pharmacological treatments for control of NAS in the neonatal period;
  2. Seizures;
  3. Neonatal and infant mortality;
  4. Neurodevelopmental outcome.
Secondary outcomes
  1. Time to control of NAS (control of symptoms or reduction of NAS score to a clinically 'safe' level);
  2. Duration of admission to newborn nursery;
  3. Duration of hospitalisation (days);
  4. Time to establishment of full sucking feeds;
  5. Success of breast feeding (e.g. absence of complementary formula feeds, adequate weight gain whilst breast feeding);
  6. Rate of weight gain;
  7. Side effects occurring after commencement of therapy: a) apnoea, b) need for resuscitation, c) need for mechanical ventilation d) any other;
  8. Duration of treatment of NAS (days);
  9. Disruption to the mother infant relationship (e.g. separation of mother and infant, admission to a newborn nursery, failure to successfully breast feed, maternal depression, or parental dissatisfaction).

Search methods for identification of studies

Electronic searches

The standard search strategy of the Cochrane Neonatal Review Group was used. See Review Group details for more information. This was supplemented by additional searches of the Oxford Database of Perinatal Trials, Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 1, 2002), MEDLINE (1966 to March 2002), PREMEDLINE (to March 2002), previous reviews including cross references (all studies cited), abstracts and conferences (American Pediatric Society-Society for Pediatric Research Annual Meetings 1999 to 2002; Perinatal Society of Australia and New Zealand Annual Meetings 1999 to 2002).

The search of MEDLINE included both MeSH searches (using terms including: "[neonatal abstinence syndrome, hypnotics and sedatives, benzodiazepines, clonidine, diazepam, phenobarbitone, antipsychotic agents] and [infant-newborn or pregnancy]") and text word searches (using terms including: "[withdrawal, abstinence, addiction, sedative, benzodiazepine, clonidine, diazepam, phenobarbitone, phenobarbital] and [infant-newborn or pregnancy]").

The search was updated in March 2005 by DO with additional searches of the Cochrane Central Register of Controlled Trials (Issue 1, 2005), MEDLINE (1966-March 2005), PREMEDLINE (to March 2005), cross references of all new studies cited, abstracts and conference proceedings (American Pediatric Society-Society for Pediatric Research Annual Meetings 2003-4; Perinatal Society of Australia and New Zealand Annual Meetings 2003-2005).

The search was updated in September 2010 by DO with additional searches of the Cochrane Central Register of Controlled Trials (Issue 1, 2010), MEDLINE (1966 to April 2010), PREMEDLINE (to April 2010), EMBASE (1988 to April 2010), cross references of all new studies cited, abstracts and conference proceedings (American Pediatric Society/Society for Pediatric Research Annual Meetings 2005 to 10; Perinatal Society of Australia and New Zealand Annual Meetings 2006 to 10).

Searching other resources

Electronic searches were supplemented by searches of citations of included studies and reviews, contact with authors and expert informants and searches of conference abstracts as documented above.

Clinical trials registries were also searched August 2010 for ongoing or recently completed trials (ClinicalTrials.gov, Controlled-Trials.com External Web Site Policy, Australian New Zealand Clinical Trials Registry External Web Site Policy, and WHO International Clinical Trials Registry Platform (ICTRP) External Web Site Policy).

Data collection and analysis

Standard methods of the Cochrane Collaboration and its Neonatal Review Group were used.

Selection of studies

Two review authors (DO and HJ) independently assessed for inclusion all the potential studies identified as a result of the search strategy for the 2002 review and 2005 review update. We resolved any disagreement through discussion. DO performed the literature search for the 2010 update.

Data extraction and management

Standard methods of the Cochrane Collaboration and its Neonatal Review Group were used. A data extraction sheet was created for critical appraisal and data extraction from all potentially eligible studies. Each author extracted data independently; authors then compared data and resolved differences for the 2002 review. DO and HJ extracted data independently; authors then compared data and resolved differences for the 2005 review update. DO extracted data for the 2010 review update.

Assessment of risk of bias in included studies

The methodological quality of each trial was assessed independently by the three authors for the 2002 review. DO assessed methodological quality for the 2010 review update. Particular emphasis was placed on allocation concealment, blinding, completeness of follow up and blinding of outcome assessment. Allocation concealment was ranked: Grade A: adequate; Grade B: uncertain; Grade C: clearly inadequate. Additional information where required was requested from authors of each trial to clarify methodology.

For the update in 2010, the authors assessed the risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008).

  1. Sequence generation (checking for possible selection bias)
    For each included study, we described the method used to generate the allocation sequence in sufficient detail to allow an assessment of whether it should produce comparable groups. We assessed the method as:
    • adequate (any truly random process, e.g. random number table; computer random number generator);
    • inadequate (any non random process, e.g. odd or even date of birth; hospital or clinic record number);
    • unclear.
  2. Allocation concealment (checking for possible selection bias)
    For each included study, we described the method used to conceal the allocation sequence in sufficient detail and determine whether intervention allocation could have been foreseen in advance of, or during recruitment, or changed after assignment.
    We assessed the methods as:
    • adequate (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes);
    • inadequate (open random allocation; unsealed or non opaque envelopes, alternation; date of birth);
    • unclear.
  3. Blinding (checking for possible performance bias)
    For each included study, we described the methods used, if any, to blind study participants and personnel from knowledge of which intervention a participant received. We judged studies to be at low risk of bias if they were blinded, or if we judged that the lack of blinding could not have affected the results. We assessed blinding separately for different outcomes or classes of outcomes.
    We assessed the methods as:
    • adequate, inadequate or unclear for participants;
    • adequate, inadequate or unclear for personnel;
    • adequate, inadequate or unclear for outcome assessors.
  4. Incomplete outcome data (checking for possible attrition bias through withdrawals, dropouts, protocol deviations)
    For each included study and for each outcome or class of outcomes, we described the completeness of data including attrition and exclusions from the analysis. We stated whether attrition and exclusions were reported, the numbers included in the analysis at each stage (compared with the total randomised participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes.
    Where sufficient information is reported or can be supplied by the trial authors, we re-included missing data in the analyses. We assessed methods as:
    • adequate (less than 20% missing data);
    • inadequate;
    • unclear.
  5. Outcome reporting bias
    For each included study, we described how we investigated the possibility of selective outcome reporting bias and what we found.
    We assessed the methods as:
    • adequate (where it is clear that all of the study’s prespecified outcomes and all expected outcomes of interest to the review have been reported);
    • inadequate (where not all the study’s pre-specified outcomes have been reported; one or more reported primary outcomes were not pre-specified; outcomes of interest are reported incompletely and so cannot be used; study fails to include results of a key outcome that would have been expected to have been reported);
    • unclear.
  6. Other sources of bias
    For each included study, we described any important concerns we had about other possible sources of bias (e.g. early termination of trial due to data-dependant process, extreme baseline imbalance, etc).We assessed whether each study was free of other problems that could put it at risk of bias. We assessed other sources of bias as:
    • yes;
    • no;
    • unclear.
  7. Overall risk of bias

We made explicit judgements about whether studies are at high risk of bias, according to the criteria given in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008). With reference to (1) and (6) above, we assessed the likely magnitude and direction of the bias and whether we consider it is likely to impact on the findings. We explored the impact of the level of bias through undertaking sensitivity analyses - see 'Sensitivity analysis’.

Measures of treatment effect

Standard methods of the Cochrane Neonatal Review Group. Treatment effect was expressed using relative risk (RR), risk difference (RD) and mean difference (MD) or weighted mean difference (WMD) where appropriate.

Unit of analysis issues

The unit of randomisation was the intended unit of analysis (individual infant).

Dealing with missing data

Additional data was requested from authors of each trial. Additional information was provided by the authors for three trials (Finnegan 1984; Kaltenbach 1986; Khoo 1995). Initial analysis was intention to treat analysis. Where data was missing then the reported infants are reported and effect of losses examined in sensitivity analysis according to study quality.

Assessment of heterogeneity

For the 2010 update, we planned to use the chi2 statistic to detect statistically significant heterogeneity and the I2 statistic to quantify heterogeneity among the trials in each analysis. Had we identified substantial heterogeneity, we planned to explore it by pre-specified subgroup analysis.We planned to grade the degree of heterogeneity as 0 to 30% (might not be important), 31% to 50% (moderate heterogeneity); 51% to 75% (substantial heterogeneity); 76% to 100% (considerable heterogeneity).

Assessment of reporting biases

For the 2010 update, reporting bias was assessed by comparing stated primary and secondary outcomes and reported outcomes. Where study protocols are available, these will be compared to publications to determine the likelihood of reporting bias.

Data synthesis

The fixed effect model was assumed for meta-analysis.

Subgroup analysis and investigation of heterogeneity

Planned subgroup analyses included the following identified subcategories:

  1. According to type of sedative used (e.g. clonidine, a benzodiazepine, barbiturate or neuroleptic agent);
  2. According to type of non-pharmacological treatment used;
  3. According to whether trials included mothers with only opiate dependence or with multiple drug use;
  4. According to age at treatment (e.g. early versus delayed treatment) and duration of treatment (e.g. short versus long course).

All outcomes were eligible for inclusion in subgroup analysis.

Sensitivity analysis

We planned sensitivity analysis on the basis of methodological quality. Trials of good methodology were defined by studies with adequate randomisation and allocation concealment, and > 90% follow up on an intention to treat basis.

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Results

Description of studies

Results of the search

One additional study (Agthe 2009) was included in the 2010 update. A total of seven studies are now included in the review (Agthe 2009; Coyle 2002; Finnegan 1984; Kahn 1969; Kaltenbach 1986; Khoo 1995; Madden 1977). Two studies (Finnegan 1984; Kaltenbach 1986) may be sequential reports in which some of the patients are the same (author communication). In view of this uncertainty, outcomes that are reported by Kaltenbach 1986 that were previously reported by Finnegan 1984 are not included in the meta-analyses tables, but are reported separately in the text (see results). One additional ongoing study of the addition of clonidine for NAS treatment was found (Singh 2010).

Included studies

Agthe 2009 enrolled infants born to mothers with a history of heroin or methadone use with two consecutive modified Finnegan scores greater than/or equal to 9. Infants were treated with oral clonidine 1 μg/kg every four hours (6 μg/kg per day) and diluted tincture of opium (clonidine/DTO), versus opium alone (placebo/DTO). Placebo was normal saline. A standardised protocol for DTO escalation and weaning was used. DTO (0.4 mg/mL morphine equivalent) starting 0.2 mL DTO orally every four hours, incrementally escalated to 0.3, 0.4, and 0.5 mL every four hours, then to 0.5, 0.7, and 0.9 mL every three hours until withdrawal symptoms (MFS < 9) were controlled.

Coyle 2002 enrolled infants born to mothers with a history of heroin or methadone use with a Finnegan score > 7. The criteria for starting medication were reported as being the same as recommended by Finnegan. All infants were treated with dilute tincture of opium (DTO) (0.4 mg/ml morphine) 0.05 mls/kg 6 to eight times per day. The dose was increased if the Finnegan score > 7, maintained if score 5 to 7 and reduced if score < 5 for three consecutive periods. The infants were 'randomised' to the addition of phenobarbitone or placebo. Phenobarbitone was given as a loading dose (30 mg/kg given as three oral doses every 12 hours) and maintenance dose 5 mg/kg/day. The dose was adjusted to maintain weekly serum levels 20 to 30 mg/dl. Allocation was unblinded prior to discharge. Infants remained in hospital whilst still on morphine but were discharged home on phenobarbitone if allocated phenobarbitone.

Finnegan 1984 enrolled infants born to mothers using narcotics. Data were reported for infants of mothers a) using only opiates and b) using opiates and another drug. This stratification was not prespecified (author communication). The Neonatal Abstinence Scoring System (Finnegan score) was used to determine need and response to treatment. Infants were allocated to phenobarbitone loading dose regimen (20 mg/kg with maintenance 5 to 10 mg/kg/day) titrated against scores, or phenobarbitone titration regimen (no loading dose), titrated on scores. The two phenobarbitone groups (i.e. with or without loading dose) have been combined in the analyses reported in this review. Infants who were allocated to paregoric are reported in a separate review (Osborn 2002a; Osborn 2005; Osborn 2010).

Kahn 1969 enrolled infants of mothers using heroin. A standardised scoring system was used and infants with tremors or irritability > grade 1 on a three-grade score were entered in the trial. Polydrug use was reported with five mothers using glutethimide, four amphetamines and two barbiturates. Infants were randomised to phenobarbitone short course (8.4 mg/kg/day in four divided doses x 4 days, then stopped), phenobarbitone long course (8.4 mg/kg/day in four divided doses x 10 days, then reduced by 1/3rd every 2nd day), chlorpromazine short course (2.8 mg/kg/day in four divided doses x 4 days, then stopped), and chlorpromazine long course (2.8 mg/kg/day in four divided doses x 10 days, then gradual reduction over six days). In this review, for the analyses comparing phenobarbitone versus chlorpromazine, the short and long course phenobarbitone groups were combined, as were the short and long course chlorpromazine groups.

Kaltenbach 1986 enrolled infants of women maintained on methadone. The Neonatal Abstinence Scoring System was used with scores averaging greater than/or equal to 8 for three consecutive scores determining need for treatment. Polydrug use was reported but incidence not given. Infants were allocated to phenobarbitone loading dose followed by titration, or phenobarbitone titration with no loading dose, or diazepam (doses not reported). Infants who were allocated to paregoric are reported in a separate review (Osborn 2002a; Osborn 2005; Osborn 2010).

Khoo 1995 enrolled infants of mothers with an opiate dependence. The trial included 100 infants of mothers on at least two weeks of methadone, eight infants of mothers with a heroin dependency and three infants of mothers with a codeine dependency. The Neonatal Abstinence Scoring System was used with scores averaging greater than/or equal to 8 for three consecutive scores determining need for treatment. Of the mothers on methadone, 94.5% were on at least one other drug, and 76.4% of infants were exposed to more than two drugs in utero. The treatment groups eligible for this review were phenobarbitone (loading dose 15 mg/kg intramuscularly, then 6 mg/kg/day in two divided doses, titrated to score, up to maximum 10 mg/kg/day) plus supportive therapy (n = 29), or supportive therapy alone, including pacifier, swaddling, close wrapping, small frequent feeds, close skin contact by carrying in sling and other methods (n = 36). Infants who were allocated to morphine are reported in a separate review (Osborn 2002a).

Madden 1977 enrolled infants of narcotic-addicted mothers in whom a clinical decision was made to treat. An abstinence score was not used. Polydrug use was reported (62 mothers were on methadone only, 18 heroin and methadone, 19 heroin only, eight heroin and another agent, nine no drugs, one an agent other than heroin or methadone). The treatment groups eligible for this review were phenobarbitone, 5 to 8 mg/kg/day in three divided doses (n = 16), or diazepam 0.5 to 2.0 mg q8h with doses "tailored day to day" (n = 16). Infants who were allocated to methadone are reported in a separate review (Osborn 2002a).

One study (Agthe 2009) reported mortality. No study reported long term neurodevelopmental outcome according to treatment group as allocated. One study (Kahn 1969) reported mortality but not according to allocated group. Kaltenbach 1986 reported the Bayley MDI at six months according to treatments received, not allocated. Four studies (Agthe 2009; Finnegan 1984; Kaltenbach 1986; Khoo 1995) reporting treatment failure used a standardised score to determine response to treatment. Madden 1977 reported need for a second agent but did not use a standardised score. One study (Kahn 1969) used a standardised score, with treatment failure taken as persistence of symptoms > 4 days. Agthe 2009 reported clinical seizures although criteria for seizures were not described. Kahn 1969 reported myoclonic jerks which were not thought to be seizures by the attending clinician. These are not reported as seizures in this review. No other study reported seizures. Coyle 2002 reported short term neurodevelopmental and behavioural outcomes of a combined group of term and preterm infants in abstract form. No neurodevelopmental data were reported in the principle publication. Coyle 2002 also reported total hospital costs exclusive of physician billings with data obtained from the hospital billing department.

Excluded studies

Twenty eight studies or reports were excluded (see table 'Characteristics of excluded studies'). One study previously awaiting assessment (Pacifico 1989) that did not report method of treatment allocation is now listed as an excluded study. It was reported to have non-random allocation in another publication (AAP 1998).

Risk of bias in included studies

Blinding of outcome measurement: reported by four studies (Agthe 2009; Finnegan 1984; Kahn 1969; Kaltenbach 1986). No other study reported blinding of outcome measurement.

Allocation

One study (Agthe 2009) reported an adequate method of random allocation and allocation concealment; two studies (Kahn 1969; Madden 1977) reported random allocation to treatment but did not report method of random allocation. Three studies used quasi-random methods of patient allocation (Finnegan 1984; Kaltenbach 1986; Khoo 1995). Coyle 2002 prospectively matched treatments groups by first Finnegan score >7, if no match was found then the infant was randomly assigned although the random method was not reported. Finnegan 1984 and Kaltenbach 1986 communicated "drug assignment pulled from envelopes which were designated according to first letter of last name". Khoo 1995 designated treatment according to the last number of the infant's hospital number. Several studies had sizeable and largely unexplained differences in the numbers of infants allocated to each group (Finnegan 1984; Kaltenbach 1986; Khoo 1995). Finnegan 1984 communicated that an interim analysis found the diazepam group had excessive complications (somnolence and respiratory depression), so enrolment in this group was stopped.

Blinding

Agthe 2009 reported blinding of treatment with use of a saline placebo. Coyle 2002 reported blinding of treatment with use of a similar appearing placebo and a standardised regimen for titrating doses. Weekly phenobarbitone levels were revealed to the treating physician. One study (Kahn 1969) reported blinding of treatment and measurement by using identical syrups. Two studies (Finnegan 1984; Kaltenbach 1986) did not blind treatment. No other study reported blinding of treatment and given the variable treatment regimens in each of the trials it is unlikely this was possible.

Incomplete outcome data

All infants were accounted for by three studies (Agthe 2009; Finnegan 1984; Madden 1977), although Agthe 2009 excluded an infant (clonidine group) who had a seizure from the analysis of treatment failure. Coyle 2002 reported one post randomisation loss. In addition, preterm infants that were reported in abstract form were not reported in the peer reviewed publication. Kahn 1969 reported deaths of two untreated infants, but it is unclear whether this occurred before or after randomisation. One study (Kaltenbach 1986) did not report numbers entered so that any losses are unknown. Khoo 1995 excluded three infants from analysis (one on phenobarbitone and two on supportive therapy) and seven infants did not have data available for time to regain birthweight. Madden 1977 reported separately, for duration of treatment and hospital stay, an infant randomised to phenobarbitone who received a second agent .

Selective reporting

Only one study had clear prespecified outcomes (Coyle 2002). The other studies all stated general aims of treatment.

Other potential sources of bias

Agthe 2009 reported infants in Clonidine + DTO group had significantly lower mean birth weight. Two studies (Finnegan 1984; Kaltenbach 1986) reported stopping enrolment in the diazepam arm early due to an interim analysis demonstrating the possibility of adverse effects. None of the other studies provided sufficient detail of reporting to be clear about balance of groups after randomisation or other potential biases.

Effects of interventions

1 Phenobarbitone versus supportive care (all infants)

All Infants (Infants Of mothers using opiates with or without other drugs)

Primary outcomes: One study (Khoo 1995) reported an increase in treatment failure of borderline statistical significance in infants receiving phenobarbitone compared to supportive therapy (62 infants, RR 2.73, 95% CI 0.94, 7.94, RD 0.20, 95% CI 0.00, 0.41). No other primary outcomes were reported.

Secondary outcomes: Khoo 1995 reported a significant increase in duration of treatment (MD 17.9 days, 95% CI 12.0, 23.8), duration of hospital stay (MD 20.8 days, 95% CI 13.6, 28.0) and duration of stay in special care nursery (MD 23.1 days, 95% CI 15.8, 30.4) in infants receiving phenobarbitone. There was no significant difference in time to regain birthweight (MD -1.4 days, 95% CI -4.1, 1.3) but a significant reduction in duration of supportive care (-162.1 minutes/day, 95% CI -249.2, -75.1) in infants receiving phenobarbitone.

2 Phenobarbitone versus diazepam

All Infants

Primary outcomes: Finnegan 1984 reported a significant reduction in treatment failure in infants receiving phenobarbitone compared to diazepam (107 infants, RR 0.33, 95% CI 0.20, 0.53). Madden 1977 reported one infant on phenobarbitone and none on diazepam received a second drug. Meta-analysis of these two studies found a significant reduction in treatment failure using phenobarbitone compared to diazepam (139 infants, typical RR 0.39, 95% CI 0.24, 0.62). Kaltenbach 1986 reported a significant reduction in treatment failure in infants given phenobarbitone compared to diazepam (46 infants, RR 0.55, 95% CI 0.40, 0.77). As some of these infants may also have been reported by Finnegan 1984, this study is not included in the meta-analysis. Data for the Bayley MDI at six months were not reported by treatment group assignment in one study (Kaltenbach 1986). No study reported mortality or seizures.

Secondary outcomes: Madden 1977 reported no significant difference in duration of treatment (MD 4.30 days, 95% CI -0.73, 9.33) or duration of hospital stay (MD 3.07 days, 95% CI -2.02, 8.16).

3 Phenobarbitone versus diazepam

Infants of mothers using only opiates

In a post hoc analysis, Finnegan 1984 separately reported outcome for 31 infants of mothers on only opiates. There was a significant reduction in treatment failure with phenobarbitone compared to diazepam (RR 0.55, 95% CI 0.35, 0.85). No other outcomes were reported.

4 Phenobarbitone versus diazepam

Infants of mothers using opiates and other drugs

Finnegan 1984 separately reported 76 infants of mothers using opiates and another drugs. There was a significant reduction in treatment failure with phenobarbitone compared to diazepam (RR 0.19, 95% CI 0.09, 0.43). No other outcomes were reported.

5 Phenobarbitone versus chlorpromazine

All Infants

Kahn 1969 reported no significant difference in treatment failure (persistent symptoms > 4 days) (38 infants, RR 0.33, 95% CI 0.08, 1.45), no infants received a second drug or had a clinical seizure. Data for mortality were not reported according to allocated group. Kahn 1969 reported a decreased incidence of clinical myoclonus (not thought to be seizures by the attending clinician) of borderline statistical significance (RR 0.33, 95% CI 0.11, 1.04, RD -0.32, 95% CI -0.59, -0.04). No study reported neurodevelopment.

No study comparing phenobarbitone and chlorpromazine reported separately infants of mothers on only opiates and those on opiates and another drug.

6 Phenobarbitone titration with loading dose versus phenobarbitone titration alone

All infants

Kaltenbach 1986 reported no significant difference between regimens in treatment failure (need for a second drug) (36 infants, RR 1.10, 95% CI 0.59, 2.07).

Other reported outcomes: Finnegan 1984 reported that infants treated with the loading dose regimen of phenobarbitone had a significantly reduced time to control of symptoms compared to infants treated with no loading dose and titration only (33 versus 64 hours, p < 0.01). No other data were given.

7 Short versus long course of phenobarbitone

All infants

Kahn 1969 compared a short and long course of phenobarbitone and reported no significant difference in treatment failure (19 infants, RR 0.58, 95% CI 0.04, 7.94) and no infant in either group was reported as receiving a second drug. No study reported neurodevelopment.

8 Short versus long course of chlorpromazine:

All infants

Kahn 1969 compared a short versus long course of chlorpromazine and reported no significant difference in treatment failure (persistent symptoms > 4 days) (19 infants, RR 3.64, 95% CI 0.52, 25.41) and no infant in either group was reported as receiving a second drug.

9 Phenobarbitone and opiate versus opiate alone

All infants

Primary outcomes: Coyle 2002 reported no infants with treatment failure (needing another drug) and no infants with a seizure in either group. Infants receiving phenobarbitone had a significant reduction in the percent time (of hospitalisation) that the Finnegan score was greater than/or equal to8 (MD -5.00%, 95% CI -9.84, -0.16). Neurodevelopment was not reported in the principle publication.

Secondary outcomes: Coyle 2002 reported a significant reduction in duration of hospitalisation in infants treated with phenobarbitone (MD -41.00 days, 95% CI -59.85, -22.15). Coyle 2002 also reported a significant reduction in the maximal daily dose of DTO (-12.10 mls, 95% CI -19.72, -4.48) and a reduction in average hospital cost ($US1000s: MD -35.86, 95%CI -52.36, -19.36) exclusive of physician billings. No infant in either group was readmitted for withdrawal to the same hospital post discharge, although other hospital admissions were not reported.

10 Clonidine and opiate versus opiate alone

All infants

Primary outcomes: Agthe 2009 reported no significant difference in treatment failure (80 infants, RR 0.09, 95% CI 0.01, 1.59), seizures (80 infants, RR 0.14, 95% CI 0.01, 2.68) or mortality (80 infants, RR 7.00, 95% CI 0.37, 131.28). However, all infants with treatment failure and seizures were in the opiate (DTO) alone group, and the three deaths in the clonidine and opiate group after cessation of clonidine. No study reported neurodevelopment.

Secondary outcomes: Agthe 2009 reported no significant difference in percent maximum weight loss (MD -0.88%, 95% CI -2.33, 0.57), ]. The median duration of therapy was significantly shorter in the clonidine and opiate group (11 days [95% CI: 8–15]) versus the opiate alone group (15 days [95% CI: 13–17]). No infant had hypotension with clonidine treatment and no infant had hypertension with cessation of clonidine. One infant had an episode of SVC after stopping clonidine.

OTHER COMPARISONS

There were no studies that compared diazepam and chlorpromazine.

SENSITIVITY ANALYSIS

Agthe 2009 met criteria for studies of good methodology with adequate randomisation and allocation concealment, blinding of intervention and no losses to follow up. The results are as reported for comparison 10 'Clonidine and opiate versus opiate alone'. No other study met eligibility criteria for inclusion as studies of good methodology because studies were either quasi-randomised or did not report method of randomisation.

Discussion

Summary of main results

This review should be considered in light of the review 'Opiate treatment for opiate withdrawal in newborn infants' (Osborn 2010). These reviews suggest that infants with NAS born to mothers using only opiates are more likely to have symptom control and less likely to have a second agent commenced if they are treated with an opiate compared to phenobarbitone or diazepam. This supports the AAP recommendation (AAP 1998). When a sedative is considered as initial therapy, phenobarbitone in addition to supportive care has not been shown to reduce treatment failure or time to regain birthweight compared to supportive care alone. However, the duration of supportive care each day was significantly reduced. The increased duration of treatment, hospital stay and stay in the special care nursery may reflect admission policies and care practices.

Phenobarbitone resulted in a significant reduction in treatment failure compared to diazepam. The benefits of phenobarbitone compared to diazepam were seen both in infants of mothers using only opiates and infants of mothers using multiple drugs. Data from one study suggests that infants treated with a loading dose of phenobarbitone have a shorter time to symptom control compared to infants treated with only a titration regimen of phenobarbitone. There is insufficient evidence to recommend the use of chlorpromazine for NAS due to opiate withdrawal.

In infants treated with an opiate, there is evidence from two studies that additional treatment with a sedative may have benefits. Agthe 2009 reported that the addition of clonidine to DTO may reduce treatment failure, although the difference is not statistically significant. The starting dose of opiate, equivalent to morphine 0.48 mg/day (not adjusted to infant weight) is relatively low. Of concern was the occurrence of adverse events in the clonidine group (one infant with a seizure, one an arrhythmia and three with post-discharge death), although none of these events were ascribed to the use of clonidine. Further trials are required to confirm the efficacy and determine safety of clonidine for treatment of NAS.

Coyle 2002 reported that the severity of withdrawal is reduced from use of phenobarbitone. Infants were weaned from the opiate (DTO) more quickly which allowed earlier hospital discharge and reduced hospital costs. Caution should be exercised in generalising these findings to other clinical settings. The starting dose of opiate, equivalent to morphine 0.12 to 0.16 mg/kg/day, is low. The policy of continuing hospital admission for infants treated with an opiate, but discharging home infants on phenobarbitone is not universal, making the hospitalisation and cost findings of this study applicable only to this setting. Total duration of pharmacological treatment was not measured and long term neurodevelopmental outcomes have not been published, particularly with infants treated with prolonged courses of phenobarbitone. Further trials are required that examine the effect of the addition of phenobarbitone to an opiate incorporating higher opiate dosing regimens, carried out in different clinical care settings including discharge based on psychosocial and infant care criteria rather than drug used for treatment, and incorporating long term follow up.

Overall completeness and applicability of evidence

This review includes studies that report random or quasi-random allocation of infants with NAS to a sedative or non-opiate control. Given the high rate of polydrug use in mothers of infants with NAS, the infants included in these studies are likely to represent the infants seen in clinical practice. However, few data are presented that differentiate response to treatment of infants of mothers using only opiates separately from those exposed to opiate using mothers with polydrug use. One study reported that treatment failure was reduced in both groups of infants with use of phenobarbitone compared to diazepam. Most studies used a standardised score to determine need for treatment and response to treatment. Few losses to follow up were reported by the individual studies, although this in some cases this could have been by omission. The studies assessing the effectiveness of a sedative (clonidine or phenobarbitone) in infants treated with an opiate used a low starting dose of opiate. This may have resulted in an increased time to control symptoms potentially resulting in an additional benefit from use of a sedative. Further studies of the addition of a sedative (either clonidine or phenobarbitone) are required in infants who are treated with a higher initial dose of opiate. Outcomes for only 385 infants enrolled in trials were reported in this review. This review has insufficient power to detect even moderate effects on infant mortality. This is especially important given the high rate of sudden unexpected death in this population of infants and the sedative and cardiovascular effects of the pharmacological treatments used.

Quality of the evidence

Only one study was included in sensitivity analysis of studies of good methodology. This assessed the effect of the addition of clonidine to DTO versus DTO alone for NAS in infants of mothers using opiates and frequently other drugs. However, the study is inadequately powered to detect important benefits or harms from the addition of clonidine. The validity of the results is affected by the methodological quality of the included studies. Four studies used quasi-random methods of patient allocation and two studies which reported random allocation did not report method of randomisation. Several studies had large differences in group allocations. The author of two studies (Finnegan 1984; Kaltenbach 1986) has communicated an interim analysis found a high incidence of adverse reactions in infants allocated diazepam so enrolment was stopped in this group. Only one study reported blinding of treatment and three blinding of measurement. The only study to differentiate infants of mothers on opiates from those born to mothers on an opiate and another drug did not pre-specify this comparison. No study reported quality of mother infant interaction, success of breast feeding, incidence of foster care or neurodevelopmental outcome (according to group of allocation). Two studies (Finnegan 1984; Kaltenbach 1986) may have reported overlapping infant groups. The data for the same outcomes of these studies were not combined in meta-analysis. In view of these limitations, the conclusions of this review should be treated with caution.

Potential biases in the review process

The review searched for published and unpublished studies in an attempt to avoid publication bias. The review included studies using quasi-random patient allocation increasing the risk of selection bias in the studies included in the review. This has been addressed using sensitivity analysis. This review prespecified the primary outcomes and the comparisons that have been made, with the exception of the comparisons between phenobarbitone with or without loading dose, and long and short course sedative regimens.

Agreements and disagreements with other studies or reviews

This review is consistent with recommendations made by other authors (Theis 1997) and the American Academy of Pediatrics (AAP 1998) recommendations for management of NAS due to opiate withdrawal. That is, if pharmacological treatment is chosen then a specific drug from the same class of drugs causing withdrawal is preferable.

Authors' conclusions

Implications for practice

In view of the findings of the review, "Opiate treatment for opiate withdrawal in newborn infants" (Osborn 2010), infants with NAS due to opiate withdrawal should receive initial treatment with an opiate. Where a sedative is used, then phenobarbitone should be used in preference to diazepam. In infants treated with an opiate, the addition of phenobarbitone or clonidine may reduce withdrawal severity. However, the initial dose of opiate was relatively low in both studies. There is insufficient evidence to confirm safety and efficacy of clonidine. There is insufficient evidence to support the use of chlorpromazine in newborn infants with NAS.

Implications for research

Further studies are needed to determine the role of sedatives in infants with NAS due to opiate withdrawal. Further, large studies of the addition of phenobarbitone or clonidine in infants treated with an opiate for NAS are needed. Consideration should be given to incorporating higher initial dosing schedules of opiate and studies should report long term outcomes. Current data are insufficient to guide the use of chlorpromazine. Studies should measure effects on infant symptoms and severity of withdrawal, quality of mother-infant interaction, growth and long term development. Trials in infants with NAS should stratify randomisation by drug of exposure of infant.

Acknowledgements

Dr Loretta Finnegan, Dr Katie Khoo and Professor Karol Kaltenbach who kindly provided additional information regarding their studies.

The Cochrane Neonatal Review Group has been funded in part with Federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA, under Contract No. HHSN267200603418C.

Contributions of authors

DO wrote the original protocol and review. All reviewers independently searched for studies, assessed eligibility, critically appraised included studies and extracted data. DO entered the characteristics of included and excluded studies data and data tables and HJ and MC checked accuracy and checked the final version of the review.
For the updated reviews 2005 and 2010, DO searched for new studies, assessed eligibility, critically appraised studies and extracted data independently. In 2005, HJ critically appraised the new study and did data extraction. In 2010, DO wrote the updated review.

Declarations of interest

  • None noted.

Differences between protocol and review

Updated to RevMan 5 format. Methods for assessment of heterogeneity, unit of analysis issues and reporting bias added.

Potential conflict of interest

  • None noted.

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Characteristics of studies

Characteristics of Included Studies

Agthe 2009

Methods

Randomised controlled trial.

Participants

Infants between 0-14 days age if they were prenatally exposed to opioids and developed moderate to severe NAS (2 consecutive modified Finnegan scores (MFS) greater than/or equal to9) requiring pharmacotherapy.

Infants excluded for (1) gestational age < 35 weeks, (2) intrauterine growth retardation, (birth weight < 5th percentile), (3) congenital anomalies, (4) illness requiring oxygen, intravenous fluids, or medications, and (5) breastfeeding.

61% of infants exposed to cocaine in utero, 6 of 80 infants had positive benzodiazepine urine screens.

Interventions

Treatment (n=): oral clonidine 1 μg/kg every 4 hours (6 μg/kg per day) and diluted tincture of opium (clonidine/DTO), versus

Control (n=): opium alone (placebo/DTO).

DTO was given as a 1:25 dilution, 0.4 mg/mL (morphine equivalent). All infants started on 0.2 mL DTO (0.08 mg morphine) orally every 4 hours. NAS symptoms were uncontrolled if there were 2 consecutive MFS < 9. DTO was incrementally escalated to 0.3, 0.4, and 0.5 mL every 4 hours, then to 0.5, 0.7, and 0.9 mL every 3 hours, until withdrawal symptoms (MFS < 9) were controlled.

When symptoms were controlled (mean daily MFS < 9), infants were continued on clonidine/placebo and DTO dose that controlled symptoms for at least 48 hours. Afterward, DTO was weaned by increments of 0.05 mL per dose, for each 24-hour period.

Outcomes

Primary outcome: total duration of pharmacotherapy for NAS.

Secondary outcomes included amount of DTO required to treat the NAS (with or without clonidine), treatment failure (0.9 mL of DTO every 3 hours), seizures, weight gain, blood pressure, heart rate, and haemoglobin saturation measured by pulse oximetry.

Diagnosis of seizures made by the clinical team; all infants received an electroencephalogram after phenobarbital was administered and no infant had an abnormal electroencephalogram.

Notes

Funded by a Thomas Wilson grant, an institutional research grant from JHH, General Clinical Research Center, and was supported by National Institute on Drug Abuse.

Risk of bias table
Item Judgement Description
Adequate sequence generation? Yes

Randomly assigned by pharmacist into 2 strata by a computerized random list in blocks of 4, stratified by hospital birth and maternal methadone dose.

Allocation concealment? Yes
Blinding? (Treatment) Yes

Placebo (isotonic saline).

Blinding? (Short term outcomes) Yes
Blinding? (Long term outcomes) No

Not measured.

Incomplete outcome data addressed? Yes

One withdrawn infant reported in intention to treat analysis.

Free of selective reporting? Unclear

Unclear prespecified outcomes.

Free of other bias? No

Infants in Clonidine + DTO group had significantly lower mean birth weight.

Coyle 2002

Methods

Probably quasi-randomised study.

Participants

Inclusion criteria: Infants born to mothers with a history of heroin or methadone use. Finnegan score >7. Criteria for starting medication same as recommendation of Finnegan.

Exclusion criteria: none reported.

Incidence of non-opiate illicit drug use not reported.

Interventions

All infants treated with dilute tincture of opium (DTO) (0.4mg/ml morphine) 0.05mls/kg 6-8 times per day. Dose increased if Finnegan score > 7, maintained if score 5-7 and reduced if score < 5 for 3 consecutive periods. 'Randomised' to:

  1. Phenobarbital (n=10) loading dose 30 mg/kg (given as 3 oral doses every 12 hours) and maintenance 5 mg/kg/day. Dose adjusted to maintain weekly serum level 20-30 mg/dl.
  2. Placebo (n = 10).
Outcomes

Primary outcome: severity of withdrawal symptoms (using Finnegan score), duration of hospitalisation, hospital cost.
Other outcomes: Neurobehavioural and developmental outcomes reported in abstract form not reported in principle publication.

Notes

A total of 35 infants (term and preterm) were reported in abstract form. The principle publication reported 21 term infants only.

Risk of bias table
Item Judgement Description
Adequate sequence generation? No

Infants prospectively matched by first Finnegan score. Method of allocation within score incompletely described. If no match then randomly assigned, method not reported.

Allocation concealment? No
Blinding? (Treatment) Unclear

Placebo used, nurses blinded to treatment, although weekly phenobarbitone levels reported to physician.

Blinding? (Short term outcomes) Unclear

Not reported.

Blinding? (Long term outcomes) Unclear

Reported in abstract form only.

Incomplete outcome data addressed? Yes

1/21 excluded after transfer due to congenital heart disease.

Free of selective reporting? Yes

Clear prespecified outcomes.

Free of other bias? Unclear

Finnegan 1984

Methods

Quasi-random study.

Participants

Inclusion criteria: Infants born to mothers with a) narcotic use only and b) narcotic and other drug use. Finnegan score determined need for treatment. Exclusion criteria: none reported.

Polydrug use = 71%.

Interventions
  1. Phenobarbital (n=87) with or without loading dose (20 mg/kg) with maintenance 5-10 mg/kg/day titrated against score. Dose increased till control obtained, serum level > 70mcg/ml or evidence of toxicity.
  2. Diazepam (n = 20): dose not reported.
    (Also compared infants given paregoric).
Outcomes

Primary outcome: need for 2nd pharmacological intervention.Other outcomes: none. Outcomes for loading dose and titration methods reported combined.

Notes

Additional information obtained from authors. Group numbers not balanced. Interim analysis found diazepam group had excessive number of complications (somnolence and respiratory depression), so enrolment in this group stopped. May include some of the infants as reported by Kaltenbach 1986. Randomisation not stratified according to type of antenatal drug use.

Risk of bias table
Item Judgement Description
Adequate sequence generation? No

Quasi-random, drug assignment from envelope designated according to first letter of last name.

Allocation concealment? No
Blinding? (Treatment) No

Treatment regimens different.

Blinding? (Short term outcomes) Unclear

Nurses unblinded, research staff blinded.

Blinding? (Long term outcomes) No

Not measured.

Incomplete outcome data addressed? Unclear

None reported.

Free of selective reporting? Unclear

Primary and secondary outcomes not clearly prespecified.

Free of other bias? Unclear

Reported stopping enrolment in the diazepam arm early due to an interim analysis demonstrating the possibility of adverse effects.

Kahn 1969

Methods

Randomised controlled trial.

Participants

Inclusion criteria: infants of mothers using heroin. Standardised scoring system. Infants with tremors or irritability > grade 1 on 3 grade score.
Exclusion criteria: tremors and irritability less than/or equal to grade 1.
Polydrug use: yes, 5 used glutethimide, 4 amphetamines and 2 barbiturates.

Interventions
  1. Phenobarbital short course (n = 12): 8.4mg/kg/day x 4 day (4 divided doses) then stopped.
  2. Phenobarbital long course (n = 7): 8.4mg/kg/day (4 divided doses) x 10 days then reduced by 1/3rd every 2nd day (stopped day 16).
  3. Chorpromazine short course (n = 11): 2.8mg/kg/day ( 4 divided doses) x 4 days then stopped.
  4. Chlorpromazine long course (n = 8): 2.8mg/kg/day (4 divided doses) x 10 days then gradual reduction over next 6 days.
Outcomes

Primary outcome: none reported.
Other outcomes: infant mortality, severity and duration of withdrawal symptoms. Persistent symptoms > 4 days.

Notes

Co-interventions: none reported.

Risk of bias table
Item Judgement Description
Adequate sequence generation? Unclear

Method not reported.

Allocation concealment? Unclear

Method not reported.

Blinding? (Treatment) Yes

Used 'identical syrups'.

Blinding? (Short term outcomes) Yes
Blinding? (Long term outcomes) No

Not measured.

Incomplete outcome data addressed? Unclear
Free of selective reporting? Unclear

Unclear prespecified outcomes.

Free of other bias? Unclear

Kaltenbach 1986

Methods

Quasi-random trial

Participants

Inclusion criteria: Infants of drug dependant women maintained on methadone. Neonatal Abstinence Scoring System score averaging greater than/or equal to 8 for 3 consecutive scores.

Polydrug use: yes, incidence not reported.

Interventions
  1. Phenobarbital loading dose followed by titration (n = 20): doses not given.
  2. Phenobarbital titration group (n = 16): doses not reported.
  3. Diazepam (n = 10): dose not reported.

(Paregoric group also reported).

Outcomes

Primary outcome: Bayley Scale of Mental Development at 6 months (not reported by intention to treat). Other outcomes: need for second agent to control symptoms.

Notes

Additional information obtained from authors. Group numbers not balanced. May include some of the infants as reported by Finnegan 1984. Randomisation not stratified according to type of antenatal drug use.

Risk of bias table
Item Judgement Description
Adequate sequence generation? No

Quasi-random, drug assignment from envelope designated according to first letter of last name.

Allocation concealment? No

Allocation predictable.

Blinding? (Treatment) No

Treatment regimens different.

Blinding? (Short term outcomes) No
Blinding? (Long term outcomes) Yes

For Bayley MDI / PDI.

Incomplete outcome data addressed? Unclear

None reported.

Free of selective reporting? Unclear

Unclear prespecified outcomes.

Free of other bias? Unclear

Khoo 1995

Methods

Quasi-randomised trial.

Participants

Inclusion criteria: infants of mothers with an opiate dependence who had Finnegan NASS scores averaging greater than/or equal to8 in 3 consecutive 4-hour periods. Urine drug screens performed during pregnancy.

Polydrug use reported by 95% of methadone mothers. 76% of infants had been exposed to more than 2 drugs in utero.

Interventions
  1. Phenobarbital loading dose (n=29) 15mg/kg (intramuscular) then 6mg/kg/day in 2 divided doses, titrated to score up to maximum 10mg/kg/day; and supportive therapy.
  2. Supportive therapy alone (n=36) (included pacifier, swaddling, close wrapping, small frequent feeds, close skin contact by carrying in sling and other methods.
Outcomes

Primary outcome: unclear.Other outcomes: need for second drug (failure to settle measured using Finnegan score), duration of supportive intervention, numbers of dose increments on therapy, number of treatment days, days in baby special care nursery, days in hospital, treatment days and days to regain weight. Brazelton Neonatal Behavioural Assessment Scale performed in the neonatal period, and an infant temperament questionnaire at 2, 4, 8 and 12 months.

Notes

Methods and data obtained from author's PhD thesis and the author. Group numbers not balanced.

Risk of bias table
Item Judgement Description
Adequate sequence generation? Unclear

Quasi-random, used last number of the subject's hospital number.

Allocation concealment? No
Blinding? (Treatment) No
Blinding? (Short term outcomes) Unclear

Not reported.

Blinding? (Long term outcomes) No

Not measured.

Incomplete outcome data addressed? Yes

1 infant allocated phenobarbital and 2 supportive therapy excluded from analysis. Data available for days to regain birthweight from 27/29 on phenobarbital and 28/36 on supportive therapy.

Free of selective reporting? Unclear

Unclear prespecified outcomes.

Free of other bias? Unclear

Madden 1977

Methods

Randomised controlled trial.

Participants

Inclusion criteria: infants of narcotic-addicted mothers. Clinical decision to treat. Abstinence score not used.
Exclusion criteria: none reported.
Polydrug use: yes, non-opiate use reported in 15% of the baseline population of mothers

Interventions
  1. Phenobarbital (n = 16): 5-8mg/kg/day (3 divided doses).
  2. Diazepam (n = 16): 0.5-2.0mg q8h.

Doses "tailored day to day".

Outcomes

Primary outcome: none reported.Other outcomes: use of second drug, duration of treatment and day of hospital discharge.

Notes

Duration of treatment and day of discharge not analysed according to original group of assignment.
Co-interventions: none reported.

Risk of bias table
Item Judgement Description
Adequate sequence generation? Unclear

Random, method not reported.

Allocation concealment? Unclear
Blinding? (Treatment) No

Unlikely, treatment regimens different.

Blinding? (Short term outcomes) Unclear
Blinding? (Long term outcomes) No

Not measured.

Incomplete outcome data addressed? Yes

None reported. One infant given diazepam non-randomly excluded. One infant in phenobarbital group treated with second drug not included in duration of treatment and hospital stay.

Free of selective reporting? Unclear

Unclear prespecified outcomes.

Free of other bias? Unclear

Characteristics of excluded studies

Alroomi 1988

Reason for exclusion

Observational study.

Calabrese 1985

Reason for exclusion

Monograph review.

Carin 1983

Reason for exclusion

Randomized trial of paregoric versus phenobarbital.

Doberczak 1991

Reason for exclusion

Observational study.

Esmaeili 2010

Reason for exclusion

Observational study - comparison of infants admitted to 2 different paediatric units treated with chloral hydrate or clonidine.

Finnegan 1975a

Reason for exclusion

Observational study.

Finnegan 1975b

Reason for exclusion

Observational study.

Finnegan 1979

Reason for exclusion

Case series report.

Finnegan 1984b

Reason for exclusion

Study comparing loading dose and titration approach to commencing phenobarbital therapy for neonatal abstinence syndrome. Method of treatment allocation not reported.

Harper 1977

Reason for exclusion

Observational study.

Herzlinger 1977

Reason for exclusion

Observational study.

Hoder 1981

Reason for exclusion

Case report.

Hoder 1984

Reason for exclusion

Non randomised study of clonidine for neonatal narcotic abstinence. No controls.

Kaltenbach 1987

Reason for exclusion

Observational study.

Kandall 1983

Reason for exclusion

Randomised study of phenobarbital and paregoric for neonatal abstinence syndrome.

Kron 1975a

Reason for exclusion

Observational study.

Kron 1975b

Reason for exclusion

Observational study.

Kron 1976

Reason for exclusion

Non random allocation to treatment.

Leikin 2009

Reason for exclusion

Case series in which clonidine was used for the prevention and management of patients with neonatal abstinence syndrome.

Nathenson 1971

Reason for exclusion

Observational study of the use of diazepam in neonatal abstinence syndrome.

Ostrea 1975

Reason for exclusion

No study of treatment.

Ostrea 1976

Reason for exclusion

Infants randomised to experimental (noise and light reduced) and control nursery.

Pacifico 1989

Reason for exclusion

Compared morphine alone versus phenobarbitone and diazepam versus phenobarbitone and diazepam and morphine in infants of mothers using heroin. Did not report method of patient allocation. Authors unable to be contacted to date.

Sutton 1990

Reason for exclusion

Case report.

Tunis 1984

Reason for exclusion

Control study of infants with neonatal abstinence syndrome given paregoric, phenobarbital or diazepam. Method of allocation not stated. No data given.

Wolman 1989

Reason for exclusion

Monograph review.

Yaster 1996

Reason for exclusion

Monograph review.

Zelson 1970

Reason for exclusion

Letter documenting observations.

Characteristics of ongoing studies

Singh 2010

Study name

Clonidine for Neonatal Abstinence Syndrome Study

Methods

Randomized, non-blinded clinical trial

Participants

Inclusion Criteria:

  • 0 to 15 days of age
  • Prenatal exposure to opioids with development of moderate to severe NAS (2 consecutive abstinence scores of greater than/or equal to8)
  • Medically stable

Exclusion Criteria:

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

Clonidine This group of infants undergoing NAS will be treated with neonatal morphine sulphate 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.

Phenobarbital 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.

Outcomes

Primary aim is to compare the length of NAS treatment with NMS in the two study groups - NMS/C versus NMS/P.

Secondary aims are to compare the total dosage of NMS, total length of hospital stay for NAS treatment, treatment failures, adverse effect profiles and neurobehavioral assessment scores (NBAS)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.

Starting date

Study Start Date: July 2010; Estimated Study Completion Date: July 2012

Contact information

Rachana Singh, MD, MS 413-794-2207 rachana.singhmd@bhs.org

Notes

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References to studies

Included studies

Agthe 2009

Agthe AG, Kim GR, Mathias KB, Hendrix CW, Chavez-Valdez R, Jansson L, et al. Clonidine as an adjunct therapy to opioids for neonatal abstinence syndrome: a randomized, controlled trial. Pediatrics 2009;123:e849-56.

Agthe AG, Mathias KB, Hendrix CW, Jansson L, Yaster M, Roark TR, et al. Clonidine in combination with diluted tincture of opium (DTO) versus DTO alone for opioid withdrawal in newborn infants: A blinded randomized clinical trial. In: ePAS. 2007.

Coyle 2002

Bier JB, Ferguson AE, Grenon D, Mullane E, Coyle M. The effects of phenobarbital on developmental outcomes in infants with methadone withdrawal: results of a randomized trial. Pediatric Research 2000;47:175A.

* Coyle MG, Ferguson A, Lagasse L, Oh W, Lester B. Diluted tincture of opium (DTO) and phenobarbital versus DTO alone for neonatal opiate withdrawal in term infants. Journal of Pediatrics 2002;140:561-4.

Ferguson AE, Coyle M, LaGasse L, Liu E, Lester B. Neurobehavioural effects of treatment for opiate withdrawal. Pediatric Research 2001;49:18A.

Finnegan 1984

Published and unpublished data

Finnegan LP, Michael H, Leifer B, Desai S. An evaluation of neonatal abstinence treatment modalities. NIDA Research Monograph 1984;49:282-8.

Kahn 1969

Kahn EJ, Neumann LL, Polk GA. The course of the heroin withdrawal syndrome in newborn infants treated with phenobarbital or chlorpromazine. Journal of Pediatrics 1969;75:495-500.

Kaltenbach 1986

Published and unpublished data

Kaltenbach K, Finnegan LP. Neonatal abstinence syndrome, pharmacotherapy and developmental outcome. Neurobehavioral Toxicology and Teratology 1986;8:353-5.

Khoo 1995

Unpublished data only

Khoo KT. The effectiveness of three treatment regimens used in the management of neonatal abstinence syndrome. University of Melbourne. PhD Thesis 1995.

Madden 1977

Madden JD, Chappel JN, Zuspan F, Gumpel J, Mejia A, Davis R. Observation and treatment of neonatal narcotic withdrawal. American Journal of Obstetrics and Gynecology 1977;127:199-201.

Excluded studies

Alroomi 1988

Alroomi LG, Davidson J, Evans TJ, Galea P, Howat R. Maternal narcotic abuse and the newborn. Archives of Disease in Childhood 1988;63:81-3.

Calabrese 1985

Calabrese JR, Gulledge AD. The neonatal narcotic abstinence syndrome: a brief review. Canadian Journal of Psychiatry 1985;30:623-6.

Carin 1983

Carin I, Glass L, Parekh A, Solomon N, Steigman J, Wong S. Neonatal methadone withdrawal effect of two treatment regimens. American Journal of Diseases of Children 1983;137:1166-9.

Doberczak 1991

Doberczak TM, Kandall SR, Wilets I. Neonatal opiate abstinence syndrome in term and preterm infants. Journal of Pediatrics 1991;118:933-7.

Esmaeili 2010

Esmaeili A, Keinhorst AK, Schuster T, Beske F, Schlosser R, Bastanier C. Treatment of neonatal abstinence syndrome with clonidine and chloral hydrate. Acta Paediatrica 2010;99:209-14.

Finnegan 1975a

Finnegan LP, Connaughton JF Jr, Kron RE, Emich JP. Neonatal abstinence syndrome: assessment and management. Addictive Diseases 1975;2:141-58.

Finnegan 1975b

Finnegan LP, Kron RE, Connaughton JF, Emich JP. Assessment and treatment of abstinence in the infant of the drug-dependent motherInt. Journal of Clinical Pharmacology 1975;12:19-32.

Finnegan 1979

Finnegan LP, Mitros TF, Hopkins LE. Management of neonatal narcotic abstinence utilizing a phenobarbital loading dose method. NIDA Research Monograph 1979;27:247-53.

Finnegan 1984b

Finnegan LP, Michael H, Leifer B. The use of phenobarbital in treating abstinence in newborns exposed in utero to psychoactive agents. NIDA Research Monograph 1984;49:329.

Harper 1977

Harper RG, Solish G, Feingold E, Gersten Woolf NB, Sokal MM. Maternal ingested methadone, body fluid methadone, and the neonatal withdrawal syndrome. American Journal of Obstetrics and Gynecology 1977;129:417-24.

Herzlinger 1977

Herzlinger RA, Kandall SR, Vaughan HG Jr. Neonatal seizures associated with narcotic withdrawal. Journal of Pediatrics 1977;91:638-41.

Hoder 1981

Hoder EL, Leckman JF, Ehrenkranz R, Kleber H, Cohen DJ, Poulsen JA. Clonidine in neonatal narcotic-abstinence syndrome. New England Journal of Medicine 1981;305:1284.

Hoder 1984

Hoder EL, Leckman JF, Poulsen J, Caruso KA, Ehrenkranz RA, Kleber HD, Cohen DJ. Clonidine treatment of neonatal narcotic abstinence syndrome. Psychiatry Research 1984;13:243-51.

Kaltenbach 1987

Kaltenbach K, Finnegan LP. Perinatal and developmental outcome of infants exposed to methadone in-utero. Neurotoxicology and Teratology 1987;9:311-3.

Kandall 1983

Kandall SR, Doberczak TM, Mauer KR, Strashun RH, Korts DC. Opiate v CNS depressant therapy in neonatal drug abstinence syndrome. American Journal of Diseases of Children 1983;137:378-82.

Kron 1975a

Kron RE, Kaplan SL, Finnegan LP, Litt M, Phoenix MD. The assessment of behavioural change in infants undergoing narcotic withdrawal: comparative data from clinical and objective methods. Addicitive Diseases 1975;2:257-75.

Kron 1975b

Kron RE, Litt M, Finnegan LP. Narcotic addiction in the newborn: differences in behaviour generated by methadone and heroin. International Journal of Clinical Pharmacology, Therapy and Toxicology 1975;12:63-9.

Kron 1976

Kron RE, Litt M, Eng D, Phoenix MD, Finnegan LP. Neonatal narcotic abstinence: Effects of pharmacotherapeutic agents and maternal drug usage on nutritive sucking behavior. Journal of Pediatrics 1976;88:637-41.

Leikin 2009

Leikin JB, Mackendrick WP, Maloney GE, Rhee JW, Farrell E, Wahl M, Kelly K. Use of clonidine in the prevention and management of neonatal abstinence syndrome. Clinical Toxicology 2009;47:551-5.

Nathenson 1971

Nathenson G, Golden GS, Litt IF. Diazepam in the management of the neonatal narcotic withdrawal syndrome. Pediatrics 1971;48:523-7.

Ostrea 1975

Ostrea EM, Chavez CJ, Strauss ME. A study of factors that influence the severity of neonatal narcotic withdrawal. Addict Diseases 1975;2:187-99.

Ostrea 1976

* Ostrea EM, Chavez CJ, Strauss ME. A study of factors that influence the severity of neonatal narcotic withdrawal. Addict Diseases 1975;2:187-99.

Ostrea EM, Chavez CJ, Strauss ME. A study of factors that influence the severity of neonatal narcotic withdrawal. Journal of Pediatrics 1976;88:642-5.

Pacifico 1989

Pacifico P, Nardelli E, Pantarotto MF. Neonatal heroin withdrawal syndrome; evaluation of different pharmacological treatments. Pharmacological Research 1989;21 (S1):63-4.

Sutton 1990

Sutton LR, Hinderliter SA. Diazepam abuse in pregnant women on methadone maintenance. Implications for treatment. Clinical Pediatrics 1990;29:108-11.

Tunis 1984

Tunis SL, Webster DM, Izes JK, Finnegan LP. Maternal drug use and the effectiveness of pharmacotherapy for neonatal abstinence. NIDA Research Monograph 1984;55:158.

Wolman 1989

Wolman I, Niv D, Yoval I, Pausner D, Geller E, David MP. Opioid-addicted parturient, labor, and outcome: a reappraisal. Obstetrical & Gynecological Survey 1989;44:592-7.

Yaster 1996

Yaster M, Kost-Byerly S, Berde C, Billet C. The management of opioid and benzodiazepine dependence in infants, children, and adolescents. Pediatrics 1996;98:135-40.

Zelson 1970

Zelson C. Heroin withdrawal syndrome. Journal of Pediatrics 1970;76:483-6.

Studies awaiting classification

  • None noted.

Ongoing studies

Singh 2010

Unpublished data only

Singh R. Clonidine for Neonatal Abstinence Syndrome Study. ClinicalTrials.gov Identifier: NCT01175668.

Other references

Additional references

AAP 1998

American Academy of Pediatrics Committee on Drugs. Neonatal drug withdrawal. Pediatrics 1998;101:1079-88.

Bell 1995

Bell GL, Lau K. Perinatal and neonatal issues of substance abuse. Pediatric Clinics of North America 1995;42:261-81.

de Cubas 1993

de Cubas MM, Field T. Children of methadone-dependent women: developmental outcomes. American Journal of Orthopsychiatry 1993;63:266-76.

Fricker 1978

Fricker HS, Segal S. Narcotic addiction, pregnancy, and the newborn. American Journal of Diseases of Children 1978;132:360-6.

Higgins 2008

Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.2 [updated September 2009]. The Cochrane Collaboration 2009;Available from www.cochrane-handbook.org.

Hulse 1998

Hulse GK, Milne E, English DR, Holman CD. Assessing the relationship between maternal opiate use and neonatal mortality. Addiction 1998;93:1033-42.

Kandall 1974

Kandall SR, Gartner LM. Late presentation of drug withdrawal symptoms in newborns. American Journal of Diseases of Children 1974;127:58-61.

Kandall 1977

Kandall SR, Albin S, Gartner LM, Lee KS, Eidelman A, Lowinson J. The narcotic-dependent mother: fetal and neonatal consequences. Early Human Development 1977;1:159-69.

Kandall 1993

Kandall SR, Gaines J, Habel L, Davidson G, Jessop D. Relationship of maternal substance abuse to subsequent sudden infant death syndrome in offspring. Journal of Pediatrics 1993;123:120-6.

Lam 1992

Lam SK, To WK, Duthie SJ, Ma HK. Narcotic addiction in pregnancy with adverse maternal and perinatal outcome. Australian & New Zealand Journal of Obstetrics & Gynaecology 1992;32:216-21.

Lipsitz 1975

Lipsitz PJ. A proposed narcotic withdrawal score for use with newborn infants. A pragmatic evaluation of its efficacy. Clinical Pediatrics 1975;14:592-4.

Maas 1990

Maas U, Kattner E, Weingart Jesse B, Schafer A, Obladen M. Infrequent neonatal opiate withdrawal following maternal methadone detoxification during pregnancy. Journal of Perinatal Medicine 1990;18:111-8.

Madden 1977

Madden JD, Chappel JN, Zuspan F, Gumpel J, Mejia A, Davis R. Observation and treatment of neonatal narcotic withdrawal. American Journal of Obstetrics and Gynecology 1977;127:199-201.

NDSHS 1998

Adhikari P, Summerill A. 1998 National Drug Strategy Household Survey: Detailed findings. AIHW cat. no. PHE 27. Canberra: AIHW (Drug Statistics Series No. 6). 2000.

NHSDA 1999

Office of Applied Statistics, Substance Abuse and Mental Health Administration (SAMHSA). National household survey on drug abuse. 1999. http://www.DrugAbuseStatistics.samhsa.gov/ 2001.

O'Brien 2002

O' Brien C, Jeffery HE. Sleep deprivation, disorganisation and fragmentation during opiate withdrawal in newborns. Journal of Paediatrics and Child Health 2002;38:66-71.

Olofsson 1983

Olofsson M, Buckley W, Andersen GE, Friis Hansen BSO. Investigation of 89 children born by drug-dependent mothers. I. Neonatal course. Acta Paediatrica Scandinavica 1983;72:403-6.

Olson 1997

Olson GA, Olson RD, Kastin AJ. Endogenous opiates: 1996. Peptides 1997;18:1651-88.

Ornoy 1996

Ornoy A, Michailevskaya V, Lukashov I, Bar Hamburger R, Harel S. The developmental outcome of children born to heroin-dependent mothers, raised at home or adopted. Child Abuse & Neglect 1996;20:385-96.

Osborn 2002a

Osborn DA, Jeffery HE, Cole MJ. Opiate treatment for opiate withdrawal in newborn infants. Cochrane Database of Systematic Reviews 2002, Issue 3. Art. No.: CD002059. DOI: 10.1002/14651858.CD002059.

Osborn 2005

Osborn DA, Jeffery HE, Cole M. Opiate treatment for opiate withdrawal in newborn infants. Cochrane Database of Systematic Reviews 2005, Issue 3. Art. No.: CD002059. DOI: 10.1002/14651858.CD002059.pub2.

Osborn 2010

Osborn DA, Jeffery HE, Cole M. Opiate treatment for opiate withdrawal in newborn infants. Cochrane Database of Systematic Reviews 2010, Issue 10.

Strauss 1976

Strauss ME, Andresko M, Stryker JC, Wardell JN. Relationship of neonatal withdrawal to maternal methadone dose. American Journal of Drug and Alcohol Abuse 1976;3:339-45.

Theis 1997

Theis JG, Selby P, Ikizler Y, Koren GS. Current management of the neonatal abstinence syndrome: a critical analysis of the evidence. Biology of the Neonate 1997;71:345-56.

Zahorodny 1998

Zahorodny W, Rom C, Whitney W, Giddens S, Samuel M, Maichuk G, Marshall R. The neonatal withdrawal inventory: a simplified score of newborn withdrawal. Journal of Developmental and Behavioral Pediatrics 1998;19:89-93.

Other published versions of this review

Osborn 2002b

Osborn DA, Jeffery HE, Cole MJ. Sedatives for opiate withdrawal in newborn infants. Cochrane Database of Systematic Reviews 2002, Issue 3. Art. No.: CD002053. DOI: 10.1002/14651858.CD002053.

Osborn 2005b

Osborn DA, Jeffery HE, Cole MJ. Sedatives for opiate withdrawal in newborn infants. Cochrane Database of Systematic Reviews 2005, Issue 3. Art. No.: CD002053. DOI: 10.1002/14651858.CD002053.pub2.

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Data and analyses

1 Phenobarbitone versus supportive care (all infants)

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
1.1 Treatment failure 1 62 Risk Ratio (M-H, Fixed, 95% CI) 2.73 [0.94, 7.94]
1.2 Duration of treatment (days) 1 62 Mean Difference (IV, Fixed, 95% CI) 17.90 [11.98, 23.82]
1.3 Duration of hospital stay (days) 1 62 Mean Difference (IV, Fixed, 95% CI) 20.80 [13.64, 27.96]
1.4 Duration of stay in special care nursery (days) 1 62 Mean Difference (IV, Fixed, 95% CI) 23.10 [15.84, 30.36]
1.5 Time to regain birth weight (days) 1 55 Mean Difference (IV, Fixed, 95% CI) -1.40 [-4.07, 1.27]
1.6 Duration of supportive care per day (minutes) 1 62 Mean Difference (IV, Fixed, 95% CI) -162.10 [-249.14, -75.06]

2 Phenobarbitone versus diazepam (all infants)

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
2.1 Treatment failure 2 139 Risk Ratio (M-H, Fixed, 95% CI) 0.39 [0.24, 0.62]
2.2 Duration of treatment (days) 1 31 Mean Difference (IV, Fixed, 95% CI) 4.30 [-0.73, 9.33]
2.3 Duration of hospital stay (days) 1 31 Mean Difference (IV, Fixed, 95% CI) 3.07 [-2.02, 8.16]
2.4 Treatment failure (probable sequential report) 1 46 Risk Ratio (M-H, Fixed, 95% CI) 0.55 [0.40, 0.77]

3 Phenobarbitone versus diazepam (infants of mothers using only opiates)

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
3.1 Treatment failure 1 31 Risk Ratio (M-H, Fixed, 95% CI) 0.55 [0.35, 0.85]

4 Phenobarbitone versus diazepam (infants of mothers using opiates and other drugs)

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
4.1 Treatment failure 1 76 Risk Ratio (M-H, Fixed, 95% CI) 0.19 [0.09, 0.43]

5 Phenobarbitone versus chlorpromazine (all infants)

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
5.1 Treatment failure 1 38 Risk Ratio (M-H, Fixed, 95% CI) 0.33 [0.08, 1.45]
5.2 Need for second drug 1 38 Risk Ratio (M-H, Fixed, 95% CI) Not estimable
5.3 Seizures 1 40 Risk Ratio (M-H, Fixed, 95% CI) Not estimable

6 Phenobarbitone titration with loading dose versus phenobarbitone titration alone (all infants)

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
6.1 Treatment failure 1 36 Risk Ratio (M-H, Fixed, 95% CI) 1.10 [0.59, 2.07]

7 Short versus long course of phenobarbitone (all infants)

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
7.1 Treatment failure 1 19 Risk Ratio (M-H, Fixed, 95% CI) 0.58 [0.04, 7.94]

8 Short versus long course of chlorpromazine (all infants)

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
8.1 Treatment failure 1 19 Risk Ratio (M-H, Fixed, 95% CI) 3.64 [0.52, 25.41]

9 Phenobarbitone and opiate versus opiate alone

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
9.1 Treatment failure 1 20 Risk Ratio (M-H, Fixed, 95% CI) Not estimable
9.2 Seizures 1 20 Risk Ratio (M-H, Fixed, 95% CI) Not estimable
9.3 Percent time Finnegan score less than/or equal to8 1 20 Mean Difference (IV, Fixed, 95% CI) -5.00 [-9.84, -0.16]
9.4 Duration of hospital stay (days) 1 20 Mean Difference (IV, Fixed, 95% CI) -41.00 [-59.85, -22.15]
9.5 Maximal daily dose of DTO (mls) 1 20 Mean Difference (IV, Fixed, 95% CI) -12.10 [-19.72, -4.48]
9.6 Hospital costs exclusive of physicians charges ($US1000s) 1 20 Mean Difference (IV, Fixed, 95% CI) -35.86 [-52.36, -19.36]

10 Clonidine and opiate versus opiate alone (all infants)

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
10.1 Treatment failure 1 80 Risk Ratio (M-H, Fixed, 95% CI) 0.09 [0.01, 1.59]
10.2 Seizures 1 80 Risk Ratio (M-H, Fixed, 95% CI) 0.14 [0.01, 2.68]
10.3 Mortality 1 80 Risk Ratio (M-H, Fixed, 95% CI) 7.00 [0.37, 131.28]
10.4 Maximum weight loss (%) 1 80 Mean Difference (IV, Fixed, 95% CI) -0.88 [-2.33, 0.57]
10.5 Adverse event 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
10.5.1 Hypotension 1 80 Risk Ratio (M-H, Fixed, 95% CI) Not estimable
10.5.2 Hypertension 1 80 Risk Ratio (M-H, Fixed, 95% CI) Not estimable
10.5.3 Arrhythmia 1 80 Risk Ratio (M-H, Fixed, 95% CI) 3.00 [0.13, 71.51]

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Sources of support

Internal sources

  • RPA Newborn Care, Royal Prince Alfred Hospital, Sydney, Australia

External sources

  • Australian Satellite of the Cochrane Neonatal Group, Australia
  • Mentorship, assistance with obtaining, appraising studies and extracting data.

This review is published as a Cochrane review in The Cochrane Library, Issue 10, 2010 (see http://www.thecochranelibrary.com External Web Site Policy for information). Cochrane reviews are regularly updated as new evidence emerges and in response to feedback. The Cochrane Library should be consulted for the most recent version of the review.