Documents
Resources
Learning Center
Upload
Plans & pricing Sign in
Sign Out

Sedatives for opiate withdrawal in newborn infants

VIEWS: 24 PAGES: 19

									  Sedatives for opiate withdrawal in newborn infants




                     Sedatives for opiate withdrawal in newborn infants
                                                                     Osborn DA, Jeffery HE, Cole MJ

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




Cover sheet
Title
Sedatives for opiate withdrawal in newborn infants

Reviewers
Osborn DA, Jeffery HE, Cole MJ

Dates
Date edited: 28/05/2002
Date of last substantive update: 24/05/2002
Date of last minor update: / /
Date next stage expected / /
Protocol first published: Issue 2, 2000
Review first published: Issue 3, 2002

Contact reviewer
Dr David A Osborn
Staff Specialist
Neonatal Medicine
Royal Prince Alfred Hospital
Missenden Rd
Camperdown
NSW AUSTRALIA
2050
Telephone 1: 61 2 95158760
Telephone 2: 61 2 95156111
Facsimile: 61 2 95504375
E-mail: davido@peri.rpa.cs.nsw.gov.au
Secondary address:
37 Station St
Pymble
NSW AUSTRALIA
2073
Telephone: 61 2 91441050

Contribution of reviewers

Intramural sources of support
None



  http://www.nichd.nih.gov/cochrane/Osborn7/osborn.htm (1 de 19)10/05/2005 14:50:08
  Sedatives for opiate withdrawal in newborn infants


Extramural sources of support
None


What's new
Dates
Date review re-formatted: / /
Date new studies sought but none found: / /
Date new studies found but not yet included/excluded: / /
Date new studies found and included/excluded: / /
Date reviewers' conclusions section amended: / /
Date comment/criticism added: / /
Date response to comment/criticisms added: / /


Text of review
Synopsis
Synopsis pending.

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 strategy

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

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 & analysis

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

Main results

Five studies enrolling a total of 285 patients met inclusion criteria (Finnegan 1984, Kahn 1969, Kaltenbach 1986, Khoo 1995, Madden

  http://www.nichd.nih.gov/cochrane/Osborn7/osborn.htm (2 de 19)10/05/2005 14:50:08
  Sedatives for opiate withdrawal in newborn infants


1977); however, two (Finnegan 1984, Kaltenbach 1986) may be sequential reports that include some identical patients. Methodological
concerns included the use of quasi-random rather than random patient allocation methods in three studies, and sizeable, largely
unexplained differences in reported numbers allocated to each group in three studies.

Phenobarbital compared to supportive care alone has not been shown to reduce treatment failure or time to regain birthweight (one
study). However, the duration of supportive care required to be given to infants each day was significantly reduced (MD -162.1
minutes/day, 95% CI -249.2, -75.1). Comparing phenobarbital to diazepam, meta-analysis of two studies found that phenobarbital
produced a significant reduction in treatment failure (typical RR 0.39, 95% CI 0.24, 0.62). There was no significant difference in
duration of treatment or duration of hospital stay. Comparing phenobarbital with chlorpromazine, one study found no significant
difference in treatment failure rate. No data for neurodevelopment were available, reported by treatment group as allocated. No trials
were eligible that assessed clonidine for NAS.

Reviewers' conclusions

In newborn infants with NAS, there is no evidence that phenobarbital, compared with supportive care alone, reduces treatment failure;
however, phenobarbital may reduce the daily duration of supportive care needed. Phenobarbital, compared to diazepam, reduces
treatment failure. There is insufficient evidence to support the use of chlorpromazine or clonidine in newborn infants with NAS.
Clonidine and chlorpromazine should only be used in the context of a randomised clinical trial.

The results of this review, taken in conjunction with the related review, Opiate treatment for opiate withdrawal in newborn infants
(Osborn 2002), indicate that treatment with opiates is the preferred initial therapy for NAS. It is hypothesised that this is particularly
true for infants whose mothers have used only opiates during pregnancy. If a sedative is used, phenobarbital is preferred to diazepam.
The results of an ongoing trial of the addition of phenobarbital to an opiate are awaited.

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, diarrhea 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


  http://www.nichd.nih.gov/cochrane/Osborn7/osborn.htm (3 de 19)10/05/2005 14:50:08
  Sedatives for opiate withdrawal in newborn infants


is the preferred drug. For sedative-hypnotic withdrawal, phenobarbital is the agent of choice.

Sedatives used for opiate withdrawal have included clonidine (an alpha2 presynaptic blocker), chlorpromazine, phenobarbital 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. A separate review (Osborn 2002) 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.

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 (eg. 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 (eg 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) apnea, b) need for resuscitation, c) need for mechanical ventilation d) any

  http://www.nichd.nih.gov/cochrane/Osborn7/osborn.htm (4 de 19)10/05/2005 14:50:08
  Sedatives for opiate withdrawal in newborn infants


other
8. Duration of treatment of NAS (days)
9. Disruption to the mother infant relationship (eg separation of mother and infant, admission to a newborn nursery, failure to
successfully breast feed, maternal depression, or parental dissatisfaction).

Planned subgroup analyses included the following identified subcategories:
1. According to type of sedative used (eg. 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 (eg early versus delayed treatment) and duration of treatment (eg short versus long course).
All outcomes were eligible for inclusion in subgroup analysis.

Search strategy for identification of studies
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 Controlled Trials Register (The
Cochrane Library, Issue 1, 2002), MEDLINE (1966-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
1999-2002; Perinatal Society of Australia and New Zealand Annual Meetings 1999-2002).

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

Methods of the review
Standard methods of the Cochrane Collaboration and its Neonatal Review Group were used. The methodological quality of each trial
was assessed independently by the three authors. 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.

Methods used to collect data from the included trials: Each author extracted data independently; authors then compared data and
resolved differences. 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).

Methods used to analyse the data: 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. The fixed
effect model was assumed for meta-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.

Description of studies
Five studies met criteria for inclusion (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). Twenty four studies or reports were excluded
(see 'table of excluded studies'). One study awaiting assessment (Pacifico 1989) did not report method of treatment allocation, although
this was said to be non-random in another publication (AAP 1998). One study of opiate and phenobarbital versus opiate and placebo is
ongoing with two reports in abstract form to date (Bier 2000). One study of clonidine has just commenced (Lawson 2002).

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 phenobarbital loading dose
regimen (20mg/kg with maintenance 5-10mg/kg/day) titrated against scores, or phenobarbital titration regimen (no loading dose),
titrated on scores. The two phenobarbital groups (i.e. with or without loading dose) have been combined in the analyses reported in this

  http://www.nichd.nih.gov/cochrane/Osborn7/osborn.htm (5 de 19)10/05/2005 14:50:08
  Sedatives for opiate withdrawal in newborn infants


review. Infants who were allocated to paregoric are reported in a separate review (Osborn 2002).

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 phenobarbital short course (8.4mg/kg/day in 4 divided doses x 4 days,
then stopped), phenobarbital long course (8.4mg/kg/day in 4 divided doses x 10 days, then reduced by 1/3rd every 2nd day),
chlorpromazine short course (2.8mg/kg/day in 4 divided doses x 4 days, then stopped), and chlorpromazine long course (2.8mg/kg/day
in 4 divided doses x 10 days, then gradual reduction over 6 days). In this review, for the analyses comparing phenobarbital versus
chlorpromazine, the short and long course phenobarbital 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 >= 8 for 3 consecutive scores determining need for treatment. Polydrug use was reported but incidence not given. Infants
were allocated to phenobarbital loading dose followed by titration, or phenobarbital titration with no loading dose, or diazepam (doses
not reported). Infants who were allocated to paregoric are reported in a separate review (Osborn 2002).

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 >= 8 for 3 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 phenobarbital (loading dose 15mg/kg intramuscularly, then 6mg/kg/day in two divided
doses, titrated to score, up to maximum 10mg/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 2002).

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
phenobarbital, 5-8mg/kg/day in three divided doses, (n=16) or diazepam, 0.5-2.0mg q8h with doses "tailored day to day", (n=16).
Infants who were allocated to methadone are reported in a separate review (Osborn 2002).

No study reported mortality or 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 6 months according to
treatments received, not allocated. Three studies (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. One study
(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.

Methodological quality of included studies
Randomisation: 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). 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 of treatment: two studies (Finnegan 1984; Kaltenbach 1986) did not blind treatment. One study (Kahn 1969) reported blinding
of treatment and measurement by using identical syrups. No other study reported blinding of treatment and given the variable treatment
regimens in each of the trials it is unlikely this was possible.

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

Losses to follow up: all infants were accounted for by two studies (Finnegan 1984; Madden 1977). Kahn 1969 reported deaths of two


  http://www.nichd.nih.gov/cochrane/Osborn7/osborn.htm (6 de 19)10/05/2005 14:50:08
  Sedatives for opiate withdrawal in newborn infants


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 phenobarbital 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 phenobarbital who received a second agent .

Results
PHENOBARBITAL VERSUS SUPPORTIVE CARE
• All Infants (Infants Of Mothers Using Opiates With Or Without Other Drugs)
Primary outcomes: One study of 62 infants (Khoo 1995) found a trend towards an increase in treatment failure in infants receiving
phenobarbital compared to supportive therapy which is not quite statistically significant (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).
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).

PHENOBARBITAL VERSUS DIAZEPAM
• All Infants
Primary outcomes: One study (Finnegan 1984) of 107 infants reported a significant reduction in treatment failure for infants receiving
phenobarbital compared to diazepam (RR 0.33, 95% CI 0.20, 0.53). Madden 1977 reported one infant on phenobarbital and none on
diazepam who received a second drug. Meta-analysis of these two studies including 139 infants found a significant reduction in
treatment failure using phenobarbital compared to diazepam (typical RR 0.39, 95% CI 0.24, 0.62). Kaltenbach 1986 reported a
significant reduction in treatment failure in infants given phenobarbital compared to diazepam (RR 0.53, 95% CI 0.39, 0.72). 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).

• Infants Of Mothers Using Only Opiates
In a post hoc analysis, one study (Finnegan 1984 ) separately reported 31 infants of mothers on only opiates. There was a significant
reduction in treatment failure with phenobarbital compared to diazepam (RR 0.50, 95% CI 0.34, 0.73). No other outcomes were
reported.

• Infants Of Mothers Using Opiates And Another Drug
One study (Finnegan 1984 ) separately reported 76 infants of mothers using opiates and another drug. There was a significant reduction
in treatment failure with phenobarbital compared to diazepam (RR 0.19, 95% CI 0.09, 0.43). No other outcomes were reported.

PHENOBARBITAL VERSUS CHLORPROMAZINE
• All Infants
One study (Kahn 1969) involving 38 infants including those born to mothers using multiple drugs, found no significant difference in
treatment failure (persistent symptoms > 4 days) (RR 0.33, 95% CI 0.08, 1.45) and no infants in either group were reported as receiving
a second drug or having seizures. Data for mortality were not reported according to allocated group. Kahn 1969 reported a trend
towards a decreased incidence of clinical myoclonus (not thought to be seizures by the attending clinician); this was 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 phenobarbital and chlorpromazine reported separately infants of mothers on only opiates and those on opiates and
another drug.

PHENOBARBITAL TITRATION WITH VERSUS WITHOUT LOADING DOSE

One study (Kaltenbach 1986) compared phenobarbital treatment regimens which did or did not use a loading dose, with each regimen
using maintenance doses titrated against scores. Thirty-six infants were reported, including those born to mothers using multiple drugs.
There was no significant difference between regimens in need for a second drug (RR 1.10, 95% CI 0.59, 2.07).


  http://www.nichd.nih.gov/cochrane/Osborn7/osborn.htm (7 de 19)10/05/2005 14:50:08
  Sedatives for opiate withdrawal in newborn infants


Other reported outcomes: Finnegan 1984 reported that infants treated with the loading dose regimen of phenobarbital 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.

SHORT VERSUS LONG COURSE OF PHENOBARBITAL OR CHLORPROMAZINE

PHENOBARBITAL: Kahn 1969 comparing a short and long course of phenobarbital in 19 infants reported no significant difference in
treatment failure (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.

CHLORPROMAZINE: One study (Kahn 1969) comparing a short versus long course of chlorpromazine in 21 infants, including those
born to mothers using multiple drugs, found no significant difference (RR 3.64, 95% CI 0.52, 25.41) in treatment failure (persistent
symptoms > 4 days) and no infants in either group were reported as receiving a second drug.

OTHER COMPARISONS

There were no studies that compared diazepam and chlorpromazine or used clonidine.

No study eligible for this review assessed the effect of sedative plus opiate, versus opiate alone, in treating infants for NAS. One study
of opiate and phenobarbital versus opiate and placebo is ongoing (Bier 2000).

SENSITIVITY ANALYSIS

No study met eligibility criteria for inclusion as studies of good methodology because studies were either quasi-randomised or did not
report method of randomisation. The authors have been contacted so as to obtain missing information.

Discussion
This review includes studies that reported 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. 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. This review
prespecified the primary outcomes and the comparisons that have been made, with the exception of the comparisons between
phenobarbital with or without loading dose, and long and short course sedative regimens.

The validity of the results is affected by the methodological quality of the included studies. Three 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 of these studies (Finnegan 1984; Kaltenbach 1986) has communicated that 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 prespecify 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.

This review should be considered in light of the review 'Opiate treatment for opiate withdrawal in newborn infants' (Osborn 2002).
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 phenobarbital or diazepam. This supports the
AAP recommendation (AAP 1998). When a sedative is considered, phenobarbital 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. Phenobarbital resulted in a significant reduction in treatment failure compared to diazepam. The
benefits of phenobarbital compared to diazepam were seen both in infants of mothers using only opiates and infants of mothers using
multiple drugs. Data from one study suggest that infants treated with a loading dose of phenobarbital have a shorter time to symptom
control compared to infants treated with only a titration regimen. Results of an ongoing trial (Bier 2000) of phenobarbital versus
placebo in infants treated with an opiate for NAS are awaited. There is insufficient evidence to recommend the use of chlorpromazine
for NAS due to opiate withdrawal. There are no trials using random allocation to clonidine or control, although a trial of clonidine has


  http://www.nichd.nih.gov/cochrane/Osborn7/osborn.htm (8 de 19)10/05/2005 14:50:08
  Sedatives for opiate withdrawal in newborn infants


commenced (Lawson 2002).


Reviewers' conclusions

Implications for practice

In view of the findings of the review opiates for opiate withdrawal (Osborn 2002), infants with NAS due to opiate withdrawal should
receive initial treatment with an opiate. Where a sedative is used, then phenobarbital should be used in preference to diazepam. There is
insufficient evidence to support the use of chlorpromazine or clonidine 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. The results of a trial of
phenobarbital or placebo in infants treated with an opiate for NAS are awaited. Clonidine and chlorpromazine should only be used in
the context of a randomised clinical trial. Studies should measure effects on infant symptoms of withdrawal, quality of mother-infant
interaction, growth and long term development.

Acknowledgements
Dr Loretta Finnegan and Dr Katie Khoo who kindly provided additional information regarding their studies.

Potential conflict of interest
None


Characteristics of included studies
                                                                                                                                          Allocation
Study                  Methods                         Participants            Interventions       Outcomes              Notes
                                                                                                                                          concealment
Finnegan               Randomisation:                  Inclusion               1. Phenobarbital    Primary outcome:      Additional        C
1984                   quasi-random,                   criteria: Infants       (n=87) with or      need for 2nd          information
                       drug assignment                 born to mothers         without loading     pharmacological       obtained from
                       from envelope                   with a) narcotic        dose (20 mg/kg)     intervention. Other   authors. Group
                       designated                      use only and b)         with maintenance    outcomes: none.       numbers not
                       according to first              narcotic and            5-10 mg/kg/day                            balanced. Interim
                       letter of last name.            other drug use.         titrated against                          analysis found
                       Blinding of                     Finnegan score          score. Dose                               diazepam group
                       treatment: no,                  determined need         increased till                            had excessive
                       treatment                       for treatment.          control obtained,                         number of
                       regimens different.             Exclusion               serum level >                             complications
                       Blinding of                     criteria: none          70mcg/ml or                               (somnolence and
                       measurement: yes.               reported.               evidence of                               respiratory
                       Losses to follow                                        toxicity.                                 depression), so
                       up: none reported.                                      2. Diazepam (n =                          enrolment in this
                                                                               20): dose not                             group stopped.
                                                                               reported.                                 May include
                                                                               (Also compared                            some of the
                                                                               infants given                             infants as
                                                                               paregoric).                               reported by
                                                                                                                         Kaltenbach 1986.
                                                                                                                         Randomisation
                                                                                                                         not stratified
                                                                                                                         according to type
                                                                                                                         of antenatal drug
                                                                                                                         use.




  http://www.nichd.nih.gov/cochrane/Osborn7/osborn.htm (9 de 19)10/05/2005 14:50:08
 Sedatives for opiate withdrawal in newborn infants


Kahn 1969             Randomisation:                  Inclusion               1. Phenobarbital       Primary outcome:   Co-interventions:       B
                      yes, method not                 criteria: infants       short course (n =      none reported.     none reported.
                      reported.                       of mothers using        12): 8.4mg/kg/day      Other outcomes:
                      Blinding of                     heroin.                 x 4 day (4 divided     infant mortality,
                      treatment: yes,                 Standardised            doses) then            severity and
                      used 'identical                 scoring system.         stopped.               duration of
                      syrups'.                        Infants with            2. Phenobarbital       withdrawal
                      Blinding of                     tremors or              long course (n =       symptoms.
                      measurement: yes.               irritability >          7): 8.4mg/kg/day       Persistent
                      Losses to follow                grade 1 on 3            (4 divided doses) x    symptoms > 4 days.
                      up: none reported.              grade score.            10 days then
                                                      Exclusion               reduced by 1/3rd
                                                      criteria: tremors       every 2nd day
                                                      and irritability        (stopped day 16).
                                                      <= grade 1.             3. Chorpromazine
                                                      Polydrug use:           short course (n =
                                                      yes, 5 used             11): 2.8mg/kg/day
                                                      glutethimide, 4         ( 4 divided doses)
                                                      amphetamines            x 4 days then
                                                      and 2                   stopped.
                                                      barbiturates.           4. Chlorpromazine
                                                                              long course (n =
                                                                              8): 2.8mg/kg/day
                                                                              (4 divided doses) x
                                                                              10 days then
                                                                              gradual reduction
                                                                              over next 6 days.
Kaltenbach            Randomisation:                  Inclusion               1. Phenobarbital       Primary outcome:       Additional          C
1986                  quasi-random,                   criteria: Infants       loading dose           Bayley Scale of        information
                      drug assignment                 of drug                 followed by            Mental                 obtained from
                      from envelope                   dependant               titration (n = 20):    Development at 6       authors. Group
                      designated                      women                   doses not given.       months (not            numbers not
                      according to first              maintained on           2. Phenobarbital       reported by            balanced. May
                      letter of last name.            methadone.              titration group (n =   intention to treat).   include some of
                      Blinding of                     Neonatal                16): doses not         Other outcomes:        the infants as
                      treatment: no,                  Abstinence              reported.              need for second        reported by
                      treatment                       Scoring System          3. Diazepam (n =       agent to control       Finnegan 1984.
                      regimens different.             score averaging         10): dose not          symptoms.              Randomisation
                      Blinding of                     >= 8 for 3              reported.                                     not stratified
                      measurement: yes.               consecutive             (Paregoric group                              according to type
                      Losses to follow                scores.                 also reported).                               of antenatal drug
                      up: none reported.              Exclusion                                                             use.
                                                      criteria:
                                                      Polydrug use:
                                                      yes, incidence
                                                      not reported.
Khoo 1995             Randomisation:                  Inclusion               1. Phenobarbital       Primary outcome:       Methods and data C
                      quasi-random,                   criteria: infants       loading dose           unclear. Other         obtained from
                      used last number                of mothers with         (n=29) 15mg/kg         outcomes: need for     author's PhD
                      of the subject's                an opiate               (intramuscular)        second drug (failure   thesis and the
                      hospital number.                dependence who          then 6mg/kg/day in     to settle measured     author. Group
                      Blinding of                     had 3 Finnegan          2 divided doses,       using Finnegan         numbers not
                      treatment: no.                  NASS scores             titrated to score up   score), duration of    balanced.
                      Blinding of                     averaging >=8 in        to maximum 10mg/       supportive
                      measurement: not                3 consecutive 4-        kg/day; and            intervention,
                      reported.                       hour periods.           supportive therapy.    numbers of dose
                      Losses to follow                Urine drug              2. Supportive          increments on
                      up: 1 infant                    screens                 therapy alone          therapy, number of
                      allocated                       performed               (n=36) (included       treatment days,
                      phenobarbital and               during                  pacifier,              days in baby


 http://www.nichd.nih.gov/cochrane/Osborn7/osborn.htm (10 de 19)10/05/2005 14:50:08
 Sedatives for opiate withdrawal in newborn infants


                      2 supportive                    pregnancy.              swaddling, close       special care
                      therapy excluded                Polydrug use            wrapping, small        nursery, days in
                      from analysis.                  reported by 95%         frequent feeds,        hospital, treatment
                      Data available for              of methadone            close skin contact     days and days to
                      days to regain                  mothers. 76% of         by carrying in sling   regain weight.
                      birthweight from                infants had been        and other methods.     Brazelton Neonatal
                      27/29 on                        exposed to more                                Behavioural
                      phenobarbital and               than 2 drugs in                                Assessment Scale
                      28/36 on                        utero.                                         performed in the
                      supportive                                                                     neonatal period,
                      therapy.                                                                       and an infant
                                                                                                     temperament
                                                                                                     questionaire at 2, 4,
                                                                                                     8 and 12 months.
Madden 1977 Randomisation:                            Inclusion               1. Phenobarbital (n    Primary outcome:        Duration of       B
            yes, method not                           criteria: infants       = 16): 5-8mg/kg/       none reported.          treatment and day
            reported.                                 of narcotic-            day (3 divided         Other outcomes:         of discharge not
            Blinding of                               addicted                doses).                use of second drug,     analysed
            treatment:                                mothers. Clinical       2. Diazepam (n =       duration of             according to
            unlikely, treatment                       decision to treat.      16): 0.5-2.0mg         treatment and day       original group of
            regimens different.                       Abstinence score        q8h.                   of hospital             assignment.
            Blinding of                               not used.               Doses "tailored day    discharge.              Co-interventions:
            measurement: not                          Exclusion               to day".                                       none reported.
            reported.                                 criteria: none
            Losses to follow                          reported.
            up: none reported.                        Polydrug use:
            One infant given                          yes, non-opiate
            diazepam non-                             use reported in
            randomly                                  15% of the
            excluded. One                             baseline
            infant in                                 population of
            phenobarbital                             mothers
            group treated with
            second drug not
            included in
            duration of
            treatment and
            hospital stay.


Characteristics of excluded studies
Study                     Reason for exclusion
Alroomi 1988              Observational study.
Calabrese 1985            Monograph review.
Carin 1983                Randomized trial of paregoric versus phenobarbital.
Doberczak 1991 Observational study.
Finnegan 1975a Observational study.
Finnegan 1975b Observational study.
Finnegan 1979             Case series report.
Finnegan 1984b Study comparing loading dose and titration approach to commencing phenobarbital therapy for neonatal abstinence
               syndrome. Method of treatment allocation not reported.
Harper 1977               Observational study.
Herzlinger 1977 Observational study.
Hoder 1981                Case report.
Hoder 1984                Non randomised study of clonidine for neonatal narcotic abstinence. No controls.


 http://www.nichd.nih.gov/cochrane/Osborn7/osborn.htm (11 de 19)10/05/2005 14:50:08
  Sedatives for opiate withdrawal in newborn infants


Kaltenbach 1987 Observational study.
Kandall 1983               Randomised study of phenobarbital and paregoric for neonatal abstinence syndrome.
Kron 1975a                 Observational study.
Kron 1975b                 Observational study.
Kron 1976                  Non random allocation to treatment.
Nathenson 1971 Observational study of the use of diazepam in neonatal abstinence syndrome.
Ostrea 1975                No study of treatment.
Ostrea 1976                Infants randomised to experimental (noise and light reduced) and control nursery.
Sutton 1990                Case report.
Tunis 1984                 Control study of infants with neonatal abstinence syndrome given paregoric, phenobarbital or diazepam. Method of
                           allocation not stated. No data given.
Wolman 1989                Monograph review.
Yaster 1996                Monograph review.
Zelson 1970                Letter documenting observations.


Characteristics of ongoing studies
                   Trial
                                                                                                             Starting   Contact
Study              name           Participants             Interventions               Outcomes                                       Notes
                                                                                                             date       information
                   or title
Bier 2000                         Infants with             Randomised to               Growth in weight,                              Reported as 2
                                  neonatal                 addition of                 length, head                                   sequential
                                  methadone                phenobarbital or            circumference,                                 abstracts from
                                  withdrawal               placebo                     neurobehaviour to 3                            conference
                                  receiving                                            weeks, 3 months                                proceedings
                                  tincture of                                          Bayley MDI, Alberta                            with increasing
                                  opium (DTO).                                         Infant Motor Scale                             numbers of
                                                                                       and neurological                               patients. No
                                                                                       examination.                                   response from
                                                                                                                                      authors. Trial
                                                                                                                                      assumed to be
                                                                                                                                      still in progress.
Lawson
2002


References to studies
References to included studies
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 {published data only}

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

Kaltenbach 1986 {published and unpublished data}

Kaltenbach K, Finnegan LP. Neonatal abstinence syndrome, pharmacotherapy and developmental outcome. Neurobehav Toxicol

  http://www.nichd.nih.gov/cochrane/Osborn7/osborn.htm (12 de 19)10/05/2005 14:50:08
  Sedatives for opiate withdrawal in newborn infants


Teratol 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 {published data only}

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

References to excluded studies
Alroomi 1988 {published data only}

Alroomi LG, Davidson J, Evans TJ, Galea P, Howat R. Maternal narcotic abuse and the newborn.. Arch Dis Child 1988;63:81-3.

Calabrese 1985 {published data only}

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

Carin 1983 {published data only}

Carin I, Glass L, Parekh A, Solomon N, Steigman J, Wong S. Neonatal methadone withdrawal. Effect of two treatment regimens. Am J
Dis Child 1983;137:1166-9.

Doberczak 1991 {published data only}

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

Finnegan 1975a {published data only}

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

Finnegan 1975b {published data only}

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

Finnegan 1979 {published data only}

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 {published data only}

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 {published data only}

Harper RG, Solish G, Feingold E, Gersten Woolf NB, Sokal MM. Maternal ingested methadone, body fluid methadone, and the
neonatal withdrawal syndrome. Am J Obstet Gynecol 1977;129:417-24.

Herzlinger 1977 {published data only}


  http://www.nichd.nih.gov/cochrane/Osborn7/osborn.htm (13 de 19)10/05/2005 14:50:08
  Sedatives for opiate withdrawal in newborn infants


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

Hoder 1981 {published data only}

Hoder EL, Leckman JF, Ehrenkranz R, Kleber H, Cohen DJ, Poulsen JA. Clonidine in neonatal narcotic-abstinence syndrome. New
Engl J Med 1981;305:1284.

Hoder 1984 {published data only}

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

Kaltenbach 1987 {published data only}

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

Kandall 1983 {published data only}

Kandall SR, Doberczak TM, Mauer KR, Strashun RH, Korts DC. Opiate v CNS depressant therapy in neonatal drug abstinence
syndrome. Am J Dis Child 1983;137:378-82.

Kron 1975a {published data only}

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 {published data only}

Kron RE, Litt M, Finnegan LP. Narcotic addiction in the newborn: differences in behaviour generated by methadone and heroin. Int J
Clin Pharmacol 1975;12:63-9.

Kron 1976 {published data only}

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. J Pediatr 1976;88(4):637-41.

Nathenson 1971 {published data only}

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

Ostrea 1975 {published data only}

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

Ostrea 1976 {published data only}

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

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

Sutton 1990 {published data only}

Sutton LR, Hinderliter SA. Diazepam abuse in pregnant women on methadone maintenance. Implications for treatment. Clin Pediatr


  http://www.nichd.nih.gov/cochrane/Osborn7/osborn.htm (14 de 19)10/05/2005 14:50:08
  Sedatives for opiate withdrawal in newborn infants


1990;29:108-11.

Tunis 1984 {published data only}

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 {published data only}

Wolman I, Niv D, Yoval I, Pausner D, Geller E, David MP. Opioid-addicted parturient, labor, and outcome: a reappriasal. Obstet
Gynecol Surv 1989;44:592-7.

Yaster 1996 {published data only}

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 {published data only}

Zelson C. Heroin withdrawal syndrome. J Pediatr 1970;76:483-6.

References to studies awaiting assessment
Pacifico 1989 {published data only}

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

References to ongoing studies
Bier 2000 {published data only}

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

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

Lawson 2002 {unpublished data sought but not used}

Lawson E. Trial of clonidine for neonatal abstinence syndrome. Personal communication.

* indicates the primary reference for the study


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. Pediatr Clin North Am 1995;42:261-81.



  http://www.nichd.nih.gov/cochrane/Osborn7/osborn.htm (15 de 19)10/05/2005 14:50:08
  Sedatives for opiate withdrawal in newborn infants


de Cubas 1993

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

Fricker 1978

Fricker HS, Segal S. Narcotic addiction, pregnancy, and the newborn. Am J Dis Child 1978;132:360-6.

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. Am J Dis Child 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 Hum Dev 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. J Pediatr 1993;123:120-6.

Lam 1992

Lam SK, To WK, Duthie SJ, Ma HK. Narcotic addiction in pregnancy with adverse maternal and perinatal outcome. Aust NZ J Obstet
Gynaecol 1992;32:216-21.

Lipsitz 1975

Lipsitz PJ. A proposed narcotic withdrawal score for use with newborn infants. A pragmatic evaluation of its efficacy. Clin Pediatr
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. J Perinat Med 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. Am J
Obstet Gynecol 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


  http://www.nichd.nih.gov/cochrane/Osborn7/osborn.htm (16 de 19)10/05/2005 14:50:08
  Sedatives for opiate withdrawal in newborn infants



O' Brien C, Jeffery HE. Sleep deprivation, disorganisation and fragmentation during opiate withdrawal in newborns. J Paed 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 Paediatr Scand 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 Negl 1996;20:385-96.

Osborn 2002

Osborn DA, Jeffery HE, Cole MJ. Opiate treatment for opiate withdrawal in newborn infants. In: Cochrane Library, 2002. Oxford:
Update Software.

Strauss 1976

Strauss ME, Andresko M, Stryker JC, Wardell JN. Relationship of neonatal withdrawal to maternal methadone dose. Am J Drug
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.
Biol 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. J Dev Behav Pediatr 1998;19:89-93.


Comparisons and data
01 Phenobarbital versus supportive care (all infants)
01.01 Treatment failure
01.02 Duration of treatment (days)
01.03 Duration of hospital stay (days)
01.04 Duration of stay in special care nursery (days)
01.05 Time to regain birth weight (days)
01.06 Duration of supportive care per day (minutes)

02 Phenobarbital versus diazepam (all infants)
02.01 Treatment failure
02.02 Duration of treatment (days)
02.03 Duration of hospital stay (days)

03 Phenobarbital versus diazepam (infants of mothers using only opiates)
03.01 Treatment failure

04 Phenobarbital versus diazepam (infants of mothers using opiates and other drugs)


  http://www.nichd.nih.gov/cochrane/Osborn7/osborn.htm (17 de 19)10/05/2005 14:50:08
  Sedatives for opiate withdrawal in newborn infants


04.01 Treatment failure

05 Phenobarbital versus chlorpromazine (all infants)
05.01 Treatment failure
05.02 Need for second drug

06 Phenobarbital titration with versus without loading dose (all infants)
06.01 Treatment failure

07 Short versus long course of phenobarbital (all infants)
07.01 Treatment failure

08 Short versus long course of chlorpromazine (all infants)
08.01 Treatment failure




Notes
Published notes

Amended sections
None selected


Contact details for co-reviewers
  http://www.nichd.nih.gov/cochrane/Osborn7/osborn.htm (18 de 19)10/05/2005 14:50:08
  Sedatives for opiate withdrawal in newborn infants




A/Prof Heather E Jeffery
Head of Department
Department of Neonatal Medicine
Royal Prince Alfred Hospital
Missenden Rd
Camperdown
NSW AUSTRALIA
2050
Telephone 1: 61 2 95158760
Telephone 2: 61 2 95158248
Facsimile: 61 2 95504375
E-mail: hjeffery@med.usyd.edu.au

Dr Michael J Cole
Senior staff specialist
Neonatal Medicine
Westmead Hospital
Darcy Rd
Westmead
AUSTRALIA
2145
Telephone 1: 61 2 98456665
Facsimile: 61 2 98455000
E-mail: michaelc@westgate.wh.usyd.edu.au




  http://www.nichd.nih.gov/cochrane/Osborn7/osborn.htm (19 de 19)10/05/2005 14:50:08

								
To top