One additional study included, which compared phenobarbitone versus placebo in infants treated with dilute tincture of opium for neonatal abstinence syndrome.
When a sedative is needed to ameliorate symptoms in newborn infants with an 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. However, the long term effects of use of phenobarbitone on an infant's development have not been determined.
Phenobarbitone compared to supportive care alone has not been shown to reduce treatment failure or time to regain birthweight (one study). However, the duration of supportive care given to infants was significantly reduced (MD -162.1 mins/day, 95% CI -249.2, -75.1). Comparing phenobarbitone to diazepam, meta-analysis of two studies found phenobarbitone produced a significant reduction in treatment failure (typical RR 0.39, 95% CI 0.24, 0.62). There was no significant difference in duration of treatment or hospital stay. Comparing phenobarbitone with chlorpromazine, one study found no significant difference in treatment failure rate. No data for neurodevelopment reported by treatment group of allocation were available. No trials were eligible that assessed clonidine for NAS. In infants treated with an opiate, a small quasi-random study reported a reduced severity of withdrawal. Infants were weaned from an opiate more quickly which allowed earlier hospital discharge and reduced hospital costs. These findings may reflect the low dose of opiate used for initial treatment and the policy of discharging infants home on phenobarbitone but not morphine.
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. A separate review (Osborn 2002a) examines the evidence for the use of opiates in infants with NAS due to opiate withdrawal.
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.
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) apnea,
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)
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
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, 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 (CENTRAL, The Cochrane Library, 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).
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.
One additional study (Coyle 2002) was included in this update. A total of six studies are now included in the review (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). 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 clonidine has yet to be reported (Agthe 2002).
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 6-8 times per day. The dose was increased if the Finnegan score >7, maintained if score 5-7 and reduced if score <5 for 3 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 3 oral doses every 12 hours) and maintenance dose 5 mg/kg/day. The dose was adjusted to maintain weekly serum levels 20-30 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 5-10 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).
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 >= 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).
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 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, 5-8 mg/kg/day in three divided doses, (n=16) or diazepam, 0.5-2.0 mg q8h with doses "tailored day to day", (n=16). Infants who were allocated to methadone are reported in a separate review (Osborn 2002a).
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. 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.
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). Coyle 2002 prospectively matched treatments groups by first Finnegan score >7, if no match was found then the infants 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 of treatment: two studies (Finnegan 1984; Kaltenbach 1986) did not blind treatment. 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. 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). 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 .
01 PHENOBARBITONE 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
phenobarbitone 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).
02 PHENOBARBITONE VERSUS NO TREATMENT IN INFANTS TREATED WITH AN OPIATE
All infants
Primary outcomes: One study (Coyle 2002) reported the outcomes of 20 infants treated with DTO and allocated to addition of either phenobarbitone or placebo. Coyle 2002
reported no infants with treatment failure (needing another drug) and no
infants with seizures in either group. Infants receiving phenobarbitone had
a significant reduction in the percent time (of hospitalisation) that the
Finnegan score was >=8 (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.
PHENOBARBITONE VERSUS DIAZEPAM
03 All Infants
Primary outcomes: One study (Finnegan 1984)
of 107 infants reported a significant reduction in treatment failure for
infants receiving phenobarbitone compared to diazepam (RR 0.33, 95% CI 0.20,
0.53). Madden 1977 reported one infant on phenobarbitone
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 phenobarbitone 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 phenobarbitone
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).
04 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 phenobarbitone compared to
diazepam (RR 0.50, 95% CI 0.34, 0.73). No other outcomes were reported.
05 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 phenobarbitone compared
to diazepam (RR 0.19, 95% CI 0.09, 0.43). No other outcomes were reported.
06 PHENOBARBITONE 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 phenobarbitone and chlorpromazine reported separately infants of mothers on only opiates and those on opiates and another drug.
07 PHENOBARBITONE TITRATION WITH LOADING DOSE VERSUS WITHOUT LOADING DOSE
One study (Kaltenbach 1986) compared
phenobarbitone 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).
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.
SHORT VERSUS LONG COURSE OF PHENOBARBITONE OR CHLORPROMAZINE
08 PHENOBARBITONE : Kahn 1969 comparing a short and long course of phenobarbitone 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.
09 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.
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.
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 phenobarbitone 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. 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 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 2002a). 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 suggest 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. 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 commenced (Agthe 2002).
In infants treated with an opiate, there is evidence from one small study (Coyle 2002) that the severity of withdrawal is reduced. 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 0.12-0.16 mg/kg/day, is very low compared to other studies. The policy of continuing hospital admission for infants treated with an opiate but discharged home 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 reported, 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 longer term follow up.
| Study | Methods | Participants | Interventions | Outcomes | Notes | Allocation concealment |
| Coyle 2002 | Randomisation:
infants prospectively matched by first Finnegan score. Method of allocation
within score incompletely described. If no match then randomly assigned,
method not reported. Blinding of treatment: yes, placebo used, nurses blinded to treatment, although weekly phenobarbitone levels reported to physician. Blinding of measurement: not reported. Losses to follow up: yes, 1/21 excluded after transfer due to congenital heart disease. | 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. | 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). | 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. | A
total of 35 infants (term and preterm) were reported in abstract form. The
principle publication reported 21 term infants only. | B |
| Finnegan 1984 | Randomisation: quasi-random, drug assignment from envelope designated according to first letter of last name. Blinding of treatment: no, treatment regimens different. Blinding of measurement: yes. Losses to follow up: none reported. | 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. | 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). | Primary outcome: need for 2nd pharmacological intervention. Other outcomes: none. | 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. | C |
| Kahn 1969 | Randomisation: yes, method not reported. Blinding of treatment: yes, used 'identical syrups'. Blinding of measurement: yes. Losses to follow up: none reported. | 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 <= grade 1. Polydrug use: yes, 5 used glutethimide, 4 amphetamines and 2 barbiturates. | 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. | Primary outcome: none reported. Other outcomes: infant mortality, severity and duration of withdrawal symptoms. Persistent symptoms > 4 days. | Co-interventions: none reported. | B |
| Kaltenbach 1986 | Randomisation: quasi-random, drug assignment from envelope designated according to first letter of last name. Blinding of treatment: no, treatment regimens different. Blinding of measurement: yes. Losses to follow up: none reported. | Inclusion criteria: Infants of drug dependant women maintained on methadone. Neonatal Abstinence Scoring System score averaging >= 8 for 3 consecutive scores. Exclusion criteria: Polydrug use: yes, incidence not reported. | 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). | 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. | 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. | C |
| Khoo 1995 | Randomisation: quasi-random, used last number of the subject's hospital number. Blinding of treatment: no. Blinding of measurement: not reported. Losses to follow up: 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. | Inclusion criteria: infants of mothers with an opiate dependence who had 3 Finnegan NASS scores averaging >=8 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. | 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. | 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. | Methods and data obtained from author's PhD thesis and the author. Group numbers not balanced. | C |
| Madden 1977 | Randomisation: yes, method not reported. Blinding of treatment: unlikely, treatment regimens different. Blinding of measurement: not reported. Losses to follow up: 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. | 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 | 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". | Primary outcome: none reported. Other outcomes: use of second drug, duration of treatment and day of hospital discharge. | Duration of treatment and day of discharge not analysed according to original group of assignment. Co-interventions: none reported. | B |
| 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. |
| 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. |
| Study | Trial name or title | Participants | Interventions | Outcomes | Starting date | Contact information | Notes |
| Agthe 2002 | Clonidine in neonatal withdrawal | Infants with history of maternal opiate use during pregnancy - stratified for maternal methadone use | Randomized, blinded administration of DTO or DTO and clonidine in infants with severe NAS | Primary: length of treatment Secondary: amount of DTO, weight gain, caloric intake | Alexander Agthe or Estelle Gauda, Johns Hopkins Hospital, 600 N. Wolfe St. Baltimore, MD 21287, USA | ||
| Bier 2000 | Infants with neonatal methadone withdrawal receiving tincture of opium (DTO). | Randomised to addition of phenobarbital or placebo | Growth in weight, length, head circumference, neurobehaviour to 3 weeks, 3 months Bayley MDI, Alberta Infant Motor Scale and neurological examination. | Reported as 2 sequential abstracts from conference proceedings with increasing numbers of patients. No response from authors. Trial assumed to be still in progress. |
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 {published data only}
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 {published data only}
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.
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 {published data only}
Calabrese JR, Gulledge AD. The neonatal narcotic abstinence syndrome: a brief review. Canadian Journal of 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. American Journal of Diseases of Children 1983;137:1166-9.
Doberczak 1991 {published data only}
Doberczak TM, Kandall SR, Wilets I. Neonatal opiate abstinence syndrome in term and preterm infants. Journal of Pediatrics 1991;118:933-7.
Finnegan 1975a {published data only}
Finnegan LP, Connaughton JF Jr, Kron RE, Emich JP. Neonatal abstinence syndrome: assessment and management. Addictive Diseases 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. Journal of Clinical Pharmacology 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. American Journal of Obstetrics and Gynecology 1977;129:417-24.
Herzlinger 1977 {published data only}
Herzlinger RA, Kandall SR, Vaughan HG Jr. Neonatal seizures associated with narcotic withdrawal. Journal of Pediatrics 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 England Journal of Medicine 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 Research 1984;13:243-51.
Kaltenbach 1987 {published data only}
Kaltenbach K, Finnegan LP. Perinatal and developmental outcome of infants exposed to methadone in-utero. Neurotoxicology and Teratology 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. American Journal of Diseases of Children 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. International Journal of Clinical Pharmacology, Therapy and Toxicology 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. Journal of Pediatrics 1976;88:637-41.
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 Diseases 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. Journal of Pediatrics 1976;88:642-5.
* Ostrea EM, Chavez CJ, Strauss ME. A study of factors that influence the severity of neonatal narcotic withdrawal. Addict Diseases 1975;2:187-99.
Sutton 1990 {published data only}
Sutton LR, Hinderliter SA. Diazepam abuse in pregnant women on methadone maintenance. Implications for treatment. Clinical Pediatrics 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. Obstetrical & Gynecological Survey 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. Journal of Pediatrics 1970;76:483-6.
Pacifico P, Nardelli E, Pantarotto MF. Neonatal heroin withdrawal syndrome; evaluation of different pharmacological treatments. Pharmacological Research 1989;21 (S1):63-4.
Agthe A, Gauda E. Trial of clonidine for neonatal abstinence syndrome. Personal communication.
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. Pediatric Research 2000;47:175A.
Ferguson A, Coyle M, LaGasse L, Liu E, Lester B. Neurobehavioural effects of treatment for opiate withdrawal. Pediatric Research 2001;49:18A.
* indicates the primary reference for the study
American Academy of Pediatrics Committee on Drugs. Neonatal drug withdrawal. Pediatrics 1998;101:1079-88.
Bell GL, Lau K. Perinatal and neonatal issues of substance abuse. Pediatric Clinics of North America 1995;42:261-81.
de Cubas MM, Field T. Children of methadone-dependent women: developmental outcomes. American Journal of Orthopsychiatry 1993;63:266-76.
Fricker HS, Segal S. Narcotic addiction, pregnancy, and the newborn. American Journal of Diseases of Children 1978;132:360-6.
Hulse GK, Milne E, English DR, Holman CD. Assessing the relationship between maternal opiate use and neonatal mortality. Addiction 1998;93:1033-42.
Kandall SR, Gartner LM. Late presentation of drug withdrawal symptoms in newborns. American Journal of Diseases of Children 1974;127:58-61.
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 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 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 PJ. A proposed narcotic withdrawal score for use with newborn infants. A pragmatic evaluation of its efficacy. Clinical Pediatrics 1975;14:592-4.
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 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.
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.
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 C, Jeffery HE. Sleep deprivation, disorganisation and fragmentation during opiate withdrawal in newborns. Journal of Paediatrics and Child Health 2002;38:66-71.
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 GA, Olson RD, Kastin AJ. Endogenous opiates: 1996. Peptides 1997;18:1651-88.
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 DA, Jeffery HE, Cole MJ. Opiate treatment for opiate withdrawal in newborn infants. In: The Cochrane Database of Systematic Reviews, Issue 3, 2002.
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 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 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.
Osborn DA, Jeffery HE, Cole MJ. Sedatives for opiate withdrawal in newborn infants. In: The Cochrane Database of Systematic Reviews, Issue 3, 2002.
| Comparison or outcome | Studies | Participants | Statistical method | Effect size |
|---|---|---|---|---|
| 01 Phenobarbitone versus supportive care (all infants) | ||||
| 01 Treatment failure | 1 | 62 | RR (fixed), 95% CI | 2.73 [0.94, 7.94] |
| 02 Duration of treatment (days) | 1 | 62 | WMD (fixed), 95% CI | 17.90 [11.98, 23.82] |
| 03 Duration of hospital stay (days) | 1 | 62 | WMD (fixed), 95% CI | 20.80 [13.64, 27.96] |
| 04 Duration of stay in special care nursery (days) | 1 | 62 | WMD (fixed), 95% CI | 23.10 [15.84, 30.36] |
| 05 Time to regain birth weight (days) | 1 | 55 | WMD (fixed), 95% CI | -1.40 [-4.07, 1.27] |
| 06 Duration of supportive care per day (minutes) | 1 | 62 | WMD (fixed), 95% CI | -162.10 [-249.14, -75.06] |
| 02 Phenobarbitone versus placebo/no treatment in infants treated with an opiate | ||||
| 01 Treatment failure | 0 | 0 | RR (fixed), 95% CI | No numeric data |
| 02 Seizures | 0 | 0 | RR (fixed), 95% CI | No numeric data |
| 03 Percent time Finnegan score >=8 | 1 | 20 | WMD (fixed), 95% CI | -5.00 [-9.84, -0.16] |
| 04 Duration of hospital stay (days) | 1 | 20 | WMD (fixed), 95% CI | -41.00 [-59.85, -22.15] |
| 05 Maximal daily dose of DTO (mls) | 1 | 20 | WMD (fixed), 95% CI | -12.10 [-19.72, -4.48] |
| 06 Hospital costs exclusive of physicians charges ($US1000s) | 1 | 20 | WMD (fixed), 95% CI | -35.86 [-52.36, -19.36] |
| 03 Phenobarbitone versus diazepam (all infants) | ||||
| 01 Treatment failure | 2 | 139 | RR (fixed), 95% CI | 0.39 [0.24, 0.62] |
| 02 Duration of treatment (days) | 1 | 31 | WMD (fixed), 95% CI | 4.30 [-0.73, 9.33] |
| 03 Duration of hospital stay (days) | 1 | 31 | WMD (fixed), 95% CI | 3.07 [-2.02, 8.16] |
| 04 Phenobarbitone versus diazepam (infants of mothers using only opiates) | ||||
| 01 Treatment failure | 1 | 31 | RR (fixed), 95% CI | 0.50 [0.34, 0.73] |
| 05 Phenobarbitone versus diazepam (infants of mothers using opiates and other drugs) | ||||
| 01 Treatment failure | 1 | 76 | RR (fixed), 95% CI | 0.19 [0.09, 0.43] |
| 06 Phenobarbitone versus chlorpromazine (all infants) | ||||
| 01 Treatment failure | 1 | 38 | RR (fixed), 95% CI | 0.33 [0.08, 1.45] |
| 02 Need for second drug | 0 | 0 | RR (fixed), 95% CI | No numeric data |
| 07 Phenobarbitone titration with versus without loading dose (all infants) | ||||
| 01 Treatment failure | 1 | 36 | RR (fixed), 95% CI | 1.10 [0.59, 2.07] |
| 08 Short versus long course of phenobarbitone (all infants) | ||||
| 01 Treatment failure | 1 | 19 | RR (fixed), 95% CI | 0.58 [0.04, 7.94] |
| 09 Short versus long course of chlorpromazine (all infants) | ||||
| 01 Treatment failure | 1 | 19 | RR (fixed), 95% CI | 3.64 [0.52, 25.41] |
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
| The review is published as a Cochrane review in The
Cochrane Library, Issue 3, 2005 (see http://www.thecochranelibrary.com for
information). Cochrane reviews are regularly updated as new evidence emerges
and in response to comments and criticisms, and The Cochrane Library should
be consulted for the most recent version of the Review. |