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Maintenance agonist treatments for opiate-dependent pregnant women

  1. Silvia Minozzi1,*,
  2. Laura Amato1,
  3. Cristina Bellisario2,
  4. Marica Ferri3,
  5. Marina Davoli1

Editorial Group: Cochrane Drugs and Alcohol Group

Published Online: 23 DEC 2013

Assessed as up-to-date: 7 OCT 2013

DOI: 10.1002/14651858.CD006318.pub3


How to Cite

Minozzi S, Amato L, Bellisario C, Ferri M, Davoli M. Maintenance agonist treatments for opiate-dependent pregnant women. Cochrane Database of Systematic Reviews 2013, Issue 12. Art. No.: CD006318. DOI: 10.1002/14651858.CD006318.pub3.

Author Information

  1. 1

    Lazio Regional Health Service, Department of Epidemiology, Rome, Italy

  2. 2

    AO Città della Salute e della Scienza di Torino Via San Francesco da Paola 31, CPO Piemonte, Dipartimento Interaziendale di Prevenzione Secondaria dei Tumori S.C. Epidemiologia dei Tumori, Torino, Italy

  3. 3

    European Monitoring Centre for Drugs and Drug Addiction, Interventions, Best Practice and Scientific Partners, Lisbon, Portugal

*Silvia Minozzi, Department of Epidemiology, Lazio Regional Health Service, Via di Santa Costanza, 53, Rome, 00198, Italy. minozzi.silvia@gmail.com.

Publication History

  1. Publication Status: New search for studies and content updated (conclusions changed)
  2. Published Online: 23 DEC 2013

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Characteristics of included studies [ordered by study ID]
Fischer 1999

MethodsRandomised controlled trial
Open


ParticipantsParticipants: 48 pregnant adults; mean age 26 years; 39.6% unmarried; duration of opioid dependence: mean 57.2 months
Mean gestational age at entry: 22 weeks
Inclusion criteria: opioid-dependent and polysubstance abusing pregnant females meeting DSM-IV criteria


Interventions(1) oral methadone (24 participants) versus (2) oral slow-release morphine (24 participants) after an induction period of 10 days. At delivery mean methadone dose was 53.48 mg, mean morphine dose was 300.43 mg
Outpatients
Follow-up mean: 15 weeks


OutcomesNeonatal outcomes: fetal distress; birth weight; NAS (Finnegan scale)

Maternal outcomes: retention; cocaine and benzodiazepine consumption (urinalysis); opioid use (identification of injection sites for morphine-maintained group and urinalysis for methadone-maintained group)


NotesCountry of origin: Austria


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "The women were randomly assigned to receive either oral methadone or oral slow-release morphine, and induction occurred over a period of 10 days"

Allocation concealment (selection bias)Unclear riskNo information provided concerning allocation concealment

Blinding of participants and personnel (performance bias)
subjective outcomes
High riskOpen-label

Blinding of participants and personnel (performance bias)
objective outcomes
Low riskCOMMENT: open trial but objective outcomes unlikely to be biased by lack of blinding

Blinding of outcome assessment (detection bias)
subjective outcomes
High riskOpen-label

Blinding of outcome assessment (detection bias)
objective outcomes
Low riskCOMMENT: open trial but objective outcomes unlikely to be biased by lack of blinding

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing outcome data

Fischer 2006

MethodsRandomised controlled trial
Double-blind


ParticipantsParticipants: 18 pregnant adults; mean age 25.9 years; 66.6% single; 61.1% completed 9 years of education; duration of heroin consumption: mean 20.6 months
Mean gestational age at entry: 24 weeks
Inclusion criteria: opioid-dependent pregnant females meeting DSM-IV criteria
Exclusion criteria: severe somatic or other severe psychiatric diseases, high-risk pregnancy


Interventions(1) oral methadone (9 participants) versus (2) oral buprenorphine (9 participants). Dose of methadone between 40 and 100 mg/day; dose of buprenorphine between 8 and 24 mg/day
Outpatients
Follow-up: mean 16 weeks


OutcomesNeonatal outcomes: birth weight; NAS (Finnegan scale); child health status APGAR score

Maternal outcomes: retention; maternal withdrawal symptoms (Wang Withdrawal Questionnaire); illicit drugs use: opioid, cocaine, benzodiazepine (urinalysis)


NotesCountry of origin: Austria


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInformation concerning method of random sequence generation not provided

Allocation concealment (selection bias)Low riskQuote: "Subjects were randomised externally by the hospital pharmacy using a double-blind, double-dummy design and received supervised medication daily from the study pharmacist at the addiction clinic"

Blinding of participants and personnel (performance bias)
subjective outcomes
Low riskQuote: "To maintain study blinding, placebo treatment matched the active treatment. Methadone (EBEWE Arzneimittel GesmbH and Gatt/Koller GesmbH KG, Austria) was prepared at the hospital pharmacy as an oral solution at the required concentration. Placebo for the methadone arm consisted of 30 mg dextromethorphan oral solution (Nowak GmbH, Germany) to simulate the taste of methadone, as used previously in double-dummy trials"

Blinding of participants and personnel (performance bias)
objective outcomes
Low riskQuote: "To maintain study blinding, placebo treatment matched the active treatment. Methadone (EBEWE Arzneimittel GesmbH and Gatt/Koller GesmbH KG, Austria) was prepared at the hospital pharmacy as an oral solution at the required concentration. Placebo for the methadone arm consisted of 30 mg dextromethorphan oral solution (Nowak GmbH, Germany) to simulate the taste of methadone, as used previously in double-dummy trials"

Blinding of outcome assessment (detection bias)
subjective outcomes
Low riskQuote: "Neonates were observed for a minimum of 10 days on an in-patient basis under blinded conditions for the mothers’ treatment condition and scored every 4 hours using the Finnegan scale (range 0–45)"

Quote: "The double-blind, double-dummy code remained blinded until 30 days after delivery"

Blinding of outcome assessment (detection bias)
objective outcomes
Low riskQuote: "Neonates were observed for a minimum of 10 days on an in-patient basis under blinded conditions for the mothers’ treatment condition and scored every 4 hours using the Finnegan scale (range 0–45)"

Quote: "The double-blind, double-dummy code remained blinded until 30 days after delivery"

Incomplete outcome data (attrition bias)
All outcomes
High risk4 drop-outs occurred during the study period. One participant maintained on methadone (70 mg/day) experienced a stillbirth caused by a sudden intrauterine death during week 38 of pregnancy. A second woman maintained on methadone had a late abortion during week 28. 2 other participants were withdrawn from the study due to lack of compliance with the scheduled visits. 1 patient was taking buprenorphine and the other methadone. This attrition left 14 participants who completed the study, 6 in the methadone group and 8 in the buprenorphine group. The 4 women who failed to complete the study were older and had a longer duration of opioid dependency than those who completed the study, whereas no significant differences in socio-demographic characteristics were seen at enrolment (see Table 1)
COMMENT: high drop-out (33.3%) in the methadone group and unbalanced (11.1% in the buprenorphine group) Reason for drop-out given and likely to be linked to treatments received

Jones 2005

MethodsRandomised controlled trial
Double-blind


ParticipantsParticipants: 30 pregnant adults; mean age 30.1 years; 75% African-American, 20% white, 5% other; 55% unemployed seeking, 40% unemployed not seeking, 5% homemaker; mean years of education 10.2; use cocaine: past 30 days 75%; opioid use: > 4 x day 55%
Mean gestational age at entry: 23 weeks
Inclusion criteria: estimated gestational age of 16 to 30 weeks; opioid-dependent pregnant females meeting DSM-IV criteria Exclusion criteria: current diagnosis of alcohol abuse or dependence; self reported use of benzodiazepines; serious medical illness; diagnosis of preterm labour; evidence of fetal malformation; positive HIV test


Interventions(1) Oral methadone (15 participants) versus (2) oral buprenorphine (15 participants). Dose of methadone: mean 60 mg/day; dose of buprenorphine: mean 12 mg /day
Setting: inpatients
Follow-up mean: 18 weeks


OutcomesNeonatal outcomes: number of neonates treated for NAS; peaks of NAS score; length of neonatal hospitalisation; birth weight; child health status; APGAR score

Maternal outcomes: retention; illicit drug use (urinalysis)


NotesCountry of origin: USA


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "They were assigned to one of the two treatment groups using a computerized dynamic balanced randomisation"

Allocation concealment (selection bias)Low riskQuote: "Research staff, with no other study involvement, generated the randomised allocation sequence"

Blinding of participants and personnel (performance bias)
subjective outcomes
Low riskOnce medically cleared and randomised, participants were switched from their individualised dose of immediate-release morphine onto an equivalent dose of double-blind study medication

To maintain the double-blind, the actual dose changes were known only to pharmacy staff

Blinding of participants and personnel (performance bias)
objective outcomes
Low riskOnce medically cleared and randomised, participants were switched from their individualised dose of immediate-release morphine onto an equivalent dose of double-blind study medication

To maintain the double-blind, the actual dose changes were known only to pharmacy staff

Blinding of outcome assessment (detection bias)
subjective outcomes
Low riskOnce medically cleared and randomised, participants were switched from their individualised dose of immediate-release morphine onto an equivalent dose of double-blind study medication

To maintain the double-blind, the actual dose changes were known only to pharmacy staff

Blinding of outcome assessment (detection bias)
objective outcomes
Low riskOnce medically cleared and randomised, participants were switched from their individualised dose of immediate-release morphine onto an equivalent dose of double-blind study medication

To maintain the double-blind, the actual dose changes were known only to pharmacy staff

Incomplete outcome data (attrition bias)
All outcomes
High riskOf the 30 randomised patients, 20 delivered while enrolled in the study; the remaining 10 dropped out during
the study. Of those randomised to buprenorphine reasons for drop-out included: discharged for medical condition (n = 1), missed consecutive dosing days (n = 4) and elected to withdraw (n = 1). Of those randomised to methadone reasons for discharge included: missed consecutive dosing days (n = 3) and elected to withdraw (n = 1)

COMMENT: high drop-out (40%) in the methadone group and unbalanced (26% in the buprenorphine group)

MOTHER Study

MethodsMulticentre, randomised controlled trial

Double-blind, double-dummy


Participants175 pregnant adults; mean age 27.3 years; 83.2% white; employed 13.3%; mean years of education 11.3; substance use: heroin previous 30 days 10.2, cocaine previous 30 days 4.8, any alcohol previous 30 days 0.4, benzodiazepines previous 30 days 0.8
Mean estimated gestational age of fetus: 18.6 weeks

Inclusion criteria: opioid-dependent women between the ages of 18 and 41 years with a singleton pregnancy between 6 and 30 weeks of gestation

Exclusion criteria: no medical or other conditions contraindicating participation; pending legal action; disorders related to the use of benzodiazepines or alcohol; planning to give birth outside the hospital at the study site


Interventions(1) Sublingual tablets of buprenorphine (58 participants) versus (2) oral methadone (73 participants). Flexible dose range of 2 to 32 mg of buprenorphine; dose range of 20 to 140 mg of methadone
Setting: outpatients
Follow-up: up to 10 days after delivery


OutcomesNeonatal outcome measures: neonates requiring treatment for NAS, peak NAS score, total amount of morphine needed for treatment of NAS, length of hospital stay and head circumference, number of days during which medication was given for NAS, weight and length at birth, preterm birth, gestational age at delivery, and 1-minute and 5-minute APGAR scores

Maternal outcomes measures: caesarean section, weight gain, abnormal fetal presentation during delivery, anaesthesia during delivery, the results of drug screening at delivery, medical complications at delivery, study discontinuation, amount of voucher money earned for drug-negative tests and number of prenatal obstetric visits

Adverse events for children and mothers


NotesCountry of origin: United States, Austria, Canada


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "Patients were randomised within three stratification factors: (i) site; (ii) EGA (6 weeks and 0/7 days–18 weeks and 6/7 days; 19 weeks and 0/7–30 weeks and 6/7 days) to control for differences in duration of medication exposure; and (iii) cocaine use in the past 30 days (yes/no)"

COMMENT: no further detail provided on the randomisation procedure

Allocation concealment (selection bias)Low riskQuote: "The Center for Substance Abuse Research (CESAR) at the University of Maryland, College Park, was the coordinating center responsible for across-site randomisation, data collection, coordination and protocol adherence monitoring. Randomization assignment was communicated from CESAR directly to the site’s pharmacy."

Blinding of participants and personnel (performance bias)
subjective outcomes
Low riskQuote: "A blinded, individualized dosing schedule was used for the study medications, and a double blind
method was used to implement dose-unit increases or decreases (with dose adjustments of 2 mg for buprenorphine and 5 or 10 mg for methadone). Patients received seven tablets (three in the size of an 8-mg tablet and four in the size of a 2-mg tablet) to place under the tongue for 5 minutes, or until the tablets dissolved. Each tablet contained buprenorphine or placebo. After receiving these tablets, participants received liquid containing methadone or placebo. Oral methadone and flavour-masking concentrates were diluted
to provide the dose in a fixed volume (e.g., 40 ml at U.S. sites and 50 ml in Vienna). Methadone placebo was given in the same fixed volume and included the same flavour-masking concentrates as the active drug concentrate."

Blinding of participants and personnel (performance bias)
objective outcomes
Low riskQuote: "A blinded, individualized dosing schedule was used for the study medications, and a double blind
method was used to implement dose-unit increases or decreases (with dose adjustments of 2 mg for buprenorphine and 5 or 10 mg for methadone). Patients received seven tablets (three in the size of an 8-mg tablet and four in the size of a 2-mg tablet) to place under the tongue for 5 minutes, or until the tablets dissolved. Each tablet contained buprenorphine or placebo. After receiving these tablets, participants received liquid containing methadone or placebo. Oral methadone and flavour-masking concentrates were diluted
to provide the dose in a fixed volume (e.g., 40 ml at U.S. sites and 50 ml in Vienna). Methadone placebo was given in the same fixed volume and included the same flavour-masking concentrates as the active drug concentrate."

Blinding of outcome assessment (detection bias)
subjective outcomes
Low riskQuote: "With limited exceptions, data were submitted to CESAR using a paper document capture and processing methodology. The Center for Substance Abuse Research (CESAR) at the University of Maryland, College Park, was the coordinating centre responsible for data collection"

COMMENT: not specified whether the trained personnel who collected data were blinded, but given the double-blind condition for personnel who provided dugs and participants, we judged that they were

Blinding of outcome assessment (detection bias)
objective outcomes
Low riskThe outcomes are not likely to be influenced by lack of blinding

Incomplete outcome data (attrition bias)
All outcomes
High riskQuote: "A total of 16 of the 89 women in the methadone group (18%) and 28 of the 86 women in the buprenorphine group (33%) discontinued treatment before delivery (P = 0.02). Dissatisfaction with the study medication was reported as the reason for discontinuation by 71% of participants in the buprenorphine
group, as compared with only 13% of those in the methadone group"

COMMENT: high drop-out (33.%) in the buprenorphine group and unbalanced (18% in the methadone group) Reason for drop-out given and likely to be linked to treatments received

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Bandstra 2012Editorial

Bell 2007Commentary on a randomised controlled trial where pregnant women were not included

Binder 2008Study defined as randomised but not clear from the text if women were randomised to different maintenance treatments; it seems that they were not

Carroll 1995Excluded as the type of control intervention was not among our inclusion criteria: both groups received methadone at the same dose

Dawe 2007Participants did not meet the inclusion criteria: not pregnant women

Ebner 2007Excluded as the study design did not meet the inclusion criteria: not a randomised controlled trial

Fisher 1998Excluded as the study design did not meet the inclusion criteria: not a randomised controlled trial

Gordon 2004Excluded as the study design did not meet the inclusion criteria: not a randomised controlled trial

Hulse 2004Excluded as the study design did not meet the inclusion criteria: not a randomised controlled trial

Jackson 2004Excluded as the type of participants did not meet the inclusion criteria: newborns randomised to receive different treatments after the delivery

Jones 2008Narrative review

Jones 2011Intervention did not meet the inclusion criteria: psychosocial intervention

Keyser-Marcus 2002Excluded as the study design did not meet the inclusion criteria: not a randomised controlled trial

Lacroix 2011Study design did not meet the inclusion criteria: not a randomised study

Laken 1997Excluded as the study design did not meet the inclusion criteria: not a randomised controlled trial

Martin 2011Narrative review

Newman 2009Comment, letter

Stine 2009Study design did not meet the inclusion criteria: comparison of women who did and did not give consent to participate in the MOTHER study

Suchman 2007Participants did not meet the inclusion criteria: non-pregnant women

Tuten 2012Intervention did not meet the inclusion criteria: psychosocial treatment

 
Comparison 1. Methadone versus buprenorphine

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Drop-out3223Risk Ratio (M-H, Fixed, 95% CI)0.64 [0.41, 1.01]

 2 Use of primary substance2151Risk Ratio (M-H, Fixed, 95% CI)1.81 [0.70, 4.69]

 3 Birth weight2150Mean Difference (IV, Random, 95% CI)-365.45 [-673.84, -57.07]

 4 APGAR score2163Mean Difference (IV, Fixed, 95% CI)0.0 [-0.03, 0.03]

 5 Number treated for NAS3166Risk Ratio (M-H, Fixed, 95% CI)1.22 [0.89, 1.67]

 6 Mean duration of NAS treatment2145Mean Difference (IV, Fixed, 95% CI)1.08 [-0.03, 0.03]

 7 Length of hospital stay2152Mean Difference (IV, Random, 95% CI)4.01 [-1.29, 9.30]

 8 Total amount of morphine for NAS2145Mean Difference (IV, Random, 95% CI)5.06 [-3.36, 13.47]

 9 Serious AE for the mother1175Risk Ratio (M-H, Fixed, 95% CI)1.69 [0.75, 3.83]

 10 Serious AE for the child1131Risk Ratio (M-H, Fixed, 95% CI)4.77 [0.59, 38.49]

 11 Non-serious AE for the mother1175Risk Ratio (M-H, Fixed, 95% CI)1.22 [1.07, 1.38]

 12 Non-serious AE for the child1131Risk Ratio (M-H, Fixed, 95% CI)1.08 [0.74, 1.59]

 
Comparison 2. Methadone versus oral slow-release morphine

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Use of substance148Risk Ratio (M-H, Fixed, 95% CI)2.4 [1.00, 5.77]

 2 Birth weight148Mean Difference (IV, Fixed, 95% CI)124.00 [-186.94, 434.94]

 3 NAS mean duration148Mean Difference (IV, Fixed, 95% CI)-5.0 [-10.97, 0.97]

 4 Nicotine consumption148Mean Difference (IV, Fixed, 95% CI)4.43 [-1.47, 10.33]

 
Summary of findings for the main comparison. Methadone compared to buprenorphine for opiate-dependent pregnant women

Methadone compared to buprenorphine for opiate-dependent pregnant women

Patient or population: opiate-dependent pregnant women
Settings:
Intervention: methadone
Comparison: buprenorphine

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

BuprenorphineMethadone

Drop-out
Objective
Follow-up: 15 to 18 weeks
Study populationRR 0.64
(0.41 to 1.01)
223
(3 studies)
⊕⊕⊝⊝
low1,2

318 per 1000204 per 1000
(130 to 321)

Moderate

326 per 1000209 per 1000
(134 to 329)

Use of primary substance
Objective
Follow-up: 15 to 18 weeks
Study populationRR 1.81
(0.7 to 4.69)
151
(2 studies)
⊕⊕⊝⊝
low1,2

75 per 1000135 per 1000
(52 to 350)

Moderate

43 per 100078 per 1000
(30 to 202)

Birth weight
Objective
Follow-up: mean 18 weeks
The mean birth weight ranged across control groups from
3.53 to 3.09 grams
The mean birth weight in the intervention groups was
224.91 lower
(248.46 to 201.36 lower)
150
(2 studies)
⊕⊕⊝⊝
low1,2,3,4

APGAR score
Objective. Scale from: 0 to 10
Follow-up: mean 18 weeks
The mean APGAR score ranged across control groups from
8.9 to 9.0
The mean APGAR score in the intervention groups was
0 higher
(0.03 lower to 0.03 higher)
163
(2 studies)
⊕⊕⊝⊝
low1,2

Number treated for NAS
Objective
Follow-up: 15 to 18 weeks
Study populationRR 1.22
(0.89 to 1.67)
166
(3 studies)
⊕⊝⊝⊝
very low1,2,5

447 per 1000546 per 1000
(398 to 747)

Moderate

466 per 1000569 per 1000
(415 to 778)

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
APGAR score: Activity, Pulse, Grimace, Appearance and Respiration score; CI: confidence interval; RR: risk ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1For incomplete outcome data, we judged the studies at high risk of attrition bias because the attrition rate was high and unbalanced between groups.
2Small sample size.
3Statistically significant heterogeneity.
4No explanation was provided.
5Variability in results.
 
Summary of findings 2. Methadone compared to oral slow-release morphine for opiate-dependent pregnant women

Methadone compared to oral slow-release morphine for opiate-dependent pregnant women

Patient or population: opiate-dependent pregnant women
Settings:
Intervention: methadone
Comparison: oral slow-release morphine

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

Oral slow-release morphineMethadone

Use of substance
Objective
Follow-up: 15 weeks
Study populationRR 2.4
(1 to 5.77)
48
(1 study)
⊕⊕⊕⊝
moderate1

208 per 1000500 per 1000
(208 to 1000)

Moderate

208 per 1000499 per 1000
(208 to 1000)

Birth weight
Objective
Follow-up: 15 weeks
The mean birth weight in the control groups was
2.912 grams
The mean birth weight in the intervention groups was
124 higher
(186.94 lower to 434.94 higher)
48
(1 study)
⊕⊕⊕⊝
moderate1

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; RR: risk ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1Only one study with small sample size.