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Detoxification treatments for opiate dependent adolescents

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

Editorial Group: Cochrane Drugs and Alcohol Group

Published Online: 29 APR 2014

Assessed as up-to-date: 10 APR 2014

DOI: 10.1002/14651858.CD006749.pub3


How to Cite

Minozzi S, Amato L, Bellisario C, Davoli M. Detoxification treatments for opiate dependent adolescents. Cochrane Database of Systematic Reviews 2014, Issue 4. Art. No.: CD006749. DOI: 10.1002/14651858.CD006749.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

*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 (no change to conclusions)
  2. Published Online: 29 APR 2014

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Characteristics of included studies [ordered by study ID]
Marsch 2005

MethodsRandomised controlled trial. Recruitment modality: self-referred participants.


Participants36 adolescents (13-18 years) who met the DSM-IV criteria for opioid dependence. Pregnant women and patients with significant psychiatric disorders (e.g. psychosis) or medical illnesses (e.g. cardiovascular disease) were excluded.

Mean age. 17.35 years; 39% male; 97% white. Injection route of opiate use: 36%; other drug dependence alcohol: 17.5%, cannabis: 17%, cocaine: 10%, amphetamine: 6%.


Interventions(1) Buprenorphine detoxification: sublingual buprenorphine tablets daily with flexible dosing procedure based on weight and self-reported opiate use at intake (starting dose range: 6 mg- 8 mg). Buprenorhine dose that decreased by 2 mg every 7 days. Behavioural therapy 3 one-hour individual sessions per week. Contingency management approach: participants could earn a voucher on the provision of opioid negative urine samples. At the end of the study, participants were offered naltrexone.

(2) Transdermal clonidine patches 0.1 mg on intake day and day 1; a second patch was added on day 2 and worn until day 6. An optional third patch (depending on the severity of withdrawal symptoms) may have been added on day 4 and worn until day 6. All patches were removed on day 7 and replaced with a 0.2 mg doses. On day 14 the patches were removed again and replaced with a 0.1 mg dose patch. On day 21 the patches were removed again and replaced with a 0 mg dose. Behavioural therapy 3 one-hour individual session per week. Contingency management approach: participants could earn a voucher on the provision of opioid negative urine samples. At the end of the study, participants were offered naltrexone.

Durattion of the trials: 28 days.


OutcomesDrop out from treatment measured as the percentage of patients who did not complete the entire detoxification treatment. Time retained in treatment. Opiate abstinence as the percentage of scheduled urine samples opiate negative. Other drug use as percentage of urine samples positives. Acceptability of the treatment: withdrawal effect measured by the Adjective rating scale. Initiation of naltrexone treatment as percentage of patients who initiated.


NotesCountry: USA
Setting: outpatients


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"participants were randomly assigned to either detoxification with clonidine or with buprenorphine. In this process participants were stratified for sex and past month route of opiate use (injection vs intranasal)"

Allocation concealment (selection bias)Unclear risk"participants were randomly assigned to either detoxification with clonidine or with buprenorphine. In this process participants were stratified for sex and past month route of opiate use (injection vs intranasal)"

Blinding (performance bias and detection bias)
objective outcomes (drop out, use of substance measured by urine-analysis, abstinent at follow-up, initiation of naltrexone treatment)
Low risk"The study used a parallel group, double blind, double dummy design". Participants in the clonidine group received placebo buprenorphine tablets and patients in the buprenorphine group received placebo clonidine patches"

COMMENT: the outcomes are unlikely to be influenced by lack of blinding

Blinding (performance bias and detection bias)
Subjective outcome
Low risk"The study used a parallel group, double blind, double dummy design". Participants in the clonidine group received placebo buprenorphine tablets and patients in the buprenorphine group received placebo clonidine patches"
COMMENT: blinding of participants and personnel. Not specified if research staff members who assessed subjective outcomes were blind but we judge that they probably were.

Incomplete outcome data (attrition bias)
All outcomes
Low risk"the primary analysis (drop out, time retained, use of substance) included all participants randomised independently to drop out/non compliance, consistent with an intention to treat approach. All secondary outcomes (withdrawals symptoms and signs) were confined to the data from treatment intake to the end of the first week when retention was still high in both condition"

Selective reporting (reporting bias)Low risk

Woody 2008

MethodsMulticentre randomised controlled trial. Recruitment modality described.


Participants154 participants who met the DSM IV diagnostic criteria for opioid dependence and who sought outpatient treatment.152 randomised. Mean age: 19 years. Only one participant was 15 years old and no participants were 14 years old. Male: 59%. White: 56%.


Interventions(1) Maintenance group:12 weeks buprenorphine. Naloxone: up to 24 mg/day buprenorphine and 0.5 mg naloxone for 9 weeks and then tapered to week 12. :74 patients.

(2) Detoxification group: 2 weeks buprenorphine. Naloxone: up to 14 mg/day buprenorphine and then tapered to day 14: 78 patients.

Both groups were offered 1 weekly individual and 1 group counselling.


OutcomesPrimary outcome: opioid positive urine test results at weeks 4, 8 and 12.

Secondary outcomes: drop out, self-reported use, enrolment in addiction treatment outside the assigned condition, other drug use, adverse events. Results at 6,9,12 months follow-up: self-reported opioid use, self-reported other drug use, other addiction treatment received.


NotesCountry: USA

Setting: outpatients


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandomisation occurred through an automated 24-hour service at the Veterans Affairs Cooperative Studies Program in Perry Point, Maryland, that was programmed
to randomise patients separately by site. At each site, a biased coin randomisation protected against severe imbalance of sex, ethnicity, route of administration, and age across the treatment groups.

Age was dichotomised as 14 to 18 years or 18 to 21 years, ethnicity as the majority ethnic group vs all others within the site, and route of administration as injecting or non injecting.

Allocation concealment (selection bias)High riskBalance was assessed by comparing the group sum of the binary indicators as each new patient was randomised. If both groups were balanced when a new patient was being randomised, then each group had an allocation probability of 1/2; if there was an imbalance, then the group with the higher score on the sum of indicators received an allocation probability of 1/3 and the other group a probability of 2/3.

Blinding (performance bias and detection bias)
objective outcomes (drop out, use of substance measured by urine-analysis, abstinent at follow-up, initiation of naltrexone treatment)
Low riskPatients and providers impossible to be blinded for the nature of the intervention (14 days detox vs 12 weeks maintenance).

COMMENT: objective outcomes unlikely to be biased by lack of blinding.

Blinding (performance bias and detection bias)
Subjective outcome
High riskPatients and providers impossible to be blinded for the nature of the intervention (14 days detox vs 12 weeks maintenance)

Outcome assessor not blinded: "Research assistant likely knew groups assignment because the study was not blinded"

Incomplete outcome data (attrition bias)
All outcomes
Low riskNumber of participants withdrawn from the study reported for each group. Reason for withdrawal given. Analysis on the basis of the Intention-to-treat principle: "patients were contacted at all assessment point regardless of whether they remained in treatment".

Selective reporting (reporting bias)Low risk

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Baer 2007Type of intervention not in the inclusion criteria: only psychosocial intervention without pharmacological detoxification

Chakrabarti 2010Outcome not in the inclusion criteria: baseline patient characteristics of Woody 2008 trial

Ebner 2007Study design not in the inclusion criteria: not RCT or CCT

Fiellin 2008Study design not in the inclusion criteria: not RCT or CCT

Forcehimes 2008Type of intervention not in the inclusion criteria: psychosocial intervention; the same pharmacological intervention given to both groups

Godley 2004Study design not in the inclusion criteria: not RCT or CCT

Hill 2013Outcome not in the inclusion criteria: association between cannabis use during opioid dependence treatment and positive urine drug screens for opioids; no raw data about cannabis use in the two groups provided

Kemp 2007Type of intervention not in the inclusion criteria: only psychosocial intervention without pharmacological detoxification

Lehmann 1973Type of intervention not in the inclusion criteria: maintenance treatment

Lloyd 1974Study design not in the inclusion criteria: not RCT or CCT

Mannelli 2011Participants not in the inclusion criteria: adults

Moore 2011Secondary analysis of the all sample of the Marsch 2005 study without distinction between experimental and control condition

Moore 2014Study design not in the inclusion criteria: qualitative study

Mullen 2010Study design and participants not in the inclusion criteria: observation cohort study on adult population

Polsky 2010Outcome not in the inclusion criteria: cost effectiveness analysis of the Woody 2008 trial

Subramaniam 2011Outcome not in the inclusion criteria: Predictors of Abstinence: secondary analysis of the Woody 2008 trial

Warden 2012Outcome not in the inclusion criteria:Predictors of attrition: secondary analysis of the Woody 2008 trial

Wilcox 2013Outcome not in the inclusion criteria: Concordance between self-report and urine drug screen data: secondary analysis of the Woody 2008 trial

 
Characteristics of studies awaiting assessment [ordered by study ID]
Marsh 2009

MethodsDouble blind randomised controlled trial

Participants53 opioid dependents adolescents and young adults (age 13-24 eligible)

InterventionsExperimental: buprenorphine taper of 28 days

Control: buprenorphine taper of 63 days

OutcomesRetention in treatment; use of primary substance of abuse measured by urine analysis

NotesAuthor contacted; study ended but definite results not yet published

 
Comparison 1. Buprenorphine versus clonidine

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

 1 drop out136Risk Ratio (M-H, Fixed, 95% CI)0.45 [0.20, 1.04]

 2 withdrawal score132Mean Difference (IV, Fixed, 95% CI)3.97 [-1.38, 9.32]

 3 initiation of naltrexone treatment136Risk Ratio (M-H, Fixed, 95% CI)11.0 [1.58, 76.55]

 
Comparison 2. Buprenorphine detox versus buprenorphine maintenance

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

 1 drop out1152Risk Ratio (M-H, Fixed, 95% CI)2.67 [1.85, 3.86]

 2 patients with positive urine at the end of treatment1152Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.82, 1.28]

 3 self-reported use at 12 months follow-up1152Risk Ratio (M-H, Fixed, 95% CI)1.36 [1.05, 1.76]

 4 enrolment in addiction treatment at 12-month follow-up1152Risk Ratio (M-H, Fixed, 95% CI)0.75 [0.53, 1.07]

 5 self-reported alcohol use1152Risk Ratio (M-H, Fixed, 95% CI)1.13 [0.63, 2.02]

 6 self-reported marijuana use1152Risk Ratio (M-H, Fixed, 95% CI)1.58 [0.83, 3.00]

 7 self-reported cocaine use1152Risk Ratio (M-H, Fixed, 95% CI)8.54 [1.11, 65.75]

 
Summary of findings for the main comparison. Buprenorphine versus clonidine for opiate dependent adolescents

Buprenorphine versus clonidine for opiate dependent adolescents

Patient or population: patients with opiate dependent adolescents
Settings:
Intervention: buprenorphine versus clonidine

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

Assumed riskCorresponding risk

ControlBuprenorphine versus clonidine

Drop out
Number of participants who did not complete the detoxification treatment
Follow-up: 28 days
Study populationRR 0.45
(0.2 to 1.04)
36
(1 study)
⊕⊕⊕⊝
moderate1,2

611 per 1000275 per 1000
(122 to 636)

Moderate

611 per 1000275 per 1000
(122 to 635)

Duration and severity of signs and symptoms of withdrawal
Adjective rating scale
Follow-up: 28 days
The mean duration and severity of signs and symptoms of withdrawal in the control groups was
-18.8 score
The mean duration and severity of signs and symptoms of withdrawal in the intervention groups was
3.97 higher
(1.38 lower to 9.32 higher)
32
(1 study)
⊕⊕⊕⊝
moderate1,2

Initiation of naltrexone treatment
Number of participants initiating naltrexone
Follow-up: 28 days
Study populationRR 11
(1.58 to 76.55)
36
(1 study)
⊕⊕⊕⊝
moderate1,2

56 per 1000611 per 1000
(88 to 1000)

Moderate

56 per 1000616 per 1000
(88 to 1000)

*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.

 1 only one study included
2 only one study with 36 participants included
 
Summary of findings 2. Buprenorphine detox compared with buprenorphine maintenance for opiate dependent adolescents

Buprenorphine detox compared with buprenorphine maintenance for opiate dependent adolescents

Patient or population: patients with opiate dependent adolescents
Settings:
Intervention: buprenorphine detox
Comparison: buprenorphine maintenance

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

Assumed riskCorresponding risk

Buprenorphine maintenanceBuprenorphine detox

Drop out
Number of participants who dropped out from the study

Follow-up: 12 weeks
Study populationRR 2.67
(1.85 to 3.86)
152
(1 study)
⊕⊕⊝⊝
low1,2,3

297 per 1000794 per 1000
(550 to 1000)

Moderate

297 per 1000793 per 1000
(549 to 1000)

Patients with positive urine at the end of treatment
Number of participants with urine positive for opiates

Follow-up: 12 weeks
Study populationRR 1.03
(0.82 to 1.28)
152
(1 study)
⊕⊕⊝⊝
low1,2

662 per 1000682 per 1000
(543 to 848)

Moderate

662 per 1000682 per 1000
(543 to 847)

Self-reported use at 12 months follow-up
Number of participants who reported heroin used at follow-up

Follow-up: 12 months
Study populationRR 1.36
(1.05 to 1.76)
152
(1 study)
⊕⊕⊝⊝
low1,2,3,4

527 per 1000717 per 1000
(553 to 928)

Moderate

527 per 1000717 per 1000
(553 to 928)

Enrolment in addiction treatment at 12 month follow-up
Number of participants enrolled in addiction treatment at follow-up

Follow-up: 12 months
Study populationRR 0.75
(0.53 to 1.07)
152
(1 study)
⊕⊕⊝⊝
low1,2,3

527 per 1000395 per 1000
(279 to 564)

Moderate

527 per 1000395 per 1000
(279 to 564)

*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.

 1 no allocation concealment
2 only one study with 154 participants
3 participants, providers and outcome assessor not blinded
4