Detoxification treatments for opiate dependent adolescents

  • Review
  • Intervention

Authors


Abstract

Background

The scientific literature examining effective treatments for opioid dependent adults clearly indicates that pharmacotherapy is a necessary and acceptable component of effective treatments for opioid dependence. Nevertheless, no studies have been published that systematically assess the effectiveness of the pharmacological detoxification among adolescents.

Objectives

To assess the effectiveness of any detoxification treatment alone or in combination with psychosocial intervention compared with no intervention, other pharmacological intervention or psychosocial interventions on completion of treatment, reducing the use of substances and improving health and social status.

Search methods

We searched the Cochrane Central Register of Controlled Trials (2014, Issue 1), PubMed (January 1966 to January 2014), EMBASE (January 1980 to January 2014), CINHAL (January 1982 to January 2014), Web of Science (1991-January 2014) and reference lists of articles.

Selection criteria

Randomised controlled clinical trials comparing any pharmacological interventions alone or associated with psychosocial intervention aimed at detoxification with no intervention, placebo, other pharmacological intervention or psychosocial intervention in adolescents (13 to 18 years).

Data collection and analysis

We used standard methodological procedures recommended by The Cochrane Collaboration

Main results

Two trials involving 190 participants were included. One trial compared buprenorphine with clonidine for detoxification. No difference was found for drop out: risk ratio (RR) 0.45 (95% confidence interval (CI): 0.20 to 1.04) and acceptability of treatment: withdrawal score mean difference (MD): 3.97 (95% CI -1.38 to 9.32). More participants in the buprenorphine group initiated naltrexone treatment: RR 11.00 (95% CI 1.58 to 76.55), quality of evidence moderate.

The other trial compared maintenance treatment versus detoxification treatment: buprenorphine-naloxone maintenance versus buprenorphine detoxification. For drop out the results were in favour of maintenance treatment: RR 2.67 (95% CI 1.85, 3.86), as well as for results at follow-up RR 1.36 [95% CI 1.05to 1.76); no differences for use of opiate, quality of evidence low.

Authors' conclusions

It is difficult to draw conclusions on the basis of two trials with few participants. Furthermore, the two studies included did not consider the efficacy of methadone that is still the most frequent drug utilised for the treatment of opioid withdrawal. One possible reason for the lack of evidence could be the difficulty in conducting trials with young people due to practical and ethical reasons.

Résumé scientifique

Traitements de désintoxication pour les adolescents présentant une dépendance aux opiacés

Contexte

La littérature scientifique examinant les traitements efficaces pour les adultes présentant une dépendance aux opiacés indique clairement que la pharmacothérapie est un élément nécessaire et acceptable des traitements efficaces contre la dépendance aux opiacés. Néanmoins, aucune étude évaluant de manière systématique l'efficacité de la désintoxication pharmacologique chez les adolescents n'a été publiée.

Objectifs

Évaluer l'efficacité de tout traitement de désintoxication seul ou associé à une intervention psychosociale par comparaison avec l'absence d'intervention, avec une autre intervention pharmacologique ou avec des interventions psychosociales sur l'achèvement du traitement, la réduction de la consommation de substances et l'amélioration de l'état de santé et du statut social.

Stratégie de recherche documentaire

Nous avons effectué des recherches dans le registre Cochrane des essais contrôlés (2014, numéro 1), PubMed (de janvier 1966 à janvier 2014), EMBASE (de janvier 1980 à janvier 2014), CINHAL (de janvier 1982 à janvier 2014), Web of Science (de 1991 à janvier 2014) et dans les références bibliographiques des articles.

Critères de sélection

Essais cliniques randomisés contrôlés comparant toute intervention pharmacologique seule ou associée à une intervention psychosociale destinée à la désintoxication avec l'absence d'intervention, un placebo ou une autre intervention pharmacologique ou psychosociale chez les adolescents (de 13 à 18 ans).

Recueil et analyse des données

Nous avons utilisé les procédures méthodologiques standard recommandées par la Collaboration Cochrane.

Résultats principaux

Deux essais portant sur 190 participants ont été inclus. Le premier comparait la buprénorphine à la clonidine en matière de désintoxication. Aucune différence n'a été trouvée pour les sorties d'étude : risque relatif (RR) de 0,45 (intervalle de confiance (IC) à 95 % de 0,20 à 1,04) ou pour l'acceptabilité du traitement : différence moyenne (DM) des taux de sortie 3,97 (IC à 95 % de -1,38 à 9,32). Davantage de participants dans le groupe sous buprénorphine ont entrepris un traitement à la naltréxone : RR 11,00 (IC à 95 % de 1,58 à 76,55), preuves de qualité modérée.

L'autre essai comparait le traitement d'entretien au traitement de désintoxication : entretien à la buprénorphine-naloxone versus désintoxication à la buprénorphine. Pour les sorties d'étude, les résultats étaient en faveur du traitement d'entretien : RR 2,67 (IC à 95 % de 1,85 à 3,86), ainsi que pour les résultats au suivi (RR 1,36 [IC à 95 % de 1,05 à 1,76) ; aucune différence pour la consommation d'opiacés, preuves de qualité faible.

Conclusions des auteurs

Il est difficile de tirer des conclusions sur la base de deux essais portant sur un petit nombre de participants. Par ailleurs, aucune des deux études incluses n'a examiné l'efficacité de la méthadone qui reste le médicament le plus utilisé dans le traitement du sevrage des opiacés. La pénurie de données pourrait notamment s'expliquer par la difficulté de réaliser des essais portant sur des jeunes, tant pour des raisons pratiques qu'éthiques.

Plain language summary

Detoxification treatments for opiate dependent adolescents

Detoxification treatment for heroin dependents adolescents

Review question

We reviewed the evidence on the effect of detoxification treatment compared with pharmacological maintenance treatment or psychosocial intervention in achieving abstinence on adolescents heroin dependents.

Background

Substance abuse among adolescents (13 to 18 years old) is a serious and growing problem. It is important to identify effective treatments for those who are opioid dependent. For adults, pharmacotherapy is a necessary and acceptable part of effective treatment. Detoxification agents are used to reduce withdrawal symptoms during managed withdrawal but the rate of completion of detoxification tends to be low, and rates of relapse are high. Withdrawal symptoms, particularly drug craving, may continue for weeks and even months after detoxification. The period of recovery from dependence is typically influenced by a range of psychological, social and treatment- related factors. Detoxification treatments include methadone, buprenorphine, and alpha2-adrenergic agonists.

Study characteristics

The review authors searched the literature for randomised controlled trials investigating pharmacological interventions with or without psychosocial intervention aimed at detoxification in adolescents. They found only two trials, both conducted in the USA; one compared 28-day treatment with buprenorphine, using tablets placed under the tongue, to wearing a clonidine patch in 36 opiate dependent adolescents who were treated as outpatients. The other trial compared maintenance treatment versus detoxification treatment: buprenorphine-naloxone maintenance versus buprenorphine detoxification.

Key results

The trial comparing buprenorphine with clonidine reported a trend in favour of buprenorphine in reducing the drop-out rate but no difference between treatments in the duration and severity of withdrawal symptoms. More participants in the buprenorphine group went on to long-term naltrexone treatment. Side effects were not reported. In the second trial comparing buprenorphine maintenance versus buprenorphine for detoxification, for drop out the results were in favour of maintenance treatment, At one-year follow- up, self-reported opioid use was clearly less in the maintenance group and more adolescents were enrolled in other addiction programs. Conducting trials with young people may be difficult for both practical and ethical reasons.

Quality of the evidence

This review was limited by the very few number of trials retrieved and the quality of the evidence was moderate for the comparison between buprenorphine and clonidine and low for the comparison between buprenorphine detoxification and buprenorphine maintenance. The evidence is current to January 2014.

Résumé simplifié

Traitements de désintoxication pour les adolescents présentant une dépendance aux opiacés

Traitement de désintoxication pour les adolescents ayant une dépendance à l'héroïne

Question de la revue

Nous avons examiné les preuves sur l'effet d'un traitement de désintoxication par rapport à un traitement d'entretien pharmacologique ou une intervention psychosociale pour obtenir une abstinence chez les adolescents dépendants à l'héroïne.

Contexte

L'abus de substances est un problème sérieux et croissant chez les adolescents (de 13 à 18 ans). Il est important d'identifier les traitements efficaces pour ceux qui présentent une dépendance aux opiacés. Pour les adultes, la pharmacothérapie est un élément nécessaire et acceptable du traitement efficace. Les agents de désintoxication sont utilisés pour réduire les symptômes de sevrage pendant le sevrage encadré, mais le taux d'achèvement de la désintoxication tend à être faible, et les taux de rechute sont élevés. Les symptômes de sevrage, en particulier les envies impérieuses de consommer de la drogue, peuvent perdurer pendant des semaines et même des mois après la désintoxication. Le délai de guérison de la dépendance est typiquement influencé par une gamme de facteurs psychologiques, sociaux et liés au traitement. Les traitements de désintoxication comprennent la méthadone, la buprénorphine et les agonistes alpha2-adrénergiques.

Caractéristiques des études

Les auteurs de la revue ont effectué une recherche dans la littérature pour identifier des essais randomisés contrôlés examinant les interventions pharmacologiques avec ou sans intervention psychosociale destinées à la désintoxication chez les adolescents. Deux essais seulement ont été trouvés, les deux réalisés aux États-Unis. Le premier essai comparait un traitement de 28 jours à la buprénorphine, sous forme de comprimés placés sous la langue, au port d'un patch de clonidine chez 36 adolescents présentant une dépendance aux opiacés qui recevaient un traitement en tant que patients non hospitalisés. L'autre essai comparait un traitement d'entretien à un traitement de désintoxication : entretien à la buprénorphine-naloxone versus désintoxication à la buprénorphine.

Résultats

L'essai comparant la buprénorphine à la clonidine faisait apparaître une tendance en faveur de la buprénorphine au niveau de la réduction du taux de sortie d'étude, mais aucune différence entre les traitements au niveau de la durée et de la sévérité des symptômes. Davantage de participants du groupe sous buprénorphine ont ensuite suivi un traitement de longue durée à la naltréxone. Les effets secondaires n'étaient pas indiqués. Dans le deuxième essai comparant la buprénorphine dans l'entretien et dans la désintoxication, pour les sorties d'étude, les résultats étaient en faveur du traitement d'entretien. Au suivi à un an, la consommation d'opiacés déclarée était nettement inférieure dans le groupe recevant le traitement d'entretien et davantage d'adolescents de ce groupe participaient à d'autres programmes de traitement de la toxicomanie. La réalisation d'essais portant sur des jeunes peut être délicate, aussi bien pour des raisons pratiques qu'éthiques.

Qualité des preuves

Cette revue était limitée par le très petit nombre d'essais identifiés et la qualité des preuves était modérée pour la comparaison entre la buprénorphine et la clonidine et faible pour la comparaison entre la buprénorphine de désintoxication et la buprénorphine d'entretien. Les preuves sont à jour en janvier 2014.

Notes de traduction

Traduit par: French Cochrane Centre
Traduction financée par: Ministère du Travail, de l'Emploi et de la Santé Français

Laički sažetak

Detoksifikacijska terapija za adolescente ovisne o opioidima

Detoksifikacijska terapija za adolescente ovisne o heroinu

Pitanje koje postavlja sustavni pregled

Pregledani su dokazi o učinku detoksifikacije u usporedbi s farmakološkom terapijom održavanja ili psihosocijalnom intervencijom za postizanje apstinencije u adolescenata ovisnih o heroinu.

Dosadašnje spoznaje

Zloporaba droga među adolescentima (13 do 18 godina starosti) ozbiljan je i sve veći problem. Važno je pronaći učinkovite terapije za one koji su ovisni o opioidima. Za odrasle je terapija lijekovima nužan i prihvatljiv dio učinkovite terapije. Detoksifikacijski lijekovi koriste se za ublažavanje simptoma ustezanja tijekom upravljanog ustezanja, ali stope završavanja detoksifikacije su niske i stope relapsa su visoke. Simptomi ustezanja, posebice želja za drogom, mogu se nastaviti tjednima i čak mjesecima nakon detoksifikacije. Razdoblje oporavka od ovisnosti je obično pod utjecajem raspona psiholoških, socijalnih i faktora povezanih s terapijom. Detoksifikacijske terapije uključuju metadon, buprenorfin i alfa2 adrenergičke agoniste.

Značajke studija

Autori Cochrane sustavnog pregleda pretražili su literaturu kako bi pronašli randomizirane kontrolirane studije koje su istraživale farmakološke intervencije sa ili bez psihosocijalnih s ciljem detoksifikacije u adolescenata. Pronašli su samo dvije studije, obje provedene u SAD-u; jedna je uspoređivala 28-dnevnu terapiju buprenorfinom, koja je koristila tablete ispod jezika s nošenjem flastera s klonidinom u 36 adolescenata ovisnih o opijatima koji su bili izvan bolničkog okruženja. Druga studija je uspoređivala terapiju održavanja s detoksifikacijskom terapijom: buprenorfin-nalokson održavanje u usporedbi s detoksifikacijom buprenorfinom.

Ključni rezultati

Studija koja je uspoređivala klonidin i buprenorfin opisala je veće smanjenje stope napuštanja terapije za buprenorfin, ali nikakvu razliku u trajanju i težini simptoma ustezanja među terapijama. Više sudionika u skupini buprenorfina prešlo je na dugotrajnu terapiju naloksonom. Nisu zabilježene nuspojave. U drugoj studiji koja je uspoređivala buprenorfin u terapiji održavanja i buprenorfin za detoksifikaciju, rezultati napuštanja terapije bili su u korist terapije održavanja. Na kontroli nakon godinu dana samoprijavljeno korištenje opioida bilo je značajno niže i više adolescenata je bilo uključeno u programe odvikavanja. Provođenje istraživanja na mladim osobama može biti teško iz praktičnih i etičkih razloga.

Kvaliteta dokaza

Ovaj sustavni pregled ograničen je jako malim brojem provedenih studija te je kvaliteta dokaza bila umjerena za studiju koja je uspoređivala buprenorfin i klonidin i niska za usporedbu detoksifikacije i održavanja buprenorfinom. Dokazi se temelje na literaturi objavljenoj do siječnja 2014.

Bilješke prijevoda

Hrvatski Cochrane
Preveo: Adam Galkovski
Ovaj sažetak preveden je u okviru volonterskog projekta prevođenja Cochrane sažetaka. Uključite se u projekt i pomozite nam u prevođenju brojnih preostalih Cochrane sažetaka koji su još uvijek dostupni samo na engleskom jeziku. Kontakt: cochrane_croatia@mefst.hr

Summary of findings(Explanation)

Summary of findings for the main comparison. Buprenorphine versus clonidine for opiate dependent adolescents
  1. 1 only one study included
    2 only one study with 36 participants included

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
Control Buprenorphine versus clonidine
Drop out
Number of participants who did not complete the detoxification treatment
Follow-up: 28 days
Study population RR 0.45
(0.2 to 1.04)
36
(1 study)
⊕⊕⊕⊝
moderate 1,2
 
611 per 1000 275 per 1000
(122 to 636)
Moderate
611 per 1000 275 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)
⊕⊕⊕⊝
moderate 1,2
 
Initiation of naltrexone treatment
Number of participants initiating naltrexone
Follow-up: 28 days
Study population RR 11
(1.58 to 76.55)
36
(1 study)
⊕⊕⊕⊝
moderate 1,2
 
56 per 1000 611 per 1000
(88 to 1000)
Moderate
56 per 1000 616 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.

Summary of findings 2 Buprenorphine detox compared with buprenorphine maintenance for opiate dependent adolescents

Summary of findings 2. Buprenorphine detox compared with buprenorphine maintenance for opiate dependent adolescents
  1. 1 no allocation concealment
    2 only one study with 154 participants
    3 participants, providers and outcome assessor not blinded
    4

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 maintenance Buprenorphine detox
Drop out
Number of participants who dropped out from the study

Follow-up: 12 weeks
Study population RR 2.67
(1.85 to 3.86)
152
(1 study)
⊕⊕⊝⊝
low 1,2,3
 
297 per 1000 794 per 1000
(550 to 1000)
Moderate
297 per 1000 793 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 population RR 1.03
(0.82 to 1.28)
152
(1 study)
⊕⊕⊝⊝
low 1,2
 
662 per 1000 682 per 1000
(543 to 848)
Moderate
662 per 1000 682 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 population RR 1.36
(1.05 to 1.76)
152
(1 study)
⊕⊕⊝⊝
low 1,2,3,4
 
527 per 1000 717 per 1000
(553 to 928)
Moderate
527 per 1000 717 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 population RR 0.75
(0.53 to 1.07)
152
(1 study)
⊕⊕⊝⊝
low 1,2,3
 
527 per 1000 395 per 1000
(279 to 564)
Moderate
527 per 1000 395 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.

Background

Description of the condition

Several studies have demonstrated that adolescent (less than 18 years old) substance abuse is a serious and growing problem (Altobelli 2005).

In Europe, the estimate of lifetime prevalence of use for young adults 15 to 34 years old is of 32.5% for cannabis, 6.3 % for cocaine, ranging from 0.7 % to 13.6 % in different countries, 5.5 % for amphetamines, ranging from under 0.6 % to 12.4 %; most countries reported estimates in the range of 2.1 to 5.8 % for ectasy and from 0.1 % to 5.4 % for LSD. National estimates vary widely between countries in all measures of prevalence. Opioids, mainly heroin, were cited as the primary drug by more than 200,000 clients reported entering specialist drug treatment in 29 European countries in 2010, or 48 % of all reported treatment entrants (EMCDDA 2012).

In Europe in 2011, the European School Survey Project on Alcohol and Other Drugs (ESPAD) collected data on substance use of more than 100,000 15 to 16-year-old European students from 36 countries. Nearly one in three (29%) students in the ESPAD countries perceived cannabis to be (fairly or very) easily available. On average, 18% of students have tried illicit drugs at least once during their lifetime. Most of them (17%) have used cannabis while 6% reported experience with drugs other than cannabis. After cannabis, amphetamines and ecstasy are in second position, each being mentioned by 3% of the students. Lifetime use of cocaine, crack and LSD or other hallucinogens was reported by fewer students (2%) and the rates for heroin and GHB were even lower (1%). Use of cannabis in the past 12 months was 13%, while use in the past 30 days was claimed to be 7% (ESPAD 2012).

In the USA, recent household survey data indicate 9.5 % of youths aged 12 to 17 were current illicit drug users. This rate was similar to the rates of current illicit drug use in 2005 to 2011, but it was lower than the rates from 2002 to 2004. In addition, 7.2 % of youths aged 12 to 17 were current users of marijuana, 2.8 % were current non medical users of psychotherapeutic drugs, 0.8 % were current users of inhalants, 0.6% were current users of hallucinogens, and 0.1 % were current users of cocaine (SAMHSA 2013).

In the USA after 1992, the proportion of young Americans with lifetime use of any drugs rose considerably to a recent high point of 55% in 1999; it then declined gradually to 47% in 2007 through 2009, and stands at 49% in 2012. The annual prevalence of heroin use among 12th graders fell by half between 1975 and 1979, from 1.0% to 0.5%. The rate then held amazingly steady until 1994. Use rose in the mid and late 1990s, along with the use of most drugs; it reached peak levels in 1996 among 8th graders (1.6%), in 1997 among 10th graders (1.4%), and in 2000 among 12th graders (1.5%), suggesting a cohort effect. Since those peak levels, use has declined, with annual prevalence in all three grades fluctuating between 0.7% and 0.9% from 2005 through 2011. Use has declined some in the past two years; in the three grades combined, the 2011 to 2012 decline from 0.7% to 0.6% was significant (Monitoring the Future 2013).

In 2010, most Australians aged 14 years and over (60%) had never used an illicit drug. However, around 15% had used one or more illicit drugs in the past 12 months. Cannabis was the most common illicit drug used recently (10.3%), followed by ecstasy (3.0%) and amphetamines and cocaine (each used by 2.1% of people). Many people who used an illicit drug in 2010 also used other drugs, illicit or licit ( AIHW 2011).

Patterns of drug use have changed over time. An analysis of treatment entry data between 2000 and 2009 showed a decrease in drug injection among primary heroin clients in all European countries (from 58 % to 36 %), particularly in western Europe (EMCDDA 2012). In addition, among opioid users entering treatment in outpatient settings since 2009, those smoking the drug outnumbered those injecting it (EMCDDA 2012).

Description of the intervention

Numerous medications have been successfully used in the treatment of adolescents with a broad array of psychiatric disorders (Hunt 1990; Kaminer 1995). In contrast, medications have been infrequently used in treating substance abuse disorders among adolescents, nevertheless they have generally been shown to be a promising component of such interventions (Kaminer 1995).

The scientific literature examining effective treatments for opioid dependent adults clearly indicates that pharmacotherapy is a necessary and acceptable component of effective treatments for opioid dependence. Nevertheless, when young people must be treated, it probably is necessary to monitor the interventions in order to adapt them to this specific population. Different pharmacological agents have been used as detoxification agents to ameliorate withdrawal symptoms, however, the rate of completion of detoxification tends to be low, and rates of relapse to opioid use following detoxification are high (Gossop 1989; Vaillant 1988). Methadone may still be the medication that is most widely used but buprenorphine is seen as having some advantages for adolescents because of its excellent safety profile and the absence of long-term complications (Levy 2007; Smith 2012). Younger patients who present for treatment of drug dependence often have a shorter history of drug use than treatment-seeking adults. Treatment early in the course of the disorder presents the opportunity to prevent co-morbidities associated with drug use, including acute and chronic medical conditions, and psychiatric and social complications (Levy 2007).

How the intervention might work

Managed withdrawal, or detoxification, is not in itself a treatment for dependence (Lipton 1983; Mattick 1996) but detoxification remains a required first step for many forms of longer-term treatment (Kleber 1982). Withdrawal symptoms, particularly drug craving, may continue to be experienced for weeks and even for months after detoxification, and the period of recovery from dependence is typically influenced by a range of psychological, social and treatment- related factors.

Why it is important to do this review

We did not find any reviews in the published literature that assessed the effectiveness of detoxification treatment for adolescents. Many other Cochrane systematic reviews have been published on the effectiveness of various detoxification treatments: methadone (Amato 2013), buprenorphine (Gowing 2009), alpha2-adrenergic agonists (Gowing 2014), opioid antagonists with minimal sedation (Gowing 2009b) and under heavy sedation (Gowing 2010), psychosocial combined with detoxification treatment (Amato 2011) and one review comparing inpatient versus outpatient settings for opioid detoxification (Day 2005), but none address the question of the effectiveness of treatments for adolescents.

Objectives

To assess the effectiveness of any detoxification treatment alone or in combination with psychosocial intervention compared with no intervention, other pharmacological intervention or psychosocial interventions on completion of treatment, reducing the use of substances and improving health and social status.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs) and controlled clinical trials (CCTs).

Types of participants

Opiate dependent adolescents (13 to 18 years of age). There was no restriction for participants with physical or psychological illness.

Types of interventions

Experimental intervention

  • Any pharmacological interventions (methadone, buprenorphine, adrenergic agonists, symptomatics) alone or associated with psychosocial intervention aimed at detoxification

Control intervention

  • No intervention

  • Other pharmacological interventions

  • Psychosocial interventions alone

Types of comparisons foreseen

  • Any detoxification treatment versus no treatment

  • Any detoxification treatment versus other pharmacological treatment (e.g. methadone versus buprenorphine)

  • Any pharmacological treatment plus psychosocial treatment versus any pharmacological treatment alone

  • Any detoxification treatment versus any psychosocial treatment

Types of outcome measures

Primary outcomes
  1. Drop outs measured as number of participants who did not complete the detoxification treatment.

  2. Use of primary substance measured as number of participants with opiate positive urine analysis during and at the end of treatment or self-reported data.

  3. Acceptability of the treatment as A) duration and severity of signs and symptoms of withdrawal, including patient self-rating B) side effects.

  4. Results at follow-up measured as number of participants who relapsed at the end of follow-up.

Secondary outcomes
  1. Engagement in further treatment measured as number of participants who enrolled in any psychosocial or pharmacological treatment.

  2. Use of other substances of abuse.

  3. Overdose, fatal or nonfatal.

  4. Criminal activity.

  5. Social functioning (integration at school or at work, family relationship).

Search methods for identification of studies

Electronic searches

For this update, we revised the search strategy and re-ran searches in the following databases.

  1. Cochrane Drugs and Alcohol Group's trials register (Jannuary 2014).

  2. The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2014, Issue 1).

  3. MEDLINE (PubMed) (from 1966 - to Jannuary 2014).

  4. EMBASE (embase.com) (from 1980 - to Jannuary 2014).

  5. CINAHL (EBSCO) (1982 - to Jannuary 2014).

  6. Web of Science (1991 - to Jannuary 2014).

Databases were searched using a strategy developed by incorporating the filter for identification of RCTs (Lefebvre 2011) combined with selected MeSH terms and free-text terms related to alcohol dependence. For details on searchessee Appendix 1; Appendix 3; Appendix 4; Appendix 5; Appendix 6.

We also searched some of the main electronic sources of ongoing trials.

  1. Current Controlled Trials (www.controlled-trials.com/).

  2. Clinical Trials.gov (www.clinicaltrials.gov/).

  3. International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/en).

Searching other resources

We also searched the following.

  1. References of the articles obtained by any means.

  2. Conference proceedings likely to contain trials relevant to the review (Annual Scientific Meeting of the College on Problems of Drug Dependence, European College of Neuropsychopharmacology, American Psychiatric Association).

  3. By contacting investigators, and relevant trial authors seeking information about unpublished or incomplete trials.

All searches included non-English language literature and studies with English abstracts were assessed for inclusion. When considered likely to meet inclusion criteria, studies were translated.

Data collection and analysis

Selection of studies

Two review authors (SM, CB) independently inspected the search 'hits' by reading titles and abstracts. Each potentially relevant study located in the search was obtained in full text and assessed for inclusion independently by two review authors (SM, LA). Any disagreements were resolved by discussion between the authors.

Data extraction and management

Three review authors (SM, LA, CB) independently extracted data. Any disagreements were discussed and resolved by consensus.

Assessment of risk of bias in included studies

We changed the criteria to assess methodological quality of included studies from that outlined in the protocol to conform the review to the recommended methods outlined in the Cochrane Reviewers Handbook version 5.0.0 and to the requirements of RevMan5 (Cochrane Handboook 2008).

The recommended approach for assessing risk of bias in studies included in Cochrane Review is a two-part tool, addressing six specific domains (namely sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting and other issues). The first part of the tool involves describing what was reported to have happened in the study. The second part of the tool involves assigning a judgement relating to the risk of bias for that entry. This is achieved by answering a pre-specified question about the adequacy of the study in relation to the entry, such that a judgement of "Yes" indicates low risk of bias, "No" indicates high risk of bias, and "Unclear" indicates unclear or unknown risk of bias. To make these judgments we used the criteria indicated by the handbook and their applicability in the addiction field. For a detailed description of the criteria used see Cochrane Handboook 2008.

The domains of sequence generation, allocation concealment (avoidance of selection bias) and selective outcome reporting (avoidance of reporting bias) have been addressed in the tool by a single entry for each study.

Blinding of participants, personnel and outcome assessors (avoidance of performance bias and detection bias) was considered separately for objective outcomes (drop out, use of substance of abuse measured by urine-analysis, subjects relapsed at the end of follow up, subjects engaged in further treatments) and subjective outcomes (duration and severity of signs and symptoms of withdrawal, including patient self-rating, side effects, social functioning as integration at school or at work, family relationships).

Incomplete outcome data (avoidance of attrition bias) were considered for all outcomes except for drop out from the treatment, which is very often the primary outcome measure in trials on addiction. It have been assessed separately for results at the end of the study period and for results at follow up.

For drop out from treatment we judged that only sequence generation and allocation concealment could be relevant because lack of blinding is unlikely to influence data collection and incomplete outcome data could not be used for this outcome. For use of substances assessed by urine analysis we judged that sequence generation, allocation concealment and incomplete outcome data could influence results. For subjective outcomes we judged that also lack of blinding of outcome assessor could influence data.

Measures of treatment effect

Dichotomous outcomes were analysed calculating the risk ratio (RR) for each trial with the uncertainty in each result being expressed by their confidence intervals (CIs). Continuous outcomes were analysed calculating the mean difference (MD), again with 95% CIs.

The drop out from treatment was reported as the number of participants who did not complete the detoxification treatment. The use of primary substance was reported as the number of participants with opiate positive urine analysis during and at the end of treatment, or self-report data.The results at follow-up were measured as number of participants who had relapsed at the end of follow-up. We did not use data presented as number of positive urine tests over total number of tests in the experimental and control group as a measure of substance abuse. This is because using the number of tests instead of the number of participants as the unit of analysis violates the hypothesis of independence among observations. In fact, the results of tests done in each participant are not independent. For outcomes assessed by scales, we compared and pooled the mean score differences from the end of treatment to baseline (post minus pre) in the experimental and control group. In case of missing data about the standard deviation of the change, we imputed this measure using the standard deviation at the end of treatment for each group.

Assessment of heterogeneity

Heterogeneity was analysed by means of the I2 statistic and Chi2 test for heterogeneity.The cut-off points were I2 > 50% and P of the Chi2 test < 0.1.

Assessment of reporting biases

We planned to use funnel plots (plots of the effect estimate from each study against the sample size or effect standard error) to assess the potential for bias related to the size of the trials, which could indicate possible publication bias, but did not as we included only two trials.

Data synthesis

We planned to combine the relative risk (RR) or the weighted mean difference (WMD) from the individual trials through meta-analysis where possible (comparability of intervention and outcomes between trials) using a random-effects model as some variability was expected in the studies included. We included only two trials with different comparisons, which prevented the possibility of performing meta-analysis. Accordingly, we used a fixed-effect method with risk ratio (RR) for dichotomous data and mean difference (MD) for continuous data..

Sensitivity analysis

To incorporate assessment of risk of bias in the review process, we planned to first plot intervention effects estimates stratified for risk of bias for each relevant domain. If differences in results were present among studies at different risk of bias, we planned to perform sensitivity analysis excluding from the analysis studies with a high risk of bias. This was not done because only one study was included in each comparison of the review.

Results

Description of studies

Results of the search

This is an update of a Cochrane review first published in 2009. In the first version of our review we identified 2917 references. After excluding duplicate articles, we identified 2595 potentially relevant references. We excluded 2586 on the basis of title and abstracts leaving 10 studies which were acquired in full text for more evaluation. Out of these, seven studies were excluded, one was included, one is an ongoing trial and one study was classified as study awaiting assessment because it is finished but not yet published and the authors could not give us the data. Immediately before the publication of the review (November 2008) the ongoing study was published, so we decided to include it. See Figure 1.

Figure 1.

Flow chart of studies of the review published in 2009

In the 2014 update, we retrieved 1004 further references after excluding duplicates. We further excluded 986 articles on the basis of title and abstract and 15 were acquired in full text for more detailed evaluation. Out of the 15 studies, two (Woody 2009 and Woody 2013) were errata corrige of Woody 2008. One study (with two conference proceedings) was classified as awaiting classification because although the study is finished, it is not yet published and the authors could not give us the data (Marsh 2009).The other 11 retrieved studies were excluded. See Figure 2.

Figure 2.

Study flow diagram. 2014 update

For substantive descriptions of studies see Characteristics of included studies and Characteristics of excluded studies tables.

Included studies

Two studies met the inclusion criteria (Marsch 2005; Woody 2008). No further studies were retrieved for inclusion in the 2014 update.

  • Type of comparison: buprenorphine sublingual tablets versus clonidine patch (Marsch 2005; buprenorphine-naloxone maintenance versus buprenorphine detox (Woody 2008)

  • Participants: 190 opiate dependent adolescents (13 to 21 years old)

  • Duration of the trial: 28 days (Marsch 2005); 12 weeks (Woody 2008)

  • Setting: outpatients

  • Country: USA

Excluded studies

Overall, 18 studies did not meet the criteria for inclusion in this review. The grounds for exclusion were: study design not in the inclusion criteria: not RCT or CCT: five studies (Ebner 2007; Fiellin 2008; Godley 2004; Lloyd 1974; Moore 2014); experimental intervention not in the inclusion criteria: only psychosocial intervention without pharmacological detoxification: two studies (Baer 2007; Kemp 2007); maintenance treatment: one study (Lehmann 1973); different psychosocial intervention given to two groups receiving the same pharmacological intervention: one study (Forcehimes 2008); outcome not in the inclusion criteria: six studies (Chakrabarti 2010, Hill 2013, Polsky 2010; Subramaniam 2011; Warden 2012; Wilcox 2013); participant not in the inclusion criteria: one study (Mannelli 2011); study design and participants not in the inclusion criteria: one study (Mullen 2010); secondary analysis of the Marsch 2005 study without distinction between experimental and control condition (Moore 2011).

Risk of bias in included studies

see Figure 3; Figure 4

Figure 3.

Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.

Figure 4.

Methodological quality summary: review authors' judgements about each methodological quality item for each included study.

Allocation

Sequence generation and allocation concealment: we judged one study as at unclear risk of bias (Marsch 2005). The other study (Woody 2008) was judged to be at low risk of bias for sequence generation and at high risk of bias for allocation concealment.

Blinding

Both studies were judged to be at a low risk of bias for objective outcomes. For subjective outcomes, one study (Marsch 2005) was judged at low risk of bias, whereas the other (Woody 2008), was judged to be at a high risk of bias.

Incomplete outcome data

Both studies were judged as at low risk of bias.

Selective reporting

Both studies were judged as at low risk of bias.

Effects of interventions

See: Summary of findings for the main comparison Buprenorphine versus clonidine for opiate dependent adolescents; Summary of findings 2 Buprenorphine detox compared with buprenorphine maintenance for opiate dependent adolescents

No meta-analysis was performed because the two studies assessed different comparisons.

Comparison 1: any detoxification treatment versus other pharmacological treatment: buprenorphine versus clonidine

See Summary of findings for the main comparison

Primary outcomes

Drop out from treatment: risk ratio (RR): 0.45 (95% confidence interval (CI): 0.20 to 1.04); the result is not statistically significant but there is a trend in favour of buprenorphine. See Analysis 1.1.

Acceptability of the treatment:

  • duration and severity of signs and symptoms of withdrawal: Adjective rating scale: mean difference (MD): 3.97 (95% CI -1.38 to 9.32); the result is not statistically significant. See Analysis 1.2.

  • side effects: side effects were not reported in the study.

Secondary outcomes

Engagement in further treatment: measured as the number of participants who enrolled in any psychosocial or pharmacological treatment: initiation of naltrexone treatment: RR 11.00 (95% CI 1.58 to 76.55); the result is in favour of buprenorphine. See Analysis 1.3.

Comparison 2: maintenance treatment versus detoxification treatment: buprenorphine-naloxone maintenance for nine weeks then tapered to 12 weeks versus buprenorphine detoxification 14 days

See Summary of findings 2

Primary outcomes
  • Drop out from treatment: RR 2.67 (95% CI 1.85 to 3.86); in favour of maintenance treatment. See Analysis 2.1.

  • Use of substance of abuse: no significant difference. See Analysis 2.2.

  • Results at follow-up: self-reported heroin use at 12 months: RR 1.36 (95% CI 1.05 to 1.76); in favour of maintenance treatment. See Analysis 2.3.

  • Enrolment in addiction treatment at 12 months: RR: 0.75 (0.53 to 1.07); there is a trend in favour of maintenance treatment. See Analysis 2.4.

Secondary outcomes
  • Use of other substances of abuse: no significant difference for alcohol and marijuana; RR 8.54 (95%CI 1.11 to 65.75); in favour of maintenance treatment. See Analysis 2.5; Analysis 2.6; Analysis 2.7.

  • Side effects: the authors reported that no serious side effects attributable to buprenorphine-naloxone were reported and no patients were removed from the study for side effects. The most common side effect was headache, which was reported by 16% to 21% of patients in both groups.

  • Mortality any cause: one death for methadone overdose occurred in the maintenance group in a patient who dropped out after three doses and was not located until her obituary appeared in a newspaper three months later.

Discussion

Summary of main results

Despite a comprehensive search of published and unpublished literature only two studies were found. One (Marsch 2005) compared buprenorphine and clonidine for detoxification of adolescents. The study found no difference in drop-out rate and in withdrawal symptoms even if the difference in drop-out rate is nearly significant in favour of buprenorphine. More participants in the buprenorphine group initiated naltrexone treatment. The other study (Woody 2008) compared maintenance treatment with buprenorphine-naloxone for nine weeks then tapered until 12 weeks with 14 days detoxification with buprenorphine. Maintenance treatment seems more efficacious in retaining patients in treatment but not in reducing patients with positive urine at the end of the study. Self-reported opioid use at one year follow-up was significantly lower in the maintenance group even if both groups reported high level of opioid use and more patients in the maintenance group were enrolled in other addiction treatment at 12-month follow-up.

Overall completeness and applicability of evidence

One study (Marsch 2005) with few participants has too little evidence to draw any conclusions about the superiority of buprenorphine over clonidine. Moreover, there are no studies comparing pharmacological detoxification with psychosocial intervention alone, which is the most used approach to treat opioid dependent adolescents. The study of Woody 2008 compares a short-term maintenance treatment with a 14-day detoxification. More than a maintenance treatment, the 12 week buprenorphine-naloxone could be considered a long-term detoxification following a two-month stabilisation period. Only one study with 150 participants has too little evidence to draw any firm conclusions.

Quality of the evidence

The quality of evidence was judged as moderate for the comparison between buprenorphine versus clonidine . The main reason for downgrading was due to the fact that only one study with 36 participants was found for this comparison. The quality of evidence was judged as low for the comparison between buprenorphine detoxification versus buprenorphine maintenance The reasons were that there was no allocation concealment, no blinding of participants, personnel and outcome assessor, and because only one trial with 154 participants has been found for this comparison.

Potential biases in the review process

A particularly important component of a review is the identification of relevant studies. Publication bias has long been recognised as a problem in this regard since it means that the likelihood of finding studies is related to the results of those studies. One way to investigate whether a review is subject to publication bias is to prepare a ‘funnel plot’ and examine this for signs of asymmetry. We could not explore the possibility of publication bias by funnel plot because only two studies was retrieved. We looked for all potentially relevant studies by a comprehensive search, which considered also conference proceedings and registers of ongoing trials. We wrote to the author of the only published trial asking for other trials but she did not answer. We also looked at references of published narrative reviews.

Authors' conclusions

Implications for practice

It is difficult to draw conclusions on the basis of two trials with few participants. One possible reason for the lack of evidence could be the difficulty in conducting trials with young people due to practical and ethical reasons.

Implications for research

There is an urgent need of randomised controlled trials comparing pharmacological detoxification versus psychosocial intervention and trials comparing pharmacological intervention plus psychosocial intervention versus psychosocial intervention alone before realising trials which compare different pharmacological approaches. These studies should have a long follow-up measuring results of relapse after the end of treatment.

Acknowledgements

We want thank Zuzana Mitrova for her help in all the steps of the review process and Simona Vecchi who performed the bibliographic search.

Data and analyses

Download statistical data

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]
Analysis 1.1.

Comparison 1 Buprenorphine versus clonidine, Outcome 1 drop out.

Analysis 1.2.

Comparison 1 Buprenorphine versus clonidine, Outcome 2 withdrawal score.

Analysis 1.3.

Comparison 1 Buprenorphine versus clonidine, Outcome 3 initiation of naltrexone treatment.

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]
Analysis 2.1.

Comparison 2 Buprenorphine detox versus buprenorphine maintenance, Outcome 1 drop out.

Analysis 2.2.

Comparison 2 Buprenorphine detox versus buprenorphine maintenance, Outcome 2 patients with positive urine at the end of treatment.

Analysis 2.3.

Comparison 2 Buprenorphine detox versus buprenorphine maintenance, Outcome 3 self-reported use at 12 months follow- up.

Analysis 2.4.

Comparison 2 Buprenorphine detox versus buprenorphine maintenance, Outcome 4 enrolment in addiction treatment at 12-month follow-up.

Analysis 2.5.

Comparison 2 Buprenorphine detox versus buprenorphine maintenance, Outcome 5 self-reported alcohol use.

Analysis 2.6.

Comparison 2 Buprenorphine detox versus buprenorphine maintenance, Outcome 6 self-reported marijuana use.

Analysis 2.7.

Comparison 2 Buprenorphine detox versus buprenorphine maintenance, Outcome 7 self-reported cocaine use.

Appendices

Appendix 1. Cochrane Drugs and Alcohol Group's trials register search strategy

Free text=detox* or withdraw* or abstinen* or abstain* AND Diagnosis = opiate* or opioid*

Appendix 2. CENTRAL search strategy

  1. MeSH descriptor: [Opioid-Related Disorders] explode all trees

  2. ((drug or substance) near (abuse* or addict* or dependen* or disorder*)):ti,ab,kw (Word variations have been searched)

  3. ((opioid* or opiate*) near (abuse* or addict* or dependen*)):ti,ab,kw (Word variations have been searched)

  4. (detox* or desintoxi* or disintoxi*):ti,ab,kw

  5. #1 or #2 or #3 or #4

  6. MeSH descriptor: [Heroin] explode all trees

  7. (opioid* or opiate* or opium or heroin):ti,ab,kw (Word variations have been searched)

  8. MeSH descriptor: [Methadone] explode all trees

  9. "methadone":ti,ab,kw (Word variations have been searched)

  10. #6 or #7 or #8 or #9

  11. #5 AND #10

Appendix 3. PubMed search strategy

  1. "Opioid-Related Disorders"[MeSH]

  2. (detox*[tiab] OR withdraw*[tiab] OR abstinen*[tiab] OR abstain*[tiab])

  3. (opioid*[tiab] AND (abuse*[tiab] OR addict*[tiab] OR dependen*[tiab]))

  4. ((drug[tiab] OR substance[tiab]) AND (use*[tiab] OR abuse*[tiab] OR misuse*[tiab] OR addict*[tiab] OR dependen*[tiab] OR disorder*[tiab]))

  5. #1 OR #2 OR #3 OR #4

  6. heroin [MeSH]

  7. heroin [tiab]

  8. opioid*[tiab] OR opiate* [tiab]

  9. methadone [MeSH]

  10. methadone [MeSH]

  11. #6 OR #7 OR #8 OR #9 OR #10

  12. adolescent [MeSH]

  13. adolescen* OR teen* OR young people OR young person* OR young adult* OR youth* OR girl* OR boy* OR juvenile*

  14. #12 OR #13

  15. randomized controlled trial [pt]

  16. controlled clinical trial [pt]

  17. random*[tiab]

  18. placebo [tiab]

  19. drug therapy [sh]

  20. randomly [tiab]

  21. trials [tiab]

  22. groups [tiab]

  23. #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21 OR #22

  24. animals [mh] NOT humans [mh]

  25. #23 NOT #24

  26. #5 AND #11 AND #14 AND #25

Appendix 4. Embase search strategy

  1. drug abuse/exp

  2. addiction/exp

  3. ((drug OR substance) NEAR/5 (abuse* OR depend* OR addict*)):ab,ti

  4. detox*:ab,ti OR withdraw*:ab,ti OR abstinen*:ab,ti OR abstain*:ab,ti

  5. #1 or #2 or #3 or #4

  6. 'diamorphine'/exp

  7. 'methadone'/exp

  8. heroin:ab,ti OR methadone:ab,ti OR opioid*:ab,ti OR opiate*:ab,ti

  9. #6 or #7 or #8 or 9

  10. 'adolescent'/exp OR adolescen*:ab,ti OR teen*:ab,ti OR youth*:ab,ti OR girl$*:ab,ti OR boy*:ab,ti OR juvenile*:ab,ti OR (young NEAR/3 people):ab,ti OR (young NEAR/3 person*):ab,ti OR (young NEAR/3 adult*):ab,ti

  11. 'crossover procedure'/exp OR 'double blind procedure'/exp OR 'single blind procedure'/exp OR 'controlled clinical trial'/exp OR 'clinical trial'/exp OR 'randomized controlled trial'/exp OR placebo:ab,ti OR 'double blind':ab,ti OR 'single blind':ab,ti OR assign*:ab,ti OR allocat*:ab,ti OR volunteer*:ab,ti OR random*:ab,ti OR factorial*:ab,ti OR crossover:ab,ti OR (cross:ab,ti AND over:ab,ti)

  12. #5 AND #9 AND #10 AND #11AND [embase]/lim

Appendix 5. CINAHL search strategy

  1. (MH "Substance Use Disorders+")

  2. TX(detox* or withdraw* or abstinen* or abstain*)

  3. TX((opioid* or opiate*) and (abuse* or addict* or dependen*))

  4. S1 or S2 or S3

  5. MH heroin or TX heroin

  6. TX (opioid* or opiate*)

  7. TX opium

  8. MH methadone or  TX methadone

  9. S5 or S6 or S7 or S8

  10. MH adolescence

  11. TI adolescen* or TI teen* or TI young people or TI young person* or TI young adult* or TI youth* or TI girl* OR TIboy* or TI juvenile*

  12. AB adolescen* or AB teen* or AB young people or AB young person* or AB young adult* or AB youth* or AB girl* OR AB boy* or AB juvenile*

  13. S10 or S11 or S12

  14. MH "Clinical Trials+"

  15. PT Clinical trial

  16. TI clinic* N1 trial* or AB clinic* N1 trial*

  17. TI ( singl* or doubl* or trebl* or tripl* ) and TI ( blind* or mask* )

  18. AB ( singl* or doubl* or trebl* or tripl* ) and AB ( blind* or mask* )

  19. TI randomi?ed control* trial* or AB randomi?ed control* trial*

  20. MH "Random Assignment"

  21. TI random* allocat* or AB random* allocat*

  22. MH "Placebos"

  23. TI placebo* or AB placebo*

  24. MH "Quantitative Studies"

  25. S14 or S15 or S16 or S17 or S18 or S19 or S20 or S21 or S22 or S23 or S24

  26. S4 and S9 and S13 and S25

Appendix 6. Web of Science search strategy

  1. TS=((( heroin OR opiate* OR opioid* OR methadone) same (abuse* OR depend* OR addict* OR disorder* OR detox* OR withdraw* OR abstinen* OR abstain*))) AND TS=(adolescen* OR teen* OR young people OR young person* OR young adult* OR early adult* OR youth* OR girl* OR boy* OR juvenile*)

  2. TS= clinical trial* OR TS=research design OR TS=comparative stud* OR TS=evaluation stud* OR TS=controlled trial* OR TS=follow-up stud* OR TS=prospective stud* OR TS=random* OR TS=placebo* OR TS=(single blind*) OR TS=(double blind*)

  3. #2 AND #1

Databases=SCI-EXPANDED, SSCI, A&HCI Timespan=2008-2013

What's new

Last assessed as up-to-date: 10 April 2014.

DateEventDescription
10 April 2014New citation required but conclusions have not changedNo new studies included.
10 April 2014New search has been performedNew search. Backround updated, 'Summary of findings' tables created.

History

Protocol first published: Issue 4, 2007
Review first published: Issue 2, 2009

DateEventDescription
28 July 2009AmendedWe emended the abstract's errors
10 February 2009New search has been performedto be published as review in the issue 2, 2009
15 October 2008New search has been performedstage changed in review
20 March 2008AmendedConverted to new review format.
27 June 2007New citation required and major changesSubstantive amendment

Contributions of authors

Silvia Minozzi and Cristina Bellisario inspected the search 'hits' by reading titles and abstracts. Silvia Minozzi, Laura Amato and Cristina Bellisario extracted data, Silvia Minozzi wrote the review, Laura Amato commented and drafted conclusions. Marina Davoli commented on the final draft.

Declarations of interest

None known.

Sources of support

Internal sources

  • Department of Epidemiology, ASL RM E, Italy.

External sources

  • No sources of support supplied

Differences between protocol and review

We changed the criteria to assess methodological quality of included studies from that described in the protocol to conform to the recommended methods outlined in the Cochrane Handboook 2008 and to the requirements of RevMan5.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Marsch 2005

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

36 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

  1. a

    DSM IV: Diagnostic and Statistical Manual of Mental Disorders, 4th edition
    vs: versus

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.

Outcomes

Primary 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.

Notes

Country: USA

Setting: outpatients

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk

Randomisation 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 risk

Patients 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 risk

Patients 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
  1. a

    CCT: controlledclinical trial
    RCT: randomised controlled trial

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)
Interventions

Experimental: 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

Ancillary