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Methadone at tapered doses for the management of opioid withdrawal

  1. Laura Amato1,*,
  2. Marina Davoli1,
  3. Silvia Minozzi1,
  4. Eliana Ferroni2,
  5. Robert Ali3,
  6. Marica Ferri4

Editorial Group: Cochrane Drugs and Alcohol Group

Published Online: 28 FEB 2013

Assessed as up-to-date: 20 JUL 2012

DOI: 10.1002/14651858.CD003409.pub4


How to Cite

Amato L, Davoli M, Minozzi S, Ferroni E, Ali R, Ferri M. Methadone at tapered doses for the management of opioid withdrawal. Cochrane Database of Systematic Reviews 2013, Issue 2. Art. No.: CD003409. DOI: 10.1002/14651858.CD003409.pub4.

Author Information

  1. 1

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

  2. 2

    Public Health Agency of Lazio Region, Infectious Diseases Unit, Rome, Italy

  3. 3

    University of Adelaide, Discipline of Pharmacology, Adelaide, SA, Australia

  4. 4

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

*Laura Amato, Department of Epidemiology, Lazio Regional Health Service, Via di Santa Costanza, 53, Rome, 00198, Italy. l.amato@deplazio.it.

Publication History

  1. Publication Status: New search for studies and content updated (no change to conclusions)
  2. Published Online: 28 FEB 2013

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Summary of findings    [Explanations]

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Index terms

 
Summary of findings for the main comparison. Tapered methadone versus any other treatment for the management of opioid withdrawal

Tapered methadone versus any other treatment for the management of opioid withdrawal

Patient or population: patients with the management of opioid withdrawal
Settings: Inpatient and outpatient
Intervention: Tapered methadone versus any other treatment

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

Assumed riskCorresponding risk

ControlTapered methadone versus any other treatment

Completion of treatment
Objective
Follow-up: mean 30 days
Study populationRR 1.08
(0.97 to 1.21)
1381
(16 studies)
⊕⊕⊕⊕
high

547 per 1000591 per 1000
(531 to 662)

Moderate

505 per 1000545 per 1000
(490 to 611)

Number of participants abstinent at follow-up
Objective
Follow-up: mean 1.5 months
Study populationRR 0.98
(0.7 to 1.37)
386
(3 studies)
⊕⊕⊕⊕
high

255 per 1000250 per 1000
(179 to 350)

Moderate

267 per 1000262 per 1000
(187 to 366)

*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

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Index terms
 

Description of the condition

Recent figures for illicit drug use indicate that the prevalence of opiate abuse among persons from 15 to 64 years old is around 0.5% in most Western countries (EU, USA, Canada and Australia) (UNODC 2011). Opioid dependence is a worldwide health problem that has enormous economic, personal and public health consequences. There are an estimated 15.6 million illicit opioid users in the world, of whom 11 million use heroin (UNODC 2011). Opioids are the main drugs of abuse in Asia, Europe and much of Oceania, and it is estimated that globally the consumption of the opioid class of drugs is increasing (UNODC 2011).

In Europe heroin is still one of the main illegal substance recorded in indicators of problem drug use (EMCDDA 2011). Recent national estimates vary between one and eight cases per 1000 population aged 15–64 (EMCDDA 2011). The average prevalence of problem opioid use in the European Union and Norway, computed from national studies, is estimated to be between 3.6 and 4.4 cases per 1000 population aged 15–64 (EMCDDA 2011). The latest US data, show that, on average, three persons per 100 annual drug users had to undergo treatment for drug use in 2008. Opiates use is far more problematic than the use of other illicit drugs (UNODC 2011). Australia has an estimated 67,000–92,000 illicit heroin users (540–750 per 100,000 population aged 15 to 64) (Hall 1999).

Opioids, mainly heroin, were cited as the primary drug for entering treatment by around 216,000 or 51 % of all those reported entering specialist drug treatment in 29 European countries in 2009. The provision of treatment is central to the reduction of the harms to the individual and the community from opioid dependence.

The effect of chronic opioid exposure on opioid receptor levels has not been well-defined in humans. Tolerance develops through multiple mechanisms, including an acute desensitisation of the opioid receptor (which develops within minutes of opioid use and resolves within hours after use), and a long-term desensitisation of the opioid receptor (which persists for several days after removal of opioid agonists). Changes also occur in the number of opioid receptors (Williams 2001), and there is compensatory up-regulation of the cyclic adenosine monophosphate (cAMP) producing enzymes. When the opioid is withdrawn, the cAMP cascade becomes overactive, leading to the “noradrenergic storm” seen clinically as opioid withdrawal, which may create a drive to reinstate substance use. The intensely dysphoric withdrawal syndrome is characterised by watery eyes, runny nose, yawning, sweating, restlessness, irritability, tremor, nausea, vomiting, diarrhoea, increased blood pressure, chills, cramps and muscles aches that can last seven days or even longer.

 

Description of the intervention

Treatment of opioid dependence is a set of pharmacological and psychosocial interventions aimed at reducing or ceasing opioid use, preventing future harms associated with opioid use, improving quality of life and well-being of the opioid-dependent patient. Opioid withdrawal can be managed by controlling the rate of cessation of opioids and by providing medication that relieves symptoms, or by a combination of the two. Methadone at adequate doses prevents or reverses withdrawal symptoms (Ward 1992), and thus reduces the need to use illegal heroin (Jaffe 1990). Methadone remains effective for approximately 24 hours, requiring a single daily dose rather than the more frequent administration of three to four times daily that occurs with the shorter-acting heroin (Jaffe 1990).

 

How the intervention might work

Methadone can "block" the euphoric effects of heroin, discouraging illicit use and thereby relieving the user of the need or desire to seek heroin (Dole 1969). This allows the opportunity to engage in normative activities, and "rehabilitation" if necessary. Methadone can cause death in overdosage, like other similar medications such as morphine, and for this reason it is a treatment which is dispensed under medical supervision and relatively strict rules. In summary, methadone is a long-acting opioid analgesic with well-understood pharmacological characteristics, which make it suitable for stabilising opioid-dependent patients in a maintenance treatment approach. Methadone was first used to treat heroin dependence as a tapering agent in US facilities after the second world war and had been introduced in the treatment of opioid dependence for maintenance purposes rather than detoxification until the 1960's. Even though now it is often used for detoxification, sometimes this occurs for economical reasons, sometimes for ideological ones. Despite the risk of relapse being high, detoxification with methadone is common in many countries. The upper limit of duration of the tapered methadone withdrawal period appears to be relatively arbitrary; a period of three to four weeks has been recommended and used in clinical practice (Gossop 1987).

 

Why it is important to do this review

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 1989B; Valliant 1988). The present review focuses on detoxification from illicit opiate use through the use of tapered methadone.There are no systematic reviews already published on the effectiveness of methadone at tapered doses on completion of detoxification or relapse rate.

The previous version of this review was published in 2005 and an update is required.

 

Objectives

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Index terms

To assess the effectiveness of methadone at tapered doses versus placebo or other pharmacological treatments for the management of detoxification on completion and acceptability of the treatment and relapse rate.

 

Methods

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Index terms
 

Criteria for considering studies for this review

 

Types of studies

All randomised controlled trials (RCTs) and controlled clinical trials (CCTs) on tapered methadone treatment (maximum 30 days) to manage withdrawal from opiates.

 

Types of participants

Opioid users enrolled in short-term tapered methadone treatment to manage withdrawal from heroin or methadone or buprenorphine, no matter what the characteristic of the setting.Trials including patients with additional diagnoses such as benzodiazepine dependence were also eligible.

Pregnant women, newborn infants with neonatal dependence and people with iatrogenic dependence (e.g. through treatment of chronic pain) were excluded. The absence in these patient groups of social and psychological factors that underlie opioid dependence makes for a substantially different approach to clinical management. This was the basis for excluding these groups from this review (Gowing 2008).

 

Types of interventions

 

Experimental Intervention

  1. Methadone aimed at the detoxification from opiates, maximum length of treatment: 30 days

 

Control Interventions

  1. Other opioid agonists (LAAM (levo-α-acetyl-methadol), Buprenorphine, propoxyphene, etc).
  2. Adrenergic agonists (clonidine, lofexidine, guanfacine).
  3. Opioid antagonists (naltrexone, naloxone).
  4. Placebo.

All aimed at the detoxification from opiate.

The setting in which withdrawal occurs is a factor that can be expected to influence outcomes. The degree of its effect has been explored by examining rate of completion of withdrawal.

 

Types of outcome measures

 

Primary outcomes

  1. Completion of treatment as number of participants completing the detoxification program.
  2. Acceptability of the treatment as a) duration and severity of signs and symptoms of withdrawal, including patient self-rating, b) side effects.
  3. Results at follow-up as (a) number of participants abstinent at follow-up, (b) naloxone challenge.

 

Secondary outcomes

  1. Use of primary substance of abuse as a) number of participants who referred to the use of opioid during the treatment, b) number of participants with urine samples positive for opiate.

Different factors were considered as confounders and taken into account in the analysis wherever possible: setting ( inpatient or outpatient treatment); starting methadone dose/rate and pattern of dose reduction; scheduled duration of treatment; severity of dependence (duration of use, route of administration, frequency of assumption); health status; other treatment offered (psychosocial support); social status; number of previous treatment attempts and previous treatment outcomes.

 

Search methods for identification of studies

 

Electronic searches

We identified relevant studies that met the predefined inclusion criteria by searching the following sources from the earliest available date to December 2007. Relevant trials were obtained from the following sources:

  1. Cochrane Central Register of Controlled Trials (The Cochrane Library 2012, Issue 4) which include the Cochrane Drugs and Alcohol Group's Register of Trials.
  2. PubMed (from 2003 - May 2012).
  3. EMBASE (from 2003 - May 2012).
  4. CINAHL (from 2003 - December 2011).
  5. PsycINFO (January 1985 to December 2004).

To see the search strategies see Appendix 1; Appendix 2; Appendix 3; Appendix 4.

There were no language or publication year restriction.

 

Searching other resources

We also searched:

  1. Reference lists of all relevant papers to identify further studies.
  2. Some of the main electronic sources of ongoing trials (meta-Register of Controlled Trials; Clinical Trials.gov).
  3. Conference proceedings likely to contain trials relevant to the review (College on Problems of Drug Dependence -CPDD).
  4. National focal points for drug  research (e.g., National Institute of Drug Abuse (NIDA), National Drug & Alcohol Research Centre (NDARC).

We contacted authors of included studies and experts in the field in various countries to find out if they know any other published or unpublished controlled trials

 

Data collection and analysis

 

Selection of studies

One review author (Amato) inspected the search hits by reading the titles and the abstracts. We obtained each potentially relevant study located in the search in full text and two review authors (Amato, Minozzi) independently assessed for inclusion. Doubts were resolved by discussion between the review authors.

 

Data extraction and management

Two review authors (Amato, Minozzi) independently extracted data from published sources using a data extraction form. Where differences in data extracted occurred this was resolved through discussion. Study quality was assessed by Silvia Minozzi according to the criteria indicated in Cochrane Handbook for Systematic Reviews of Interventions 4.2. (Higgins 2008)

 

Assessment of risk of bias in included studies

The risk of bias assessment  for RCTs and CCTs in this review were performed using the five criteria recommended by the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008). The recommended approach for assessing risk of bias in studies included in Cochrane reviews is a two-part tool, addressing five specific domains (namely sequence generation, allocation concealment, blinding, incomplete outcome data, 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 adapted to the addiction field.

Blinding of participants, personnel and outcome assessor (avoidance of performance bias and detection bias) were considered separately for objective outcomes (e.g. drop-out, use of substance of abuse measured by urinalysis, participants relapsed at the end of follow-up, participants engaged in further treatments) and subjective outcomes (e.g. duration and severity of signs and symptoms of withdrawal, patient self-reported use of substance, side effects, social functioning as integration at school or at work, family relationship).

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

 

Grading of evidence

The quality of evidence was assessed according to a systematic and explicit method (Guyatt 2008). In order to indicate the extent to which one can be confident that an estimate of effect is correct, judgments about the quality of evidence are made for each comparison and outcome. These judgments consider study design (RCT, quasi-RCT or observational study), study quality (detailed study design and execution), consistency of results (similarity of estimates of effect across studies), precision of estimates, and directness (the extent to which people, interventions and outcome measures are similar to those of interest). The following definitions in grading the quality of evidence for each outcome are used: High: further research is very unlikely to change our confidence in the estimate of effect. Moderate: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low: further research is very likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Very low: any estimate of effect is very uncertain.

 

Measures of treatment effect

We compared the treatment and control groups for outcomes at post-test and at different follow-up times. Post-intervention data were collected immediately after the intervention ended. For continuous data it was not possible to pool data due to the heterogeneity of reporting in the included studies.

 

Dealing with missing data

Statisticians often use the terms ‘missing at random’, and ‘not missing at random’ to represent different scenarios. Data are said to be ‘missing at random’ if the fact that they are missing is unrelated to actual values of the missing data. Data are said to be ‘not missing at random’ if the fact that they are missing is related to the actual missing data. In cases where we assumed that data were missing at random, we analysed only the available data. If we assumed that the data were not missing at random, we planned to impute the missing data with replacement values, and to treat these as if they were observed. We planned to do this in different ways and compare the results (e.g. last observation carried forward, imputing an assumed outcome such as assuming all were poor outcomes, imputing the mean, imputing based on predicted values from a regression analysis). For the included studies in this review we did not impute data.

 

Assessment of heterogeneity

Statistically significant heterogeneity among primary outcome studies was assessed with Chi2 (Q) test and I2 (Higgins 2003). A significant Q ( P <.05) and I-squared of at least 50% was considered as statistical heterogeneity.

 

Assessment of reporting biases

We used funnel plots for information about possible publication bias. But asymmetric funnel plots are not necessarily caused by publication bias (and publication bias does not necessarily cause asymmetry in a funnel plot). Whenever asymmetry was present, likely reasons were explored.

 

Data synthesis

Dichotomous outcomes (completion of treatment, number of participants with negative urinalysis) were analysed calculating the risk ratio (RR) for each trial with the uncertainty in each result being expressed by their confidence intervals (CIs). The RRs from the individual trials were combined through meta-analysis where possible (comparability of intervention between trials) using a random-effects model. The completion of the treatment was reported as the number of patients who completed the detoxification program. The use of primary substance was reported as the number of participants with consecutive negative urinalysis. The results at follow-up were reported as the number of participants abstinent at the follow-up interview (range of follow-up period: one to six months). We used the Chi2 test to determine the heterogeneity of the results. A P value of the Chi2 test less than 0.005 indicated a significant heterogeneity.

 

Sensitivity analysis

The following sensitivity analyses were planned a priori: Generation of allocation sequence, concealment of allocation, blinding of patients and providers, blinding of assessors, incomplete outcome data addressed, selective reporting, and other bias.

 

Results

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Index terms
 

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies.

 

Results of the search

The literature searching process resulted in the identification of 8545 reports (6860 after duplicates removed), 6754 were excluded on the basis of title and abstract, 106 were retrieved in full text; 74 have been excluded and 23 (32 references) included, 17 studies included in quantitative synthesis (meta-analysis). See Figure 1

 FigureFigure 1. Flow chart of studies

 

Included studies

Twenty-three studies (32 reports) meet the inclusion criteria for this review see Characteristics of included studies.

Duration of trials: range three to 30 days.
Treatment regimens and setting: The countries in which the 23 studies were conducted are: USA (six studies), United Kingdom (five studies), Spain (four studies), China, Irane and Germany (two studies each), Austria and Italy (one study each). Eighteen trials were conducted with inpatients, five with outpatients. Information on methadone doses were available for 19 of the 23 included studies. The mean starting dose of methadone was 29 mg/day (range 15 to 60). The other four studies reported that the starting doses of methadone were variable, tailored on individual body weight or heroin consumption in the previous month.

Participants: 2467 opiate addicts. Age range was 18 to 70 years; one study (Howells 2002) did not report age characteristics only that participants were required to be under 55 years old.

Comparisons:
In the 23 studies included in the review, tapered methadone was compared with the following.

  1. Tapered methadone versus any other treatments: 23 studies, 2467 participants.
  2. Tapered methadone versus adrenergic agonists: 11 studies, (Bearn 1996; Camí 1985; Dawe 1995; Gerra 2000; Howells 2002; Jiang 1993; Kleber 1985; San 1990; San 1994; Umbricht 2003; Washton 1981), 952 participants.
  3. Tapered methadone versus other opioid agonists: eight studies, (Madlung-Kratzer 2009; Seifert 2002; Sorensen 1982; Steinmann 2007;Tennant 1975; Umbricht 2003; Wright 2011; Zarghami 2012), 869 participants.
  4. Tapered methadone versus anxiolytic: two studies (Buydens-Branchey 2005; Drummond 1989), 47 participants.
  5. Tapered methadone versus placebo: two studies (Buydens-Branchey 2005; San 1992), 38 participants.
  6. Tapered methadone versus paiduyangsheng: one study (Yang 2006), 580 participants.

One study (Umbricht 2003) has three arms, comparing methadone (arm 1) with buprenorphine (arm 2) and with clonidine (arm 3). For this study the participants in the methadone arm (21 people) are considered both in the comparison with adrenergic agonists and in the comparison with other opioid agonists. Another study (Buydens-Branchey 2005) has four arms comparing methadone (arm 1) with placebo (arm 2), buspirone 30 mg (arm 3), buspirone 45 mg (arm 4). For this study the participants in the methadone arm (eight people) are considered in all the comparisons.

Two studies (Gerra 2000; San 1994) had three arms comparing methadone with different dosages of adrenergic agonist. For these studies we summarised the results of the two different dosages of adrenergic agonists. One study (San 1990) compared methadone with two different adrenergic agonists and we summarised the results of the two different adrenergic agonists.

Outcomes:
Outcomes were either dichotomous or continuous, as reported by authors. The following principal outcomes were considered by the authors.

  1. Completion of treatment as number of participants completing the detoxification program (16/23 studies).
  2. Withdrawal scores (21/23 studies).
  3. Side effects (16/23 studies).
  4. Use of primary substance measured as number of opiate positive urine samples (3/23 studies).
  5. Results at follow-up as (a) number of participants abstinent at follow-up (4/23 studies) and (b) naloxone challenge (2/23 studies).

Scales
The 23 studies that used withdrawal scales to assess withdrawal symptoms used 22 different scales (see  Table 1), of which 15 were published. Furthermore, four studies considered craving using four different methods to assess it: Craving questionnaire (Dawe 1995), Craving Scale (Gerra 2000), Severity of Dependence Scale (SDS) (Howells 2002) and Addiction Severity Index ( Kleber 1985). Five studies use questionnaires to assess psychological and behavioural characteristics: State Trait Anxiety Inventory (Camí 1985; San 1990; San 1994), Beck Depression Inventory (Kleber 1985, San 1994), Eysenck Personality Questionnaire (San 1994), Hamilton Anxiety Rating Scale (Yang 2006) Profile of Mood State (San 1990), Hospital Anxiety Depression (San 1994). One study used an Intelligence Quotient test: Wechsler Adult Intelligence Scale (San 1990).

 

Excluded studies

Seventhy-four studies did not meet the criteria for inclusion in this review. The grounds for exclusion were: type of intervention: 39 studies; study design: 29 studies; study design and type of intervention: three studies; type of participants:one study; type of intervention and type of participants: one study, type of intervention and type of outcomes: one study; see Characteristics of excluded studies

 

Risk of bias in included studies

Overall the quality of the included studies was good, see Figure 2; Figure 3. Below the results of the single risk of bias are considered.

 FigureFigure 2. Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.
 FigureFigure 3. Methodological quality summary: review authors' judgements about each methodological quality item for each included study.

 

Allocation

Random Sequence Generation: three studies (Madlung-Kratzer 2009; Sorensen 1982; Wright 2011) were judged at low risk of selection bias because the investigators described a random component in the sequence generation process. The other 20 studies were judged as having an unclear risk of bias because there was insufficient information about the sequence generation process to permit judgement.

Allocation concealment: seven studies (Drummond 1989; Howells 2002; Madlung-Kratzer 2009; San 1992; San 1994; Sorensen 1982; Wright 2011) were judged at low risk of selection bias because investigators enrolling participants could not foresee assignment and the method of allocation concealment was described. The other 16 studies were judged at unclear risk because they did not describe the method of concealment or did not describe it in sufficient detail to allow a definite judgement.

 

Blinding

Blinding of participants and personnel: 18 studies (Bearn 1996; Buydens-Branchey 2005; Camí 1985; Dawe 1995; Drummond 1989; Howells 2002; Kleber 1985; Madlung-Kratzer 2009; Salehi 2007; San 1990; San 1992; Seifert 2002; Sorensen 1982; Tennant 1975; Umbricht 2003; Washton 1981; Wright 2011; Yang 2006) were judged to be at low risk of performance bias because participants and  providers were blinded and it was unlikely that the blinding could have been broken. One study (Gerra 2000) was judged at high risk of bias because it was not blinded and the remaining four studies (Jiang 1993; San 1994; Steinmann 2007; Zarghami 2012) were judged at unclear risk because it was not clear if a blinding condition had been undertaken.

Blinding of outcomes assessor: 12 studies (Bearn 1996; Buydens-Branchey 2005; Camí 1985; Howells 2002; Kleber 1985; Salehi 2007; San 1990; San 1992; Sorensen 1982; Washton 1981; Wright 2011; Yang 2006) were judged at low risk of detection bias because it was specified that the outcome assessor was blinded. One study (Gerra 2000) was judged at high risk of bias because there was no blinding of outcome assessment. The remaining 10 studies were judged as having an unclear risk of bias because it was not clear if the outcome assessor was blind to treatment allocation.

 

Incomplete outcome data

Fiftheen studies (Bearn 1996; Camí 1985; Drummond 1989; Gerra 2000; Madlung-Kratzer 2009; Salehi 2007; San 1990; San 1992; San 1994; Seifert 2002; Steinmann 2007; Tennant 1975; Umbricht 2003; Washton 1981; Wright 2011) were judged at low risk of attrition bias because all randomised patients were reported/analysed in the group to which they were allocated by randomisation, irrespective of non-compliance and co-interventions (intention-to-treat) or had no missing outcome data. Two studies (Buydens-Branchey 2005; Zarghami 2012) were judged at high risk and the remaining six studies were judged at unclear risk.

Nevertheless, many outcomes could not be summarised because they were presented in graphical form or only provided statistical tests and P values. For most of the continuous variables standard deviation was not provided. Furthermore, the authors used different scales to compare the same or very similar outcomes and this makes it impossible to compare them.

In particular for the outcomes which we considered as possible confounders such as setting, starting methadone dose, severity of dependence, health status etc. and for others for example, patients' motivation at enrolment, it was not possible to perform statistical analysis because many authors did not report the relevant data and, were these were available, the data were heterogeneously reported.

 

Effects of interventions

See:  Summary of findings for the main comparison Tapered methadone versus any other treatment for the management of opioid withdrawal

The results were summarised, with comparison of quantitative data where possible, first for methadone versus any other treatment and then comparing separately methadone versus single different treatments.

 

1. Tapered methadone versus any other pharmacological treatment

 

1.1 Completion of treatment

Sixteen studies (Bearn 1996; Buydens-Branchey 2005; Drummond 1989; Howells 2002; Kleber 1985; Madlung-Kratzer 2009; Salehi 2007; San 1990; San 1994; Seifert 2002; Sorensen 1982; Steinmann 2007; Tennant 1975; Umbricht 2003; Washton 1981; Wright 2011), 1381 participants risk ratio (RR) 1.08 (95% confidence interval (CI) 0.97 to 1.21); the difference was not statistically significant, see Figure 4 or  Analysis 1.1,

 FigureFigure 4. Forest plot of comparison: 1 Tapered methadone versus any other treatment, outcome: 1.1 Completion of treatment.

 

1.2 Results at follow-up as number of participants abstinent at follow-up

Three studies (Kleber 1985; Tennant 1975; Wright 2011), 386 participants (RR 0.98; 95% CI 0.70 to 1.37); the difference was not statistically significant, see Figure 5 or  Analysis 1.2

 FigureFigure 5. Forest plot of comparison: 1 Tapered methadone versus any other treatment, outcome: 1.2 Number of participants abstinent at follow-up.

 
Results at follow-up as naloxone challenge

Two studies reported data on this outcome, but only Gerra 2000 reported the rate of participants who accepted and continued naltrexone treatment: in the methadone group 9/34, in clonidine five days 17/32; RR 0.50 (95% CI 0.26 to 0.95), the difference was statistically significant in favour of clonidine.
Washton 1981 referred data for all the participants without distinction between the groups: of the eight participants who were opiate free at completion of the study, six began treatment with naltrexone.

 
Duration and severity of signs and symptoms of withdrawal

The diversity of approaches used for rating withdrawal severity, prevented a direct comparison of scores across studies. Different rating instruments were utilised and for many of them, the authors did not indicate the scores considered to represent boundaries of mild, moderate and severe to allow comparison of results between studies. The 21/23 studies that considered this outcome varied in how severity was rated and in the form in which results were reported. In some studies withdrawal was assessed by observers only, in others it was reported by participants and in others by both. In one study (Washton 1981), withdrawal was not systematically assessed and it was unclear how the assessment was undertaken. The diversity of approaches used for rating withdrawal severity prevented a direct comparison of scores across studies, consequently, we have not been able to make a quantitative analysis of the intensity of withdrawal. We tried to summarise the results in  Table 2;  Table 3;  Table 4;  Table 5;  Table 6.

 
Side effects

Adverse effects were reported in 12/23 studies and assessed in different ways. This variability prevented quantitative analysis of this outcome. Data are reported in  Table 2;  Table 3;  Table 4;  Table 5.

 
Use of primary substance as Number of participants with opiate positive urinalysis during the treatment

Only 3/22 studies (Gerra 2000; Sorensen 1982; Tennant 1975) reported data on the use of opiate during the treatment but their modalities of reporting results of urinalysis was heterogeneous, making meta-analysis difficult to be carried out. Results as reported in the articles are hardly informative, and data presented as number of positive tests over number of tests cannot be properly analysed through meta-analysis. In fact using tests instead of the participants as the unit of analysis violates the hypothesis of independence among observations, and makes the results of tests done in each patient not independent.

 

2. Tapered methadone versus adrenergic agonists

 

2.1 Completion of treatment

Seven studies (Bearn 1996; Howells 2002; Kleber 1985; San 1990; San 1994; Umbricht 2003; Washton 1981), 577 participants RR 1.10 (95% CI 0.91to 1.32); the difference was not statistically significant, see  Analysis 2.1,

 
Use of primary substance as number of participants with opiate positive urinalysis during the treatment

One study (Gerra 2000), reported results of urine screening that showed a significantly higher rate of positive samples for morphine catabolites in the methadone and clonidine five-days groups in respect of clonidine three days plus oxazepam, baclofen and ketoprofen group. No significant difference was found between the first two groups. In the methadone group, the positive urine rate increased significantly from day one to day 10.

 
Results at follow-up as number of participants abstinent at follow-up

One study (Kleber 1985), reported the number of participants abstinent at follow-up at one month: 6/18 in methadone group and 4/15 in the clonidine group; at three months 5/19 in methadone and 4/15 in clonidine groups; at six months 7/18 in methadone and 3/13 in clonidine group. The differences were never statistically significant.

 

3. Tapered methadone versus any other opioid agonist

 

3.1 Completion of treatment

Seven studies (Madlung-Kratzer 2009; Seifert 2002; Sorensen 1982; Steinmann 2007; Tennant 1975; Umbricht 2003; Wright 2011), 695 participants RR 1.10 (95% CI 0.89 to 1.37); the difference was not statistically significant, see  Analysis 3.1.

 
Use of primary substance as number of participants with opiate positive urinalysis during the treatment

Two studies (Sorensen 1982; Tennant 1975) considered this outcome.

  • Sorensen 1982, (tapered methadone versus LAAM) reported that the proportion of participants using opiates never dropped below 50% for any group at any time. Exact figures were not reported, data were presented only in a graph. The groups did not differ in the percentage of urine samples that contained opiates overall.
  • Tennant 1975, (tapered methadone versus propoxyphene) reported the number of participants who had opiate-negative urine on at least one occasion: 27/36 (75%) in methadone group and 19/36 (53%) in propoxyphene group; the difference is not statistically significant.

 
Results at follow-up as number of participants abstinent at follow-up

Three studies reported this outcome.

  • Sorensen 1982: (tapered methadone versus LAAM), the data were reported for all the participants without distinction between the groups of treatment 57/61 participants gave consent to be interviewed: 24/49 reported that they abstained from heroin > one day after detoxification, at three months 2/49 abstinent, 25/49 sought further treatment and 9/49 enrolled in methadone maintenance treatment.
  • Tennant 1975: (tapered methadone versus propoxyphene) reported that at one month follow-up the number of abstinent were 15/32 in the methadone group and 13/32 in propoxyphene group; the difference is not statistically significant.
  • Wright 2011: (tapered methadone versus tapered buprenorphine) reported that at eight days post detoxification, there was no statistically significant difference in the odds of achieving abstinence between the methadone and buprenorphine arms (odds ratio (OR) = 1.69; 95% CI = 0.81 to 3.51; P = 0.163). Similarly, there was no statistically significant difference at one month (OR = 0.38; 95% CI = 0.13 to 1.10; P = 0.074) or three months (OR = 0.38; 95% CI = 0.13 to 1.10; P = 0.074), and insufficient data at the six-month time point to undertake statistical analysis.

 

3.2 Tapered methadone versus buprenorphine

 
Completion of treatment

Four studies (Seifert 2002; Steinmann 2007; Umbricht 2003; Wright 2011) 390 participants RR 0.97 (CI 95% 0.69 to 1.37), the difference was not statistically significant, see  Analysis 3.2.

 

3.3 Furthermore, single studies considered completion of treatment for the following comparisons

  • versus LAAM (Sorensen 1982), 5/15 patients in the methadone group and 4/13 in the LAAM group completed the treatment; RR 1.08 (CI 95% 0.37 to 3.21), the difference was not statistically significant but showed a trend in favour of LAAM;
  • versus propoxyphene (Tennant 1975), 25/36 in the methadone group and 15/36 in the propoxyphene group completed the treatment; RR 1.67 (CI 95% 1.07 to 2.60), the difference was statistically significant in favour of methadone group;
  • versus slow release morphine (Madlung-Kratzer 2009), 49/100 in the methadone group and 50/102 in the slow release morphine group completed the treatment, RR 1.00 (CI 95% 0.75 to 1.32), the difference was not statistically significant.

 

4. Tapered methadone versus anxiolytic

 

4.1 Completion of treatment

Two studies (Buydens-Branchey 2005; Drummond 1989), 47 participants RR 0.63 (CI 95% 0.18 to 2.24), the difference was not statistically significant and it should be considered that in one of the two studies (Buydens-Branchey 2005) all the participants in both groups completed the treatment, see  Analysis 4.1.

 

5.Tapered methadone versus placebo

 

5.1 Completion of treatment

Two studies (Buydens-Branchey 2005; San 1992), 38 participants RR 1.95 (CI 95% 1.21 to 3.13), in favour of methadone, see  Analysis 5.1,

 

Discussion

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Index terms
 

Summary of main results

Comparing methadone with other pharmacological treatments aimed at detoxification, studies showed no substantial clinical difference between the treatments in terms of completion of treatment, 16 studies 1381 participants, risk ratio (RR) 1.08 (95% confidence interval (CI) 0.97 to 1.21), number of participants abstinent at follow-up, three studies, 386 participants (RR 0.98; 95% CI 0.70 to 1.37) and degree of discomfort for withdrawal symptoms and adverse events.

Comparing methadone with adrenergic agonists, studies showed no substantial clinical difference between the treatments in terms of completion of treatment, seven studies, 577 participants RR 1.10 (95% CI 0.91 to 1.32). with regard to the withdrawal symptoms and side effects, early withdrawal symptoms were less adequately controlled with lofexidine than methadone; in the methadone groups the symptoms were experienced only in the latter stages of treatment when the dosage of the substance was drastically reduced. Only in two single studies (San 1990; San 1994) was methadone more effective than adrenergic agonists in decreasing withdrawal signs and symptoms and causing fewer side effects.

Comparing methadone with other opioid agonists, the results did not show differences between the groups with regard to completion of treatment, seven studies, 695 participants RR 1.10 (95% CI 0.89 to 1.37) and the acceptability of the treatment. Comparing methadone with buprenorphine, no differences were found for completion of treatment, four studies, 390 participants RR 0.97 (CI 95% 0.69 to 1.37).

Comparing methadone with the anxiolytic buspirone (Buydens-Branchey 2005) and chlordiazepoxide (Drummond 1989) results did not show differences between the groups in terms of completion of treatment, two studies, 47 participants RR 0.91 (95% CI 0.47 to 1.77).

Comparing tapered methadone with placebo, studies showed, as expected, results in favour of methadone for completion of treatment, two studies, 38 participants RR1.95 (95% CI 1.21 to 3.13) and control of withdrawal symptoms.

 

Overall completeness and applicability of evidence

The extent to which a Cochrane review can draw conclusions about the effects of an intervention depends on whether the data and results from the included studies are valid. However, systematic reviews should evaluate and take into account not only the internal validity (i.e., the extent to which systematic errors or bias are avoided) of each trial included but also the applicability and generalisability or external validity (i.e., whether the results of a trial can be reasonably applied to a definable group of patients in a particular setting in routine practice) (Dekkers 2009). The main threat to external validity comes from the clinical setting, and the social and cultural context in which the studies were conducted, and this is particularly true in the field of addiction, where these contexts can actively affect the overall treatment outcome.

In this review, besides the limits in external validity due to the general requirement of RCTs in terms of strict inclusion criteria, highly homogenous study groups, limitations in dose adjustment, etc., the types of participants (adults abusers/dependents on opioids) are quite representative of the general population of opioid dependents. Moreover, the interventions, the settings and the outcomes investigated (completion of treatment, abstinence during the treatment and at follow-up, adverse events) are important to populations, practitioners and decision makers, and relevant for the context of current practice.

However, there are general questions difficult to answer on the basis of our results such as what are the treatment expectations? what defines treatment success? is success strictly limited to suppression of withdrawal symptoms? The studies included did not examine any carried over effects bearing on sustained abstinence or eventual remission of disease and this certanly is a limit. Furthermore onether important limitation to the generalisation of the evidence is the impossibility to cumulate results of very important outcomes such as abstinence at follow-up and control of withdrawal symptoms due the different ways in which these outcomes are rated and reported in the single studies. Finally 17 out of 22 included trials were conducted in an inpatients' setting, which is probably not the most common setting in clinical practice for this type of intervention, and this could act as an effect modifier in the estimation of efficacy of treatment.

 

Quality of the evidence

The quality of evidence, assessed according to the GRADE method, may be judged as high for the efficacy of tapered methadone versus any other treatment for the management of opioid withdrawal, see Summary of findings table 1. In respect of risk of bias, the quality of evidence was moderate to high, the percentage of included studies judged at low risk of bias were as follow: selection bias 13% for sequence generation and 30% for allocation concealment; performance bias 78%; detection bias 52% and 65% for attrition bias.

Finally, the great heterogeneity of the scales used in the primary studies and the way in which results were reported made it not possible to undertake a cumulative analysis.

 

Potential biases in the review process

None known.

 

Authors' conclusions

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Index terms

 

Implications for practice

The results indicate that tapered methadone and the other substances used in the included studies are effective in the treatment of heroin withdrawal syndrome, although symptoms presented by participants differed according to the drug used. The studies confirm the issue that with the increasing availability of substances that allow slow tapering and temporary substitution of long-acting narcotics, with good medical supervision and ancillary medications for tranquillisation and sleep, withdrawal can be relatively painless. Managed withdrawal, or detoxification, is not in itself a treatment for dependence but detoxification remains a required first step for many forms of longer-term treatment. Moreover, different conditions of detoxification can affect at least an immediate outcome: heroin use during treatment and produce different responses in terms of intensity and time course of withdrawal response.

Nevertheless, a majority of patients relapsed in heroin use, and relapse from the drug-free state to re-addiction is the main problem in heroin addiction.

Research suggests that for some important outcomes such as withdrawal symptoms, treatment programs are difficult to compare due to the variability of the methods used to assess them. Withdrawal limited to 30 days has the disadvantage that many persons, due to the rapid tapering, are prematurely withdrawn and consequently resume heroin use.

There has been a general pessimism among both clinicians and researchers about the utility of brief detoxification treatment because many patients soon returned to regular heroin use. This pessimism is probably based on the unrealistic expectation that a brief, inexpensive intervention could dramatically alter the course of a chronic, relapsing disorder such as heroin addiction. Whether people relapse to heroin use again has no bearing on the success or otherwise of a detoxification procedure and the investment in methadone detoxification could be justified if more modest goals were being achieved for example, the reduction, even temporarily, of the daily heroin dosage, with its consequent reduction of dependence on illegal income and the possibility of reaching drug addicts who would otherwise not have applied for treatment.

 
Implications for research

To enable comparison and pooling of results, standardised criteria for reporting urinalysis results should be used, data should be reported as number of participants with positive or negative samples instead of mean number of positive/negative tests for each group. When different rating instruments are used, researchers should try to utilise only published instruments, indicate the scores to represent boundaries of mild, moderate and severe withdrawal to allow comparison of results between studies and report the standard deviation of the means.

 

Acknowledgements

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Index terms

We would like to thank Zuzana Mitrova for help in searching and retrieving articles.

 

Data and analyses

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Index terms
Download statistical data

 
Comparison 1. Tapered methadone versus any other treatment

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

 1 Completion of treatment161381Risk Ratio (M-H, Random, 95% CI)1.08 [0.97, 1.21]

 2 Number of participants abstinent at follow-up3386Risk Ratio (M-H, Random, 95% CI)0.98 [0.70, 1.37]

 
Comparison 2. Tapered methadone versus adrenergic agonists

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

 1 Completion of treatment7577Risk Ratio (M-H, Random, 95% CI)1.10 [0.91, 1.32]

 
Comparison 3. Tapered methadone versus other opioid agonists

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

 1 Completion of treatment methadone versus any other opioid agonist7695Risk Ratio (M-H, Random, 95% CI)1.10 [0.89, 1.37]

 2 Completion of treatment methadone versus buprenorphine4390Risk Ratio (M-H, Random, 95% CI)0.97 [0.69, 1.37]

 
Comparison 4. Tapered methadone versus anxiolytic

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

 1 Completion of treatment247Risk Ratio (M-H, Random, 95% CI)0.91 [0.47, 1.77]

 
Comparison 5. Tapered methadone versus placebo

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

 1 Completion of treatment238Risk Ratio (M-H, Fixed, 95% CI)1.95 [1.21, 3.13]

 

Appendices

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Index terms
 

Appendix 1. CENTRAL search strategy

 

Appendix 2. PubMed search strategy

  1. Opioid-Related Disorders[Mesh]
  2. ((substance*[tiab] or drug[tiab]) AND (abuse*[tiab] or dependen*[tiab] or use* or disorder* or addict*[tiab]))
  3. intoxicat*[tiab] or detox*[tiab] or disintox*[tiab] or withdraw*[tiab] or abstinen*[tiab] or abstain*[tiab])
  4. #2 OR #3 OR #4                                                
  5. opiat*[tiab] OR opioid*[tiab] OR morphin*[tiab]
  6. Heroin[MeSH Terms] OR heroin                                              
  7. Methadone[Mesh]
  8. methadone [tiab]
  9. #5 OR #6 OR #7 OR #8
  10. #4 AND #9
  11. randomized controlled trial [pt]
  12. controlled clinical trial [pt]
  13. randomized [tiab]
  14. placebo [tiab]
  15. clinical trials as topic [mesh: noexp] 
  16. randomly [tiab]
  17. trial [tiab]
  18. #11 or #12 or #13 or #14 or #15 or #16 or #17
  19. #10 and #18

 

Appendix 3. EMBASE search strategy

  1. 'addiction'/exp                                                                                                                                            
  2. substance:ab,ti OR drug:ab,ti AND (abuse*:ab,ti OR dependen*:ab,ti OR use*:ab,ti OR disorder*:ab,ti OR addict*:ab,ti)
  3. 'detoxification'/exp                                                                                                                                     
  4. intoxicat*:ab,ti OR detox*:ab,ti OR disintox*:ab,ti OR withdraw*:ab,ti OR abstinen*:ab,ti OR abstain*:ab,ti
  5. #1 OR #2 OR #3 OR #4                                                                                                                               
  6. opiat*:ab,ti OR opioid*:ab,ti  
  7. heroin:ab,ti     
  8. morphine:ab,ti
  9. 'dimorphine'/exp
  10. 'methadone'/exp
  11. methadone:ab,ti
  12. #6 OR #7 OR #8 OR #9 OR #10                                                                                                
  13. 'crossover procedure'/exp
  14. 'double blind procedure'/exp   
  15. 'single blind procedure'/exp       
  16. 'controlled clinical trial'/exp
  17. 'clinical trial'/exp  
  18. 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
  19. random*:ab,ti OR factorial*:ab,ti OR crossover:ab,ti OR (cross:ab,ti AND over:ab,ti)  
  20. 'randomized controlled trial'/exp
  21. #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20
  22. #5 AND #12 AND #21 AND [humans]/lim AND [embase]/lim AND [2008-2012]/py

                                                                                                                                 

 

Appendix 4. CINAHL search strategy

  1. (MH "Substance Use Disorders+")
  2. TX ((drug or substance) and (addict* or dependen* or abuse*or disorder*))
  3. TX ((opioid* or opiate*) and (abuse* or addict* or dependen*))
  4. S3 or S2 or S1
  5. TX (opioid* or opiate*)
  6. TX methadone or MH methadone
  7. TX heroin or NT heroin
  8. S7 or S6 or S5
  9. TX random*
  10. TX (clin* and trial*)
  11. TX (singl* or doubl* or tripl* or trebl*) and (mask* or blind*)
  12. TX crossover*
  13. TX allocate*
  14. TX assign*
  15. TX ((random*) and (allocate* or assign*))
  16. (MH "Random Assignment")
  17. (MH "Clinical Trials+")
  18. S17 or S16 or S15 or S14 or S13 or S12 or S11 or S10 or S9
  19. S8 and S4
  20. S18 and S19

 

What's new

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Index terms

Last assessed as up-to-date: 20 July 2012.


DateEventDescription

20 July 2012New citation required but conclusions have not changedNew search, new studies, new assessment of risk of bias

20 July 2012New search has been performedSubstantially updated

20 October 2008AmendedContact details amended



 

History

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Index terms

Protocol first published: Issue 1, 2001
Review first published: Issue 1, 2002


DateEventDescription

21 July 2008AmendedMinor changes

2 July 2008AmendedMinimal changes in the abstract

28 March 2008AmendedInserted GRADE summary of findings table

27 March 2008New search has been performedThe search strategy was updated and launched for all the database, we found four new trials to be included. Conclusions did not changed

26 March 2008New search has been performedConverted to new review format.

18 May 2005New citation required and conclusions have changedSubstantive amendment



 

Contributions of authors

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Index terms

Marica Ferri drafted the original protocol. Laura Amato and Silvia Minozzi searched and selected trials, extracted data and wrote the review. Silvia Minozzi evaluated the methodological quality of the studies and commented on the updated version of the review. Marina Davoli supervised the entire review and Robert Ali commented on the draft. Laura Amato updated the review.

 

Declarations of interest

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Index terms

None known.

 

Sources of support

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Index terms
 

Internal sources

  • Department of Epidemiology, ASL RM E, Italy.

 

External sources

  • No sources of support supplied

* Indicates the major publication for the study

References

References to studies included in this review

  1. Top of page
  2. Abstract
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Characteristics of studies
  19. References to studies included in this review
  20. References to studies excluded from this review
  21. Additional references
  22. References to other published versions of this review
Bearn 1996 {published data only}
  • Bearn J, Gossop M, Strang J. Randomised double-blind comparison of lofexidine and methadone in the in-patient treatment of opiate withdrawal. Drug and Alcohol Dependence 1996;43(1-2):87-91.
Buydens-Branchey 2005 {published data only}
Camí 1985 {published data only}
  • Cami J, De Torres S, San L, Sole A, Guerra D, Ugena B. Efficacy of clonidine and of methadone in the rapid detoxification of patients dependent on heroin. Clinical Pharmacology and Therapeutics 1985;38(3):336-41.
Dawe 1995 {published data only}
Drummond 1989 {published data only}
  • Drummond DC, Turkington D, Rahman MZ, Mullin PJ, Jackson P. Chlordiazepoxide versus Methadone in opiate withdrawal: a preliminary double blind trial. Drug and Alcohol Dependence 1989;23(1):63-71.
Gerra 2000 {published data only}
  • Gerra G, Zaimovic A, Rustichelli P, Fontanesi B, Zambelli U, Timpano M, et al. Rapid opiate detoxification in outpatient treatment: relationship with naltrexone compliance. Journal of Substance Abuse Treatment 2000;18(2):185-91.
Howells 2002 {published data only}
  • Howells C, Allen S, Gupta J, Stillwell G, Marsden J, Farrel M. Prison based detoxification for opioid dependence: a randomised double blind controlled trial of lofexidine and methadone. Drug and Alcohol Dependence 2002;67:169-76.
Jiang 1993 {published data only}
  • Jiang Z. Rapid detoxification with clonidine for heroin addiction. A comparative study on its efficacy vs methadone. Chinese Journal of Neurology and Psychiatry 1993;26(1):10-3.
Kleber 1985 {published data only}
  • Kleber HD, Riordan CE, Rounsaville B, Kosten T, Charney D, Gaspari J, et al. Clonidine in outpatient detoxification from methadone maintenance. Archives of General Psychiatry 1985;42(4):391-4.
  • Kosten RT, Rounsaville J, Kleber HD. Relationship of depression to clonidine detoxification of opiate addicts. Comprehensive Psychiatry 1984;25(5):503-8.
  • Kosten TR, Rounsaville BJ, Kleber HD. Comparison of clinician ratings to self reports of withdrawal during clonidine detoxification of opiate addicts. American Journal of Drug and Alcohol Abuse 1985;11(1-2):1-10.
  • Rounsaville BJ, Kosten T, Kleber H. Success and failure at outpatient opioid detoxification. Evaluating the process of clonidine and methadone assisted withdrawal. Journal of Nervous and Mental Disease 1985;173(2):103-10.
Madlung-Kratzer 2009 {published data only}
  • Madlung-Kratzer E, Spitzer B, Brosch R, Dunkel D, Haring C. A double-blind, randomised, parallel group study to compare the efficacy, safety and tolerability of slow-release oral morphine versus methadone in opioid-dependent in-patients willing to undergo detoxification. Addiction 2009; Vol. 104, issue 9:1549-57.
Salehi 2007 {published data only}
  • Salehi M, Amanatkar M, Barekatain M. Comparison of the efficacy of methadone and tramadol in opioid-assisted detoxification. Iranian Journal of Medical Science 2007;32(1):28-31.
  • Salehi M, Amanatkar M, Barekatain M. Tramadol versus methadone for the management of acute opioid withdrawal: An add-on study. Journal of Research in Medical Sciences 2006;11(3):185-9.
San 1990 {published data only}
San 1992 {published data only}
San 1994 {published data only}
  • San L, Fernandez T, Camì J, Gossop M. Efficacy of methadone versus methadone and guanfacine in the detoxification of heroin addicted patients. Journal of Substance Abuse Treatment 1994;11(5):463-9.
Seifert 2002 {published data only}
Sorensen 1982 {published data only}
Steinmann 2007 {published data only}
  • Steinmann C, Artmann S, Henneberg B, Paul HW. Should methadone or buprenorphine be preferred for opiate detoxification?: [Methadon-Racemat versus Buprenorphin zur stationären Entgiftungsbehandlung Opiatabhängiger]. Psychiatrische Praxis 2007;34(S1):103-5.
  • Steinmann C, Artmann S, Schachtschneider A, Paul HW. Methadone versus buprenorphine for inpatient detoxification treatment [Methadon-Racemat versus Buprenorphin zur stationaren Entgiftungsbehandlung]. Sucht 2008;54(4):217-21.
Tennant 1975 {published data only}
Umbricht 2003 {published data only}
  • Umbricht A, Hoover DR, Tucker MJ, Leslie JM, Chaisson RE, Preston KL. Opioid detoxification with buprenorphine, clonidine or methadone in hospitalized heroin dependent patients with HIV infection. Drug and Alcohol Dependence 2003;69:263-72.
Washton 1981 {published data only}
  • Washton AM, Resnick RB. Clonidine versus methadone for opiate detoxification. Lancet 1980;2(8207):1297.
  • Washton AM, Resnick RB. Clonidine vs methadone for opiate detoxification: double-blind outpatient trials. In: Harris LS editor(s). NIDA Research Monograph. Vol. 34, Washington DC: Department of Health and Human Services, 1981:89-94.
Wright 2011 {published data only}
  • Sheard L, Wright NM, Adams CE, Bound N, Rushforth B, Hart R, et al. The Leeds Evaluation of Efficacy of Detoxification Study (LEEDS)Prisons Project Study: protocol for a randomised controlled trial comparing methadone and buprenorphine for opiate detoxification. Trials 2009;10:53.
  • Wright NM, Sheard L, Adams CE, Rushforth BJ, Harrison W, Bound N, et al. Comparison of methadone and buprenorphine for opiate detoxification (LEEDS trial): a randomised controlled trial. The British Journal of General Practice: the journal of the Royal College of General Practitioners 2011;61(593):772-80.
Yang 2006 {published data only}
  • Yang L, Chen J, Li L, Wen P, Zhang X. Controlled clinical study on Paiduyangsheng capsule in detoxification of heroin abuse. Chinese Journal of Drug Abuse Prevention 2006;12(2):86-8.
Zarghami 2012 {published data only}
  • Zarghami M, Masoum B, Shiran MR. Tramadol versus methadone for treatment of opiate withdrawal: a double blind, randomised, clinical trial. Journal of Addictive Diseases 2012;31:112-7.

References to studies excluded from this review

  1. Top of page
  2. Abstract
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Characteristics of studies
  19. References to studies included in this review
  20. References to studies excluded from this review
  21. Additional references
  22. References to other published versions of this review
Albizu-Garcia 2012 {published data only}
  • Albizu-Garcia CE, Caraballo JN, Caraballo-Correa G, Hernandez-Viver A, Roman-Badenas L. Assessing need for medication-assisted treatment for opiate-dependent prison inmates. Substance Abuse 2012;33(1):60-9.
Bakhshani 2008 {published data only}
  • Bakhshani NM, Lashkaripour K, Sadjadi SA. A randomised effectiveness trial of methadone, TENS and methadone plus TENS in management of opiate withdrawal symptoms. Journal of the Pakistan Medical Association 2008; Vol. 58, issue 12:667-71.
Bearn 1998 {published data only}
  • Bearn J, Gossop M, Strang J. Accelerated lofexidine treatment regimen compared with conventional lofexidine and methadone treatment for inpatient opiate detoxification. Drug and Alcohol Dependence 1998;50(3):227-32.
Bearn 2008 {published data only}
  • Bearn J, Swami A, Stewart D, Atnas C, Giotto L, Gossop M. Auricular acupuncture as an adjunct to opiate detoxification treatment: Effects on withdrawal symptoms. Journal of Substance Abuse Treatment 2008; Vol. 36, issue 3:345-9.
Bell 2009 {published data only}
  • Bell J, Shearer J, Ryan A, Graham R, Korompay K, Rizzo S, et al. The acceptability, safety, and tolerability of methadone/naloxone in a 50:1 ratio. Experimental and Clinical Psychopharmacology 2009; Vol. 17, issue 3:146-53.
Bickel 1988 {published data only}
  • Bickel WK, Stitzer ML, Bigelow GE, Liebson IA, Jasinski DR, Johnson RE. A clinical trial of buprenorphine: comparison with methadone in the detoxification of heroin addicts. Clinical Pharmacology and Therapeutics 1988;43(1):72-8.
Brewin 1989 {published data only}
Bux 1993 {published data only}
  • Bux DA, Iguchi MY, Lidz V, Baxter RC, Platt JJ. Participation in an outreach-based coupon distribution program for free methadone detoxification. Hospital and Community Psychiatry 1993;44(11):1066-72.
Byrne 2006 {published data only}
Cameron 2006 {published data only}
  • Cameron IM,   Matheson CI, Bond CM, McNamee P, Lawrie T, Robinson A, et al  . Pilot randomised controlled trial of community pharmacy administration of buprenorphine versus methadone. International Journal of Pharmacy Practice 2006;14(4):243-8.
Critchlow 2006 {published data only}
Dawe 1991 {published data only}
De Los Cobos 2000 {published data only}
  • De Los Cobos JP, Duro P, Trujols J, Tejero A, Batle F, Ribalta E, et al. Methadone tapering plus amantadine to detoxify heroin dependent inpatients with or without an active cocaine use disorder: two randomised controlled trials. Drug and Alcohol Dependence 2001;63:187-95.
Deniker 1975 {published data only}
  • Deniker P, Loo H, Zarifian E, Cuche H. A french experience with methadone [A propos d'une expèrience française de la mèthadone]. Encéphale 1975;1(1):75-91.
Dijkstra 2010 {published data only}
Ebner 2004 {published data only}
  • Ebner R, Schreiber W, Zierer C. Buprenorphine or methadone for detoxification of young opioid addicts? [Buprenorphin oder methadon im entzug junger opiatabhangiger?]. Psychiatrische Praxis 2004;31(S1):108-10.
Fulwiler 1979 {published data only}
  • Fulwiler RL, Hargreaves WA, Bortman RA. Detoxification from heroin using self vs physician regulation of methadone dose. The International Journal of the Addictions 1979;14(2):289-98.
Gerra 2004 {published data only}
  • Gerra G, Borella F, Zaimovic A, Moi G, Bussandri M, Bubici C, et al. Buprenorphine versus methadone for opioid dependence: predictor variables for treatment outcome. Drug and Alcohol Dependence 2004;75:37-45.
Gerra 2007 {published data only}
  • Gerra G, Zaimovic A, Raggi MA, Moi G, Branchi B, Moroni M, et al. Experimentally induced aggressiveness in heroin-dependent patients treated with buprenorphine: comparison of patients receiving methadone and healthy subjects. Psychiatry Research 2007;149(1-3):201-13.
Glasper 2008 {published data only}
Goldstein 1972 {published data only}
Gossop 1989A {published data only}
Green 1988 {published data only}
Greenwald 2006 {published data only}
  • Greenwald MK. Early impact of methadone induction for heroin dependence: differential effects of two dose sequences in a randomised controlled study. Experimental and Clinical Psychopharmacology 2006;14(1):52-67.
Gruber 2008 {published data only}
  • Gruber VA, Delucchib KL, Kielsteinc A, Batkid SL. A randomised trial of six-month methadone maintenance with standard or minimal counselling versus 21-day methadone detoxification. Drug and Alcohol Dependence 2008;94(1-3):199-206.
Hall 1979 {published data only}
  • Hall SM, Bass A, Hargreaves WA, Loeb P. Contingency management and information feedback in outpatient heroin detoxification. Behavior Therapy 1979;10:443-51.
Hall 2008 {published data only}
Hasson 2007 {published data only}
  • Hasson A, Thomas C, Jenkins J, Ling W. Buprenorphine retention in the CTN START study: an unexpected observation. 69th Annual Scientific Meeting of the College on Problems of Drug Dependence. 2007.
Highfield 2007 {published data only}
Hser 2012 {published data only}
  • Hser YI, Fu L, Wu F, Du J, Zhao, M. Pilot trial of a recovery management intervention for heroin addicts released from compulsory rehabilitation in China. Journal of Substance Abuse Treatment 2012 April 18 [Epub ahead of print].
Jaffe 1972 {published data only}
JI 2007 {published data only}
  • JI H, YE S, NIE Z, Zeng Y, Liu Y, XIE L, et al. Clinical research of withdrawal syndrome treatment with phenytoin in heroin addicts. Chinese Journal of Drug Abuse Prevention and Treatment 2006;12(1):28-30.
Johnson 1992 {published data only}
Kheirabadi 2008 {published data only}
  • Kheirabadi GR, Ranjkesh M, Maracy MR, Salehi M. Effect of add-on gabapentin on opioid withdrawal symptoms in opium-dependent patients. Addiction 2008; Vol. 103, issue 9:1495-9.
Krabbe 2003 {published data only}
  • Krabbe PF, Koning JP, Heinen N, Laheij RJ, Van Cauter V, De Jong CA. Rapid detoxification from opioid dependence under general anaesthesia versus standard methadone tapering: abstinence rates and withdrawal distress experiences. Addiction Biology 2003;8:349-56.
Kristensen 2005 {published data only}
  • Kristensen O, Espegren O, Asland R, Jakobsen E, Lie O, Seiler S. A randomised clinical trial of methadone vs. buprenorphine to opioid dependants [Buprenorfin og metadon til opiatavhengige- en randomisert studie]. Tidsskrift for Den Norske Laegeforening 2005;125(2):148-51.
Lal 1976 {published data only}
Liu 2009 {published data only}
  • Liu TT, Shi J, Epstein DH, Bao YP, Lu L. A meta-analysis of acupuncture combined with opioid receptor agonists for treatment of opiate-withdrawal symptoms. Cellular and Molecular Neurobiology 2009;29(4):449-54.
Liu 2009a {published data only}
  • Liu TT, Shi J, Epstein DH, Bao YP, Lu L. A meta-analysis of Chinese herbal medicine in treatment of managed withdrawal from heroin. Cellular and Molecular Neurobiology 2009;29(1):17-25.
Lobmaier 2010 {published data only}
  • Lobmaier P, Gossop M, Waal H, Bramness J. The pharmacological treatment of opioid addiction--a clinical perspective. European Journal of Clinical Pharmacology 2010;66(6):537-45.
Madden 1986 {published data only}
  • Madden C, Singer G, Jagoda J, Jetwa J, Croxford R. Opiate-seeeking behavior under conditions of methadone detoxification and removal. The International Journal of the Addictions 1986;21(8):947-53.
Maddux 1980 {published data only}
Mannelli 2008 {published data only}
McCambridge 2006 {published data only}
  • McCambridge J, Gossop M, Beswick T, Best D, Bearn J, Rees S, et al. In-patient detoxification procedures, treatment retention, and post-treatment opiate use: comparison of lofexidine + naloxone, lofexidine + placebo, and methadone. Drug and Alcohol Dependence 2007;88(1):91-5.
McCaul 1984 {published data only}
  • Mc Caul ME, Stitzer ML, Bigelow GE, Liebson IA. Methadone detoxification: effects of methadone dose versus time in treatment. NIDA Research Monograph 1984;49:269-74.
Meader 2010 {published data only}
  • Meader N. A comparison of methadone, buprenorphine and alpha2 adrenergic agonists for opioid detoxification: A mixed treatment comparison meta-analysis. Drug Alcohol Dependence 2010;108(1-2):110-4.
Mintz 1975 {published data only}
  • Mintz J, O'Brien CP, O'Hare K, Goldschimidt J. Double-blind detoxification of methadone maintenance patients. The International Journal of the Addictions 1975;10(5):815-24.
Mitchell 2012 {published data only}
  • Mitchell SG, Kelly SM, Gryczynski J, Myers CP, Jaffe JH, O'Grady KE, et al. African American patients seeking treatment in the public sector: Characteristics of buprenorphine vs. methadone patients. Drug and Alcohol Dependence 2012;122(1-2):55-60.
Mokhber 2008 {published data only}
  • Mokhber N, Soltanifar A, Talebi M. Efficacy of topiramate as an adjunct medication in heroin withdrawal: A randomized control trial. Journal of Pakistan Psychiatric Society 2008;5(1):22-6.
Neale 2005 {published data only}
O'Connor 1997 {published data only}
Pjrek 2012 {published data only}
  • Pjrek E, Frey R, Naderi-Heiden A, Strnad A, Kowarik A, Kasper S, et al. Actigraphic measurements in opioid detoxification with methadone or buprenorphine. Journal of Clinical Psychopharmacology 2012;32(1):75-82.
Rawson 1983 {published data only}
  • Rawson RA, Mann AJ, Tennant FS Jr, Clabough D. Efficacy of psychotherapeutic counselling during 21-day ambulatory heroin detoxification. NIDA Research Monograph 1983;43:310-4.
Reed 2007 {published data only}
  • Reed LJ, Glasper A, de Wet CJ, Bearn J, Gossop M. Comparison of buprenorphine and methadone in the treatment of opiate withdrawal: possible advantages of buprenorphine for the treatment of opiate-benzodiazepine co dependent patients?. Journal of Clinical Psychopharmacology 2007;27(2):188-92.
Reilly 1995 {published data only}
  • Reilly PM, Banys P, Tusel DJ, Sees KL, Krumenaker CL, Shopshire MS. Methadone transition treatment: a treatment model for 180-day methadone detoxification. The International Journal of the Addictions 1995;30(4):387-402.
Sees 2000 {published data only}
  • Sees LK, Delucchi KL, Masson C, Rosen A, Clark HW, Robillard H, et al. Methadone maintenance vs 180-day psychosocially enriched detoxification for treatment of opioid dependence. JAMA 2000;283(10):1303-10.
Semba 2007 {published data only}
  • Semba RD, Ricketts EP, Mehta SF, Kirk GD, Latkin C, Galai N, et al. Adherence and retention of female injection drug users in a phase III clinical trial in inner city Baltimore. American Journal of Drug and Alcohol Abuse 2007;33(1):71-80.
Shaygani 2009 {published data only}
  • Shaygani S, Waal H. Treatment of opioid withdrawal. Tidsskr Nor Laegeforen 2009;129(2):114-5.
Sheard 2006 {published data only}
  • Sheard L, Adams CE, Wright NM, El-Sayeh H, Dalton R, Tompkins CNE. The Leeds Evaluation of Efficacy of Detoxification Study (LEEDS) prisons project pilot study: Protocol for a randomised controlled trial comparing dihydrocodeine and buprenorphine for opiate detoxification. Trials 2007;8(8):1-5.
Soyka 2009 {published data only}
  • Soyka M, Zingg C. Feasability and safety of transfer from racemic methadone to (R)-methadone in primary care: Clinical results from an open study. World Journal of Biological Psychiatry 2009;10(3):217-24.
Stimmel 1982 {published data only}
  • Stimmel B, Hanbury R, Cohen M. Factors affecting detoxification from methadone. Journal of Psychiatric Treatment and Evaluation 1982;4:377-81.
Stotts 2012 {published data only}
  • Stotts AL, Green C, Masuda A, Grabowski J, Wilson K, Northrup TF, et al. A Stage I pilot study of acceptance and commitment therapy for methadone detoxification. Drug and Alcohol Dependence 2012;Mar 14:Epub ahead of print.
Strain 1993 {published data only}
Strang 1990 {published data only}
Strang 1997 {published data only}
Sullivan 2004 {published data only}
  • Sullivan LE, Chawarski M, O'Connor PG, Schottenfeld RS, Fiellin DA. The practice of office-based buprenorphine treatment of opioid dependence: is it  associated with new patients entering into treatment?. Drug and Alcohol Dependence 2005;79(1):113-6.
Teesson 2006 {published data only}
Tennant 1978 {published data only}
  • Tennant FS Jr, Shannon J A. Detoxification from methadone maintenance: double blind comparison of two methods. Drug and Alcohol Dependence 1978;3:85-92.
Van Beek-Verbeek 1983 {published data only}
  • Van Beek-Verbeek G, Fraenkel HM, Van Ree JM. Des-gly9-[arg8]-vasopressin may facilitate methadone detoxification of heroin addicts. Substance and Alcohol Actions/Misuse 1983;4(5):375-82.
Veilleux 2010 {published data only}
  • Veilleux JC, Colvin PJ, Anderson J, York C, Heinz AJ. A review of opioid dependence treatment: pharmacological and psychosocial interventions to treat opioid addiction. Clinical Psychology Review 2010;30(2):155-66.
Wang 1982 {published data only}
  • Wang RI, Kochar C, Hasegawa AT, Roh BL. Clinical comparison of propoxyphene napsylate and methadone in the treatment of opiate dependence. NIDA Research Monograph 1982;41:253-60.
Yang 2008 {published data only}
Zeng 2005 {published data only}
  • Zeng X, Lei L, Lu Y, Wang Z. Treatment of heroinism with acupuncture at points of the Du Channel. Journal of Traditional Chinese Medicine 2005;25(3):166-70.
Ziaadini 2011 {published data only}
  • Ziaadini H, Parvaresh N, Afshar N, Hoseinian SM, Sarhadi R, Hahdoost AA. Comparison of the outcomes of three detoxification methods (clonidin, methadon, rapid) in opioid-dependents referred to kerman shaheed beheshti hospital in a 6-month follow- up. Journal of Kerman University of Medical Sciences 2011;18(3):246-59.

Additional references

  1. Top of page
  2. Abstract
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Characteristics of studies
  19. References to studies included in this review
  20. References to studies excluded from this review
  21. Additional references
  22. References to other published versions of this review
Bradley 1987
Dekkers 2009
  • Dekkers OM, von Elm E, Algra A, Romijn JA, Vandenbroucke JP. How to assess the external validity of therapeutic trials: a conceptual approach. International Journal of Epidemiology 2009;39:89-94.
EMCDDA 2011
  • European Monitoring Centre for Drugs and Drug Addiction Annual report 2011: the state of the drugs problem in EuropeLuxembourg. Publications Office of the European Union, available at www.emcdda.europa.eu. [DOI: 10.2810/44330]
Gerra 1995
  • Gerra G, Marcato A, Cavaccari R, Fontanesi B, Delsignore R, Fertonani G, et al. Clonidine and opiate receptor antagonists in the treatment of heroin addiction. Journal of Substance Abuse treatment 1995;12:35-41.
Gossop 1987
  • Gossop M, Bradley B, Phillips GT. Investigation of withdrawal symptoms shown by opiate addicts during and subsequent to a 21 day inpatient methadone detoxification procedure. Addictive Behaviors 1987;12:1-6.
Gossop 1989B
Gossop 1990
Gowing 2008
  • Gowing L, Ali R, White J. Alpha2 adrenergic agonists for the management of opioid withdrawal. Cochrane Database of Systematic Reviews 2008, Issue 3. [DOI: 10.1002/14651858.CD002024.pub3]
Guyatt 2008
  • Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ 2008;336(7650):924-6.
Haertzen 1968
Hall 1999
  • Hall W, Lynskey M, Degenhardt L. Heroin use in Australia: its impact on public health and public order. NDARC Monograph No. 42. Sydney, National Drug and Alcohol Research Centre 1999.
Handelsman 1987
Higgins 2008
  • Higgins JPT, Green S (editors). The Cochrane Collaboration, 2008. Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.0 [updated February 2008]. Available from www.cochrane-handbook.org..
Himmelsbach 1941
  • Himmelsbach CK. The morphine abstinence syndrome, its nature and treatment. Annals of Internal Medicine 1941;15:829-39.
Himmelsbach 1942
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Jaffe 1990
  • Jaffe J. Drug addiction and drug abuse. In: A Gilman, T Rall, A Nies, P Taylor editor(s). The Pharmacological Basis of Therapeutics. 8th edition. New York: Pergamon Press, 1990:522-73.
Kolb 1938
  • Kolb L, Himmelsbach CK. Clinical studies of drug addiction III. American journal of Psichiatry 1938;94:759-99.
Peachey 1988
Powell 1990
  • Powell J, Gray JA, Bradley BP, Kasvikis Y, Strang J, Barratt L, et al. The effects of cue exposure to drug-related cues in detoxified opiate addicts: a theoretical review and some new data. Addictive Behavior 1990;15:339-54.
Schubert 1984
UNODC 2011
  • UNODC, World Drug Report, 2011. Retrieved May 18, 2012, from the United Nation Office on Drug and Crime  web site at: http://www.unodc.org.
Valliant 1988
Ward 1992
  • Ward J, Mattick RP, Hall W. Key Issues in Methadone Maintenance Treatment. Sydney: New South Wales University Press, 1992.
Wesson 2003

References to other published versions of this review

  1. Top of page
  2. Abstract
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Characteristics of studies
  19. References to studies included in this review
  20. References to studies excluded from this review
  21. Additional references
  22. References to other published versions of this review
Amato 2003
  • Amato L, Davoli M, Ferri M, Ali R. Methadone at tapered doses for the management of opioid withdrawal. Cochrane Database of Systematic Reviews 2003, Issue 2. [DOI: 10.1002/14651858.CD003409.pub2]
Amato 2005