Summary of findings
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 When the opioid is withdrawn, the cAMP cascade becomes overactive, leading to the “noradrenergic storm” seen clinically as opioid withdrawal, which may create a drive to reinstate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.
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.
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
- Methadone aimed at the detoxification from opiates, maximum length of treatment: 30 days
- Other opioid agonists (LAAM (levo-α-acetyl-methadol), Buprenorphine, propoxyphene, etc).
- Adrenergic agonists (clonidine, lofexidine, guanfacine).
- Opioid antagonists (naltrexone, naloxone).
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
- Completion of treatment as number of participants completing the detoxification program.
- Acceptability of the treatment as a) duration and severity of signs and symptoms of withdrawal, including patient self-rating, b) side effects.
- Results at follow-up as (a) number of participants abstinent at follow-up, (b) naloxone challenge.
- 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
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:
- Cochrane Central Register of Controlled Trials (The Cochrane Library 2012, Issue 4) which include the Cochrane Drugs and Alcohol Group's Register of Trials.
- PubMed (from 2003 - May 2012).
- EMBASE (from 2003 - May 2012).
- CINAHL (from 2003 - December 2011).
- PsycINFO (January 1985 to December 2004).
There were no language or publication year restriction.
Searching other resources
We also searched:
- Reference lists of all relevant papers to identify further studies.
- Some of the main electronic sources of ongoing trials (meta-Register of Controlled Trials; Clinical Trials.gov).
- Conference proceedings likely to contain trials relevant to the review (College on Problems of Drug Dependence -CPDD).
- 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 Chi
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.
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 Chi
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.
Description of 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
|Figure 1. Flow chart of 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.
In the 23 studies included in the review, tapered methadone was compared with the following.
- Tapered methadone versus any other treatments: 23 studies, 2467 participants.
- 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 were either dichotomous or continuous, as reported by authors. The following principal outcomes were considered by the authors.
- Completion of treatment as number of participants completing the detoxification program (16/23 studies).
- Withdrawal scores (21/23 studies).
- Side effects (16/23 studies).
- Use of primary substance measured as number of opiate positive urine samples (3/23 studies).
- Results at follow-up as (a) number of participants abstinent at follow-up (4/23 studies) and (b) naloxone challenge (2/23 studies).
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).
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
|Figure 2. Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.|
|Figure 3. Methodological quality summary: review authors' judgements about each methodological quality item for each included study.|
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 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
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,
|Figure 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
|Figure 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.
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
- 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
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
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
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.
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.
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.
We would like to thank Zuzana Mitrova for help in searching and retrieving articles.
Data and analyses
- Top of page
- Summary of findings [Explanations]
- Authors' conclusions
- Data and analyses
- What's new
- Contributions of authors
- Declarations of interest
- Sources of support
- Index terms
Appendix 1. CENTRAL search strategy
Appendix 2. PubMed search strategy
- Opioid-Related Disorders[Mesh]
- ((substance*[tiab] or drug[tiab]) AND (abuse*[tiab] or dependen*[tiab] or use* or disorder* or addict*[tiab]))
- intoxicat*[tiab] or detox*[tiab] or disintox*[tiab] or withdraw*[tiab] or abstinen*[tiab] or abstain*[tiab])
- #2 OR #3 OR #4
- opiat*[tiab] OR opioid*[tiab] OR morphin*[tiab]
- Heroin[MeSH Terms] OR heroin
- methadone [tiab]
- #5 OR #6 OR #7 OR #8
- #4 AND #9
- randomized controlled trial [pt]
- controlled clinical trial [pt]
- randomized [tiab]
- placebo [tiab]
- clinical trials as topic [mesh: noexp]
- randomly [tiab]
- trial [tiab]
- #11 or #12 or #13 or #14 or #15 or #16 or #17
- #10 and #18
Appendix 3. EMBASE search strategy
- 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)
- intoxicat*:ab,ti OR detox*:ab,ti OR disintox*:ab,ti OR withdraw*:ab,ti OR abstinen*:ab,ti OR abstain*:ab,ti
- #1 OR #2 OR #3 OR #4
- opiat*:ab,ti OR opioid*:ab,ti
- #6 OR #7 OR #8 OR #9 OR #10
- 'crossover procedure'/exp
- 'double blind procedure'/exp
- 'single blind procedure'/exp
- 'controlled clinical trial'/exp
- 'clinical trial'/exp
- 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
- random*:ab,ti OR factorial*:ab,ti OR crossover:ab,ti OR (cross:ab,ti AND over:ab,ti)
- 'randomized controlled trial'/exp
- #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20
- #5 AND #12 AND #21 AND [humans]/lim AND [embase]/lim AND [2008-2012]/py
Appendix 4. CINAHL search strategy
- (MH "Substance Use Disorders+")
- TX ((drug or substance) and (addict* or dependen* or abuse*or disorder*))
- TX ((opioid* or opiate*) and (abuse* or addict* or dependen*))
- S3 or S2 or S1
- TX (opioid* or opiate*)
- TX methadone or MH methadone
- TX heroin or NT heroin
- S7 or S6 or S5
- TX random*
- TX (clin* and trial*)
- TX (singl* or doubl* or tripl* or trebl*) and (mask* or blind*)
- TX crossover*
- TX allocate*
- TX assign*
- TX ((random*) and (allocate* or assign*))
- (MH "Random Assignment")
- (MH "Clinical Trials+")
- S17 or S16 or S15 or S14 or S13 or S12 or S11 or S10 or S9
- S8 and S4
- S18 and S19
Last assessed as up-to-date: 20 July 2012.
Protocol first published: Issue 1, 2001
Review first published: Issue 1, 2002
Contributions of authors
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
Sources of support
- Department of Epidemiology, ASL RM E, Italy.
- No sources of support supplied
Medical Subject Headings (MeSH)
Methadone [*administration & dosage]; Narcotics [*administration & dosage; adverse effects]; Opiate Substitution Treatment [*methods]; Opioid-Related Disorders [*rehabilitation]; Randomized Controlled Trials as Topic; Substance Withdrawal Syndrome [*rehabilitation]
MeSH check words
* Indicates the major publication for the study