Methods

Allocation: randomised controlled trial;
Randomization performed centrally;
Blindness of the patients and or care providers in respect to treatment: not performed, all the patients were orally informed about the treatment they had been allocated

Duration of treatment within the study: 12 months

Participants

Diagnosis: heroin addicts (intravenous use) registered in the local methadone maintenance programs, who had failed several methadone programs
N= 174

Age=38.5 years (5.7 SD)

Sex= male 82.2%

History=a history of heroin dependency (DSM‐IV) of at least five years; a minimum dose level of 50 mg (inhaling) or 60 mg (injecting) of methadone per day for an uninterrupted period of at least four week in the previous five years; in the previous year registered in a methadone program, and during the previous six months in regular contact with the methadone program; chronic heroin addiction and unsuccessfully treated in methadone maintenance treatment; daily or nearly daily use of illicit heroin; poor physical, and/or mental, and/or social functioning;
Criminal activity=at study entrance at least six days in the previous month of drug‐related illegal activities
Mental State= at study entrance a SCL‐90 total score of at least 41 (males) or 60 (females)

Interventions

Group A (no. = 98) 12 months methadone; Group B (no. = 76) 12 months methadone+heroin injectable

Psychosocial interventions: Psychosocial treatment was offered throughout

Outcomes

Dichotomous, multidomain response index, including validated indicators of physical health, mental status, and social functioning. Information on Substance use; Retention in treatment, Death, Adverse events

Notes

Country: The Netherlands 1998‐2001

website: www.ccbh.nl/ENG/publications.htm

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

There are no information about procedure of sequence generationand in agreement with the CDAG rule, the judgment has to be "unclear".

Allocation concealment (selection bias)

Low risk

"the randomization was organized centrally by an independent monitoring organization, and conducted separately for the trials on injectable heroin and inhalable heroin." Authors were contacted for further details and correspondence is available by the reviewer's author.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

"In the present study, it could not be ruled out that the probability of response would systematically and considerably differ between patients with and without endpoint‐assessments. However, since the primary analysis of effectiveness concerned the total treatment‐offer, regardless of possible deviations from the protocol, statistical methods to correct for bias in the findings caused by missing endpoint‐assessments, like multiple imputation or propensity score estimation, were only
of limited applicability. It was therefore considered crucial to minimize the occurrence of missing endpoint‐assessments as much as possible, by conducting intensive field work and by providing additional financial compensation for participating in the endpoint‐assessments. Nevertheless it could not be excluded that some missing endpoint‐assessments would occur in the study population. In case of such missing endpoint‐assessments, and because of lack of satisfactory
alternatives, the "last observation carried forward" (LOCF) method was used in the primary analysis."

Selective reporting (reporting bias)

Low risk

prespecified outcomes available from the website of the study, details available on table 3.

Blinding (objective outcomes: drop out, use of substances measured by urine analysis)

Low risk

In order to reduce the risk of information bias, outcome assessments were conducted by
independent assessors, who used standardized instruments and evaluation procedures.

Blinding (subjective outcomes: use of substances as measured by self report, side effects)

Low risk

The validity of the self‐report data was checked through the application of urinalysis, with regard to the concurrent use of illicit drugs, and collection of registered data from the police and justice system, with regard to committed offenses and periods of detention. These latter types of data are insensitive to information bias.

Methods

Allocation: randomised controlled trial;
Randomization performed centrally;
Blindness of the patients and or the care providers in respect to treatment: not performed, all the patients were orally informed about the treatment they had been allocated

Duration of treatment within the study: 12 months

Participants

Diagnosis: heroin addicts (inhaling use) registered in the local methadone maintenance programs, who had failed several methadone programs.
N=256

Age=39.6 (5.7 SD)
Sex= 79.7% male;

History=a history of heroin dependency (DSM‐IV) of at least five years; a minimum dose level of 50 mg (inhaling) or 60 mg (injecting) of methadone per day for an uninterrupted period of at least four week in the previous five years; in the previous year registered in a methadone program, and during the previous six months in regular contact with the methadone program; chronic heroin addiction and unsuccessfully treated in methadone maintenance treatment; daily or nearly daily use of illicit heroin; poor physical, and/or mental, and/or social functioning;
Criminal activity=at study entrance at least six days in the previous month of drug‐related illegal activities
Mental State= at study entrance a SCL‐90 total score of at least 41 (males) or 60 (females)

Interventions

Group A (no. = 139) 12 months methadone; Group B (no. = 117) 12 months heroin (inhalable) + methadone; Group C (n=119) 6months methadone+ 6 months

Psychosocial interventions: Psychosocial treatment was offered throughout

Outcomes

Dichotomous, multidomain response index, including validated indicators of physical health, mental status, and social functioning. Information on Substance use; Retention in treatment, Death, Adverse events

Notes

Country: The Netherlands 1998‐2001

Website: www.ccbh.nl/ENG/publications.htm

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

no description of sequence generation could be traced in the articles and the report of the study and in agreement with the CDAG rule, the judgment has to be "unclear".

Allocation concealment (selection bias)

Low risk

"the randomization was organized centrally by an independent monitoring organization, and conducted separately for the trials on injectable heroin and inhalable heroin." Authors were contacted for further details and correspondence is available by the reviewer's author.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

"In the present study, it could not be ruled out that the probability of response would systematically and considerably differ between patients with and without endpoint‐assessments. However, since the primary analysis of effectiveness concerned the total treatment‐offer, regardless of possible deviations from the protocol, statistical methods to correct for bias in the findings caused by missing endpoint‐assessments, like multiple imputation or propensity score estimation, were only
of limited applicability. It was therefore considered crucial to minimize the occurrence of missing
endpoint‐assessments as much as possible, by conducting intensive field work and by providing additional financial compensation for participating in the endpoint‐assessments. Nevertheless it
could not be excluded that some missing endpoint‐assessments would occur in the study
population. In case of such missing endpoint‐assessments, and because of lack of satisfactory
alternatives, the "last observation carried forward" (LOCF) method was used in the primary
analysis."

Selective reporting (reporting bias)

Low risk

Yes prespecified outcomes available on the website of the study, details on table 3.

Blinding (objective outcomes: drop out, use of substances measured by urine analysis)

Low risk

In order to reduce the risk of information bias, outcome assessments were conducted by
independent assessors, who used standardized instruments and evaluation procedures.

Blinding (subjective outcomes: use of substances as measured by self report, side effects)

Low risk

The validity of the self‐report data was checked through the application of urinalysis, with regard to the concurrent use of illicit drugs, and collection of registered data from the police and justice system, with regard to committed offenses and periods of detention. These latter types of data are insensitive to information bias.

Methods

Allocation: Randomized controlled trial, multicenter

Randomization: 4x2 stratified randomization

Blindness of patients and or care providers in respect to treatment: not specified

Duration of threatment within the study: 12 months

Participants

Diagnosis: ICD10 for opiate dependence for at least 5 years (World Health Organization, 1993).

(a) people with heroin dependence who were insufficiently responding to treatment owing to continuous intravenous heroin use (n=492); and (b) people with heroin dependence who were not in treatment in the previous 6 months (n=540).

N=1032

Age=35.9 ( SD 6.8)
Sex= Male 81.8
History=Intravenous drug use in the past month days 26.5 (SD 7.4)
Criminal activity=Illegal activities past month, days,mean 22.6 (SD9.8)
Mental State=At least one lifetime psychiatric diagnosis 59.3%; Previous suicide attempts,39.7%

Interventions

Arms 1,2 of each stratum:

Heroin+education or  Heroin + Case management

Maximum single dose of 400mg and a maximum daily dose of 1000mg (none to take home) individually adjusted dose of injectable heroin self‐administered under direct supervision of medical staff

Maximally three times a day, 7 days a week out‐patient setting;

Up to 60mg of methadone could also be given for take‐home nighttime use to suppress withdrawal

Arms 3,4 of each stratum:

Methadone + education or Methadone + case‐management

minimum daily dose of 60mg oral individually adjusted according to clinical judgement

Outcomes

Two prespecified dichotomous, multidomain primary outcome measures:

Primary outcome measure on health.

Second primary outcome measure, people were considered responders if they showed a reduction in the use of street heroin and no increase in cocaine use (hair analysis).

Notes

Country: Germany, 2002‐2004

Website: http://www.heroinstudie.de/english.html

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

computer generated list of numbers

Allocation concealment (selection bias)

Low risk

"Randomisation took place separately for each target group (methadone treatment failure and not in treatment), and treatment allocation was performed using sealed and consecutively numbered envelopes at each study site".

Incomplete outcome data (attrition bias)
All outcomes

Low risk

In the intent‐to‐treat analysis, all those randomised were assessed regardless of
treatment retention. Data from the baseline and 12‐month assessments were used for
analysis of the primary outcome measures; the last‐observation‐carried‐forward (LOCF)
procedure from data at 6 months was used if data at 12 months were missing. If no
data were available for 6 and 12 months, the outcome was coded according to a worst‐case analysis (i.e. as a responder in the methadone group and a non‐responder in the heroin group).

Selective reporting (reporting bias)

Low risk

Prespecified outcomes available from the website of the study, details on table 3.

Blinding (objective outcomes: drop out, use of substances measured by urine analysis)

Unclear risk

No mention of blinding of assessors.The assessment by independent research assistants included administration of the European version of the Addiction Severity Index (EuropASI; Kokkevi & Hartgers, 1995), and gathering data on criminal behaviour and on subjective aspects of treatment.

Blinding (subjective outcomes: use of substances as measured by self report, side effects)

Unclear risk

see above

Methods

Allocation: computer generated list of random number;

Randomization: unspecified

Blindness of patients and or care providers in respect of treatment: patients were aware of the treatment provided but they were not aware of being part of a trial; blindness over interventions by patients and treatment providers and outcomes measurers not mentioned;

Duration of treatment within the study: 12 months

Participants

Diagnosis: regular opiate use including daily heroin injection in the last three months sufficient to convince clinical staff to be entered in a substitution program
N= 96
Age= 18‐35 years; mean 23.9
Sex= 75% male; 25% female;
History= mean duration of opiate use : 5.9 years; age at first use: 18.0yrs
Criminal activity: 87% had criminal convictions; the mean number of convictions 4.3; the 52% had been convicted at least once in the 12 months before intake
Mental State: at intake 60% were recorded as mildly; 27% anxious; 35% mildly depressed and 3% euphoric

Interventions

Heroin Maintenance (N= 44); dosages 30‐120 mg/day;
Oral Methadone (N=52) dosages 10‐120 mg/day

Psychosocial interventions: Interviews by a clinic psychiatrist at 3,9 and 12 months;

Outcomes

Health; Use of substances:Total Opiate Consumption (prescribed+illicit); Frequency of Injection during 12 months;

Proportion of days spent with other users; Crime activity: Crime as source of outcome during 12 moths; Arrests during 12 months

Employment. Retention in treatment, relapse to street heroin use, death

Notes

Country: UK 1972‐75

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"A computer generated list of random numbers was consulted (without patients being aware of this) and the patients prescribed either HM or refused it and offered Oral Methadone instead."

Allocation concealment (selection bias)

Unclear risk

not reported

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Information where obtained by almost all of the patients some of them where interviewed in the United States and for others family members were interviewed an parallel sources of informations were compared.

Selective reporting (reporting bias)

Unclear risk

Protocol of the study not available, due to the older date of the study.

Blinding (objective outcomes: drop out, use of substances measured by urine analysis)

Low risk

Data collected by independent research but no blinding of assessors mentioned nevertheless any limitations to validity of objective results are described and taken into consideration in the study results.

Blinding (subjective outcomes: use of substances as measured by self report, side effects)

Unclear risk

Data collected by independent research but no blinding of assessors mentioned nevertheless any limitations to validity of subjective results are described and taken into consideration in the study results.

Methods

Allocation: "A computer‐generated randomisation list of permuted blocks of two, four, and six was used. Patients were assigned to receive diacetylmorphine, methadone, or hydromorphone in a 45:45:10 ratio.
Randomization was stratified according to centre and according to the number of previous methadone
treatments (two or fewer vs. three or more)."
Blindness of patients and or care providers in respect to treatment:"The investigators and participants were aware of whether the assigned study drug was oral methadone or one of the injectable drugs, but diacetylmorphine and hydromorphone were administered in a double‐blind fashion". "Evaluations were performed at a separate research office that operated independently from the treatment clinic in each city" there is no mention whether the assessors were blinded to treatment allocation.
Duration of treatment within the study: 12 months

Participants

Opiate‐dependent using injected heroin on regular basis,
not responding in the past or currently in MMT.

Diagnosis: opioid dependence (meeting three or more of seven criteria listed in the Diagnostic and Statistical
Manual of Mental Disorders, fourth edition,14 including tolerance or withdrawal)

N= 251
Age=25 years or older
Sex= Male154 (61.4)
History= duration of injecting drug use yr 16.5±9.8

Interventions

Injected heroin + oral methadone (N = 115)

oral methadone (N = 111)

injected Dilaudid + oral methadone (N = 25)

Psychosocial interventions: All patients were offered a comprehensive range of psychosocial and primary care services in keeping with Health Canada best practices.

Outcomes

retention in addiction treatment

reduction in illicit‐drug use or other illegal activity

Notes

Country: Canada 2005‐2008

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

The authors describe "a computer‐generated randomisation list of permuted blocks of two, four, and six". "Randomization was stratified according to center and according to the number of previous methadone treatments (two or fewer vs. three or more)."

Allocation concealment (selection bias)

Low risk

central allocation

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Almost no missing outcome data: "We obtained 12‐month retention data on 245 of 251participants (97.6%) and response data on 240 of 251 participants (95.6%). The baseline characteristics of the groups were similar"

Selective reporting (reporting bias)

Low risk

Details from the published protocol on table 3.

Blinding (objective outcomes: drop out, use of substances measured by urine analysis)

Low risk

No blinding but the objective outcome measurement were not likely to be influenced by lack of blinding: "Retention was assessed with the use of detailed data on daily prescription‐drug use and, when possible, with the use of administrative data and pharmacy and physician records."

Blinding (subjective outcomes: use of substances as measured by self report, side effects)

Low risk

Self‐reported nonuse of illicit heroin was confirmed by means of urine testing at 100% of 46 visits in the group of patients randomly assigned to receive hydromorphone (the double‐blind portion of the study).

(information obtained by the authors on request)

Methods

Allocation: Permuted blocks of two, four, and six were used (not generated by a list, but ‘manually’ (see risk of bias documents). Patients were assigned to receive diacetylmorphine or methadone in a 50:50 ratio.
Randomization was not stratified (information provided by the authors on request).

Blindnessof patients and or care providers in respect to treatment: given the administration routes and different treatment schedules in each group, it was impossible to blind health care personnel to the treatment condition. Nevertheless, the professional who made the assessments and the statistical analysis was blind to the treatment condition.

Duration: 12 months

Participants

Diagnosis: opiate dependency for more than 2 years in line with International Statistical Classification of Diseases, 10th Revision criteria; ongoing intravenous opioid habit; have been in MT in the past at least twice according to official certificates issued by authorized centers

N= 62
Age= mean 37.2 (SD 5.5)
Sex= male 90.3%
History= opiate dependency for more than 2 years , resident in Granada over the preceding year.
Criminal activity:number of days in the prior month M=9,8 (SD=12,2) (information provided by the authors on request)

Mental State:mental health problems, and social maladjustment (according to scores of the assessment of severity by the interviewerQ in the social/family situation and legal Addiction Severity Index [ASI] subscales)

Interventions

Experimental group: injected DAM, twice a day, plus oral methadone, once a day. The average DAM dosage was 274.5 mg/day (range: 15–600 mg), and average methadone 42.6 mg/day (range: 18–124 mg).

Control group: daily methadone (once a day) 105 mg/day (range:40–180 mg).

Comprehensive clinical, psychological, social, and legal support was given to both groups.

Psychosocial interventions: see above

Outcomes

General state of health, Quality of life, Severity of the addiction. Consumption of illegal opiate. Consumption of cocaine. 

Consumption of other psychoactive substances, illegal or legal, not prescribed. Behavior that puts the patient at risk of contracting HIV and hepatitis C

Psychological adjustment Symptoms of depression Symptoms of anxiety Family situation Social support Rate of retention. 

Level of utilization of the psychosocial services of the trial

Notes

Country: Spain 2001‐2004

Website: http://www.easp.es/pepsa/inicio/ensayo_english.htm#Design

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

no information

Allocation concealment (selection bias)

Low risk

Treatment name ‘Metadona’ or ‘Heroína’ were introduced in identical opaque envelopes at a 50/50 ratio (i.e. six patients, 3 envelopes will say methadone, 3 will say heroin).  There were shuffled in the presence of the participants and each participant will pick an envelope.

Our guys had ‘trust’ issues.  We early realized that a physician calling the center and tell the participant the treatment he or she randomly got, would generate problems.  We knew this from our contact with them, some of them where convinced we were going to ‘cheat’ in the randomisation.  Therefore, we had to show them that they had a fifty fifty chance to enter the heroin or methadone arm.

(information provided by the authors)

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Intention to treat and per protocol analysis were performed (completers in the experimental group: 23/27( 85.1%), and in the control group: 21/23 (91.3%).

Selective reporting (reporting bias)

Low risk

Protocol available and study registered, details on table 3.

Blinding (objective outcomes: drop out, use of substances measured by urine analysis)

Unclear risk

"Independent interviewers of the research and clinical teams were responsible for applying the assessment instruments".

Blinding (subjective outcomes: use of substances as measured by self report, side effects)

Unclear risk

Our outcomes were based on the ASI, administered by independent interviewers.  This instrument is based on self‐report.

We tested the use of street heroin with the acetylcodeine test.  It did not work; 95% of the test came back ‘negative’ regardless of the allocation group and self‐reported use of street heroin.

Methods

Allocation: randomised controlled trial;

Randomization

Blindness of patients in respect to treatment: non described.

Duration of treatment within the study: 6 months

Participants

Diagnosis: Heroin addicts;
N=51
age >20;
use >2yrs (12 years on average); more previous attempt of drug treatments (average 8 range 2‐21) and had experienced four drug overdoses (range 0‐30); high prevalence of mental disorders and health status scores 1‐2 SD below population norms.

Interventions

Heroin injected by the patients themselves + oral methadone if the patient travels or want to reduce the attendance of the clinic; mean daily dosages of intravenous heroin was 509 mg/day in one to three injections; in addition to heroin all the patients occasionally received oral opiates and 16 patients received clorazepate substitution therapy (median dose 60 mg/day)
psychological support (N=27) Any other conventional drug treatment (N=24)

control: waiting list (control patients were encouraged to select any drug treatment program available in Geneva and were enrolled immediately whenever possible).

Psychosocial treatment: all patients received psychological counselling, HIV prevention counselling, social and legal support services, and somatic primary care.

Outcomes

Consumption of street heroin; frequency of overdoses; risk behaviour for HIV; number of days ill in the past months; use of health services, health status, work status, living arrangements, quality of social relationships, monthly living and drug related expenditures, sources of income, and criminal behaviour, retention in treatment.

Notes

Country: Switzerland 1995‐1996

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"computer generated list of numbers placed in sealed envelopes".

Allocation concealment (selection bias)

Low risk

Patients are allocated by the psychiatrist during the first visit through the sealed envelopes.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All experimental group patients and 22 in the control group were reassessed 196 days on
average after enrolment (range 168­248); one person from the control group filled only the SF­36 questionnaire. The two remaining patients in the control group were alive at follow up but refused to cooperate.

Selective reporting (reporting bias)

Unclear risk

Protocol not identified probably due to the date of the study.

Blinding (objective outcomes: drop out, use of substances measured by urine analysis)

High risk

no objective measures adopted: all outcome measures were self reported, which raises the issue of information bias.

Blinding (subjective outcomes: use of substances as measured by self report, side effects)

High risk

no actions to reduce the risks reported

Methods

Allocation: Randomisation was undertaken independently by the Clinical Trials Unit (IoP). 

Blindness: Researchers unblinded to treatment allocation, informed both clinicians and patients together of treatment allocation prior to treatment commencing.

Duration of treatment within the study: 6 months

Participants

Diagnosis:regular heroin injecting no active significant medical condition

N=127

Age= Aged between 18 and 65 years at recruitment to study

History= >3 years injecting, in treatment >6 months

Mental state= no active significant psychiatric conditions

Interventions

experimental group:supervised injectable heroin (SIH) attendance at clinic twice daily for prescribed split daily dose of injectable heroin; self‐administered under supervision; supplementary oral methadone available (as take‐home dose at clinician's discretion).

experimental group :supervised injectable methadone (SIM) attendance at clinic once daily for prescribed single daily dose of injectable methadone; self‐administered under supervision; supplementary oral methadone available (as take‐home dose at clinician's discretion);

control group:optimised oral methadone (OOM) enhanced oral methadone treatment, daily doses of >80mg actively encouraged, consumed under supervision on >5 days per week for 3 months; thereafter frequency of supervision reduced if clinically appropriate;

Outcomes

1. Reduction of regular use of street‐heroin :

1.a. objective: (operationally defined as urinalysis negative for street‐heroin for 50% or more of weekly random urines between weeks 14‐26);

1.b. subjective: self‐reported street‐heroin use (over 30 days prior to interview) was elicited through face‐to‐face research interviews with patients and 1.undertaken by independent researchers at baseline, three‐months and six months.

Notes

Country: UK 2005‐2008

Website:http://www.iop.kcl.ac.uk/projects/?id=10114

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Eligible consenting patients were randomised by minimisation in the ratio (1:1:1) to one of three treatment options (OOM, SIM, SIH), with stratification for a) regular cocaine/crack use (>50% days in previous 4 weeks), b) previous optimised oral methadone treatment (doses of >80mg/day; supervised >5 days/week) and c) clinic site (London, Darlington, Brighton). Randomisation was undertaken independently by the Clinical Trials Unit (IoP). 

Allocation concealment (selection bias)

Unclear risk

Researchers unblinded to treatment allocation, informed both clinicians and patients together of treatment allocation prior to treatment commencing

Incomplete outcome data (attrition bias)
All outcomes

Low risk

For the primary outcome measure, missing data were handled using multiple imputation in cases where missing urines occurred due to hospitalisation, imprisonment, pre‐agreed absence (holiday), safety reasons or clinical omission/error. Missing urines from a patient who attempted abstinence were similarly managed. Urine samples not provided due to non‐compliance (refusal to provide or unplanned non‐attendance) were presumed positive.

Data were analysed on an Intention‐To‐Treat basis for the primary analysis (all patients randomised included in analyses). Per‐Protocol analyses (only patients who received trial interventions according to protocol) were also conducted: any substantial differences in findings are reported alongside the primary ITT analyses.

All the data for each of the groups to which participants were randomised were presented so that the risk of bias of multiple‐intervention study are minimised.

Selective reporting (reporting bias)

Low risk

Protocol published and study registered see table 3.

Blinding (objective outcomes: drop out, use of substances measured by urine analysis)

Low risk

Urinalysis (primary outcome measure) was preformed by laboratory personnel blinded to treatment allocation and the statistician was blinded to injectable group.

Blinding (subjective outcomes: use of substances as measured by self report, side effects)

Low risk

Interviews with patients and undertaken by independent researchers at baseline, three‐months and six months.