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Methodological quality summary: review authors' judgements about each methodological quality item for each included study.
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Figure 1

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

Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.
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Figure 2

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

Supervised injected heroin versus oral methadone: retention in treatment
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Figure 3

Supervised injected heroin versus oral methadone: retention in treatment

Heroin provision (any route of administration) versus any other treatment: retention in treatment
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Figure 4

Heroin provision (any route of administration) versus any other treatment: retention in treatment

Supervised Injected Heroin + methadone vs oral methadone, outcome: Mortality.
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Figure 5

Supervised Injected Heroin + methadone vs oral methadone, outcome: Mortality.

Heroin Provision (various modality and route of administration) vs methadone different modalities, outcome: Mortality.
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Figure 6

Heroin Provision (various modality and route of administration) vs methadone different modalities, outcome: Mortality.

Comparison 1 Supervised Injected Heroin + methadone vs oral methadone, Outcome 1 Retention in treatment.
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Analysis 1.1

Comparison 1 Supervised Injected Heroin + methadone vs oral methadone, Outcome 1 Retention in treatment.

Comparison 1 Supervised Injected Heroin + methadone vs oral methadone, Outcome 2 Mortality.
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Analysis 1.2

Comparison 1 Supervised Injected Heroin + methadone vs oral methadone, Outcome 2 Mortality.

Comparison 1 Supervised Injected Heroin + methadone vs oral methadone, Outcome 3 Adverse events related to intervention medications.
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Analysis 1.3

Comparison 1 Supervised Injected Heroin + methadone vs oral methadone, Outcome 3 Adverse events related to intervention medications.

Comparison 2 Heroin Provision (various modality and route of administration) vs any other treatment, Outcome 1 Retention in treatment.
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Analysis 2.1

Comparison 2 Heroin Provision (various modality and route of administration) vs any other treatment, Outcome 1 Retention in treatment.

Comparison 2 Heroin Provision (various modality and route of administration) vs any other treatment, Outcome 2 Mortality.
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Analysis 2.2

Comparison 2 Heroin Provision (various modality and route of administration) vs any other treatment, Outcome 2 Mortality.

Table 1. Heroin and methadone dosages across groups

Study

N Participants

Intervention Heroin mean dosage/day

Intervention Methadone mean dosage/day

Control Methadone mean dosage/day

Haasen 2007

1015

442 mg

39 mg

99 mg

CCBHA 2002

174

mean heroin dosage 254 mg
per visit (sd=62.5 mg) and 549 mg per day (sd=193 mg).

maximum daily dose 1000 mg, and the maximum single dosage 400 mg

Decided with the help of the treating physician with a minimum daily dose of 30‐50 mg and a maximum of 150 mg.

CCBHB 2002

256

''

''

Perneger 1998

51

509 mg

unspecified

unspecified

Hartnoll 1980

96

30‐120 mg

unspecified

10‐120 mg

RIOTT 2010

127

Injected
diamorphine doses in the range of 300 to 600 mg per day,
with an upper total daily dose of 900 mg (450 mg per
injection)

Injected methadone doses calculated with the formula: injected methadone dose=0·8×oral dose; dose reassessed continually,

Maximum dose of injectable methadone: up to 200 mg/day

Once daily doses of ≥80 mg actively encouraged;

optimum doses individually titrated

NAOMI 2009

226 (+26 INJECTED HYDROMORPHONE)

392.3 mg

(patients receiving diacetylmorphine plus methadone) mean daily dose of diacetylmorphine was 365.5
mg and the mean daily dose of methadone was
34.0 mg

96.0 mg.

PEPSA 2003

62

DAM dosage was 274.5 mg/day (range: 15–600 mg),

methadone dosage was 42.6 mg/day (range: 18–124 mg).

The daily methadone dosage in the control group was 105 mg/day (range:40–180 mg)

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Table 1. Heroin and methadone dosages across groups
Table 2. Primary outcomes of the enclosed studies

Study

Definition

Outcome measures

Hartnoll 1980

Total opiate consumption, frequency of injection, involvment with drug subculture.

Interviews (questionnaires not specified), direct observations

Perneger 1998

Self reported drug use, health status , and social functioning

Unpublished questionnaire based on ASI and SF­36.

CCBHA/B 2002

Prespecified dichotomous, multidomain outcome index including physical, mental, social dimensions and also completion of
treatment and sustained response.

ASI / MAP‐HSS, Case Report Forms (CRF), Composite International
Diagnostic Interview (CIDI),SCL‐90, urinalysis

PEPSA 2003

Dichotomous multidimension outcome (MDO) including general health, quality of life, drug‐addiction‐related problems, nonmedical use of heroin, risk behavior for HIV and HCV, and psychological, family, and social status

The ASI, Opiate Treatment Index, Symptom Checklist‐90, and the 12‐item shortform (SF‐12).

Haasen 2007

Two prespecified dichotomous, multidomain primary outcome measures about health and reduction in illicit drug use, were considered.

EuropASI

OTI Health Scale (physical health)

GSI (mental health)

NAOMI 2009

Retention in addiction treatment at 12 months (defined as receipt of the study medication on at least 10 of the 14 days before the 12‐month assessment, or confirmation of retention in any other treatment program or abstinence from opioids during this interval). Reduction in illicit drug‐use or other illegal activities

Retention in treatment: Data on daily prescription‐drug use and, when possible, with the use of administrative data and pharmacy and physician records

Illicit drug use or other illegal activities: Composite scores on the European Addiction Severity Index17 (see the Supplementary Appendix, available with the full text of this article at NEJM.org),

RIOTT 2010

Reduction of regular use of street heroin defined as 50% or more of negative specimens on urinalysis during weeks 14‐26 (responders).

Reduction of regular use of street heroin defined as two, one, or zero positive specimens during weeks 14‐26, and a test of zero positive specimens during weeks 23‐26.

Self‐reported abstinence from street heroin (zero use) in the past 30 days.

Urine specimens were obtained at random once a week for 26 weeks;

Independent researchers in face‐to‐face interviews with patients at baseline (0 weeks), 13 weeks, and 26 weeks.

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Table 2. Primary outcomes of the enclosed studies
Table 3. Definition of responders across the studies and results of comparisons

study name

definition of responder

Measure of effect as reported in the published studies (ARR calculated for NNT)

NNT

CCBH (A) 2002 and

Responders: at least 40% improvement in at least one of the 3 domains of inclusion (physical, mental, social) at the end of the treatment compared with baseline; if this improvement was not at the expense of a serious ( ≥ 40%) deterioration in functioning in any of the other outcome domains; and if the improvement was not accompanied by a substantial ( ≥ 20%) increase in use of cocaine or amphetamines.

risk difference difference = 22.8%, 95% CI 11.0%‐ 34.6%;

ARR= 0.24

NNT=4.2 (95%CI 2.6‐11.1)

CCBH (B) 2002

see above

risk difference 24.3%, 95% CI 9.6% to 39.0%;

ARR= 0.23

NNT=4.3 (95%CI 2.85‐9.09)

Haasen 2007

Health

Responders: at least a 20% improvement and at least 4 points on the OTI Health Scale (physical health) and/or at least a 20% improvement in the GSI
(mental health), without a deterioration of more than 20% in the other area of health.

Reduction in Illicit drug use

Responders: reduction in the use of street heroin with at least 3 of 5 urine samples negative for the drug in the month prior to the 12‐month assessment and no increase in cocaine use (hair analysis). If less than 3 urine samples or no hair was available at 12 months, data from urine or hair testing at 6 months were used (LOCF).

Health Improvement Adjusted OR=1.54, 95% CI 1.02–2.34, P=0.042.

ARR= 0.06

‘illicit drug use’ Adjusted OR=1.91, 95% CI 1.30–2.79, P=0.001.

ARR=0.14

NNT=16.7 (95% CI 9.09‐100)

NNT=7.2 (95%CI 5‐12.5)

NAOMI 2009

Responders: improvement of at least 20% from the baseline score for illicit‐drug use or legal status (or both). In addition, to rule out deterioration in other variables, a patient with a response could have a decrease of 10% or more on at most one of the remaining composite scores.

Reduction in illicit‐drug use or other illegal activities : 67.0% diacetylmorphine group 47.7% methadone group (rate ratio, 1.40; 95% confidence interval [CI], 1.11 to 1.77; P = 0.004)

ARR=0.20

Retention in treatment : 87.8% in the diacetylmorphine group 54.1% in the methadone group (rate ratio, 1.62; 95% CI, 1.35 to 1.95; P<0.001).

ARR=0.34

NNT=5.3 (95% CI 3.1‐14.3)

NNT=3 (95% CI 2.22‐4.34)

PEPSA 2006

Responders: patients showed at least 20% improvement at 9 months, compared with the baseline values, in general health or psychological or family adjustment, without a deterioration superior to 20% in any of these dimensions evaluated with the respective ASI composite scores.

MDO index 70.4% experimental group; 60.9% control group, difference not statistically significant.

ARR=0.10

NNT=10 (95% CI ‐6.6‐3 *not significant)

RIOTT 2010

Responders: Reduction of regular use of street heroin defined as 50% or more of negative specimens on urinalysis during weeks 14‐26

ITT weeks 14–26 responders: (72% [n=31]) injectable heroin; oral methadone (27% [n=11], OR 7·42, 95% CI 2·69–20·46, p<0·0001

ARR=0.46

NNT=2·17 (95% CI 1·60 to 3·97)

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Table 3. Definition of responders across the studies and results of comparisons
Table 4. Assessment of risk of selective publication

Study

protocol outcomes

published outcomes

source of protocol information

Hartnoll

not available

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.

info not available

Perneger

not available

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.

info not available

CCBH

Physical health, Mental status, Social functioning, Substance use

Dichotomous, multidomain response index, including validated indicators of physical health, mental status, and social functioning.

http://www.ccbh.nl/

PEPSA

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

General health status
Quality of life
Problems related to drug use
Use of nonprescribed drugs (in days per month)
Heroin
HIV risk behavior
Related to drug use
Related to sexual behavior
Psychological adjustment
Family and social adjustment
Family and social relations,
Social functioning
Number of days involved in illegal activities (in days per month)

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

http://www.controlled‐trials.com/ISRCTN52023186

NAOMI

A participant was defined as “retained at 12 months” if he or she met any of the following 4 criteria: 

was compliant with study medication (DAM, HMO and/or MMT) on at least 10 of 14 days prior to the 12‐month date; or

was confirmed to be enrolled in detoxification program at the 12‐month date; or

was confirmed to be enrolled in a drug‐free program at the 12‐month date; or

was confirmed to be abstinent at the 12‐month date.

The first primary outcome was retention in addiction treatment at 12 months (defined as receipt of the study medication
on at least 10 of the 14 days before the 12‐month assessment, or confirmation of retention in any other treatment program or abstinence from opioids during this interval).

The second primary outcome was reduction in illicit‐drug use or other illegal activities. On the basis of composite scores on
the European Addiction Severity Index17 patients were considered to have a response at 12 months if they had an improvement of at least 20% from the baseline score for illicit‐drug use or legal status (or both).

Scientific and political challenges in North America's first randomized controlled trial of heroin‐assisted treatment for severe heroin addiction: rationale and design of the NAOMI study.

Oviedo‐Joekes E, Nosyk B, Marsh DC, Guh D, Brissette S, Gartry C, Krausz M, Anis A, Schechter MT. Clin Trials. 2009 Jun;6(3):261‐71.

RIOTT

Reduction in illicit heroin, measured by urine drug screens taken on a weekly basis over 6 months.

Self‐reported to researcher at baseline, 3 months and 6 months (in or out of treatment):
1. Changes in illicit heroin use:
2. Changes in other illicit opiate drug use (non‐prescribed):
3. Changes in illicit cocaine use:
4. Other illicit drug use and alcohol ‐ benzodiazepines, alcohol, cannabis:
5. Changes in high‐risk injecting practices:
6. Changes in general health status:
7. Changes in psychosocial functioning:
8. Changes in criminality: self‐report using adapted OTI Crime Section of MAP
9. Use of other health and social services: health, social and voluntary sector services used, days off work due to illness, criminal justice sector contacts ‐ adapted REDUCE questionnaire for cost effectiveness analysis
10. Measures of patient expectation of and satisfaction with treatment

In addition, we are monitoring injecting practices and complications, any post dosing side effects and serious and non‐serious adverse event data and collecting data on retention.

Retention;
Reduction in street heroin use;
Serious adverse events.

Lintzeris et al 2006 (Nicholas Lintzeris, John Strang, Nicola Metrebian, Sarah Byford,Christopher Hallam, Sally Lee, Deborah Zador and RIOTT Group. Methodology for the Randomised Injecting Opioid Treatment Trial (RIOTT): evaluating injectable methadone and injectable heroin treatment versus optimised oral methadone treatment in the UK. Harm Reduction Journal 2006;3:28.)

http://www.controlled‐trials.com/ISRCTN01338071

Haasen

improvement of health,
reduction of illicit drug use,
decrease of criminal behaviour,
increase of accessibility and retainment in treatment,
detachment from a social drug context,
social stabilisation in the sense of new drug‐free contacts, improved ability to work, financial security, stabilisation of housing situation and
enrolment in subsequent treatment.

‘health’

‘illicit drug use’

http://www.heroinestudie.de/english.html

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Table 4. Assessment of risk of selective publication
Comparison 1. Supervised Injected Heroin + methadone vs oral methadone

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Retention in treatment Show forest plot

4

1388

Risk Ratio (IV, Random, 95% CI)

1.44 [1.19, 1.75]

2 Mortality Show forest plot

4

1477

Risk Ratio (IV, Random, 95% CI)

0.65 [0.25, 1.69]

3 Adverse events related to intervention medications Show forest plot

3

373

Risk Ratio (IV, Random, 95% CI)

13.50 [2.55, 71.53]

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Comparison 1. Supervised Injected Heroin + methadone vs oral methadone
Comparison 2. Heroin Provision (various modality and route of administration) vs any other treatment

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Retention in treatment Show forest plot

6

1535

Risk Ratio (IV, Random, 95% CI)

1.44 [1.16, 1.79]

2 Mortality Show forest plot

5

1573

Risk Ratio (IV, Random, 95% CI)

0.78 [0.32, 1.89]

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Comparison 2. Heroin Provision (various modality and route of administration) vs any other treatment