Table 2 Findings by outcome

PRIMARY OUTCOMES

Retention in (Interim/Standard) Treatment (4 studies)

Interim versus Waiting List for Standard OAT (1 study)

Moderate quality of evidence due to risk of bias (the trial did not describe the efforts to conceal the allocation sequence, and had a high performance and attrition risk of bias)

Retention at 3 months

23/25 versus 20/25 (no significant difference) (NCT02360007) [41]

Interim versus Standard OAT (2 studies)

Moderate quality of evidence due to risk of bias (effects estimates at least from one observational study)

Retention at 3 months

245/314 versus 557/663 (no significant difference) (Friedmann et al. 1994) [33]

Retention at 4 months

91/99 versus 84/104 with SM (Standard Methadone Treatment) versus 24/27 with RM (Restored Methadone Treatment) (p = 0.06) (NCT00712036) [37]

Retention at 6 months

217/314 versus 504/663 (no significant difference) (Friedmann et al. 1994) [33]

Retention at 12 months

60/99 versus 57/104 with SM versus 10/27 with RM (p = 0.09) (NCT00712036) [37]

173/314 versus 404/663 (no significant difference) (Friedmann et al. 1994) [33]

Interim with Buprenorphine versus Interim with Placebo (1 study)

Low quality of evidence due to indirectness (comparison of two interim treatment modalities) and imprecision in effect estimates

Retention at 3 months

16/55 versus 1/51 (p < 0.001) (Krook et al. 2002) [35]

Access to Standard OAT (2 studies)

Interim versus Waiting List for Standard OAT (2 studies)

Moderate quality of evidence due to risk of bias (although trials were at low risk of selection bias, were limited in terms of performance, detection and attrition bias)

Access at 4 months

151/199 versus 25/120 (p < 0.001) (Schwartz et al. 2006) [21]

Access at 10 months

129/199 versus 33/120 (p < 0.001) (Schwartz et al. 2006) [21]

Access at 16 months

107/149 versus 85/152 (p < 0.005) (Yancovitz et al. 1991) [44]

There were no studies that assessed this outcome for the following comparisons:

Interim versus standard OAT

Interim with buprenorphine versus interim with placebo

Quality of Life or Well-Being (1 study)

Interim with Buprenorphine versus Interim with Placebo (1 study)

Low quality of evidence due to indirectness (comparison of two interim treatment modalities) and imprecision in effect estimates

Subjective well-being at 3 months [Visual analogue Scale (VAS); 10 = very bad, 0 = very well]

4.82 (SD not reported) versus 5.92 (SD not reported) (p < 0.001) (Krook et al. 2002) [35]

Change in well-being at 3 months

− 2.00 (Confidence Interval (CI) − 2.95; − 1.04) versus − 0.43 (CI − 1.32;0.45) (p < 0.001) (Krook et al. 2002) [35]

Temporal satisfaction with life scale (TSLS) at 3 months [TSLS; 15 items, 7 point Likert response, 0 = “very well” and 7 = “very bad”]

4.81 (SD not reported) versus 5.11(SD not reported) (p < 0.05) (Krook et al. 2002) [35]

Change in temporal satisfaction with life scale at 3 months

− 0.65 (CI − 1.00; − 0.31) versus − 0.24 (CI − 0.57;0.09) (p < 0.05) (Krook et al. 2002) [35]

There were no studies that assessed this outcome for the following comparisons:

Interim versus waiting list to standard OAT

Interim versus standard OAT

Satisfaction with Treatment (1 study)

Interim versus Waiting List for Standard OAT (1 study)

Very low quality of evidence due to risk of bias (some concerns about selection bias, and high risk for performance and attrition bias), indirectness (effect estimate obtained only from the intervention arm from one trial) and imprecision in effect estimates

User satisfaction for patients at the interim intervention group at 3 months [according to a 5-point Likert score, with a higher score corresponding to greater satisfaction]

4.6 (SD 0.7) (NCT02360007) [41]

There were no studies that assessed this outcome for the following comparisons:

Interim versus standard OAT

Interim with buprenorphine versus interim with placebo

SECONDARY OUTCOMES

Use of Illicit Drugs and/or Non-Prescribed Psychoactive Substances (Heroin Positive Urine Tests) (4 studies)

Interim versus Waiting List for Standard OAT (3 studies)

At 1 month

22/75 versus 56/94 (Odds Ratio (OR) 3.55; CI 95% 1.862–6.771) (p < 0.001) (Yancovitz et al. 1991) [44]

At 3 months

17/25 versus 0/25 (number of negative tests) (p < 0.001) (NCT02360007) [41]

At 4 months

99/175 versus 80/113 (p < 0.001) (Schwartz et al. 2006) [21]

At 10 months

75/156 versus 73/101 (p = 0.001) (Schwartz et al. 2006) [21]

Interim versus Standard OAT (1 study)

At 4 months

44/96 versus 47/92 with SM versus 10/25 with RM (p = 0.98) (NCT00712036) [37]

At 12 months

0.46 (Standard error (SE) 0.05) versus 0.48 (SE 0.05) with SM versus 0.51 (SE 0.11) with RM (p = 0.91) (NCT00712036) [37]

There were no studies that assessed this outcome for the following comparison:

Interim with buprenorphine versus interim with placebo

Use of Illicit Drugs and/or Non-Prescribed Psychoactive Substances (Heroin Self-Reported) (4 studies)

Interim versus Waiting List for Standard OAT (2 studies)

At 1 month

21/75 versus 83/94 (p < 0.001) (Yancovitz et al. 1991) [44]

At 4 months

Days of heroin use in the past 30 days: 4.2 (SD 8.6) versus 26.4 (SD 8.8) (p < 0.001) (Schwartz et al. 2006) [21]

At 10 months

Days of heroin use in the past 30 days: 5.7 (SE 0.90) versus 17.7 (SE 1.2) (p < 0.001) (Schwartz et al. 2006) [21]

Interim versus Standard OAT (1 study)

At 4 months

Days of heroin use in the past 30 days: 2.6 (SE 0.5) versus 3.6 (SE 0.8) with SM versus 2.8 (SE 1.0) with RM (p = 0.21) (NCT00712036) [37]

At 12 months

Days of heroin use in the past 30 days: 4.4 (SE 0.98) versus 6.2 (SE 1.2) with SM versus 6.9 (SE 2.4) with RM (p = 0.57) (NCT00712036) [37]

Interim with Buprenorphine versus Interim with Placebo (1 study)

At 3 months

3.99 (SD not reported) versus 6.63 (SD not reported) (using a VAS from 0 = “drug free” to 10 = “daily heavy drug abuse”) (p < 0.001) (Krook et al. 2002) [35]

Change in self-reported heroin use

− 3.21 (CI − 4.29; − 2.13) versus 0.52 (− 0.64; 1.68) (p < 0.001) (Krook et al. 2002) [35]

Use of Illicit Drugs and/or Non-Prescribed Psychoactive Substances

(Cocaine Positive Urine Tests)

(3 studies)

Interim versus Waiting List for Standard OAT (2 studies)

At 1 month

51/75 versus 66/94 (OR 1.109; CI 95% 0.575–2.138) (p = 0.76) (Yancovitz et al. 1991) [44]

At 4 months

107/174 versus 62/99 At 10 months (p = 0.85) (Schwartz et al. 2006) [21]

At 10 months

79/153 versus 60/101 (no significant differences) (Schwartz et al. 2006) [21]

Interim versus Standard OAT (1 study)

At 4 months

32/96 versus 41/92 with SM versus 6/25 with RM (p = 0.75) (NCT00712036) [37]

At 12 months

0.39 (SE 0.05) versus 0.36 (SE 0.05) with SM versus 0.32 (SE 0.10) with RM (p = 0.23) (NCT00712036) [37]

There were no studies that assessed this outcome for the following comparison:

Interim with buprenorphine versus interim with placebo

Use of Illicit Drugs and/or Non-Prescribed Psychoactive Substances

(Cocaine Self-Reported)

(3 studies)

Interim versus Waiting List for Standard OAT (2 studies)

At 1 month

29/75 versus 79/94 (p < 0.001) (Yancovitz et al. 1991) [44]

At 4 months

Days of cocaine use in the last 30 days: 2.4 (SD 5.5) versus 5.8 (SD 8.8) (p < 0.001) (Schwartz et al. 2006) [21]

At 10 months

Days of cocaine use in the last 30 days: 3.5 (SE 0.63) versus 5.8 (SE 0.83) (p = 0.001) (Schwartz et al. 2006) [21]

Interim versus standard OAT (1 study)

At 4 months

Days of cocaine use in the last 30 days: 1.6 (SE 3.8) versus 3.0 (SE 7.3) with SM versus 1.4 (SE 0.8) with RM (p = 0.082) (NCT00712036) [37]

At 12 months

Days of cocaine use in the last 30 days: 1.8 (SE 0.62) versus 2.9 (SE 0.74) with SM versus 1.0 (SE 0.82) with RM (p = 0.42) (NCT00712036) [37]

There were no studies that assessed this outcome for the following comparison:

Interim with buprenorphine versus interim with placebo

Use of Illicit Drugs and/or Non-Prescribed Psychoactive Substances

(Non-Prescribed Methadone Self-Reported)

(1 study)

Interim versus Waiting List for Standard OAT (1 study)

At 1 month

1/75 versus 37/94 (p < 0.001) (Yancovitz et al. 1991) [44]

There were no studies that assessed this outcome for the following comparisons:

Interim versus standard OAT

Interim with buprenorphine versus interim with placebo

Use of Illicit Drugs and/or Non-Prescribed Psychoactive Substances

(Other Drugs Self-Reported)

(1 study)

Interim with Buprenorphine versus Interim with Placebo (1 study)

At 3 months

3.56 (SD not reported) versus 4.4 (SD not reported) (using a VAS from 0 = “drug free” to 10 = “daily heavy drug abuse”) (p < 0.01) (Krook et al. 2002) [35]

Change in self-reported use of other drugs

0.66 (CI − 1.77; 0.44) versus 1.11 (CI 0.18; 2.05) (p < 0.01) (Krook et al. 2002) [35]

There were no studies that assessed this outcome for the following comparisons:

Interim versus waiting list to standard OAT

Interim versus standard OAT

Criminal Activities/Illegal Income

(Illegal Income)

(2 studies)

Interim versus Waiting List for Standard OAT (1 study)

At 4 months

36$ (SD 160) versus 412$ (SD 1391) (p < 0.02) (Schwartz et al. 2006) [21]

At 10 months

40$ (SE 18.21) versus 135$ (SE 23.69) (p = 0.018) (Schwartz et al. 2006) [21]

Interim versus Standard OAT (1 study)

At 4 months

8$ (SE 3) versus 336$ (SE 287) with SM versus 113$ (SE 113) with RM (p < 0.001) (NCT00712036) [37]

At 12 months

27$ (SE 12) versus 55$ (SE 19) with SM versus 14$ (SE 14) with RM (p < 0.001) (NCT00712036) [37]

There were no studies that assessed this outcome for the following comparison:

Interim with buprenorphine versus interim with placebo

Criminal Activities/Illegal Income

(Illegal Activities)

(2 studies)

Interim versus Waiting List for Standard OAT (1 study)

At 4 months

1.7 days (SE 0.60) versus 6.9 (SE 0.79) (p < 0.001) (Schwartz et al. 2006) [21]

At 10 months

2.1 days (SE 0.67) versus 7.3 (SE 0.88) (p < 0.001) (Schwartz et al. 2006) [21]

Interim versus Standard OAT (1 study)

At 4 months

0.48 days (SE 0.29) versus 1.11 (SE 0.47) with SM versus 1.13 (SE 1.13) with RM (p = 0.003) (NCT00712036) [37]

At 12 months

0.96 days (SE 0.47) versus 2.00 (SE 0.66) with SM versus 1.30 (SE 1.20) with RM (p = 0.46) (NCT00712036) [37]

There were no studies that assessed this outcome for the following comparison:

Interim with buprenorphine versus interim with placebo

Criminal Activities/Illegal Income

(Arrests)

(1 study)

Interim versus Waiting List for Standard OAT (1 study)

At 6 months

Number of participants arrested: 31/198 versus 24/119 (p = 0.18) (Schwartz et al. 2006) [21]

Mean number of arrests: 0.2 arrests (SE 0.06) versus 0.34 arrests (SE 0.09) (p = 0.02) (Schwartz et al. 2006) [21]

At 12 months

Number of participants arrested: 53/198 versus 31/119 (p = 0.96) (Schwartz et al. 2006) [21]

Mean number of arrests: 0.33 (SE 0.09) versus 0.39 (SE 0.11) (p = 0.16) (Schwartz et al. 2006) [21]

At 24 months

Number of participants arrested: 77/198 versus 54/119 (p = 0.75) (Schwartz et al. 2006) [21]

Mean number of arrests: 0.61 (SE 0.14) versus 0.76 (SE 0.18) (p = 0.16) (Schwartz et al. 2006) [21]

There were no studies that assessed this outcome for the following comparisons:

Interim versus standard OAT

Interim with buprenorphine versus interim with placebo

Criminal Activities/Illegal Income

(Severe Crimes)

(1 study)

Interim versus Waiting List for Standard OAT (1 study)

At 6 months

6/198 versus 1/119 (p = 0.23) (Schwartz et al. 2006) [21]

At 12 months

7/198 versus 3/119 (p = 0.62) (Schwartz et al. 2006) [21]

At 24 months

10/198 versus 6/119 (p = 1.0) (Schwartz et al. 2006) [21]

There were no studies that assessed this outcome for the following comparisons:

Interim versus standard OAT

Interim with buprenorphine versus interim with placebo

Mental/Physical Health

(Mental Health)

(3 studies)

Interim versus Waiting List for Standard OAT (1 study)

Global Severity Index (GSI) above cut-off at 3 months [a widely used indicator for distress, using a cut-off > or = 63]

7/23 versus 13/25 (significance not reported) (NCT02360007) [41]; this trial also reports more data on mental health (Beck Anxiety Inventory, Beck Depression Inventory, Brief Symptom Inventory and Addiction Severity Index (ASI) Psychiatric composite score) but further data could not be extracted because the authors reported the significances of the change in mean measures, but not the actual measures

Interim versus Standard OAT (1 study)

Psychiatric ASI composite score at 4 months [score ranging from 0 = “no problem” to 1 = “extreme problem”]

0.05 (SE 0.01) versus 0.02 (SE 0.01) with SM versus 0.01 (SE 0.02) with RM (p = 0.75) (NCT00712036) [37]

Psychiatric ASI composite score at 12 months

0.06 (SE 0.02) versus 0.06 (SE 0.02) with SM versus 0.02 (SE 0.03) with RM (p = 0.61) (NCT00712036) [37]

Interim with Buprenophine versus Interim with Placebo (1 study)

Anxiety and depression at 3 months [measured with Symptom Checklist-5 on a four-point scale ranging from 1 = ‘not at all’ to 4 = ‘extremely’]

2.51 (SD not reported) versus 2.63 (SD not reported) (no significant difference) (Krook et al. 2002) [35]

Change in anxiety and depression (at 3 months)

− 0.3 (CI − 0.52; − 0.08) versus − 0.17 (CI − 0.40; 0.07) (no significant difference) (Krook et al. 2002) [35]

Mental/Physical Health

(Physical Health)

(2 studies)

Interim versus Waiting List for Standard OAT (1 study)

One study (Schwartz et al. 2006) [21] reports on Human Immunodeficiency Virus (HIV) risk behaviors, but data could not be extracted as the authors only report p-values and statistic test results

Interim versus Standard OAT (1 study)

Medical ASI Composite score at 4 months [score ranging from 0 = “no problem” to 1 = “extreme problem”]

0.13 (SE 0.03) versus 0.10 (SE 0.03) with SM versus 0.19 (SE 0.06) with RM (p = 0.70) (NCT00712036) [37]

HIV risk in injector subsample at 4 months

0.08 (SE 0.06) times injected with unsterilized needles versus 0.00 (SE 0.05) with SM versus 0.04 (SE 0.04) with RM (p > 0.05) (NCT00712036) [37]

Medical ASI Composite score at 12 months

0.19 (SE 0.03) versus 0.12 (SE 0.03) with SM versus 0.12 (SE 0.06) with RM (p = 0.56) (NCT00712036) [37]

HIV risk in injector subsample at 12 months

0.00 (SE 0.00) times injected with unsterilized needles versus 0.00 (SE 0.0) with SM versus 0.00 (SE 0.0) with RM (p > 0.05) (NCT00712036) [37]

There were no studies that assessed this outcome for the following comparison:

Interim with buprenorphine versus interim with placebo

Adverse Effects (2 studies)

Interim versus Standard OAT (1 study)

Number of participants with at least one serious adverse effect at 12 months

19/99 versus 9/104 with SM versus 4/27 with RM (NCT00712036) [37]

Interim with Buprenophine versus Interim with Placebo (1 study)

One trial narratively reported that no deaths or other serious side effects were observed during the 3 months of follow-up but provided no data (Krook et al. 2002) [35]

There were no studies that assessed this outcome for the following comparison:

Interim versus waiting list to standard maintenance treatment