Buprenorphine for managing opioid withdrawal

Linda Gowing; Robert Ali; Jason M White; Dalitso Mbewe

doi:10.1002/14651858.CD002025.pub5

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Figure 1

Study flow diagram.

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Figure 2

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

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Figure 3

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

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Analysis 1.1

Comparison 1 Buprenorphine versus methadone, Outcome 1 Mean days in treatment.

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Analysis 1.2

Comparison 1 Buprenorphine versus methadone, Outcome 2 Completion of withdrawal treatment.

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Analysis 2.1

Comparison 2 Buprenorphine versus clonidine, Outcome 1 Mean peak withdrawal score.

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Analysis 2.2

Comparison 2 Buprenorphine versus clonidine, Outcome 2 Mean overall withdrawal score.

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Analysis 2.3

Comparison 2 Buprenorphine versus clonidine, Outcome 3 Mean days in treatment.

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Analysis 2.4

Comparison 2 Buprenorphine versus clonidine, Outcome 4 Number experiencing adverse effects.

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Analysis 2.5

Comparison 2 Buprenorphine versus clonidine, Outcome 5 Number with treatment stopped due to adverse effects.

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Analysis 2.6

Comparison 2 Buprenorphine versus clonidine, Outcome 6 Number completing withdrawal treatment.

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Analysis 3.1

Comparison 3 Rapid versus slow dose taper, Outcome 1 Completion of withdrawal treatment.

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Analysis 3.2

Comparison 3 Rapid versus slow dose taper, Outcome 2 Number abstinent at completion of dose taper.

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Summary of findings for the main comparison. Buprenorphine vs methadone for managing opioid withdrawal

Buprenorphine versus methadone for managing opioid withdrawal
Patient or population: Adults with opioid dependence Setting: Inpatient or outpatient Intervention: Buprenorphine Comparison: Methadone
Outcomes	*Anticipated absolute effects (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Quality of the evidence (GRADE)
	Risk with methadone	Risk with buprenorphine
Mean days in treatment	The mean days in treatment in the methadone group was 10.8 or 48.5 days.	The mean days in treatment in the buprenorphine group was 1.3 more (8.1 less to 10.7 more) than in the methadone group.	—	82 (2 RCTs)	⊕⊕⊝⊝ Low^a,b
Completion of withdrawal treatment	Study population		RR 1.04 (0.91 to 1.20)	457 (5 RCTs)	⊕⊕⊕⊝ Moderate^b
	528 per 1000	549 per 1000 (481 to 634)
	Moderate
	534 per 1000	555 per 1000 (486 to 641)
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RCT: randomised controlled trial; RR: risk ratio; OR: odds ratio.
GRADE Working Group grades of evidence High quality: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate quality: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low quality: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low quality: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
^aStudies were conducted in different settings (inpatient and outpatient). ^bSmall number of participants (N < 300).

Summary of findings for the main comparison. Buprenorphine vs methadone for managing opioid withdrawal

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Summary of findings 2. Buprenorphine vs alpha2‐adrenergic agonists for managing opioid withdrawal

Buprenorphine vs alpha₂‐adrenergic agonists for managing opioid withdrawal
Patient or population: Adults or adolescents with opioid dependence Setting: Inpatient or outpatient Intervention: Buprenorphine Comparison: Alpha₂‐adrenergic agonists (clonidine or lofexidine)
Outcomes	*Anticipated absolute effects (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Quality of the evidence (GRADE)
	Risk with alpha₂‐adrenergic agonists	Risk with buprenorphine
Mean peak withdrawal score, assessed with various scales	Not able to be summarised due to different means of assessment	The mean peak withdrawal score was lower in the buprenorphine group, indicating less severity, with a standardised mean difference of 0.43, which is a moderate effect size	SMD ‐0.43 (‐0.74 to ‐0.13)	521 (6 RCTs)	⊕⊝⊝⊝ Very low^a,b,c,d
Mean overall withdrawal score, with various methods of assessment	Not able to be summarised due to different means of assessment	The mean overall withdrawal score was lower in the buprenorphine group, indicating less severity, with a standardised mean difference of 0.43, which is a moderate effect size	SMD ‐0.43 (‐0.58 to ‐0.28)	902 (7 RCTs)	⊕⊕⊕⊝ Moderate^a
Mean days in treatment (with varying scheduled duration)	Mean days in treatment ranged across studies from 21% to 70% of scheduled treatment duration	Mean days in treatment ranged across studies from 25% to 97% of scheduled treatment duration, with a standardised mean difference of 0.92, which is a large effect size.	SMD 0.92 (0.57 to 1.27)	558 (4 RCTs)	⊕⊕⊕⊝ Moderate^c,d
Number experiencing adverse effects	Study population		RR 0.93 (0.70 to 1.26)	493 (3 RCTs)	⊕⊝⊝⊝ Very low^a,b,c
	289 per 1000	269 per 1000 (202 to 364)
	Moderate
	127 per 1000	118 per 1000 (89 to 160)
Number with treatment stopped due to adverse effects	Study population		RR 0.20 (0.04 to 1.15)	134 (3 RCTs)	⊕⊕⊝⊝ Low^b
	90 per 1000	18 per 1000 (4 to 103)
	Moderate
	79 per 1000	16 per 1000 (3 to 91)
Number completing withdrawal treatment	Study population		RR 1.59 (1.23 to 2.06)	1264 (11 RCTs)	⊕⊕⊕⊝ Moderate^d
	453 per 1000	721 per 1000 (558 to 934)
	Moderate
	536 per 1000	852 per 1000 (659 to 1000)
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RCT: randomised controlled trial; RR: risk ratio; OR: odds ratio.
GRADE Working Group grades of evidence High quality: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate quality: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low quality: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low quality: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
^aRisk of bias in blinding of subjective outcomes. ^bSmall number of events (n < 300). ^cDifferent treatment settings (outpatient and inpatient). ^dHeterogeneity > 60%.

Summary of findings 2. Buprenorphine vs alpha2‐adrenergic agonists for managing opioid withdrawal

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Summary of findings 3. Rapid vs slow taper of buprenorphine dose for managing opioid withdrawal

Rapid versus slow taper of buprenorphine dose for managing opioid withdrawal
Patient or population: Adults or adolescents with opioid dependence Setting: Inpatient or outpatient Intervention: Rapid Comparison: Slow dose taper
Outcomes	*Anticipated absolute effects (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Quality of the evidence (GRADE)
	Risk with slow dose taper	Risk with rapid taper
Completion of withdrawal treatment − Inpatient	Study population		RR 1.00 (0.84 to 1.18)	60 (2 RCTs)	⊕⊕⊝⊝ Low^a
	900 per 1000	900 per 1000 (756 to 1000)
	Moderate
	900 per 1000	900 per 1000 (756 to 1000)
Completion of withdrawal treatment − Outpatient	Study population		RR 0.86 (0.44 to 1.70)	647 (4 RCTs)	⊕⊝⊝⊝ Very low^b,c
	594 per 1000	511 per 1000 (261 to 1000)
	Moderate
	636 per 1000	547 per 1000 (280 to 1000)
Number abstinent at completion of dose taper − Inpatient	Study population		RR 1.00 (0.81 to 1.23)	40 (1 RCT)	⊕⊕⊝⊝ Low^a,d
	900 per 1000	900 per 1000 (729 to 1000)
	Moderate
	900 per 1000	900 per 1000 (729 to 1000)
Number abstinent at completion of dose taper − Outpatient	Study population		RR 0.94 (0.39 to 2.24)	619 (4 RCTs)	⊕⊝⊝⊝ Very low^b,c
	320 per 1000	301 per 1000 (125 to 717)
	Moderate
	337 per 1000	317 per 1000 (131 to 755)
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval;RCT: randomised controlled trial; RR: risk ratio; OR: odds ratio.
GRADE Working Group grades of evidence High quality: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate quality: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low quality: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low quality: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
^aSmall number of events (n < 300). ^bHigh degree of heterogeneity (>75%). ^cMost studies small. ^dOnly one study.

Summary of findings 3. Rapid vs slow taper of buprenorphine dose for managing opioid withdrawal

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Comparison 1. Buprenorphine versus methadone

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mean days in treatment Show forest plot	2	82	Mean Difference (IV, Random, 95% CI)	1.30 [‐8.11, 10.72]

2 Completion of withdrawal treatment Show forest plot	5	457	Risk Ratio (M‐H, Random, 95% CI)	1.04 [0.91, 1.20]

Comparison 1. Buprenorphine versus methadone

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Comparison 2. Buprenorphine versus clonidine

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mean peak withdrawal score Show forest plot	6	521	Std. Mean Difference (IV, Random, 95% CI)	‐0.43 [‐0.74, ‐0.13]

2 Mean overall withdrawal score Show forest plot	7	902	Std. Mean Difference (IV, Random, 95% CI)	‐0.43 [‐0.58, ‐0.28]

3 Mean days in treatment Show forest plot	4	558	Std. Mean Difference (IV, Random, 95% CI)	0.92 [0.57, 1.27]

3.1 Inpatient setting	3	213	Std. Mean Difference (IV, Random, 95% CI)	1.00 [0.33, 1.67]
3.2 Outpatient setting	2	345	Std. Mean Difference (IV, Random, 95% CI)	0.82 [0.57, 1.06]
4 Number experiencing adverse effects Show forest plot	3	493	Risk Ratio (M‐H, Random, 95% CI)	0.93 [0.70, 1.26]

4.1 Inpatient	2	148	Risk Ratio (M‐H, Random, 95% CI)	0.41 [0.12, 1.36]
4.2 Outpatient	2	345	Risk Ratio (M‐H, Random, 95% CI)	1.02 [0.66, 1.58]
5 Number with treatment stopped due to adverse effects Show forest plot	3	134	Risk Ratio (M‐H, Random, 95% CI)	0.20 [0.04, 1.15]

5.1 Inpatient	3	134	Risk Ratio (M‐H, Random, 95% CI)	0.20 [0.04, 1.15]
5.2 Outpatient	0	0	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
6 Number completing withdrawal treatment Show forest plot	11	1264	Risk Ratio (M‐H, Random, 95% CI)	1.59 [1.23, 2.06]

6.1 Inpatient	6	539	Risk Ratio (M‐H, Random, 95% CI)	1.74 [1.05, 2.89]
6.2 Outpatient	6	725	Risk Ratio (M‐H, Random, 95% CI)	1.45 [1.12, 1.88]

Comparison 2. Buprenorphine versus clonidine

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Comparison 3. Rapid versus slow dose taper

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Completion of withdrawal treatment Show forest plot	6		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.1 Inpatient	2	60	Risk Ratio (M‐H, Random, 95% CI)	1.0 [0.84, 1.18]
1.2 Outpatient	4	647	Risk Ratio (M‐H, Random, 95% CI)	0.86 [0.44, 1.70]
2 Number abstinent at completion of dose taper Show forest plot	5		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

2.1 Inpatient	1	40	Risk Ratio (M‐H, Random, 95% CI)	1.0 [0.81, 1.23]
2.2 Outpatient	4	610	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.39, 2.24]

Comparison 3. Rapid versus slow dose taper

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