Alpha<sub>2</sub>‐adrenergic agonists for the management of opioid withdrawal

Linda Gowing; Michael Farrell; Robert Ali; Jason M White

doi:10.1002/14651858.CD002024.pub5

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Figure 1

Study flow diagram.

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Figure 2

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

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Figure 3

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

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Comparison 1 Alpha2‐adrenergic agonist versus placebo, Outcome 1 Peak withdrawal score.

Analysis 1.1

Comparison 1 Alpha₂‐adrenergic agonist versus placebo, Outcome 1 Peak withdrawal score.

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Comparison 1 Alpha2‐adrenergic agonist versus placebo, Outcome 2 Participants with severe withdrawal.

Analysis 1.2

Comparison 1 Alpha₂‐adrenergic agonist versus placebo, Outcome 2 Participants with severe withdrawal.

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Comparison 1 Alpha2‐adrenergic agonist versus placebo, Outcome 3 Completion of treatment.

Analysis 1.3

Comparison 1 Alpha₂‐adrenergic agonist versus placebo, Outcome 3 Completion of treatment.

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Comparison 2 Alpha2‐adrenergic agonist versus methadone, Outcome 1 Peak withdrawal score.

Analysis 2.1

Comparison 2 Alpha₂‐adrenergic agonist versus methadone, Outcome 1 Peak withdrawal score.

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Comparison 2 Alpha2‐adrenergic agonist versus methadone, Outcome 2 Participants with severe withdrawal.

Analysis 2.2

Comparison 2 Alpha₂‐adrenergic agonist versus methadone, Outcome 2 Participants with severe withdrawal.

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Comparison 2 Alpha2‐adrenergic agonist versus methadone, Outcome 3 Overall withdrawal severity.

Analysis 2.3

Comparison 2 Alpha₂‐adrenergic agonist versus methadone, Outcome 3 Overall withdrawal severity.

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Comparison 2 Alpha2‐adrenergic agonist versus methadone, Outcome 4 Duration of treatment.

Analysis 2.4

Comparison 2 Alpha₂‐adrenergic agonist versus methadone, Outcome 4 Duration of treatment.

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Comparison 2 Alpha2‐adrenergic agonist versus methadone, Outcome 5 Number experiencing hypotensive or other adverse effects.

Analysis 2.5

Comparison 2 Alpha₂‐adrenergic agonist versus methadone, Outcome 5 Number experiencing hypotensive or other adverse effects.

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Comparison 2 Alpha2‐adrenergic agonist versus methadone, Outcome 6 Drop‐out due to adverse effects.

Analysis 2.6

Comparison 2 Alpha₂‐adrenergic agonist versus methadone, Outcome 6 Drop‐out due to adverse effects.

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Comparison 2 Alpha2‐adrenergic agonist versus methadone, Outcome 7 Completion of treatment.

Analysis 2.7

Comparison 2 Alpha₂‐adrenergic agonist versus methadone, Outcome 7 Completion of treatment.

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Comparison 2 Alpha2‐adrenergic agonist versus methadone, Outcome 8 Completion of treatment by opioid.

Analysis 2.8

Comparison 2 Alpha₂‐adrenergic agonist versus methadone, Outcome 8 Completion of treatment by opioid.

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Comparison 2 Alpha2‐adrenergic agonist versus methadone, Outcome 9 Completion of treatment by setting.

Analysis 2.9

Comparison 2 Alpha₂‐adrenergic agonist versus methadone, Outcome 9 Completion of treatment by setting.

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Summary of findings for the main comparison. Alpha2‐adrenergic agonist versus methadone for the management of opioid withdrawal

Alpha₂‐adrenergic agonist versus methadone for the management of opioid withdrawal
Patient or population: People undergoing managed opioid withdrawal Settings: Intervention: Alpha₂‐adrenergic agonist versus methadone
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control	Alpha₂‐adrenergic agonist versus methadone
Participants with severe withdrawal	Study population		RR 1.18 (0.81 to 1.73)	340 (5 studies)	⊕⊕⊝⊝ low^1,2	‐
	205 per 1000	242 per 1000 (166 to 354)
	Moderate
	80 per 1000	94 per 1000 (65 to 138)
Peak withdrawal score	‐	The mean peak withdrawal score in the intervention groups was 0.22 standard deviations higher (0.02 lower to 0.46 higher)	‐	263 (2 studies)	⊕⊕⊕⊝ moderate³	SMD 0.22 (‐0.02 to 0.46)
Overall withdrawal severity	‐	The mean overall withdrawal severity in the intervention groups was 0.13 standard deviations higher (0.24 lower to 0.49 higher)	‐	119 (3 studies)	⊕⊕⊕⊝ moderate³	SMD 0.13 (‐0.24 to 0.49)
Duration of treatment	‐	The mean duration of treatment in the intervention groups was 1.07 standard deviations lower (1.31 to 0.83 lower)	‐	310 (3 studies)	⊕⊕⊝⊝ low^3,4	SMD ‐1.07 (‐1.31 to ‐0.83)
Number experiencing hypotensive or other adverse effects	Study population		RR 1.92 (1.19 to 3.10)	464 (6 studies)	⊕⊕⊝⊝ low^2,5	‐
	79 per 1000	151 per 1000 (93 to 243)
	Moderate
	33 per 1000	63 per 1000 (39 to 102)
Drop‐out due to adverse effects	Study population		RR 3.62 (0.77 to 16.94)	153 (4 studies)	⊕⊕⊝⊝ low²	‐
	0 per 1000	0 per 1000 (0 to 0)
	Moderate
	0 per 1000	0 per 1000 (0 to 0)
Completion of treatment	Study population		RR 0.85 (0.69 to 1.05)	659 (9 studies)	⊕⊕⊝⊝ low^6,7	‐
	568 per 1000	483 per 1000 (392 to 597)
	Moderate
	750 per 1000	638 per 1000 (517 to 787)
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (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; RR: risk ratio; SMD: standardised mean difference.
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹One study at risk of selection bias, one at risk of performance and detection bias. ²Small number of events. ³Small number of participants. ⁴One study at risk of selection bias, one at risk of bias related to mandatory treatment. ⁵One study at risk of selection bias. ⁶Two studies at high risk of selection bias. ⁷Significant heterogeneity present.

Summary of findings for the main comparison. Alpha2‐adrenergic agonist versus methadone for the management of opioid withdrawal

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Summary of findings 2. Alpha2‐adrenergic agonist versus placebo for the management of opioid withdrawal

Alpha₂‐adrenergic agonist versus placebo for the management of opioid withdrawal
Patient or population: People undergoing managed opioid withdrawal Settings: Intervention: Alpha₂‐adrenergic agonist versus placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control	Alpha₂‐adrenergic agonist versus placebo
Participants with severe withdrawal	Study population		RR 0.32 (0.18 to 0.57)	148 (3 studies)	⊕⊕⊕⊝ moderate¹	‐
	589 per 1000	188 per 1000 (106 to 336)
	Moderate
	800 per 1000	256 per 1000 (144 to 456)
Completion of treatment	Study population		RR 1.95 (1.34 to 2.84)	148 (3 studies)	⊕⊕⊕⊝ moderate¹	‐
	288 per 1000	561 per 1000 (385 to 817)
	Moderate
	333 per 1000	649 per 1000 (446 to 946)
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (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; RR: risk ratio.
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹Small number of events.

Summary of findings 2. Alpha2‐adrenergic agonist versus placebo for the management of opioid withdrawal

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Comparison 1. Alpha2‐adrenergic agonist versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Peak withdrawal score Show forest plot	2		Std. Mean Difference (IV, Random, 95% CI)	Totals not selected

2 Participants with severe withdrawal Show forest plot	3	148	Risk Ratio (M‐H, Random, 95% CI)	0.32 [0.18, 0.57]

3 Completion of treatment Show forest plot	3	148	Risk Ratio (M‐H, Random, 95% CI)	1.95 [1.34, 2.84]

Comparison 1. Alpha2‐adrenergic agonist versus placebo

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Comparison 2. Alpha2‐adrenergic agonist versus methadone

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Peak withdrawal score Show forest plot	2	263	Std. Mean Difference (IV, Random, 95% CI)	0.22 [‐0.02, 0.46]

2 Participants with severe withdrawal Show forest plot	5	340	Risk Ratio (M‐H, Random, 95% CI)	1.18 [0.81, 1.73]

3 Overall withdrawal severity Show forest plot	3	119	Std. Mean Difference (IV, Random, 95% CI)	0.13 [‐0.24, 0.49]

4 Duration of treatment Show forest plot	3	310	Std. Mean Difference (IV, Random, 95% CI)	‐1.07 [‐1.31, ‐0.83]

5 Number experiencing hypotensive or other adverse effects Show forest plot	6	464	Risk Ratio (M‐H, Random, 95% CI)	1.92 [1.19, 3.10]

6 Drop‐out due to adverse effects Show forest plot	4	153	Risk Ratio (M‐H, Random, 95% CI)	3.62 [0.77, 16.94]

7 Completion of treatment Show forest plot	9	659	Risk Ratio (M‐H, Random, 95% CI)	0.85 [0.69, 1.05]

8 Completion of treatment by opioid Show forest plot	9	657	Risk Ratio (M‐H, Random, 95% CI)	0.90 [0.73, 1.11]

8.1 Heroin	4	293	Risk Ratio (M‐H, Random, 95% CI)	0.87 [0.61, 1.25]
8.2 Methadone	5	364	Risk Ratio (M‐H, Random, 95% CI)	0.97 [0.80, 1.18]
9 Completion of treatment by setting Show forest plot	9	657	Risk Ratio (M‐H, Random, 95% CI)	0.90 [0.73, 1.11]

9.1 Inpatient	5	467	Risk Ratio (M‐H, Random, 95% CI)	0.87 [0.68, 1.12]
9.2 Outpatient	4	190	Risk Ratio (M‐H, Random, 95% CI)	1.09 [0.73, 1.64]

Comparison 2. Alpha2‐adrenergic agonist versus methadone

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