Фармакологические вмешательства для прекращения приёма бензодиазепинов у хронических потребителей бензодиазепинов
Appendices
Appendix 1. Search strategy for Cochrane Drugs and Alcohol Group's Specialised Register of Trials
1. ((benzodiazepine* ):xdi) AND (INREGISTER)
2. ((((benzodiazepine* OR chlordiazepoxide OR diazepam OR alprazolam OR lorazepam OR prazepam OR clobazam OR bromazepam OR flurazepam OR triazolam OR clonazepam OR temazepam OR nitrazepam OR lormetazepam OR flunitrazepam OR oxazepam OR zopiclone OR zolpidem OR zaleplone OR eszopiclone) NEAR3 (abuse* OR abusing OR addict* OR chronic OR dependen* OR 'long‐term' OR 'misus* OR overuse)))) AND (INREGISTER)
3. #1 OR #2
4. (((abstinen* OR abstain* OR cessat* OR detox* OR discontinu* OR reduce* OR reducing OR reduct* OR stop* OR taper* OR withdraw* OR substitut*))) AND (INREGISTER)
5. #3 AND #4
Appendix 2. Search strategy for the Cochrane Central Register of Controlled Trials (CENTRAL)
1. MeSH descriptor: [Substance‐Related Disorders] this term only
2. (benzodiazepine* near (abuse* or abusing or addict* or chronic or dependen* or 'long‐term' or 'misus* or overuse)):ti,ab,kw (Word variations have been searched)
3. MeSH descriptor: [Substance Withdrawal Syndrome] this term only
4. #1 or #2 or #3
5. (benzodiazepine* or BZD or chlordiazepoxide or diazepam or alprazolam or lorazepam or prazepam or clobazam or bromazepam or flurazepam or triazolam or clonazepam or temazepam or nitrazepam or lormetazepam or flunitrazepam or oxazepam or zopiclone or zolpidem or zaleplone or eszopiclone):ti,ab,kw (Word variations have been searched)
6. MeSH descriptor: [Benzodiazepines] explode all trees
7. #5 or #6
8. (abstinen* or abstain* or cessat* or detox* or discontinu* or reduce* or reducing or reduct* or stop* or taper* or withdraw* or substitut*):ti,ab,kw (Word variations have been searched)
9. #4 and #7 and #8 in Trials
Appendix 3. PubMed search strategy
1. "Substance‐Related Disorders"[Mesh]
2. abuse*[tiab] OR abusing[tiab] OR addict*[tiab] OR chronic[tiab] OR dependen*[tiab] OR “long‐term”[tiab] OR misus*[tiab] OR overuse[tiab]
3. "Substance Withdrawal Syndrome"[Mesh]
4. #1 OR #2 OR #3
5. "Benzodiazepines"[Mesh]
6. Benzodiazepine*[tiab] OR BZD[tiab] OR chlordiazepoxide[tiab] OR diazepam[tiab] OR alprazolam[tiab] OR lorazepam[tiab] OR prazepam[tiab] OR clobazam[tiab] OR bromazepam[tiab] OR flurazepam[tiab] OR triazolam[tiab] OR clonazepam[tiab] OR temazepam[tiab] OR nitrazepam[tiab] OR lormetazepam[tiab] OR flunitrazepam[tiab] OR oxazepam[tiab] or zopiclone[tiab] OR zolpidem[tiab] OR zaleplone[tiab] OR eszopiclone[tiab]
7. #5 OR #6
8. abstinen*[tiab] OR abstain*[tiab] OR cessat*[tiab] OR detox*[tiab] OR discontinu*[tiab] OR reduce*[tiab] OR reducing[tiab] OR reduct* [tiab] OR stop*[tiab] OR taper*[tiab] OR withdraw*[tiab] OR substitut*[tiab]
9. randomised controlled trial [pt]
10. controlled clinical trial [pt]
11. randomised [tiab]
12. placebo [tiab]
13. clinical trials as topic [mesh: noexp]
14. randomly [tiab]
15. trial [ti]
16. #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15
17. animals [mh] NOT humans [mh]
18. #16 NOT #17
19. #4 AND #7 AND #8 AND #18
Appendix 4. Search strategy for Embase
1. substance abuse'/exp OR 'drug dependence'/exp
2. (benzodiazepine* NEAR/6 (abuse* OR abusing OR addict* OR chronic OR dependen* OR 'long‐term' OR 'misus* OR overuse)):ab,ti
3. withdrawal syndrome'/exp
4. #1 OR #2 OR #3
5. benzodiazepine derivative'/exp
6. enzodiazepine*:ab,ti OR BZD:ab,ti OR chlordiazepoxide:ab,ti OR diazepam:ab,ti OR alprazolam:ab,ti OR lorazepam:ab,ti OR prazepam:ab,ti OR clobazam:ab,ti OR bromazepam:ab,ti OR flurazepam:ab,ti OR triazolam:ab,ti OR clonazepam:ab,ti OR temazepam:ab,ti OR nitrazepam:ab,ti OR lormetazepam:ab,ti OR flunitrazepam:ab,ti OR oxazepam:ab,ti OR zopiclone:ab,ti OR zolpidem:ab,ti OR zaleplone:ab,ti OR eszopiclone:ab,ti
7. #5 OR #6
8. abstinen*:ab,ti OR abstain*:ab,ti OR cessat*:ab,ti OR detox*:ab,ti OR discontinu*:ab,ti OR reduce*:ab,ti OR reducing:ab,ti OR reduct* :ab,ti OR stop*:ab,ti OR taper*:ab,ti OR withdraw*:ab,ti OR substitut*:ab,ti
9. #4 AND #7 AND #8
10. 'randomised controlled trial'/exp
11. 'single blind procedure'/exp
12. 'double blind procedure'/exp
13. 'crossover procedure'/exp
14. #10 OR #11 OR #12 OR #13
15. random*:ab,ti
16. placebo*:ab,ti
17. allocat*:ab,ti
18. crossover*:ab,ti
19. 'cross over':ab,ti
20. trial:ti
21. (doubl* NEXT/1 blind*):ab,ti
22. #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21
23. #14 OR #22
24. 'animal'/de
25. 'animal experiment'/de
26. nonhuman'/de
27. #24 OR #25 OR #26
28. 'human'/de
29. #27 AND #28
30. #27 NOT #29
31. #23 NOT #30
32. #9 AND #31
Appendix 5. Search strategy for CINAHL
1. (MH "Substance Use Disorders+")
2. TX (benzodiazepine* N6 (abuse* or abusing or addict* or chronic or dependen* or 'long‐term' or 'misus* or overuse))
3. TI ( (benzodiazepine* N6 (abuse* or abusing or addict* or chronic or dependen* or 'long‐term' or 'misus* or overuse)) ) OR AB ( (benzodiazepine* N6 (abuse* or abusing or addict* or chronic or dependen* or 'long‐term' or 'misus* or overuse)) )
4. (MH "Substance Withdrawal Syndrome+")
5. S1 OR S2 OR S3 OR S4
6. TI ( benzodiazepine* or BZD or chlordiazepoxide or diazepam or alprazolam or lorazepam or prazepam or clobazam or bromazepam or flurazepam or triazolam or clonazepam or temazepam or nitrazepam or lormetazepam or flunitrazepam or oxazepam or zopiclone or zolpidem or zaleplone or eszopiclone ) OR AB ( benzodiazepine* or BZD or chlordiazepoxide or diazepam or alprazolam or lorazepam or prazepam or clobazam or bromazepam or flurazepam or triazolam or clonazepam or temazepam or nitrazepam or lormetazepam or flunitrazepam or oxazepam or zopiclone or zolpidem or zaleplone or eszopiclone )
7. (MH "Antianxiety Agents, Benzodiazepine+")
8. S6 OR S7
9. TX (abstinen* or abstain* or cessat* or detox* or discontinu* or reduce* or reducing or reduct* or stop* or taper* or withdraw* or substitut*)
10. S5 AND S8 AND S9
11. MH "Clinical Trials+"
12. PT Clinical trial
13. TI clinic* N1 trial* or AB clinic* N1 trial*
14. TI ( singl* or doubl* or trebl* or tripl* ) and TI ( blind* or mask* )
15. AB ( singl* or doubl* or trebl* or tripl* ) and AB ( blind* or mask* )
16. TI randomi?ed control* trial* or AB randomi?ed control* trial*
17. MH "Random Assignment"
18. TI random* allocat* or AB random* allocat*
19. MH "Placebos"
20. TI placebo* or AB placebo*
21. MH "Quantitative Studies"
22. S11 OR S12 OR S13 OR S14 OR S15 OR S16 OR S17 OR S18 OR S19 OR S20 OR S21
23. S10 AND S22
24. S10 AND S22Exclude MEDLINE records
Appendix 6. Search strategy for Web of Science
1. TS=((benzodiazepine* OR chlordiazepoxide OR diazepam OR alprazolam OR lorazepam OR prazepam OR clobazam OR bromazepam OR flurazepam OR triazolam OR clonazepam OR temazepam OR nitrazepam OR lormetazepam OR flunitrazepam OR oxazepam OR zopiclone OR zolpidem OR zaleplone OR eszopiclone) NEAR/6 (abuse* OR abusing OR addict* OR chronic OR dependen* OR 'long‐term' OR 'misus* OR overuse))
2. TOPIC: (abstinen* OR abstain* OR cessat* OR detox* OR discontinu* OR reduce* OR reducing OR reduct* OR stop* OR taper* OR withdraw* OR substitut*)
3. #2 AND #1
4. TS= clinical trial* OR TS=research design OR TS=comparative stud* OR TS=evaluation stud* OR TS=controlled trial* OR TS=follow‐up stud* OR TS=prospective stud* OR TS=random* OR TS=placebo* OR TS=(single blind*) OR TS=(double blind*)
5. #4 AND #3
Appendix 7. Criteria for risk of bias
Item | Judgement | Description |
1. Random sequence generation (selection bias) | Low risk | The investigators describe a random component in the sequence generation process such as: random number table; computer random number generator; coin tossing; shuffling cards or envelopes; throwing dice; drawing of lots; minimisation. |
Unclear risk | Insufficient information about the sequence generation process to permit judgement of low or high risk. | |
High risk | The investigators describe a non‐random component in the sequence generation process such as: odd or even date of birth; date (or day) of admission; hospital or clinic record number; alternation; judgement of the clinician; results of a laboratory test or a series of tests; availability of the intervention. | |
2. Allocation concealment (selection bias) | Low risk | Investigators enrolling participants could not foresee assignment because one of the following, or an equivalent method, was used to conceal allocation: central allocation (including telephone, web‐based, and pharmacy‐controlled randomisation); sequentially numbered drug containers of identical appearance; sequentially numbered, opaque, sealed envelopes. |
Unclear risk | Insufficient information to permit judgement of low or high risk. This is usually the case if the method of concealment is not described or not described in sufficient detail to allow a definitive judgement. | |
High risk | Investigators enrolling participants could possibly foresee assignments because one of the following methods was used: open random allocation schedule (e.g. a list of random numbers); assignment envelopes without appropriate safeguards (e.g. if envelopes were unsealed or nonopaque or not sequentially numbered); alternation or rotation; date of birth; case record number; any other explicitly unconcealed procedure. | |
3. Blinding of participants and providers (performance bias) | Low risk | Blinding of participants and key study personnel ensured, and unlikely that the blinding could have been broken. Placebo should be identical to the intervention regarding appearance, colour, solubility, taste, and smell. Or no blinding or incomplete blinding, but the review authors judge that the outcome is not likely to be influenced by lack of blinding. |
Unclear risk | Insufficient information to permit judgement of low or high risk. | |
High risk | No blinding or incomplete blinding, and the outcome is likely to be influenced by lack of blinding. Blinding of key study participants and personnel attempted, but likely that the blinding could have been broken, and the outcome is likely to be influenced by lack of blinding. | |
4.Blinding of outcome assessor (detection bias) | Low risk | Blinding of outcome assessment ensured, and unlikely that the blinding could have been broken. |
Unclear risk | Insufficient information to permit judgement of low or high risk. | |
High risk | No blinding of outcome assessment, and the outcome measurement is likely to be influenced by lack of blinding. OR Blinding of outcome assessment, but it is likely that the blinding could have been broken, and the outcome measurement is likely to be influenced by lack of blinding. | |
5. Incomplete outcome data (attrition bias) | Low risk | No missing outcome data. Reasons for missing outcome data unlikely to be related to true outcome (for survival data, censoring unlikely to be introducing bias). Missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups. For dichotomous outcome data, the proportion of missing outcomes compared with observed event risk not enough to have a clinically relevant impact on the intervention effect estimate. For continuous outcome data, plausible effect size (difference in means or standardised difference in means) among missing outcomes not enough to have a clinically relevant impact on observed effect size. Missing data have been imputed using appropriate methods, e.g. multiple imputation. All randomised participants are reported/analysed in the group to which they were allocated by randomisation irrespective of non‐compliance and co‐interventions (intention to treat). |
Unclear risk | Insufficient information to permit judgement of low or high risk (e.g. number randomised not stated, no reasons for missing data provided; number of dropouts not reported for each group). | |
High risk | Reason for missing outcome data likely to be related to true outcome, with either imbalance in numbers or reasons for missing data across intervention groups. For dichotomous outcome data, the proportion of missing outcomes compared with observed event risk enough to induce clinically relevant bias in intervention effect estimate. For continuous outcome data, plausible effect size (difference in means or standardised difference in means) among missing outcomes enough to induce clinically relevant bias in observed effect size. ‘As‐treated’ analysis done with substantial departure of the intervention received from that assigned at randomisation. | |
6. Selective reporting (reporting bias) | Low risk | The trial protocol is available and all of the trial’s prespecified (primary and secondary) outcomes that are of interest in the review have been reported in the prespecified way. The trial protocol is not available, but it is clear that the published reports include all expected outcomes, including those that were prespecified (convincing text of this nature may be uncommon). |
Unclear risk | Insufficient information to permit judgement of low or high risk. | |
High risk | Not all of the trial’s prespecified primary outcomes have been reported. One or more primary outcomes are reported using measurements, analysis methods, or subsets of the data (e.g. subscales) that were not prespecified. One or more reported primary outcomes were not prespecified (unless clear justification for their reporting is provided, such as an unexpected adverse effect). One or more outcomes of interest in the review are reported incompletely so that they cannot be entered in a meta‐analysis. The trial report fails to include results for a key outcome that would be expected to have been reported for such a trial. | |
7. Other bias including industry bias | Low risk | The trial appears to be free of other components that could put it at risk of bias. |
Unclear risk | The trial may or may not be free of other components that could put it at risk of bias. | |
High risk | There are other factors in the trial that could put it at risk of bias, in particular the risk of industry bias will be evaluated. |
![Study flow diagram.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-AFig-FIG01.png)
Study flow diagram.
![Risk of bias summary: review authors' judgements about each risk of bias item for each included study.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-AFig-FIG02.png)
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
![Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-AFig-FIG03.png)
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
![Trial Sequential Analysis of comparison: 2 Carbamazepine versus placebo, outcome: 2.1 Benzodiazepine discontinuation. Trial Sequential Analysis on benzodiazepine discontinuation in three trials was performed based on the proportion with benzodiazepine discontinuation in the control group set at 48%, a relative risk reduction (RRR) of 20%, a type I error of 2.5%, a type II error of 10% (90% power), and diversity of 36% as observed in the trials. The diversity‐adjusted required information size (DARIS) was 2109 participants, and the Trial Sequential Analysis‐adjusted confidence interval is 0.24 to 2.38. The blue line represents the cumulative Z‐score of the meta‐analysis. The green lines represent the conventional statistical boundaries of P = 5%. The cumulative Z‐curve (blue line) touches the conventional statistical boundaries, but does not cross the trial sequential monitoring boundaries, and the diversity‐adjusted required information size is not met, showing that insufficient information has been accrued.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-AFig-FIG04.png)
Trial Sequential Analysis of comparison: 2 Carbamazepine versus placebo, outcome: 2.1 Benzodiazepine discontinuation. Trial Sequential Analysis on benzodiazepine discontinuation in three trials was performed based on the proportion with benzodiazepine discontinuation in the control group set at 48%, a relative risk reduction (RRR) of 20%, a type I error of 2.5%, a type II error of 10% (90% power), and diversity of 36% as observed in the trials. The diversity‐adjusted required information size (DARIS) was 2109 participants, and the Trial Sequential Analysis‐adjusted confidence interval is 0.24 to 2.38. The blue line represents the cumulative Z‐score of the meta‐analysis. The green lines represent the conventional statistical boundaries of P = 5%. The cumulative Z‐curve (blue line) touches the conventional statistical boundaries, but does not cross the trial sequential monitoring boundaries, and the diversity‐adjusted required information size is not met, showing that insufficient information has been accrued.
![Trial Sequential Analysis of comparison: 6 Paroxetine versus placebo, outcome: 6.1 Benzodiazepine discontinuation. Trial Sequential Analysis on benzodiazepine discontinuation in three trials was performed based on the proportion with benzodiazepine discontinuation in the control group set at 48%, a relative risk reduction of 20%, a type I error of 2.5%, a type II error of 10% (90% power), and diversity of 86% as observed in the trials. The diversity‐adjusted required information size was 9448 participants, and the Trial Sequential Analysis‐adjusted confidence interval could not be estimated due to lack of information. The blue line represents the cumulative Z‐score of the meta‐analysis. The green lines represent the conventional statistical boundaries of P = 5%. The cumulative Z‐curve (blue line) does not cross the conventional statistical boundaries. The trial sequential monitoring boundaries and the diversity‐adjusted required information size are not shown as the accrued number of participants only amounted to 221/9448 (2.34%), showing that insufficient information has been accrued.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-AFig-FIG05.png)
Trial Sequential Analysis of comparison: 6 Paroxetine versus placebo, outcome: 6.1 Benzodiazepine discontinuation. Trial Sequential Analysis on benzodiazepine discontinuation in three trials was performed based on the proportion with benzodiazepine discontinuation in the control group set at 48%, a relative risk reduction of 20%, a type I error of 2.5%, a type II error of 10% (90% power), and diversity of 86% as observed in the trials. The diversity‐adjusted required information size was 9448 participants, and the Trial Sequential Analysis‐adjusted confidence interval could not be estimated due to lack of information. The blue line represents the cumulative Z‐score of the meta‐analysis. The green lines represent the conventional statistical boundaries of P = 5%. The cumulative Z‐curve (blue line) does not cross the conventional statistical boundaries. The trial sequential monitoring boundaries and the diversity‐adjusted required information size are not shown as the accrued number of participants only amounted to 221/9448 (2.34%), showing that insufficient information has been accrued.
![Trial Sequential Analysis of comparison: 6 Paroxetine versus placebo, outcome: 6.2 Benzodiazepine withdrawal symptoms Benzodiazepine Withdrawal Symptom Questionnaire (BWSQ). Trial Sequential Analysis on benzodiazepine withdrawal symptoms assessed with BWSQ assessing a minimal relevant clinical difference (MIREDIF) of 2.25 points, and a variance of 20 points (empirical data), was performed based on a type I error of 1.25%, a type II error of 10% (90% power), and diversity of 0%. The diversity‐adjusted required information size (DARIS) was 229 participants, and the Trial Sequential Analysis‐adjusted confidence interval is ‐7.18 to 0.05. The blue line represents the cumulative Z‐score of the meta‐analysis. The green lines represent the conventional statistical boundaries of P = 0.05. The red inward‐sloping lines represent the trial sequential monitoring boundaries. The cumulative Z‐curve touches the trial sequential monitoring boundaries, indicating that sufficient information was provided.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-AFig-FIG06.png)
Trial Sequential Analysis of comparison: 6 Paroxetine versus placebo, outcome: 6.2 Benzodiazepine withdrawal symptoms Benzodiazepine Withdrawal Symptom Questionnaire (BWSQ). Trial Sequential Analysis on benzodiazepine withdrawal symptoms assessed with BWSQ assessing a minimal relevant clinical difference (MIREDIF) of 2.25 points, and a variance of 20 points (empirical data), was performed based on a type I error of 1.25%, a type II error of 10% (90% power), and diversity of 0%. The diversity‐adjusted required information size (DARIS) was 229 participants, and the Trial Sequential Analysis‐adjusted confidence interval is ‐7.18 to 0.05. The blue line represents the cumulative Z‐score of the meta‐analysis. The green lines represent the conventional statistical boundaries of P = 0.05. The red inward‐sloping lines represent the trial sequential monitoring boundaries. The cumulative Z‐curve touches the trial sequential monitoring boundaries, indicating that sufficient information was provided.
![Trial Sequential Analysis of comparison: 6 Paroxetine versus placebo, outcome: 6.3 Anxiety, Hamilton Anxiety Rating Scale (HAM‐A). Trial Sequential Analysis on anxiety evaluated with HAM‐A assessing a minimal relevant clinical difference (MIREDIF) of 5 points, and a variance of 103 points, was performed based on a type I error of 1.25%, a type II error of 10% (90% power), and diversity of 0%. The diversity‐adjusted required information size (DARIS) was 236 participants, and the Trial Sequential Analysis‐adjusted confidence interval is ‐12.72 to ‐0.80. The blue line represents the cumulative Z‐score of the meta‐analysis. The green lines represent the conventional statistical boundaries of P = 0.05. The red inward‐sloping lines represent the trial sequential monitoring boundaries. The cumulative Z‐curve crosses the trial sequential monitoring boundaries, indicating that sufficient information was provided.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-AFig-FIG07.png)
Trial Sequential Analysis of comparison: 6 Paroxetine versus placebo, outcome: 6.3 Anxiety, Hamilton Anxiety Rating Scale (HAM‐A). Trial Sequential Analysis on anxiety evaluated with HAM‐A assessing a minimal relevant clinical difference (MIREDIF) of 5 points, and a variance of 103 points, was performed based on a type I error of 1.25%, a type II error of 10% (90% power), and diversity of 0%. The diversity‐adjusted required information size (DARIS) was 236 participants, and the Trial Sequential Analysis‐adjusted confidence interval is ‐12.72 to ‐0.80. The blue line represents the cumulative Z‐score of the meta‐analysis. The green lines represent the conventional statistical boundaries of P = 0.05. The red inward‐sloping lines represent the trial sequential monitoring boundaries. The cumulative Z‐curve crosses the trial sequential monitoring boundaries, indicating that sufficient information was provided.
![Trial Sequential Analysis of comparison: 7 Tricyclic antidepressants versus placebo, outcome: 7.1 Benzodiazepine discontinuation. Trial Sequential Analysis on benzodiazepine discontinuation in two trials was performed based on the proportion with benzodiazepine discontinuation in the control group set at 48%, a relative risk reduction (RRR) of 20%, a type I error of 2.5%, a type II error of 10% (90% power), and diversity of 0% as observed in the trials. The diversity‐adjusted required information size (DARIS) was 1343 participants, and the Trial Sequential Analysis‐adjusted confidence interval is 0.20 to 7.55. The blue line represents the cumulative Z‐score of the meta‐analysis. The green lines represent the conventional statistical boundaries of P = 5%. The cumulative Z‐curve (blue line) does not cross the conventional statistical boundaries or the trial sequential monitoring boundaries (red dotted lines), and the diversity‐adjusted required information size is not met, showing that insufficient information has been accrued.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-AFig-FIG08.png)
Trial Sequential Analysis of comparison: 7 Tricyclic antidepressants versus placebo, outcome: 7.1 Benzodiazepine discontinuation. Trial Sequential Analysis on benzodiazepine discontinuation in two trials was performed based on the proportion with benzodiazepine discontinuation in the control group set at 48%, a relative risk reduction (RRR) of 20%, a type I error of 2.5%, a type II error of 10% (90% power), and diversity of 0% as observed in the trials. The diversity‐adjusted required information size (DARIS) was 1343 participants, and the Trial Sequential Analysis‐adjusted confidence interval is 0.20 to 7.55. The blue line represents the cumulative Z‐score of the meta‐analysis. The green lines represent the conventional statistical boundaries of P = 5%. The cumulative Z‐curve (blue line) does not cross the conventional statistical boundaries or the trial sequential monitoring boundaries (red dotted lines), and the diversity‐adjusted required information size is not met, showing that insufficient information has been accrued.
![Trial Sequential Analysis of comparison: 8 Alpidem versus placebo, outcome: 8.3 Anxiety, Hamilton Anxiety Rating Scale (HAM‐A). Trial Sequential Analysis on anxiety evaluated with HAM‐A assessing a minimal relevant clinical difference (MIREDIF) of 5 points, and a variance of 103 points (empirical data), was performed based on a type I error of 1.25%, a type II error of 10% (90% power), and diversity of 0%. The diversity‐adjusted required information size (DARIS) was 235 participants, and the Trial Sequential Analysis‐adjusted confidence interval is ‐6.28 to 3.08. The blue line represents the cumulative Z‐score of the meta‐analysis. The green lines represent the conventional statistical boundaries of P = 0.05. The red inward‐sloping lines represent the trial sequential alpha‐spending monitoring boundaries, while the red outward‐sloping lines represent the beta‐spending (futility) boundaries. The cumulative Z‐curve crosses the beta‐spending (futility) boundaries, showing that an intervention effect, if any, is less than 5 points.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-AFig-FIG09.png)
Trial Sequential Analysis of comparison: 8 Alpidem versus placebo, outcome: 8.3 Anxiety, Hamilton Anxiety Rating Scale (HAM‐A). Trial Sequential Analysis on anxiety evaluated with HAM‐A assessing a minimal relevant clinical difference (MIREDIF) of 5 points, and a variance of 103 points (empirical data), was performed based on a type I error of 1.25%, a type II error of 10% (90% power), and diversity of 0%. The diversity‐adjusted required information size (DARIS) was 235 participants, and the Trial Sequential Analysis‐adjusted confidence interval is ‐6.28 to 3.08. The blue line represents the cumulative Z‐score of the meta‐analysis. The green lines represent the conventional statistical boundaries of P = 0.05. The red inward‐sloping lines represent the trial sequential alpha‐spending monitoring boundaries, while the red outward‐sloping lines represent the beta‐spending (futility) boundaries. The cumulative Z‐curve crosses the beta‐spending (futility) boundaries, showing that an intervention effect, if any, is less than 5 points.
![Trial Sequential Analysis of comparison: 9 Buspirone versus placebo, outcome: 9.1 Benzodiazepine discontinuation. Trial Sequential Analysis on benzodiazepine discontinuation in four trials was performed based on the proportion with benzodiazepine discontinuation in the control group set at 48%, a relative risk reduction of 20%, a type I error of 2.5%, a type II error of 10% (90% power), and diversity of 60% as observed in the trials. The diversity‐adjusted required information size was 3381 participants, and the Trial Sequential Analysis‐adjusted confidence interval could not be estimated due to lack of information. The blue line represents the cumulative Z‐score of the meta‐analysis. The green lines represent the conventional statistical boundaries of P = 5%. The cumulative Z‐curve (blue line) does not cross the conventional statistical boundaries. The trial sequential monitoring boundaries and the diversity‐adjusted required information size are not shown, as the accrued number of participants only amounted to 143/3381 (4.23%), showing that insufficient information has been accrued.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-AFig-FIG10.png)
Trial Sequential Analysis of comparison: 9 Buspirone versus placebo, outcome: 9.1 Benzodiazepine discontinuation. Trial Sequential Analysis on benzodiazepine discontinuation in four trials was performed based on the proportion with benzodiazepine discontinuation in the control group set at 48%, a relative risk reduction of 20%, a type I error of 2.5%, a type II error of 10% (90% power), and diversity of 60% as observed in the trials. The diversity‐adjusted required information size was 3381 participants, and the Trial Sequential Analysis‐adjusted confidence interval could not be estimated due to lack of information. The blue line represents the cumulative Z‐score of the meta‐analysis. The green lines represent the conventional statistical boundaries of P = 5%. The cumulative Z‐curve (blue line) does not cross the conventional statistical boundaries. The trial sequential monitoring boundaries and the diversity‐adjusted required information size are not shown, as the accrued number of participants only amounted to 143/3381 (4.23%), showing that insufficient information has been accrued.
![Trial Sequential Analysis of comparison: 10 Melatonin versus placebo, outcome: 10.1 Benzodiazepine discontinuation. Trial Sequential Analysis on benzodiazepine discontinuation in four trials was performed based on the proportion with benzodiazepine discontinuation in the control group set at 48%, a relative risk reduction (RRR) of 20%, a type I error of 2.5%, a type II error of 10% (90% power), and diversity of 61% as observed in the trials. The diversity‐adjusted required information size (DARIS) was 3438 participants, and the Trial Sequential Analysis‐adjusted confidence interval is 0.11 to 6.25. The blue line represents the cumulative Z‐score of the meta‐analysis. The green lines represent the conventional statistical boundaries of P = 5%. The cumulative Z‐curve (blue line) does not cross the conventional statistical boundaries or the trial sequential monitoring boundaries (red dotted lines), and the diversity‐adjusted required information size is not met, showing that insufficient information has been accrued.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-AFig-FIG11.png)
Trial Sequential Analysis of comparison: 10 Melatonin versus placebo, outcome: 10.1 Benzodiazepine discontinuation. Trial Sequential Analysis on benzodiazepine discontinuation in four trials was performed based on the proportion with benzodiazepine discontinuation in the control group set at 48%, a relative risk reduction (RRR) of 20%, a type I error of 2.5%, a type II error of 10% (90% power), and diversity of 61% as observed in the trials. The diversity‐adjusted required information size (DARIS) was 3438 participants, and the Trial Sequential Analysis‐adjusted confidence interval is 0.11 to 6.25. The blue line represents the cumulative Z‐score of the meta‐analysis. The green lines represent the conventional statistical boundaries of P = 5%. The cumulative Z‐curve (blue line) does not cross the conventional statistical boundaries or the trial sequential monitoring boundaries (red dotted lines), and the diversity‐adjusted required information size is not met, showing that insufficient information has been accrued.
![Comparison 1 Valproate versus placebo or no intervention, Outcome 1 Benzodiazepine discontinuation, end of intervention.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-CMP-001-01.png)
Comparison 1 Valproate versus placebo or no intervention, Outcome 1 Benzodiazepine discontinuation, end of intervention.
![Comparison 1 Valproate versus placebo or no intervention, Outcome 2 Relapse to benzodiazepine use, end of intervention.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-CMP-001-02.png)
Comparison 1 Valproate versus placebo or no intervention, Outcome 2 Relapse to benzodiazepine use, end of intervention.
![Comparison 1 Valproate versus placebo or no intervention, Outcome 3 Benzodiazepine discontinuation, longest follow‐up.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-CMP-001-03.png)
Comparison 1 Valproate versus placebo or no intervention, Outcome 3 Benzodiazepine discontinuation, longest follow‐up.
![Comparison 1 Valproate versus placebo or no intervention, Outcome 4 Relapse to benzodiazepine use, longest follow‐up.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-CMP-001-04.png)
Comparison 1 Valproate versus placebo or no intervention, Outcome 4 Relapse to benzodiazepine use, longest follow‐up.
![Comparison 1 Valproate versus placebo or no intervention, Outcome 5 Anxiety: HAM‐A (Hamilton Anxiety Rating Scale), end of intervention.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-CMP-001-05.png)
Comparison 1 Valproate versus placebo or no intervention, Outcome 5 Anxiety: HAM‐A (Hamilton Anxiety Rating Scale), end of intervention.
![Comparison 1 Valproate versus placebo or no intervention, Outcome 6 Benzodiazepine withdrawal symptoms, end of intervention.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-CMP-001-06.png)
Comparison 1 Valproate versus placebo or no intervention, Outcome 6 Benzodiazepine withdrawal symptoms, end of intervention.
![Comparison 1 Valproate versus placebo or no intervention, Outcome 7 Discontinuation due to adverse events.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-CMP-001-07.png)
Comparison 1 Valproate versus placebo or no intervention, Outcome 7 Discontinuation due to adverse events.
![Comparison 1 Valproate versus placebo or no intervention, Outcome 8 Serious adverse events.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-CMP-001-08.png)
Comparison 1 Valproate versus placebo or no intervention, Outcome 8 Serious adverse events.
![Comparison 2 Carbamazepine versus placebo, Outcome 1 Benzodiazepine discontinuation, end of intervention.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-CMP-002-01.png)
Comparison 2 Carbamazepine versus placebo, Outcome 1 Benzodiazepine discontinuation, end of intervention.
![Comparison 2 Carbamazepine versus placebo, Outcome 2 Benzodiazepine withdrawal symptoms.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-CMP-002-02.png)
Comparison 2 Carbamazepine versus placebo, Outcome 2 Benzodiazepine withdrawal symptoms.
![Comparison 2 Carbamazepine versus placebo, Outcome 3 Benzodiazepine discontinuation, longest follow‐up.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-CMP-002-03.png)
Comparison 2 Carbamazepine versus placebo, Outcome 3 Benzodiazepine discontinuation, longest follow‐up.
![Comparison 2 Carbamazepine versus placebo, Outcome 4 Relapse to benzodiazepine use.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-CMP-002-04.png)
Comparison 2 Carbamazepine versus placebo, Outcome 4 Relapse to benzodiazepine use.
![Comparison 2 Carbamazepine versus placebo, Outcome 5 Serious adverse events.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-CMP-002-05.png)
Comparison 2 Carbamazepine versus placebo, Outcome 5 Serious adverse events.
![Comparison 2 Carbamazepine versus placebo, Outcome 6 Non‐serious adverse events.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-CMP-002-06.png)
Comparison 2 Carbamazepine versus placebo, Outcome 6 Non‐serious adverse events.
![Comparison 2 Carbamazepine versus placebo, Outcome 7 Anxiety, HAM‐A.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-CMP-002-07.png)
Comparison 2 Carbamazepine versus placebo, Outcome 7 Anxiety, HAM‐A.
![Comparison 2 Carbamazepine versus placebo, Outcome 8 Discontinuation due to adverse events.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-CMP-002-08.png)
Comparison 2 Carbamazepine versus placebo, Outcome 8 Discontinuation due to adverse events.
![Comparison 3 Lithium versus placebo, Outcome 1 Benzodiazepine discontinuation.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-CMP-003-01.png)
Comparison 3 Lithium versus placebo, Outcome 1 Benzodiazepine discontinuation.
![Comparison 3 Lithium versus placebo, Outcome 2 Serious adverse events.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-CMP-003-02.png)
Comparison 3 Lithium versus placebo, Outcome 2 Serious adverse events.
![Comparison 3 Lithium versus placebo, Outcome 3 Non‐serious adverse events.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-CMP-003-03.png)
Comparison 3 Lithium versus placebo, Outcome 3 Non‐serious adverse events.
![Comparison 3 Lithium versus placebo, Outcome 4 Discontinuation due to adverse events.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-CMP-003-04.png)
Comparison 3 Lithium versus placebo, Outcome 4 Discontinuation due to adverse events.
![Comparison 4 Pregabalin versus placebo, Outcome 1 Benzodiazepine discontinuation, end of intervention.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-CMP-004-01.png)
Comparison 4 Pregabalin versus placebo, Outcome 1 Benzodiazepine discontinuation, end of intervention.
![Comparison 4 Pregabalin versus placebo, Outcome 2 Benzodiazepine withdrawal symptoms (Physician Withdrawal Checklist), end of intervention.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-CMP-004-02.png)
Comparison 4 Pregabalin versus placebo, Outcome 2 Benzodiazepine withdrawal symptoms (Physician Withdrawal Checklist), end of intervention.
![Comparison 4 Pregabalin versus placebo, Outcome 3 Anxiety, HAM‐A, end of intervention.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-CMP-004-03.png)
Comparison 4 Pregabalin versus placebo, Outcome 3 Anxiety, HAM‐A, end of intervention.
![Comparison 4 Pregabalin versus placebo, Outcome 4 Serious adverse events.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-CMP-004-04.png)
Comparison 4 Pregabalin versus placebo, Outcome 4 Serious adverse events.
![Comparison 4 Pregabalin versus placebo, Outcome 5 Non‐serious adverse events.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-CMP-004-05.png)
Comparison 4 Pregabalin versus placebo, Outcome 5 Non‐serious adverse events.
![Comparison 4 Pregabalin versus placebo, Outcome 6 Discontinuation due to adverse events.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-CMP-004-06.png)
Comparison 4 Pregabalin versus placebo, Outcome 6 Discontinuation due to adverse events.
![Comparison 5 Captodiame versus placebo, Outcome 1 Benzodiazepine withdrawal symptoms, BWSQ (Benzodiazepine Withdrawal Symptom Questionnaire), end of intervention.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-CMP-005-01.png)
Comparison 5 Captodiame versus placebo, Outcome 1 Benzodiazepine withdrawal symptoms, BWSQ (Benzodiazepine Withdrawal Symptom Questionnaire), end of intervention.
![Comparison 5 Captodiame versus placebo, Outcome 2 Anxiety, HAM‐A, end of intervention.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-CMP-005-02.png)
Comparison 5 Captodiame versus placebo, Outcome 2 Anxiety, HAM‐A, end of intervention.
![Comparison 5 Captodiame versus placebo, Outcome 3 Serious adverse events.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-CMP-005-03.png)
Comparison 5 Captodiame versus placebo, Outcome 3 Serious adverse events.
![Comparison 5 Captodiame versus placebo, Outcome 4 Non‐serious adverse events.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-CMP-005-04.png)
Comparison 5 Captodiame versus placebo, Outcome 4 Non‐serious adverse events.
![Comparison 6 Paroxetine versus placebo or no intervention, Outcome 1 Benzodiazepine discontinuation, end of intervention.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-CMP-006-01.png)
Comparison 6 Paroxetine versus placebo or no intervention, Outcome 1 Benzodiazepine discontinuation, end of intervention.
![Comparison 6 Paroxetine versus placebo or no intervention, Outcome 2 Benzodiazepine withdrawal symptoms: BWSQ, end of intervention.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-CMP-006-02.png)
Comparison 6 Paroxetine versus placebo or no intervention, Outcome 2 Benzodiazepine withdrawal symptoms: BWSQ, end of intervention.
![Comparison 6 Paroxetine versus placebo or no intervention, Outcome 3 Anxiety: HAM‐A, end of intervention.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-CMP-006-03.png)
Comparison 6 Paroxetine versus placebo or no intervention, Outcome 3 Anxiety: HAM‐A, end of intervention.
![Comparison 6 Paroxetine versus placebo or no intervention, Outcome 4 Benzodiazepine withdrawal symptoms: BWSQ, longest follow‐up: 6 months.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-CMP-006-04.png)
Comparison 6 Paroxetine versus placebo or no intervention, Outcome 4 Benzodiazepine withdrawal symptoms: BWSQ, longest follow‐up: 6 months.
![Comparison 6 Paroxetine versus placebo or no intervention, Outcome 5 Serious adverse events.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-CMP-006-05.png)
Comparison 6 Paroxetine versus placebo or no intervention, Outcome 5 Serious adverse events.
![Comparison 6 Paroxetine versus placebo or no intervention, Outcome 6 Non‐serious adverse events.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-CMP-006-06.png)
Comparison 6 Paroxetine versus placebo or no intervention, Outcome 6 Non‐serious adverse events.
![Comparison 7 Tricyclic antidepressants versus placebo, Outcome 1 Benzodiazepine discontinuation, end of intervention.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-CMP-007-01.png)
Comparison 7 Tricyclic antidepressants versus placebo, Outcome 1 Benzodiazepine discontinuation, end of intervention.
![Comparison 7 Tricyclic antidepressants versus placebo, Outcome 2 Anxiety: HAM‐A (change from baseline), end of intervention.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-CMP-007-02.png)
Comparison 7 Tricyclic antidepressants versus placebo, Outcome 2 Anxiety: HAM‐A (change from baseline), end of intervention.
![Comparison 7 Tricyclic antidepressants versus placebo, Outcome 3 Benzodiazepine discontinuation, longest follow‐up.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-CMP-007-03.png)
Comparison 7 Tricyclic antidepressants versus placebo, Outcome 3 Benzodiazepine discontinuation, longest follow‐up.
![Comparison 7 Tricyclic antidepressants versus placebo, Outcome 4 Benzodiazepine withdrawal symptoms (Physician Withdrawal Checklist), end of intervention.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-CMP-007-04.png)
Comparison 7 Tricyclic antidepressants versus placebo, Outcome 4 Benzodiazepine withdrawal symptoms (Physician Withdrawal Checklist), end of intervention.
![Comparison 7 Tricyclic antidepressants versus placebo, Outcome 5 Relapse to benzodiazepine use, end of intervention.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-CMP-007-05.png)
Comparison 7 Tricyclic antidepressants versus placebo, Outcome 5 Relapse to benzodiazepine use, end of intervention.
![Comparison 7 Tricyclic antidepressants versus placebo, Outcome 6 Discontinuation due to adverse events.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-CMP-007-06.png)
Comparison 7 Tricyclic antidepressants versus placebo, Outcome 6 Discontinuation due to adverse events.
![Comparison 8 Alpidem versus placebo, Outcome 1 Benzodiazepine discontinuation, end of intervention.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-CMP-008-01.png)
Comparison 8 Alpidem versus placebo, Outcome 1 Benzodiazepine discontinuation, end of intervention.
![Comparison 8 Alpidem versus placebo, Outcome 2 Withdrawal syndrome (clinical diagnosis), end of intervention.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-CMP-008-02.png)
Comparison 8 Alpidem versus placebo, Outcome 2 Withdrawal syndrome (clinical diagnosis), end of intervention.
![Comparison 8 Alpidem versus placebo, Outcome 3 Anxiety, HAM‐A, end of intervention.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-CMP-008-03.png)
Comparison 8 Alpidem versus placebo, Outcome 3 Anxiety, HAM‐A, end of intervention.
![Comparison 8 Alpidem versus placebo, Outcome 4 Relapse to benzodiazepine use, end of intervention.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-CMP-008-04.png)
Comparison 8 Alpidem versus placebo, Outcome 4 Relapse to benzodiazepine use, end of intervention.
![Comparison 8 Alpidem versus placebo, Outcome 5 Serious adverse events.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-CMP-008-05.png)
Comparison 8 Alpidem versus placebo, Outcome 5 Serious adverse events.
![Comparison 8 Alpidem versus placebo, Outcome 6 Discontinuation due to adverse events.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-CMP-008-06.png)
Comparison 8 Alpidem versus placebo, Outcome 6 Discontinuation due to adverse events.
![Comparison 9 Buspirone versus placebo, Outcome 1 Benzodiazepine discontinuation, end of intervention.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-CMP-009-01.png)
Comparison 9 Buspirone versus placebo, Outcome 1 Benzodiazepine discontinuation, end of intervention.
![Comparison 9 Buspirone versus placebo, Outcome 2 Anxiety: HAM‐A/Hospital Anxiety Depression Scale, end of intervention.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-CMP-009-02.png)
Comparison 9 Buspirone versus placebo, Outcome 2 Anxiety: HAM‐A/Hospital Anxiety Depression Scale, end of intervention.
![Comparison 9 Buspirone versus placebo, Outcome 3 Benzodiazepine withdrawal symptoms, end of intervention.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-CMP-009-03.png)
Comparison 9 Buspirone versus placebo, Outcome 3 Benzodiazepine withdrawal symptoms, end of intervention.
![Comparison 9 Buspirone versus placebo, Outcome 4 Benzodiazepine discontinuation, longest follow‐up.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-CMP-009-04.png)
Comparison 9 Buspirone versus placebo, Outcome 4 Benzodiazepine discontinuation, longest follow‐up.
![Comparison 9 Buspirone versus placebo, Outcome 5 Benzodiazepine withdrawal symptoms, longest follow‐up.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-CMP-009-05.png)
Comparison 9 Buspirone versus placebo, Outcome 5 Benzodiazepine withdrawal symptoms, longest follow‐up.
![Comparison 9 Buspirone versus placebo, Outcome 6 Anxiety, Hospital Anxiety Depression Scale, longest follow‐up.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-CMP-009-06.png)
Comparison 9 Buspirone versus placebo, Outcome 6 Anxiety, Hospital Anxiety Depression Scale, longest follow‐up.
![Comparison 9 Buspirone versus placebo, Outcome 7 Discontinuation due to adverse events.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-CMP-009-07.png)
Comparison 9 Buspirone versus placebo, Outcome 7 Discontinuation due to adverse events.
![Comparison 10 Melatonin versus placebo, Outcome 1 Benzodiazepine discontinuation, end of intervention.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-CMP-010-01.png)
Comparison 10 Melatonin versus placebo, Outcome 1 Benzodiazepine discontinuation, end of intervention.
![Comparison 10 Melatonin versus placebo, Outcome 2 Insomnia.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-CMP-010-02.png)
Comparison 10 Melatonin versus placebo, Outcome 2 Insomnia.
![Comparison 10 Melatonin versus placebo, Outcome 3 Discontinuation due to adverse events.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-CMP-010-03.png)
Comparison 10 Melatonin versus placebo, Outcome 3 Discontinuation due to adverse events.
![Comparison 10 Melatonin versus placebo, Outcome 4 Benzodiazepine discontinuation, longest follow‐up.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-CMP-010-04.png)
Comparison 10 Melatonin versus placebo, Outcome 4 Benzodiazepine discontinuation, longest follow‐up.
![Comparison 10 Melatonin versus placebo, Outcome 5 Adverse events.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-CMP-010-05.png)
Comparison 10 Melatonin versus placebo, Outcome 5 Adverse events.
![Comparison 10 Melatonin versus placebo, Outcome 6 Relapse to benzodiazepine use, longest follow‐up.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-CMP-010-06.png)
Comparison 10 Melatonin versus placebo, Outcome 6 Relapse to benzodiazepine use, longest follow‐up.
![Comparison 11 Flumazenil versus placebo, Outcome 1 Benzodiazepine withdrawal symptoms, end of intervention.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-CMP-011-01.png)
Comparison 11 Flumazenil versus placebo, Outcome 1 Benzodiazepine withdrawal symptoms, end of intervention.
![Comparison 11 Flumazenil versus placebo, Outcome 2 Anxiety, HAM‐D (Hamilton Depression Rating Scale), end of intervention.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-CMP-011-02.png)
Comparison 11 Flumazenil versus placebo, Outcome 2 Anxiety, HAM‐D (Hamilton Depression Rating Scale), end of intervention.
![Comparison 11 Flumazenil versus placebo, Outcome 3 Benzodiazepine mean dose, end of intervention.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-CMP-011-03.png)
Comparison 11 Flumazenil versus placebo, Outcome 3 Benzodiazepine mean dose, end of intervention.
![Comparison 12 Propranolol versus placebo, Outcome 1 Relapse to benzodiazepine use, end of intervention: 2 weeks.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-CMP-012-01.png)
Comparison 12 Propranolol versus placebo, Outcome 1 Relapse to benzodiazepine use, end of intervention: 2 weeks.
![Comparison 13 Progesterone versus placebo, Outcome 1 Benzodiazepine discontinuation, end of intervention.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-CMP-013-01.png)
Comparison 13 Progesterone versus placebo, Outcome 1 Benzodiazepine discontinuation, end of intervention.
![Comparison 13 Progesterone versus placebo, Outcome 2 Non‐serious adverse events.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-CMP-013-02.png)
Comparison 13 Progesterone versus placebo, Outcome 2 Non‐serious adverse events.
![Comparison 14 Magnesium aspartate versus placebo, Outcome 1 Benzodiazepine discontinuation.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-CMP-014-01.png)
Comparison 14 Magnesium aspartate versus placebo, Outcome 1 Benzodiazepine discontinuation.
![Comparison 14 Magnesium aspartate versus placebo, Outcome 2 Anxiety.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-CMP-014-02.png)
Comparison 14 Magnesium aspartate versus placebo, Outcome 2 Anxiety.
![Comparison 14 Magnesium aspartate versus placebo, Outcome 3 Relapse to benzodiazepine use.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-CMP-014-03.png)
Comparison 14 Magnesium aspartate versus placebo, Outcome 3 Relapse to benzodiazepine use.
![Comparison 14 Magnesium aspartate versus placebo, Outcome 4 Non‐serious adverse events.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-CMP-014-04.png)
Comparison 14 Magnesium aspartate versus placebo, Outcome 4 Non‐serious adverse events.
![Comparison 14 Magnesium aspartate versus placebo, Outcome 5 Discontinuation due to adverse events.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-CMP-014-05.png)
Comparison 14 Magnesium aspartate versus placebo, Outcome 5 Discontinuation due to adverse events.
![Comparison 15 Homéogène 46/Sedatif PC (homeopathic drugs) versus placebo, Outcome 1 Benzodiazepine discontinuation.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-CMP-015-01.png)
Comparison 15 Homéogène 46/Sedatif PC (homeopathic drugs) versus placebo, Outcome 1 Benzodiazepine discontinuation.
![Comparison 16 Carbamazepine versus tricyclic antidepressant, Outcome 1 Benzodiazepine discontinuation, end of intervention.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-CMP-016-01.png)
Comparison 16 Carbamazepine versus tricyclic antidepressant, Outcome 1 Benzodiazepine discontinuation, end of intervention.
![Comparison 16 Carbamazepine versus tricyclic antidepressant, Outcome 2 Relapse to benzodiazepine use.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-CMP-016-02.png)
Comparison 16 Carbamazepine versus tricyclic antidepressant, Outcome 2 Relapse to benzodiazepine use.
![Comparison 16 Carbamazepine versus tricyclic antidepressant, Outcome 3 Serious adverse events.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-CMP-016-03.png)
Comparison 16 Carbamazepine versus tricyclic antidepressant, Outcome 3 Serious adverse events.
![Comparison 17 Cyamemazine versus bromazepam, Outcome 1 Relapse to benzodiazepine use, longest follow‐up.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-CMP-017-01.png)
Comparison 17 Cyamemazine versus bromazepam, Outcome 1 Relapse to benzodiazepine use, longest follow‐up.
![Comparison 17 Cyamemazine versus bromazepam, Outcome 2 Anxiety: Maximum amplitude of rebound (HAM‐A), end of intervention.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-CMP-017-02.png)
Comparison 17 Cyamemazine versus bromazepam, Outcome 2 Anxiety: Maximum amplitude of rebound (HAM‐A), end of intervention.
![Comparison 17 Cyamemazine versus bromazepam, Outcome 3 Discontinuation due to adverse events.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-CMP-017-03.png)
Comparison 17 Cyamemazine versus bromazepam, Outcome 3 Discontinuation due to adverse events.
![Comparison 17 Cyamemazine versus bromazepam, Outcome 4 Non‐serious adverse events.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-CMP-017-04.png)
Comparison 17 Cyamemazine versus bromazepam, Outcome 4 Non‐serious adverse events.
![Comparison 18 Zopiclone versus flunitrazepam, Outcome 1 Relapse to benzodiazepine use, longest follow‐up.](/es/cdsr/doi/10.1002/14651858.CD011481.pub2/media/CDSR/CD011481/image_n/nCD011481-CMP-018-01.png)
Comparison 18 Zopiclone versus flunitrazepam, Outcome 1 Relapse to benzodiazepine use, longest follow‐up.
Valproate compared with placebo or no intervention for benzodiazepine discontinuation in chronic benzodiazepine users | ||||||
Patient or population: adults who withdraw from chronic benzodiazepine use | ||||||
Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No. of participants | Quality of the evidence | Comments | |
Assumed risk | Corresponding risk | |||||
Placebo or no intervention | Valproate | |||||
Benzodiazepine discontinuation, end of intervention | Study population | RR 2.55 | 27 | ⊕⊝⊝⊝ | The required information size of 1918 participants was not met. | |
679 per 1000 | 1000 per 1000 | |||||
Benzodiazepine discontinuation, longest follow‐up | Study population | RR 1.57 | 24 | ⊕⊝⊝⊝ | ||
500 per 1000 | 785 per 1000 | |||||
Benzodiazepine withdrawal symptoms, end of intervention | The mean benzodiazepine withdrawal symptoms in the intervention groups was | 56 | ⊕⊝⊝⊝ | SMD ‐0.15 (‐0.68 to 0.37). As a rule of thumb, 0.2 represents a small effect, 0.5 a moderate effect, and 0.8 a large effect. | ||
Benzodiazepine withdrawal symptoms, longest follow‐up | Not estimable | ‐ | (0 study) | No included study measured this outcome. | ||
*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). | ||||||
GRADE Working Group grades of evidence | ||||||
1No details provided regarding random sequence generation, allocation concealment, and blinding, leading to unclear risk of selection bias, performance and detection bias (downgraded one level). |
Carbamazepine compared with placebo for benzodiazepine discontinuation in chronic benzodiazepine users | ||||||
Patient or population: adults who withdraw from chronic benzodiazepine use | ||||||
Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No. of participants | Quality of the evidence | Comments | |
Assumed risk | Corresponding risk | |||||
Placebo | Carbamazepine | |||||
Benzodiazepine discontinuation, end of intervention | Study population | RR 1.33 | 147 | ⊕⊕⊝⊝ | Trial Sequential Analysis showed that only 7.0% of the required information size (2109) was reached, indicating that insufficient information has been obtained. | |
480 per 1000 | 638 per 1000 | |||||
Benzodiazepine discontinuation, longest follow‐up | Study population | RR 1.41 | 40 | ⊕⊝⊝⊝ | ||
524 per 1000 | 739 per 1000 | |||||
Benzodiazepine withdrawal symptoms, end of intervention | The mean benzodiazepine withdrawal symptoms in the intervention groups was | 76 | ⊕⊝⊝⊝ | SMD ‐1.14 (‐2.43 to 0.16). As a rule of thumb, 0.2 represents a small effect, 0.5 a moderate effect, and 0.8 a large effect. | ||
Benzodiazepine withdrawal symptoms, longest follow‐up | Not estimable | ‐ | (0 study) | No included study measured this outcome. | ||
*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). | ||||||
GRADE Working Group grades of evidence | ||||||
1Unclear risk of selection bias. One study with high risk of attrition, reporting, and other bias (downgraded one level). |
Lithium compared with placebo for benzodiazepine discontinuation in chronic benzodiazepine users | ||||||
Patient or population: adults who withdraw from chronic benzodiazepine use | ||||||
Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No. of participants | Quality of the evidence | Comments | |
Assumed risk | Corresponding risk | |||||
Placebo | Lithium | |||||
Benzodiazepine discontinuation, end of intervention | Study population | RR 1.05 | 230 | ⊕⊕⊝⊝ | The required information size of 1918 participants was not met. | |
617 per 1000 | 648 per 1000 | |||||
Benzodiazepine discontinuation, longest follow‐up | Not estimable | ‐ | ‐ | (0 study) | ‐ | No included studies measured this outcome. |
Benzodiazepine withdrawal symptoms, end of intervention | Not estimable | ‐ | ‐ | (0 study) | ‐ | No included studies measured this outcome. |
Benzodiazepine withdrawal symptoms, longest follow‐up | Not estimable | ‐ | ‐ | (0 study) | ‐ | No included study measured this outcome. |
*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). | ||||||
GRADE Working Group grades of evidence | ||||||
1Unclear risk of selection, attrition, and reporting bias (downgraded one level). |
Pregabalin compared with placebo for benzodiazepine discontinuation in chronic benzodiazepine users | ||||||
Patient or population: adults who withdraw from chronic benzodiazepine use | ||||||
Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No. of participants | Quality of the evidence | Comments | |
Assumed risk | Corresponding risk | |||||
Placebo | Pregabalin | |||||
Benzodiazepine discontinuation, end of intervention | Study population | RR 1.44 | 106 | ⊕⊝⊝⊝ | The required information size of 1918 participants was not met. | |
360 per 1000 | 518 per 1000 | |||||
Benzodiazepine discontinuation, longest follow‐up | Not estimable | ‐ | ‐ | (0 study) | ‐ | No included studies measured this outcome. |
Benzodiazepine withdrawal symptoms, Physician Withdrawal Checklist (PWCL), end of intervention | ‐ | The mean benzodiazepine withdrawal symptoms, PWCL, end of intervention in the intervention group was | ‐ | 106 | ⊕⊝⊝⊝ | MD ‐3.10 (‐3.51 to ‐2.69) |
Benzodiazepine withdrawal symptoms, longest follow‐up | Not estimable | ‐ | ‐ | (0 study) | ‐ | No included study measured this outcome. |
*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). | ||||||
GRADE Working Group grades of evidence | ||||||
1Unclear risk of selection bias and high risk of attrition and other bias (downgraded two levels). |
Captodiame compared with placebo for benzodiazepine discontinuation in chronic benzodiazepine users | ||||||
Patient or population: adults who withdraw from chronic benzodiazepine use | ||||||
Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No. of participants | Quality of the evidence | Comments | |
Assumed risk | Corresponding risk | |||||
Placebo | Captodiame | |||||
Benzodiazepine discontinuation, end of intervention | Not estimable | ‐ | ‐ | (0 study) | ‐ | No included studies measured this outcome. |
Benzodiazepine discontinuation, longest follow‐up | Not estimable | ‐ | ‐ | (0 study) | ‐ | No included studies measured this outcome. |
Benzodiazepine withdrawal symptoms, Benzodiazepine Withdrawal Symptom Questionnaire (BWSQ), end of intervention | ‐ | The mean benzodiazepine withdrawal symptoms, BWSQ, end of intervention in the intervention group was | ‐ | 81 | ⊕⊝⊝⊝ | MD ‐1.00 (‐1.13 to ‐0.87) The required information size of 229 participants was not met. |
Benzodiazepine withdrawal symptoms, longest follow‐up | Not estimable | ‐ | ‐ | (0 study) | ‐ | No included study measured this outcome. |
*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). | ||||||
GRADE Working Group grades of evidence | ||||||
1Unclear risk of selection and reporting bias. High risk of other bias (downgraded one level). |
Paroxetine compared with placebo or no intervention for benzodiazepine discontinuation in chronic benzodiazepine users | ||||||
Patient or population: adults who withdraw from chronic benzodiazepine use | ||||||
Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No. of participants | Quality of the evidence | Comments | |
Assumed risk | Corresponding risk | |||||
Placebo or Control | Paroxetine | |||||
Benzodiazepine discontinuation, end of intervention | Study population | RR 1.45 | 221 | ⊕⊝⊝⊝ | Trial Sequential Analysis showed that only 2.34% of the required information size (9448) was reached, indicating that insufficient information has been obtained. | |
504 per 1000 | 731 per 1000 | |||||
Benzodiazepine discontinuation, longest follow‐up | Not estimable | ‐ | (0 study) | ‐ | No included study measured this outcome. | |
Benzodiazepine withdrawal symptoms, BWSQ, end of intervention | ‐ | The mean benzodiazepine withdrawal symptoms, BWSQ, end of intervention in the intervention groups was | ‐ | 99 | ⊕⊝⊝⊝ | MD ‐3.57 (‐5.34 to ‐1.8). Trial Sequential Analysis showed that the required information size of 229 participants was not reached. However, the alpha‐spending boundaries for benefit were crossed, indicating that sufficient information was obtained, and the result was not due to random error. |
Benzodiazepine withdrawal symptoms, BWSQ, longest follow‐up: 6 months | ‐ | The mean benzodiazepine withdrawal symptoms, BWSQ, longest follow‐up: 6 months in the intervention group was | ‐ | 54 | ⊕⊝⊝⊝ | MD ‐0.13 (‐4.03 to 3.77) |
*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). | ||||||
GRADE Working Group grades of evidence | ||||||
1Unclear risk of selection and attrition bias. High risk of performance, detection, reporting, and other bias (downgraded two levels). |
Tricyclic antidepressants compared with placebo for benzodiazepine discontinuation in chronic benzodiazepine users | ||||||
Patient or population: adults who withdraw from chronic benzodiazepine use | ||||||
Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No. of participants | Quality of the evidence | Comments | |
Assumed risk | Corresponding risk | |||||
Placebo | Tricyclic antidepressants | |||||
Benzodiazepine discontinuation, end of intervention | Study population | RR 0.82 | 105 | ⊕⊝⊝⊝ | Trial Sequential Analysis showed that only 7.82% of the required information size (1343) was reached, indicating that insufficient information has been obtained. | |
451 per 1000 | 370 per 1000 | |||||
Benzodiazepine discontinuation, longest follow‐up | Study population | RR 2.2 | 47 | ⊕⊕⊝⊝ | ||
375 per 1000 | 825 per 1000 | |||||
Benzodiazepine withdrawal symptoms, Physician Withdrawal Checklist, end of intervention | ‐ | The mean benzodiazepine withdrawal symptoms in the intervention group was | ‐ | 38 (1 study) | ⊕⊝⊝⊝ | MD ‐19.78 (‐20.25 to ‐19.31) |
Benzodiazepine withdrawal symptoms, longest follow‐up | Not estimable | ‐ | ‐ | (0 study) | ‐ | No included study measured this outcome. |
*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). | ||||||
GRADE Working Group grades of evidence | ||||||
1Unclear risk of selection bias and high risk of attrition and other bias (downgraded one level). |
Alpidem compared with placebo for benzodiazepine discontinuation in chronic benzodiazepine users | ||||||
Patient or population: adults who withdraw from chronic benzodiazepine use | ||||||
Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No. of participants | Quality of the evidence | Comments | |
Assumed risk | Corresponding risk | |||||
Placebo | Alpidem | |||||
Benzodiazepine discontinuation, end of intervention | Study population | RR 0.41 | 25 | ⊕⊕⊝⊝ | The required information size of 1918 participants was not met. | |
750 per 1000 | 308 per 1000 | |||||
Benzodiazepine discontinuation, longest follow‐up | Not estimable | ‐ | ‐ | (0 study) | ‐ | No included study measured this outcome. |
Withdrawal syndrome (clinical diagnosis), end of intervention | Study population | RR 4.86 | 145 | ⊕⊝⊝⊝ | ||
29 per 1000 | 143 per 1000 | |||||
Benzodiazepine withdrawal symptoms, longest follow‐up | Not estimable | ‐ | ‐ | (0 study) | ‐ | No included study measured this outcome. |
*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). | ||||||
GRADE Working Group grades of evidence | ||||||
1Required information size not met (downgraded two levels due to imprecision). 3Unclear risk of selection and other bias, high risk of attrition bias (downgraded one level) |
Buspirone compared with placebo for benzodiazepine discontinuation in chronic benzodiazepine users | ||||||
Patient or population: adults who withdraw from chronic benzodiazepine use | ||||||
Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No. of participants | Quality of the evidence | Comments | |
Assumed risk | Corresponding risk | |||||
Placebo | Buspirone | |||||
Benzodiazepine discontinuation, end of intervention | Study population | RR 0.82 | 143 | ⊕⊕⊝⊝ | Trial Sequential Analysis showed that only 4.23% of the required information size (3381) was reached, indicating that insufficient information has been obtained. | |
563 per 1000 | 462 per 1000 | |||||
Benzodiazepine discontinuation, longest follow‐up | Study population | RR 0.60 | 23 | ⊕⊕⊝⊝ | ||
917 per 1000 | 550 per 1000 | |||||
Benzodiazepine withdrawal symptoms, end of intervention | ‐ | The mean benzodiazepine withdrawal symptoms, end of intervention in the intervention groups was | ‐ | 17 | ⊕⊝⊝⊝ | MD 4.69 (‐14.47 to 23.87) |
Benzodiazepine withdrawal symptoms, longest follow‐up | ‐ | The mean benzodiazepine withdrawal symptoms, longest follow‐up in the intervention groups was | ‐ | 15 | ⊕⊝⊝⊝ | MD ‐1.34 (‐14.31 to 11.63) |
*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). | ||||||
GRADE Working Group grades of evidence | ||||||
1Unclear risk of selection, performance, and reporting bias. High risk of attrition and other bias (downgraded one level). |
Melatonin compared with placebo for benzodiazepine discontinuation in chronic benzodiazepine users | ||||||
Patient or population: adults who withdraw from chronic benzodiazepine use | ||||||
Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No. of participants | Quality of the evidence | Comments | |
Assumed risk | Corresponding risk | |||||
Placebo | Melatonin | |||||
Benzodiazepine discontinuation, end of intervention | Study population | RR 1.20 | 219 | ⊕⊝⊝⊝ | Trial Sequential Analysis showed that only 6.37% of the required information size (3438) was reached, indicating that insufficient information has been obtained. | |
417 per 1000 | 500 per 1000 | |||||
Benzodiazepine discontinuation, longest follow‐up | Study population | RR 1.03 | 38 | ⊕⊝⊝⊝ | ||
389 per 1000 | 401 per 1000 | |||||
Benzodiazpine withdrawal symptoms, end of intervention | Not estimable | ‐ | ‐ | (0 study) | ‐ | No included study measured this outcome. |
Benzodiazepine withdrawal symptoms, longest follow‐up | Not estimable | ‐ | ‐ | (0 study) | ‐ | No included study measured this outcome. |
*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). | ||||||
GRADE Working Group grades of evidence | ||||||
1Unclear risk of selection, attrition, and reporting bias. High risk of other bias (downgraded one level). |
Flumazenil compared with placebo for benzodiazepine discontinuation in chronic benzodiazepine users | ||||||
Patient or population: adults who withdraw from chronic benzodiazepine use | ||||||
Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No. of participants | Quality of the evidence | Comments | |
Assumed risk | Corresponding risk | |||||
Placebo | Flumazenil | |||||
Benzodiazepine discontinuation, end of intervention | Not estimable | ‐ | ‐ | (0 study) | ‐ | No included study measured this outcome. |
Benzodiazepine discontinuation, longest follow‐up | Not estimable | ‐ | ‐ | (0 study) | ‐ | No included study measured this outcome. |
Benzodiazepine withdrawal symptoms, end of intervention | ‐ | The mean benzodiazepine withdrawal symptoms, end of intervention in the intervention groups was | ‐ | 58 | ⊕⊝⊝⊝ | SMD ‐0.95 (‐1.71 to ‐0.19) As a rule of thumb, 0.2 represents a small effect, 0.5 a moderate effect, and 0.8 a large effect. |
Benzodiazepine withdrawal symptoms, longest follow‐up | Not estimable | ‐ | ‐ | (0 study) | ‐ | No included study measured this outcome. |
*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). | ||||||
GRADE Working Group grades of evidence | ||||||
1Unclear risk of selection bias and high risk of performance, detection, and other bias (downgraded one level). |
Progesterone compared with placebo for benzodiazepine discontinuation in chronic benzodiazepine users | ||||||
Patient or population: adults who withdraw from chronic benzodiazepine use | ||||||
Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No. of participants | Quality of the evidence | Comments | |
Assumed risk | Corresponding risk | |||||
Placebo | Progesterone | |||||
Benzodiazepine discontinuation, end of intervention | Study population | RR 1.15 | 35 | ⊕⊝⊝⊝ | The required information size of 1918 participants was not met. | |
417 per 1000 | 479 per 1000 | |||||
Benzodiazepine discontinuation, longest follow‐up | Not estimable | ‐ | ‐ | (0 study) | ‐ | No included study measured this outcome. |
Benzodiazepine withdrawal symptoms, end of intervention | Not estimable | ‐ | ‐ | (0 study) | ‐ | No included study measured this outcome. |
Benzodiazepine withdrawal symptoms, longest follow‐up | Not estimable | ‐ | ‐ | (0 study) | ‐ | No included study measured this outcome. |
*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). | ||||||
GRADE Working Group grades of evidence | ||||||
1Unclear risk of selection and attrition bias (downgraded one level). |
Magnesium aspartate compared with placebo for benzodiazepine discontinuation in chronic benzodiazepine users | ||||||
Patient or population: adults who withdraw from chronic benzodiazepine use | ||||||
Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No. of participants | Quality of the evidence | Comments | |
Assumed risk | Corresponding risk | |||||
Placebo | Magnesium aspartate | |||||
Benzodiazepine discontinuation, end of intervention | Study population | RR 0.80 | 144 | ⊕⊝⊝⊝ | The required information size of 1918 participants was not met. | |
853 per 1000 | 683 per 1000 | |||||
Benzodiazepine discontinuation, longest follow‐up | Not estimable | ‐ | ‐ | (0 study) | ‐ | No included study measured this outcome. |
Benzodiazepine withdrawal symptoms, end of intervention | Not estimable | ‐ | ‐ | (0 study) | ‐ | No included study measured this outcome. |
Benzodiazepine withdrawal symptoms, longest follow‐up | Not estimable | ‐ | ‐ | (0 study) | ‐ | No included study measured this outcome. |
*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). | ||||||
GRADE Working Group grades of evidence | ||||||
1Unclear risk of selection, detection, and attrition bias (downgraded one level). |
Homéogène 46/Sedatif PC (homeopathic drugs) compared with placebo for benzodiazepine discontinuation in chronic benzodiazepine users | ||||||
Patient or population: adults who withdraw from chronic benzodiazepine use | ||||||
Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No. of participants | Quality of the evidence | Comments | |
Assumed risk | Corresponding risk | |||||
Placebo | Homéogène 46/Sedatif PC (homeopathic drugs) | |||||
Benzodiazepine discontinuation, end of intervention | Study population | RR 0.79 | 51 | ⊕⊝⊝⊝ | The required information size was not met. | |
381 per 1000 | 301 per 1000 | |||||
Benzodiazepine discontinuation, longest follow‐up | Not estimable | ‐ | ‐ | (0 study) | ‐ | No included study measured this outcome. |
Benzodiazepine withdrawal symptoms, end of intervention | Not estimable | ‐ | ‐ | (0 study) | ‐ | No included study measured this outcome. |
Benzodiazepine withdrawal symptoms, longest follow‐up | Not estimable | ‐ | ‐ | (0 study) | ‐ | No included study measured this outcome. |
*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). | ||||||
GRADE Working Group grades of evidence | ||||||
1Unclear risk of selection, attrition, and other bias (downgraded one level). |
Carbamazepine compared with tricyclic antidepressant for benzodiazepine discontinuation in chronic benzodiazepine users | ||||||
Patient or population: adults who withdraw from chronic benzodiazepine use | ||||||
Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No. of participants | Quality of the evidence | Comments | |
Assumed risk | Corresponding risk | |||||
Tricyclic antidepressant | Carbamazepine | |||||
Benzodiazepine discontinuation, end of intervention | Study population | RR 1.00 | 48 | ⊕⊕⊝⊝ | The required information size was not met. | |
833 per 1000 | 833 per 1000 | |||||
Benzodiazepine discontinuation, longest follow‐up | Not estimable | ‐ | ‐ | (0 study) | ‐ | No included study measured this outcome. |
Benzodiazepine withdrawal symptoms, end of intervention | Not estimable | ‐ | ‐ | (0 study) | ‐ | No included study measured this outcome. |
Benzodiazepine withdrawal symptoms, longest follow‐up | Not estimable | ‐ | ‐ | (0 study) | ‐ | No included study measured this outcome. |
*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). | ||||||
GRADE Working Group grades of evidence | ||||||
1Unclear risk of selection, detection, and attrition bias (downgraded one level). |
Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
1 Benzodiazepine discontinuation, end of intervention Show forest plot | 1 | 27 | Risk Ratio (M‐H, Random, 95% CI) | 2.55 [1.08, 6.03] |
2 Relapse to benzodiazepine use, end of intervention Show forest plot | 1 | 27 | Risk Ratio (M‐H, Random, 95% CI) | 0.31 [0.11, 0.90] |
3 Benzodiazepine discontinuation, longest follow‐up Show forest plot | 1 | 24 | Risk Ratio (M‐H, Random, 95% CI) | 1.57 [0.80, 3.09] |
4 Relapse to benzodiazepine use, longest follow‐up Show forest plot | 1 | 24 | Risk Ratio (M‐H, Random, 95% CI) | 0.43 [0.13, 1.39] |
5 Anxiety: HAM‐A (Hamilton Anxiety Rating Scale), end of intervention Show forest plot | 1 | 27 | Mean Difference (IV, Random, 95% CI) | ‐0.40 [‐6.47, 5.67] |
6 Benzodiazepine withdrawal symptoms, end of intervention Show forest plot | 2 | 56 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.15 [‐0.68, 0.37] |
6.1 Physician Withdrawal Checklist | 1 | 27 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.01 [‐0.77, 0.74] |
6.2 CIWA‐B (Clinical Institute Withdrawal Assessment Scale ‐ Benzodiazepines) | 1 | 29 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.28 [‐1.01, 0.45] |
7 Discontinuation due to adverse events Show forest plot | 1 | 29 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
8 Serious adverse events Show forest plot | 1 | 29 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
1 Benzodiazepine discontinuation, end of intervention Show forest plot | 3 | 147 | Risk Ratio (M‐H, Random, 95% CI) | 1.33 [0.99, 1.80] |
2 Benzodiazepine withdrawal symptoms Show forest plot | 2 | 76 | Std. Mean Difference (IV, Random, 95% CI) | ‐1.14 [‐2.43, 0.16] |
2.1 Physician Withdrawal Checklist | 1 | 36 | Std. Mean Difference (IV, Random, 95% CI) | ‐1.82 [‐2.61, ‐1.03] |
2.2 Patient Withdrawal Checklist | 1 | 40 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.50 [‐1.13, 0.13] |
3 Benzodiazepine discontinuation, longest follow‐up Show forest plot | 1 | 40 | Risk Ratio (M‐H, Random, 95% CI) | 1.41 [0.86, 2.29] |
4 Relapse to benzodiazepine use Show forest plot | 1 | 36 | Risk Ratio (M‐H, Random, 95% CI) | 0.33 [0.08, 1.44] |
5 Serious adverse events Show forest plot | 1 | 36 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
6 Non‐serious adverse events Show forest plot | 1 | 36 | Risk Ratio (M‐H, Random, 95% CI) | 7.0 [0.39, 126.48] |
7 Anxiety, HAM‐A Show forest plot | 1 | 36 | Mean Difference (IV, Random, 95% CI) | ‐6.0 [‐9.58, ‐2.42] |
8 Discontinuation due to adverse events Show forest plot | 1 | 36 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
1 Benzodiazepine discontinuation Show forest plot | 1 | 230 | Risk Ratio (M‐H, Random, 95% CI) | 1.05 [0.86, 1.28] |
2 Serious adverse events Show forest plot | 1 | 230 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
3 Non‐serious adverse events Show forest plot | 1 | 230 | Risk Ratio (M‐H, Random, 95% CI) | 1.06 [0.75, 1.49] |
4 Discontinuation due to adverse events Show forest plot | 1 | 230 | Risk Ratio (M‐H, Random, 95% CI) | 1.38 [0.13, 15.03] |
Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
1 Benzodiazepine discontinuation, end of intervention Show forest plot | 1 | 106 | Risk Ratio (M‐H, Random, 95% CI) | 1.44 [0.92, 2.25] |
2 Benzodiazepine withdrawal symptoms (Physician Withdrawal Checklist), end of intervention Show forest plot | 1 | 106 | Mean Difference (IV, Random, 95% CI) | ‐3.1 [‐3.51, ‐2.69] |
3 Anxiety, HAM‐A, end of intervention Show forest plot | 1 | 106 | Mean Difference (IV, Random, 95% CI) | ‐4.8 [‐5.28, ‐4.32] |
4 Serious adverse events Show forest plot | 1 | 106 | Risk Ratio (M‐H, Random, 95% CI) | 0.67 [0.16, 2.85] |
5 Non‐serious adverse events Show forest plot | 1 | 106 | Risk Ratio (M‐H, Random, 95% CI) | 1.08 [0.84, 1.40] |
6 Discontinuation due to adverse events Show forest plot | 1 | 106 | Risk Ratio (M‐H, Random, 95% CI) | 0.89 [0.31, 2.59] |
Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
1 Benzodiazepine withdrawal symptoms, BWSQ (Benzodiazepine Withdrawal Symptom Questionnaire), end of intervention Show forest plot | 1 | 81 | Mean Difference (IV, Random, 95% CI) | 1.00 [‐1.13, ‐0.87] |
2 Anxiety, HAM‐A, end of intervention Show forest plot | 1 | 81 | Mean Difference (IV, Random, 95% CI) | ‐5.7 [‐6.05, ‐5.35] |
3 Serious adverse events Show forest plot | 1 | 81 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
4 Non‐serious adverse events Show forest plot | 1 | 81 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
1 Benzodiazepine discontinuation, end of intervention Show forest plot | 3 | 221 | Risk Ratio (M‐H, Random, 95% CI) | 1.45 [0.88, 2.39] |
2 Benzodiazepine withdrawal symptoms: BWSQ, end of intervention Show forest plot | 2 | 99 | Mean Difference (IV, Random, 95% CI) | ‐3.57 [‐5.34, ‐1.80] |
3 Anxiety: HAM‐A, end of intervention Show forest plot | 2 | 99 | Mean Difference (IV, Random, 95% CI) | ‐6.75 [‐9.64, ‐3.86] |
4 Benzodiazepine withdrawal symptoms: BWSQ, longest follow‐up: 6 months Show forest plot | 1 | 54 | Mean Difference (IV, Random, 95% CI) | ‐0.13 [‐4.03, 3.77] |
5 Serious adverse events Show forest plot | 2 | 176 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
6 Non‐serious adverse events Show forest plot | 1 | 54 | Risk Ratio (M‐H, Random, 95% CI) | 1.33 [0.35, 5.03] |
Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
1 Benzodiazepine discontinuation, end of intervention Show forest plot | 2 | 105 | Risk Ratio (M‐H, Random, 95% CI) | 0.82 [0.52, 1.28] |
2 Anxiety: HAM‐A (change from baseline), end of intervention Show forest plot | 2 | 66 | Mean Difference (IV, Random, 95% CI) | ‐10.38 [‐25.96, 5.20] |
3 Benzodiazepine discontinuation, longest follow‐up Show forest plot | 1 | 47 | Risk Ratio (M‐H, Random, 95% CI) | 2.20 [1.27, 3.82] |
4 Benzodiazepine withdrawal symptoms (Physician Withdrawal Checklist), end of intervention Show forest plot | 1 | 38 | Mean Difference (IV, Random, 95% CI) | ‐19.78 [‐20.25, ‐19.31] |
5 Relapse to benzodiazepine use, end of intervention Show forest plot | 1 | 36 | Risk Ratio (M‐H, Random, 95% CI) | 2.0 [0.73, 5.47] |
6 Discontinuation due to adverse events Show forest plot | 2 | 134 | Risk Ratio (M‐H, Random, 95% CI) | 1.16 [0.42, 3.21] |
Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
1 Benzodiazepine discontinuation, end of intervention Show forest plot | 1 | 25 | Risk Ratio (M‐H, Random, 95% CI) | 0.41 [0.17, 0.99] |
2 Withdrawal syndrome (clinical diagnosis), end of intervention Show forest plot | 1 | 145 | Risk Ratio (M‐H, Random, 95% CI) | 4.86 [1.12, 21.14] |
3 Anxiety, HAM‐A, end of intervention Show forest plot | 2 | 170 | Mean Difference (IV, Random, 95% CI) | ‐1.60 [‐4.64, 1.45] |
4 Relapse to benzodiazepine use, end of intervention Show forest plot | 1 | 145 | Risk Ratio (M‐H, Random, 95% CI) | 0.33 [0.09, 1.20] |
5 Serious adverse events Show forest plot | 1 | 25 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
6 Discontinuation due to adverse events Show forest plot | 1 | 25 | Risk Ratio (M‐H, Random, 95% CI) | 0.46 [0.05, 4.46] |
Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
1 Benzodiazepine discontinuation, end of intervention Show forest plot | 4 | 143 | Risk Ratio (M‐H, Random, 95% CI) | 0.82 [0.49, 1.37] |
2 Anxiety: HAM‐A/Hospital Anxiety Depression Scale, end of intervention Show forest plot | 2 | 41 | Std. Mean Difference (IV, Random, 95% CI) | 0.18 [‐0.50, 0.86] |
3 Benzodiazepine withdrawal symptoms, end of intervention Show forest plot | 1 | 17 | Mean Difference (IV, Random, 95% CI) | 4.69 [‐14.47, 23.85] |
4 Benzodiazepine discontinuation, longest follow‐up Show forest plot | 1 | 23 | Risk Ratio (M‐H, Random, 95% CI) | 0.60 [0.34, 1.05] |
5 Benzodiazepine withdrawal symptoms, longest follow‐up Show forest plot | 1 | 15 | Mean Difference (IV, Random, 95% CI) | ‐1.34 [‐14.31, 11.63] |
6 Anxiety, Hospital Anxiety Depression Scale, longest follow‐up Show forest plot | 1 | 12 | Mean Difference (IV, Random, 95% CI) | 2.75 [‐2.83, 8.33] |
7 Discontinuation due to adverse events Show forest plot | 1 | 72 | Risk Ratio (M‐H, Random, 95% CI) | 0.33 [0.01, 7.92] |
Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
1 Benzodiazepine discontinuation, end of intervention Show forest plot | 4 | 219 | Risk Ratio (M‐H, Random, 95% CI) | 1.20 [0.73, 1.96] |
2 Insomnia Show forest plot | 3 | 150 | Std. Mean Difference (IV, Random, 95% CI) | ‐1.23 [‐2.70, 0.23] |
2.1 PSQI (Pittsburgh Sleep Quality Index) global score (higher = worse), end of intervention | 2 | 116 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.31 [‐0.92, 0.31] |
2.2 Sleep quality (1 poorest, 10 excellent), end of intervention | 1 | 34 | Std. Mean Difference (IV, Random, 95% CI) | ‐3.34 [‐4.42, ‐2.26] |
3 Discontinuation due to adverse events Show forest plot | 2 | 120 | Risk Ratio (M‐H, Random, 95% CI) | 2.10 [0.20, 22.26] |
4 Benzodiazepine discontinuation, longest follow‐up Show forest plot | 1 | 38 | Risk Ratio (M‐H, Random, 95% CI) | 1.03 [0.47, 2.27] |
5 Adverse events Show forest plot | 1 | 86 | Risk Ratio (M‐H, Random, 95% CI) | 0.97 [0.52, 1.82] |
6 Relapse to benzodiazepine use, longest follow‐up Show forest plot | 1 | 38 | Risk Ratio (M‐H, Random, 95% CI) | 1.8 [0.37, 8.68] |
Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
1 Benzodiazepine withdrawal symptoms, end of intervention Show forest plot | 3 | 58 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.95 [‐1.71, ‐0.19] |
2 Anxiety, HAM‐D (Hamilton Depression Rating Scale), end of intervention Show forest plot | 1 | 18 | Mean Difference (IV, Random, 95% CI) | ‐1.3 [‐2.28, ‐0.32] |
3 Benzodiazepine mean dose, end of intervention Show forest plot | 1 | 10 | Mean Difference (IV, Random, 95% CI) | ‐3.70 [‐22.06, 14.66] |
Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
1 Relapse to benzodiazepine use, end of intervention: 2 weeks Show forest plot | 1 | 40 | Risk Ratio (M‐H, Random, 95% CI) | 0.64 [0.31, 1.30] |
Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
1 Benzodiazepine discontinuation, end of intervention Show forest plot | 1 | 35 | Risk Ratio (M‐H, Random, 95% CI) | 1.15 [0.52, 2.54] |
2 Non‐serious adverse events Show forest plot | 1 | 35 | Risk Ratio (M‐H, Random, 95% CI) | 3.13 [1.15, 8.54] |
Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
1 Benzodiazepine discontinuation Show forest plot | 1 | 144 | Risk Ratio (M‐H, Random, 95% CI) | 0.80 [0.66, 0.96] |
2 Anxiety Show forest plot | 1 | 144 | Mean Difference (IV, Random, 95% CI) | ‐0.80 [‐2.73, 1.13] |
3 Relapse to benzodiazepine use Show forest plot | 1 | 144 | Risk Ratio (M‐H, Random, 95% CI) | 0.93 [0.46, 1.87] |
4 Non‐serious adverse events Show forest plot | 1 | 144 | Risk Ratio (M‐H, Random, 95% CI) | 0.49 [0.18, 1.35] |
5 Discontinuation due to adverse events Show forest plot | 1 | 144 | Risk Ratio (M‐H, Random, 95% CI) | 0.40 [0.13, 1.18] |
Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
1 Benzodiazepine discontinuation Show forest plot | 1 | 51 | Risk Ratio (M‐H, Random, 95% CI) | 0.79 [0.36, 1.70] |
Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
1 Benzodiazepine discontinuation, end of intervention Show forest plot | 1 | 48 | Risk Ratio (M‐H, Random, 95% CI) | 1.0 [0.78, 1.29] |
2 Relapse to benzodiazepine use Show forest plot | 1 | 48 | Risk Ratio (M‐H, Random, 95% CI) | 1.0 [0.28, 3.54] |
3 Serious adverse events Show forest plot | 1 | 48 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
1 Relapse to benzodiazepine use, longest follow‐up Show forest plot | 1 | 124 | Risk Ratio (M‐H, Random, 95% CI) | 0.33 [0.14, 0.78] |
2 Anxiety: Maximum amplitude of rebound (HAM‐A), end of intervention Show forest plot | 1 | 160 | Mean Difference (IV, Random, 95% CI) | 0.50 [‐1.23, 2.23] |
3 Discontinuation due to adverse events Show forest plot | 1 | 160 | Risk Ratio (M‐H, Random, 95% CI) | 2.87 [0.79, 10.44] |
4 Non‐serious adverse events Show forest plot | 1 | 160 | Risk Ratio (M‐H, Random, 95% CI) | 1.68 [1.01, 2.78] |
Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
1 Relapse to benzodiazepine use, longest follow‐up Show forest plot | 1 | 18 | Risk Ratio (M‐H, Random, 95% CI) | 1.05 [0.23, 4.78] |