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Meta-Analysis
. 2018 Mar 15;3(3):CD011481.
doi: 10.1002/14651858.CD011481.pub2.

Pharmacological interventions for benzodiazepine discontinuation in chronic benzodiazepine users

Lone Baandrup  1 , Bjørn H Ebdrup, Jesper Ø Rasmussen, Jane Lindschou, Christian Gluud, Birte Y Glenthøj
Affiliations
Meta-Analysis

Pharmacological interventions for benzodiazepine discontinuation in chronic benzodiazepine users

Lone Baandrup et al. Cochrane Database Syst Rev. .

Abstract

Background: Prolonged treatment with benzodiazepines is common practice despite clinical recommendations of short-term use. Benzodiazepines are used by approximately 4% of the general population, with increased prevalence in psychiatric populations and the elderly. After long-term use it is often difficult to discontinue benzodiazepines due to psychological and physiological dependence. This review investigated if pharmacological interventions can facilitate benzodiazepine tapering.

Objectives: To assess the benefits and harms of pharmacological interventions to facilitate discontinuation of chronic benzodiazepine use.

Search methods: We searched the following electronic databases up to October 2017: Cochrane Drugs and Alcohol Group's Specialised Register of Trials, CENTRAL, PubMed, Embase, CINAHL, and ISI Web of Science. We also searched ClinicalTrials.gov, the WHO ICTRP, and ISRCTN registry, and checked the reference lists of included studies for further references to relevant randomised controlled trials.

Selection criteria: We included randomised controlled trials comparing pharmacological treatment versus placebo or no intervention or versus another pharmacological intervention in adults who had been treated with benzodiazepines for at least two months and/or fulfilled criteria for benzodiazepine dependence (any criteria).

Data collection and analysis: We used standard methodological procedures expected by Cochrane.

Main results: We included 38 trials (involving 2543 participants), but we could only extract data from 35 trials with 2295 participants. Many different interventions were studied, and no single intervention was assessed in more than four trials. We extracted data on 18 different comparisons. The risk of bias was high in all trials but one. Trial Sequential Analysis showed imprecision for all comparisons.For benzodiazepine discontinuation, we found a potential benefit of valproate at end of intervention (1 study, 27 participants; risk ratio (RR) 2.55, 95% confidence interval (CI) 1.08 to 6.03; very low-quality evidence) and of tricyclic antidepressants at longest follow-up (1 study, 47 participants; RR 2.20, 95% CI 1.27 to 3.82; low-quality evidence).We found potentially positive effects on benzodiazepine withdrawal symptoms of pregabalin (1 study, 106 participants; mean difference (MD) -3.10 points, 95% CI -3.51 to -2.69; very low-quality evidence), captodiame (1 study, 81 participants; MD -1.00 points, 95% CI -1.13 to -0.87; very low-quality evidence), paroxetine (2 studies, 99 participants; MD -3.57 points, 95% CI -5.34 to -1.80; very low-quality evidence), tricyclic antidepressants (1 study, 38 participants; MD -19.78 points, 95% CI -20.25 to -19.31; very low-quality evidence), and flumazenil (3 studies, 58 participants; standardised mean difference -0.95, 95% CI -1.71 to -0.19; very low-quality evidence) at end of intervention. However, the positive effect of paroxetine on benzodiazepine withdrawal symptoms did not persist until longest follow-up (1 study, 54 participants; MD -0.13 points, 95% CI -4.03 to 3.77; very low-quality evidence).The following pharmacological interventions reduced symptoms of anxiety at end of intervention: carbamazepine (1 study, 36 participants; MD -6.00 points, 95% CI -9.58 to -2.42; very low-quality evidence), pregabalin (1 study, 106 participants; MD -4.80 points, 95% CI -5.28 to -4.32; very low-quality evidence), captodiame (1 study, 81 participants; MD -5.70 points, 95% CI -6.05 to -5.35; very low-quality evidence), paroxetine (2 studies, 99 participants; MD -6.75 points, 95% CI -9.64 to -3.86; very low-quality evidence), and flumazenil (1 study, 18 participants; MD -1.30 points, 95% CI -2.28 to -0.32; very low-quality evidence).Two pharmacological treatments seemed to reduce the proportion of participants that relapsed to benzodiazepine use: valproate (1 study, 27 participants; RR 0.31, 95% CI 0.11 to 0.90; very low-quality evidence) and cyamemazine (1 study, 124 participants; RR 0.33, 95% CI 0.14 to 0.78; very low-quality evidence). Alpidem decreased the proportion of participants with benzodiazepine discontinuation (1 study, 25 participants; RR 0.41, 95% CI 0.17 to 0.99; number needed to treat for an additional harmful outcome (NNTH) 2.3 participants; low-quality evidence) and increased the occurrence of withdrawal syndrome (1 study, 145 participants; RR 4.86, 95% CI 1.12 to 21.14; NNTH 5.9 participants; low-quality evidence). Likewise, magnesium aspartate decreased the proportion of participants discontinuing benzodiazepines (1 study, 144 participants; RR 0.80, 95% CI 0.66 to 0.96; NNTH 5.8; very low-quality evidence).Generally, adverse events were insufficiently reported. Specifically, one of the flumazenil trials was discontinued due to severe panic reactions.

Authors' conclusions: Given the low or very low quality of the evidence for the reported outcomes, and the small number of trials identified with a limited number of participants for each comparison, it is not possible to draw firm conclusions regarding pharmacological interventions to facilitate benzodiazepine discontinuation in chronic benzodiazepine users. Due to poor reporting, adverse events could not be reliably assessed across trials. More randomised controlled trials are required with less risk of systematic errors ('bias') and of random errors ('play of chance') and better and full reporting of patient-centred and long-term clinical outcomes. Such trials ought to be conducted independently of industry involvement.

PubMed Disclaimer

Conflict of interest statement

LB is the sponsor‐investigator of one of the studies included in this review (Baandrup 2016). A review author independent of this trial acted as the second review author, thus ensuring unbiased data extraction and 'Risk of bias' assessment.

BE has received lecture fees from Bristol‐Myers Squibb, Otsuka Pharma Scandinavia AB, and Eli Lilly and Company and is part of the Advisory Board of Eli Lilly Danmark A/S, Janssen‐Cilag A/S, and Takeda Pharmaceutical Company Ltd.

BG is leader of a Lundbeck Foundation Centre of Excellence for Clinical Intervention and Neuropsychiatric Schizophrenia Research, CINS. CINS is independent of H. Lundbeck A/S. The grant was awarded based on international scientific review. BG is part of the study group behind the clinical trial stated by LB in her declaration of interest.

JL, CG, and JR have no known conflicts of interest.

Figures

1
1
Study flow diagram.
2
2
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
3
3
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
4
4
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.
5
5
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.
6
6
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.
7
7
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.
8
8
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.
9
9
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.
10
10
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.
11
11
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.
1.1
1.1. Analysis
Comparison 1 Valproate versus placebo or no intervention, Outcome 1 Benzodiazepine discontinuation, end of intervention.
1.2
1.2. Analysis
Comparison 1 Valproate versus placebo or no intervention, Outcome 2 Relapse to benzodiazepine use, end of intervention.
1.3
1.3. Analysis
Comparison 1 Valproate versus placebo or no intervention, Outcome 3 Benzodiazepine discontinuation, longest follow‐up.
1.4
1.4. Analysis
Comparison 1 Valproate versus placebo or no intervention, Outcome 4 Relapse to benzodiazepine use, longest follow‐up.
1.5
1.5. Analysis
Comparison 1 Valproate versus placebo or no intervention, Outcome 5 Anxiety: HAM‐A (Hamilton Anxiety Rating Scale), end of intervention.
1.6
1.6. Analysis
Comparison 1 Valproate versus placebo or no intervention, Outcome 6 Benzodiazepine withdrawal symptoms, end of intervention.
1.7
1.7. Analysis
Comparison 1 Valproate versus placebo or no intervention, Outcome 7 Discontinuation due to adverse events.
1.8
1.8. Analysis
Comparison 1 Valproate versus placebo or no intervention, Outcome 8 Serious adverse events.
2.1
2.1. Analysis
Comparison 2 Carbamazepine versus placebo, Outcome 1 Benzodiazepine discontinuation, end of intervention.
2.2
2.2. Analysis
Comparison 2 Carbamazepine versus placebo, Outcome 2 Benzodiazepine withdrawal symptoms.
2.3
2.3. Analysis
Comparison 2 Carbamazepine versus placebo, Outcome 3 Benzodiazepine discontinuation, longest follow‐up.
2.4
2.4. Analysis
Comparison 2 Carbamazepine versus placebo, Outcome 4 Relapse to benzodiazepine use.
2.5
2.5. Analysis
Comparison 2 Carbamazepine versus placebo, Outcome 5 Serious adverse events.
2.6
2.6. Analysis
Comparison 2 Carbamazepine versus placebo, Outcome 6 Non‐serious adverse events.
2.7
2.7. Analysis
Comparison 2 Carbamazepine versus placebo, Outcome 7 Anxiety, HAM‐A.
2.8
2.8. Analysis
Comparison 2 Carbamazepine versus placebo, Outcome 8 Discontinuation due to adverse events.
3.1
3.1. Analysis
Comparison 3 Lithium versus placebo, Outcome 1 Benzodiazepine discontinuation.
3.2
3.2. Analysis
Comparison 3 Lithium versus placebo, Outcome 2 Serious adverse events.
3.3
3.3. Analysis
Comparison 3 Lithium versus placebo, Outcome 3 Non‐serious adverse events.
3.4
3.4. Analysis
Comparison 3 Lithium versus placebo, Outcome 4 Discontinuation due to adverse events.
4.1
4.1. Analysis
Comparison 4 Pregabalin versus placebo, Outcome 1 Benzodiazepine discontinuation, end of intervention.
4.2
4.2. Analysis
Comparison 4 Pregabalin versus placebo, Outcome 2 Benzodiazepine withdrawal symptoms (Physician Withdrawal Checklist), end of intervention.
4.3
4.3. Analysis
Comparison 4 Pregabalin versus placebo, Outcome 3 Anxiety, HAM‐A, end of intervention.
4.4
4.4. Analysis
Comparison 4 Pregabalin versus placebo, Outcome 4 Serious adverse events.
4.5
4.5. Analysis
Comparison 4 Pregabalin versus placebo, Outcome 5 Non‐serious adverse events.
4.6
4.6. Analysis
Comparison 4 Pregabalin versus placebo, Outcome 6 Discontinuation due to adverse events.
5.1
5.1. Analysis
Comparison 5 Captodiame versus placebo, Outcome 1 Benzodiazepine withdrawal symptoms, BWSQ (Benzodiazepine Withdrawal Symptom Questionnaire), end of intervention.
5.2
5.2. Analysis
Comparison 5 Captodiame versus placebo, Outcome 2 Anxiety, HAM‐A, end of intervention.
5.3
5.3. Analysis
Comparison 5 Captodiame versus placebo, Outcome 3 Serious adverse events.
5.4
5.4. Analysis
Comparison 5 Captodiame versus placebo, Outcome 4 Non‐serious adverse events.
6.1
6.1. Analysis
Comparison 6 Paroxetine versus placebo or no intervention, Outcome 1 Benzodiazepine discontinuation, end of intervention.
6.2
6.2. Analysis
Comparison 6 Paroxetine versus placebo or no intervention, Outcome 2 Benzodiazepine withdrawal symptoms: BWSQ, end of intervention.
6.3
6.3. Analysis
Comparison 6 Paroxetine versus placebo or no intervention, Outcome 3 Anxiety: HAM‐A, end of intervention.
6.4
6.4. Analysis
Comparison 6 Paroxetine versus placebo or no intervention, Outcome 4 Benzodiazepine withdrawal symptoms: BWSQ, longest follow‐up: 6 months.
6.5
6.5. Analysis
Comparison 6 Paroxetine versus placebo or no intervention, Outcome 5 Serious adverse events.
6.6
6.6. Analysis
Comparison 6 Paroxetine versus placebo or no intervention, Outcome 6 Non‐serious adverse events.
7.1
7.1. Analysis
Comparison 7 Tricyclic antidepressants versus placebo, Outcome 1 Benzodiazepine discontinuation, end of intervention.
7.2
7.2. Analysis
Comparison 7 Tricyclic antidepressants versus placebo, Outcome 2 Anxiety: HAM‐A (change from baseline), end of intervention.
7.3
7.3. Analysis
Comparison 7 Tricyclic antidepressants versus placebo, Outcome 3 Benzodiazepine discontinuation, longest follow‐up.
7.4
7.4. Analysis
Comparison 7 Tricyclic antidepressants versus placebo, Outcome 4 Benzodiazepine withdrawal symptoms (Physician Withdrawal Checklist), end of intervention.
7.5
7.5. Analysis
Comparison 7 Tricyclic antidepressants versus placebo, Outcome 5 Relapse to benzodiazepine use, end of intervention.
7.6
7.6. Analysis
Comparison 7 Tricyclic antidepressants versus placebo, Outcome 6 Discontinuation due to adverse events.
8.1
8.1. Analysis
Comparison 8 Alpidem versus placebo, Outcome 1 Benzodiazepine discontinuation, end of intervention.
8.2
8.2. Analysis
Comparison 8 Alpidem versus placebo, Outcome 2 Withdrawal syndrome (clinical diagnosis), end of intervention.
8.3
8.3. Analysis
Comparison 8 Alpidem versus placebo, Outcome 3 Anxiety, HAM‐A, end of intervention.
8.4
8.4. Analysis
Comparison 8 Alpidem versus placebo, Outcome 4 Relapse to benzodiazepine use, end of intervention.
8.5
8.5. Analysis
Comparison 8 Alpidem versus placebo, Outcome 5 Serious adverse events.
8.6
8.6. Analysis
Comparison 8 Alpidem versus placebo, Outcome 6 Discontinuation due to adverse events.
9.1
9.1. Analysis
Comparison 9 Buspirone versus placebo, Outcome 1 Benzodiazepine discontinuation, end of intervention.
9.2
9.2. Analysis
Comparison 9 Buspirone versus placebo, Outcome 2 Anxiety: HAM‐A/Hospital Anxiety Depression Scale, end of intervention.
9.3
9.3. Analysis
Comparison 9 Buspirone versus placebo, Outcome 3 Benzodiazepine withdrawal symptoms, end of intervention.
9.4
9.4. Analysis
Comparison 9 Buspirone versus placebo, Outcome 4 Benzodiazepine discontinuation, longest follow‐up.
9.5
9.5. Analysis
Comparison 9 Buspirone versus placebo, Outcome 5 Benzodiazepine withdrawal symptoms, longest follow‐up.
9.6
9.6. Analysis
Comparison 9 Buspirone versus placebo, Outcome 6 Anxiety, Hospital Anxiety Depression Scale, longest follow‐up.
9.7
9.7. Analysis
Comparison 9 Buspirone versus placebo, Outcome 7 Discontinuation due to adverse events.
10.1
10.1. Analysis
Comparison 10 Melatonin versus placebo, Outcome 1 Benzodiazepine discontinuation, end of intervention.
10.2
10.2. Analysis
Comparison 10 Melatonin versus placebo, Outcome 2 Insomnia.
10.3
10.3. Analysis
Comparison 10 Melatonin versus placebo, Outcome 3 Discontinuation due to adverse events.
10.4
10.4. Analysis
Comparison 10 Melatonin versus placebo, Outcome 4 Benzodiazepine discontinuation, longest follow‐up.
10.5
10.5. Analysis
Comparison 10 Melatonin versus placebo, Outcome 5 Adverse events.
10.6
10.6. Analysis
Comparison 10 Melatonin versus placebo, Outcome 6 Relapse to benzodiazepine use, longest follow‐up.
11.1
11.1. Analysis
Comparison 11 Flumazenil versus placebo, Outcome 1 Benzodiazepine withdrawal symptoms, end of intervention.
11.2
11.2. Analysis
Comparison 11 Flumazenil versus placebo, Outcome 2 Anxiety, HAM‐D (Hamilton Depression Rating Scale), end of intervention.
11.3
11.3. Analysis
Comparison 11 Flumazenil versus placebo, Outcome 3 Benzodiazepine mean dose, end of intervention.
12.1
12.1. Analysis
Comparison 12 Propranolol versus placebo, Outcome 1 Relapse to benzodiazepine use, end of intervention: 2 weeks.
13.1
13.1. Analysis
Comparison 13 Progesterone versus placebo, Outcome 1 Benzodiazepine discontinuation, end of intervention.
13.2
13.2. Analysis
Comparison 13 Progesterone versus placebo, Outcome 2 Non‐serious adverse events.
14.1
14.1. Analysis
Comparison 14 Magnesium aspartate versus placebo, Outcome 1 Benzodiazepine discontinuation.
14.2
14.2. Analysis
Comparison 14 Magnesium aspartate versus placebo, Outcome 2 Anxiety.
14.3
14.3. Analysis
Comparison 14 Magnesium aspartate versus placebo, Outcome 3 Relapse to benzodiazepine use.
14.4
14.4. Analysis
Comparison 14 Magnesium aspartate versus placebo, Outcome 4 Non‐serious adverse events.
14.5
14.5. Analysis
Comparison 14 Magnesium aspartate versus placebo, Outcome 5 Discontinuation due to adverse events.
15.1
15.1. Analysis
Comparison 15 Homéogène 46/Sedatif PC (homeopathic drugs) versus placebo, Outcome 1 Benzodiazepine discontinuation.
16.1
16.1. Analysis
Comparison 16 Carbamazepine versus tricyclic antidepressant, Outcome 1 Benzodiazepine discontinuation, end of intervention.
16.2
16.2. Analysis
Comparison 16 Carbamazepine versus tricyclic antidepressant, Outcome 2 Relapse to benzodiazepine use.
16.3
16.3. Analysis
Comparison 16 Carbamazepine versus tricyclic antidepressant, Outcome 3 Serious adverse events.
17.1
17.1. Analysis
Comparison 17 Cyamemazine versus bromazepam, Outcome 1 Relapse to benzodiazepine use, longest follow‐up.
17.2
17.2. Analysis
Comparison 17 Cyamemazine versus bromazepam, Outcome 2 Anxiety: Maximum amplitude of rebound (HAM‐A), end of intervention.
17.3
17.3. Analysis
Comparison 17 Cyamemazine versus bromazepam, Outcome 3 Discontinuation due to adverse events.
17.4
17.4. Analysis
Comparison 17 Cyamemazine versus bromazepam, Outcome 4 Non‐serious adverse events.
18.1
18.1. Analysis
Comparison 18 Zopiclone versus flunitrazepam, Outcome 1 Relapse to benzodiazepine use, longest follow‐up.
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References

References to studies included in this review

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    1. Gerra G, Zaimovic A, Giusti F, Moi G, Brewer C. Intravenous flumazenil versus oxazepam tapering in the treatment of benzodiazepine withdrawal: a randomized, placebo‐controlled study. Addiction Biology 2002;7(4):385‐95. - PubMed
GlaxoSmithKline 2002 {unpublished data only}
    1. GlaxoSmithKline. Clinical comparison of paroxetine and placebo on the symptoms emerging during the taper phase of a chronic benzodiazepine treatment, in patients suffering from a variety of anxiety disorders. GSK ‐ Clinical Study Register (www.gsk‐clinicalstudyregister.com) 2002.
Hadley 2012 {published data only}
    1. Hadley SJ, Mandel FS, Schweizer E. Switching from long‐term benzodiazepine therapy to pregabalin in patients with generalized anxiety disorder: a double‐blind, placebo‐controlled trial. Journal of Psychopharmacology 2012;26(4):461‐70. [DOI: 10.1177/0269881111405360] - DOI - PubMed
    1. Szczypa P, Hadley SJ, Donevan S, Mandel FS, Leon T. P.4.a.016 Switching from long‐term benzodiazepine therapy to pregabalin in patients with generalised anxiety disorder (GAD). European Neuropsychopharmacology 2009;19:S594‐5. [DOI: 10.1016/S0924-977X(09)70952-6] - DOI
Hantouche 1998 {published data only}
    1. Hantouche EG, Guelfi JD, Comet D. Discontinuation of long‐term benzodiazepine use: double‐blind controlled study of α‐β L‐aspartate magnesium versus placebo in 144 chronic users of benzodiazepines [α‐β L‐aspartate de magnésium dans l'arrêt de la consommation chronique des benzodiazépines: étude contrôlée en double aveugle versus placebo]. L'encéphale 1998;XXIV:469‐79. - PubMed
    1. Hantouche EG, Jacob L, Comet D, Guelfi JD. Discontinuation of long‐term benzodiazepine use: predictive model of success in a double‐blind, controlled‐study. 150th Annual Meeting of the American Psychiatric Association, 1997 May 17‐22; San Diego, (CA). 1997.
Harrison‐Read 1996 {published data only}
    1. Harrison‐Read PE, Tyrer P, Lawson C, Lack S, Fernandes C, File SE. Flumazenil‐precipitated panic and dysphoria in patients dependent on benzodiazepines: a possible aid to abstinence. Journal of Psychopharmacology 1996;10(2):89‐97. - PubMed
Klein 1994 {published data only}
    1. Klein E, Colin V, Stolk J, Lenox RH. Alprazolam withdrawal in patients with panic disorder and generalized anxiety disorder: vulnerability and effect of carbamazepine. American Journal of Psychiatry 1994;151(12):1760‐6. - PubMed
Kornowski 2002 {published data only}
    1. Kornowski J. The comparison between tianeptine and carbamazepine in benzodiazepines withdrawal syndrome. Psychiatria Polska 2002;6(Suppl):311‐8. - PubMed
Lader 1987 {published data only}
    1. Lader M, Olajide D. A comparison of buspirone and placebo in relieving benzodiazepine withdrawal symptoms. Journal of Clinical Psychopharmacology 1987;7(1):11‐5. - PubMed
Lader 1993 {published data only}
    1. Lader M, Farr I, Morton S. A comparison of alpidem and placebo in relieving benzodiazepine withdrawal symptoms. International Clinical Psychopharmacology 1993;8(1):31‐6. - PubMed
Lecrubier 2005 {published data only}
    1. Lecrubier Y, Fessard N. Benzodiazepine discontinuation in chronic users: a double‐blind trial of lithium gluconate vs placebo [Arrêt des benzodiazépines chez des consommateurs chronique: un essai en double insu du gluconate de lithium vs placebo]. Annales Médico Phychologiques 2005;163:24‐9.
Lemoine 2006 {published data only}
    1. Lemoine P, Kermadi I, Garcia‐Acosta S, Garay RP, Dib M. Double‐blind, comparative study of cyamemazine vs. bromazepam in the benzodiazepine withdrawal syndrome. Progress in Neuro‐Psychopharmacology & Biological Psychiatry 2006;30(1):131‐7. - PubMed
Mariani 2016 {published data only}
    1. Mariani JJ, Malcolm RJ, Mamczur AK, Choi JC, Brady R, Nunes E, et al. Pilot trial of gabapentin for the treatment of benzodiazepine abuse or dependence in methadone maintenance patients. American Journal of Drug and Alcohol Abuse 2016;42(3):333‐40. [PUBMED: 26962719] - PMC - PubMed
Mercier‐Guyon 2004 {published data only}
    1. Mercier‐Guyon C, Chabannes JP, Saviuc P. The role of captodiamine in the withdrawal from long‐term benzodiazepine treatment. Current Medical Research and Opinion 2004;20(9):1347‐55. [DOI: 10.1185/030079904125004457] - DOI - PubMed
Morton 1995 {published data only}
    1. Morton S, Lader M. Buspirone treatment as an aid to benzodiazepine withdrawal. Journal of Psychopharmacology 1995;9(4):331‐5. - PubMed
Nakao 2006 {published data only}
    1. Nakao M, Takeuchi T, Nomura K, Teramoto T, Yano E. Clinical application of paroxetine for chronic benzodiazepine users at an internal medicine clinic. Therapeutic Research 2006;27(5):859‐67. - PubMed
    1. Nakao M, Takeuchi T, Nomura K, Teramoto T, Yano E. Clinical application of paroxetine for tapering benzodiazepine use in non‐major‐depressive outpatients visiting an internal medicine clinic. Psychiatry and Clinical Neurosciences 2006;60(5):605‐10. - PubMed
Pat‐Horenczyk 1998 {published data only}
    1. Pat‐Horenczyk R, Hacohen D, Herer P, Lavie P. The effects of substituting zopiclone in withdrawal from chronic use of benzodiazepine hypnotics. Psychopharmacology 1998;140(4):450‐7. [DOI: 10.1007/s002130050789] - DOI - PubMed
Peles 2007 {published data only}
    1. Peles E, Hetzroni T, Bar‐Hamburger R, Adelson M, Schreiber S. Melatonin for perceived sleep disturbances associated with benzodiazepine withdrawal among patients in methadone maintenance treatment: a double‐blind randomized clinical trial. Addiction 2007;102(12):1947‐53. - PubMed
Rickels 1999 {published data only}
    1. Rickels K, Schweizer E, Garcia Espana F, Case, G, DeMartinis N, Greenblatt D. Trazodone and valproate in patients discontinuing long‐term benzodiazepine therapy: effects on withdrawal symptoms and taper outcome. Psychopharmacology 1999;141(1):1‐5. - PubMed
Rickels 2000 {published data only}
    1. Rickels K, DeMartinis N, Garcia‐Espana F, Greenblatt DJ, Mandos LA, Rynn M. Imipramine and buspirone in treatment of patients with generalized anxiety disorder who are discontinuing long‐term benzodiazepine therapy. American Journal of Psychiatry 2000;157(12):1973‐9. - PubMed
Romach 1998 {published data only}
    1. Romach MK, Kaplan HL, Busto UE, Somer G, Sellers EM. A controlled trial of ondansetron, a 5‐HT3 antagonist, in benzodiazepine discontinuation. Journal of Clinical Psychopharmacology 1998;18(2):121‐31. - PubMed
Rynn 2003 {published data only}
    1. Rynn M, Garcia‐Espana F, Greenblatt DJ, Mandos LA, Schweizer E, Rickels K. Imipramine and buspirone in patients with panic disorder who are discontinuing long‐term benzodiazepine therapy. Journal of Clinical Psychopharmacology 2003;23(5):505‐8. - PubMed
Saul 1989 {published data only}
    1. Saul PA, Korlipara K, Presley P. A randomised, multicentre, double‐blind, comparison of atenolol and placebo in the control of benzodiazepine withdrawal symptoms. Acta Therapeutica 1989;15(2):117‐23.
Schweizer 1991 {published data only}
    1. Schweizer E, Rickels, K, Case WG, Greenblatt DJ. Carbamazepine treatment in patients discontinuing long‐term benzodiazepine therapy. Effects on withdrawal severity and outcome. Archives of General Psychiatry 1991;48(5):448‐52. - PubMed
Schweizer 1995 {published data only}
    1. Schweizer E, Case WG, Garcia‐Espana F, Greenblatt DJ, Rickels K. Progesterone co‐administration in patients discontinuing long‐term benzodiazepine therapy: effects on withdrawal severity and taper outcome. Psychopharmacology 1995;117(4):424‐9. - PubMed
Tyrer 1981 {published data only}
    1. Tyrer P, Rutherford D, Huggett T. Benzodiazepine withdrawal symptoms and propranolol. Lancet 1981;1(8219):520‐2. - PubMed
Tyrer 1996 {published data only}
    1. Tyrer P, Ferguson B, Hallstrom C, Michie M, Tyrer S, Cooper S, et al. A controlled trial of dothiepin and placebo in treating benzodiazepine withdrawal symptoms. British Journal of Psychiatry 1996;168(4):457‐61. - PubMed
Udelman 1990 {published data only}
    1. Udelman HD, Udelman DL. Concurrent use of buspirone in anxious patients during withdrawal from alprazolam therapy. Journal of Clinical Psychiatry 1990;51 Suppl:46‐50. - PubMed
Vissers 2007 {published data only}
    1. Vissers FH, Knipschild PG, Crebolder HF. Is melatonin helpful in stopping the long‐term use of hypnotics? A discontinuation trial. Pharmacy World & Science 2007;29(6):641‐6. [DOI: 10.1007/s11096-007-9118-y] - DOI - PMC - PubMed
Vorma 2011 {published data only}
    1. Vorma H, Katila H. Effect of valproate on benzodiazepine withdrawal severity in opioid‐dependent subjects: a pilot study. Heroin Addiction and Related Clinical Problems 2011;13(1):15‐20.
Zhang 2013 {published data only}
    1. Zhang H, Jiang X, Ma M, Zhang J. A control study on treatment for benzodiazepine dependence with trazodone. Chinese Journal of Contemporary Neurology and Neurosurgery 2013;13(5):411‐5.
Zitman 2001 {published data only}
    1. Zitman FG, Couvee JE. Chronic benzodiazepine use in general practice patients with depression: an evaluation of controlled treatment and taper‐off: report on behalf of the Dutch Chronic Benzodiazepine Working Group. British Journal of Psychiatry 2001;178:317‐24. - PubMed

References to studies excluded from this review

Allain 1998 {published data only}
    1. Allain H, Coz F, Borderies P, Schuck S, Giclais B, Patat A, et al. Use of zolpidem 10 mg as a benzodiazepine substitute in 84 patients with insomnia. Human Psychopharmacology 1998;13(8):551‐9.
Avedisova 2007 {published data only}
    1. Avedisova AS, Iastrebov DV. Use of anxiolytic atarax as a substitutive drug for benzodiazepine tranquilizers. Zhurnal Nevrologii i psikhiatrii imeni S.S. Korsakova 2007;107(3):37‐41. - PubMed
Bobes 2012 {published data only}
    1. Bobes J, Rubio G, Teran A, Cervera G, Lopez‐Gomez V, Vilardaga I, et al. Pregabalin for the discontinuation of long‐term benzodiazepines use: an assessment of its effectiveness in daily clinical practice. European Psychiatry 2012;27(4):301‐7. - PubMed
Bourgeois 2014 {published data only}
    1. Bourgeois J, Elseviers MM, Bortel L, Petrovic M, Vander Stichele RH. Feasibility of discontinuing chronic benzodiazepine use in nursing home residents: a pilot study. European Journal of Clinical Pharmacology 2014;17(10):1251‐60. - PubMed
Cantopher 1990 {published data only}
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Cohen‐Mansfield 1999 {published data only}
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Declerck 1999 {published data only}
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Garcia‐Borreguero 1992 {published data only}
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Hallstrom 1988 {published data only}
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Isaka 2009 {published data only}
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Lahteenmaki 2014 {published data only}
    1. Lahteenmaki R, Puustinen J, Vahlberg T, Lyles A, Neuvonen PJ, Partinen M, et al. Melatonin for sedative withdrawal in older patients with primary insomnia: a randomized double‐blind placebo‐controlled trial. British Journal of Clinical Pharmacology 2014;77(6):975‐85. - PMC - PubMed
Lemoine 1997 {published data only}
    1. Lemoine P, Touchon J, Billardon M. Comparison of 6 different methods for lorazepam withdrawal. A controlled study, hydroxyzine versus placebo. Encephale 1997;23(4):290‐9. - PubMed
Lopatko 2006 {published data only}
    1. Lopatko O, Morefield K, Danz C, Davies J, Ali R, White JM. Reducing benzodiazepine consumption in opioid maintenance therapy patients: A controlled clinical trial. Proceedings of the 68th Annual Scientific Meeting of the College on Problems of Drug Dependence. 2006:20.
Nakajima 2007 {published data only}
    1. Nakajima S, Uchida H, Suzuki T, Tomita M, Tsunoda K, Kitta M, et al. An open‐label trial of discontinuing benzodiazepines in patients with chronic schizophrenia. Journal of Clinical Psychopharmacology 2007;27(4):401‐3. - PubMed
Petrovic 2002 {published data only}
    1. Petrovic M, Pevernagie D, Mariman A, Maele G, Afschrift M. Fast withdrawal from benzodiazepines in geriatric inpatients: a randomised double‐blind, placebo‐controlled trial. European Journal of Clinical Pharmacology 2002;57:759‐64. - PubMed
Rocco 1992 {published data only}
    1. Rocco PL, Giavedoni A, Pacella G. Withdrawal from benzodiazepines in a hospital setting: an open trial with buspirone. Current Therapeutic Research ‐ Clinical and Experimental 1992;52(3):386‐9.
Rubio 2009 {published data only}
    1. Rubio G, Bobes J, Cervera G, Teran A, Perez M, Lopez‐Gomez V, et al. Benzodiazepines use withdrawal tapering gradually with pregabalin: findings from the medical practice. European Neuropsychopharmacology 2009;19:S652.
Saxon 1997 {published data only}
    1. Saxon L, Hjemdahl P, Hiltunen AJ, Borg S. Effects of flumazenil in the treatment of benzodiazepine withdrawal ‐ a double‐blind pilot study. Psychopharmacology 1997;131(2):153‐60. - PubMed
Shapiro 1995 {published data only}
    1. Shapiro CM, Sherman D, Peck DF. Withdrawal from benzodiazepines by initially switching to zopiclone. European Psychiatry 1995;10:S145‐51. - PubMed
Vescovi 1987 {published data only}
    1. Vescovi PP, Gerra G, Ippolito L. Nicotinic acid effectiveness in the treatment of benzodiazepine withdrawal. Current Therapeutic Research ‐ Clinical and Experimental 1987;41(6):1017‐21.
Weizman 2003 {published data only}
    1. Weizman T, Gelkopf M, Melamed Y, Adelson M, Bleich A. Treatment of benzodiazepine dependence in methadone maintenance treatment patients: a comparison of two therapeutic modalities and the role of psychiatric comorbidity. Australian and New Zealand Journal of Psychiatry 2003;37(4):458‐63. - PubMed

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