Pharmacological interventions for benzodiazepine discontinuation in chronic benzodiazepine users

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.

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

Study flow diagram.

2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

3

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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

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

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

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

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

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

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

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. Analysis

Comparison 1 Valproate versus placebo or no intervention, Outcome 1 Benzodiazepine discontinuation, end of intervention.

1.2. Analysis

Comparison 1 Valproate versus placebo or no intervention, Outcome 2 Relapse to benzodiazepine use, end of intervention.

1.3. Analysis

Comparison 1 Valproate versus placebo or no intervention, Outcome 3 Benzodiazepine discontinuation, longest follow‐up.

1.4. Analysis

Comparison 1 Valproate versus placebo or no intervention, Outcome 4 Relapse to benzodiazepine use, longest follow‐up.

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. Analysis

Comparison 1 Valproate versus placebo or no intervention, Outcome 6 Benzodiazepine withdrawal symptoms, end of intervention.

1.7. Analysis

Comparison 1 Valproate versus placebo or no intervention, Outcome 7 Discontinuation due to adverse events.

1.8. Analysis

Comparison 1 Valproate versus placebo or no intervention, Outcome 8 Serious adverse events.

2.1. Analysis

Comparison 2 Carbamazepine versus placebo, Outcome 1 Benzodiazepine discontinuation, end of intervention.

2.2. Analysis

Comparison 2 Carbamazepine versus placebo, Outcome 2 Benzodiazepine withdrawal symptoms.

2.3. Analysis

Comparison 2 Carbamazepine versus placebo, Outcome 3 Benzodiazepine discontinuation, longest follow‐up.

2.4. Analysis

Comparison 2 Carbamazepine versus placebo, Outcome 4 Relapse to benzodiazepine use.

2.5. Analysis

Comparison 2 Carbamazepine versus placebo, Outcome 5 Serious adverse events.

2.6. Analysis

Comparison 2 Carbamazepine versus placebo, Outcome 6 Non‐serious adverse events.

2.7. Analysis

Comparison 2 Carbamazepine versus placebo, Outcome 7 Anxiety, HAM‐A.

2.8. Analysis

Comparison 2 Carbamazepine versus placebo, Outcome 8 Discontinuation due to adverse events.

3.1. Analysis

Comparison 3 Lithium versus placebo, Outcome 1 Benzodiazepine discontinuation.

3.2. Analysis

Comparison 3 Lithium versus placebo, Outcome 2 Serious adverse events.

3.3. Analysis

Comparison 3 Lithium versus placebo, Outcome 3 Non‐serious adverse events.

3.4. Analysis

Comparison 3 Lithium versus placebo, Outcome 4 Discontinuation due to adverse events.

4.1. Analysis

Comparison 4 Pregabalin versus placebo, Outcome 1 Benzodiazepine discontinuation, end of intervention.

4.2. Analysis

Comparison 4 Pregabalin versus placebo, Outcome 2 Benzodiazepine withdrawal symptoms (Physician Withdrawal Checklist), end of intervention.

4.3. Analysis

Comparison 4 Pregabalin versus placebo, Outcome 3 Anxiety, HAM‐A, end of intervention.

4.4. Analysis

Comparison 4 Pregabalin versus placebo, Outcome 4 Serious adverse events.

4.5. Analysis

Comparison 4 Pregabalin versus placebo, Outcome 5 Non‐serious adverse events.

4.6. Analysis

Comparison 4 Pregabalin versus placebo, Outcome 6 Discontinuation due to adverse events.

5.1. Analysis

Comparison 5 Captodiame versus placebo, Outcome 1 Benzodiazepine withdrawal symptoms, BWSQ (Benzodiazepine Withdrawal Symptom Questionnaire), end of intervention.

5.2. Analysis

Comparison 5 Captodiame versus placebo, Outcome 2 Anxiety, HAM‐A, end of intervention.

5.3. Analysis

Comparison 5 Captodiame versus placebo, Outcome 3 Serious adverse events.

5.4. Analysis

Comparison 5 Captodiame versus placebo, Outcome 4 Non‐serious adverse events.

6.1. Analysis

Comparison 6 Paroxetine versus placebo or no intervention, Outcome 1 Benzodiazepine discontinuation, end of intervention.

6.2. Analysis

Comparison 6 Paroxetine versus placebo or no intervention, Outcome 2 Benzodiazepine withdrawal symptoms: BWSQ, end of intervention.

6.3. Analysis

Comparison 6 Paroxetine versus placebo or no intervention, Outcome 3 Anxiety: HAM‐A, end of intervention.

6.4. Analysis

Comparison 6 Paroxetine versus placebo or no intervention, Outcome 4 Benzodiazepine withdrawal symptoms: BWSQ, longest follow‐up: 6 months.

6.5. Analysis

Comparison 6 Paroxetine versus placebo or no intervention, Outcome 5 Serious adverse events.

6.6. Analysis

Comparison 6 Paroxetine versus placebo or no intervention, Outcome 6 Non‐serious adverse events.

7.1. Analysis

Comparison 7 Tricyclic antidepressants versus placebo, Outcome 1 Benzodiazepine discontinuation, end of intervention.

7.2. Analysis

Comparison 7 Tricyclic antidepressants versus placebo, Outcome 2 Anxiety: HAM‐A (change from baseline), end of intervention.

7.3. Analysis

Comparison 7 Tricyclic antidepressants versus placebo, Outcome 3 Benzodiazepine discontinuation, longest follow‐up.

7.4. Analysis

Comparison 7 Tricyclic antidepressants versus placebo, Outcome 4 Benzodiazepine withdrawal symptoms (Physician Withdrawal Checklist), end of intervention.

7.5. Analysis

Comparison 7 Tricyclic antidepressants versus placebo, Outcome 5 Relapse to benzodiazepine use, end of intervention.

7.6. Analysis

Comparison 7 Tricyclic antidepressants versus placebo, Outcome 6 Discontinuation due to adverse events.

8.1. Analysis

Comparison 8 Alpidem versus placebo, Outcome 1 Benzodiazepine discontinuation, end of intervention.

8.2. Analysis

Comparison 8 Alpidem versus placebo, Outcome 2 Withdrawal syndrome (clinical diagnosis), end of intervention.

8.3. Analysis

Comparison 8 Alpidem versus placebo, Outcome 3 Anxiety, HAM‐A, end of intervention.

8.4. Analysis

Comparison 8 Alpidem versus placebo, Outcome 4 Relapse to benzodiazepine use, end of intervention.

8.5. Analysis

Comparison 8 Alpidem versus placebo, Outcome 5 Serious adverse events.

8.6. Analysis

Comparison 8 Alpidem versus placebo, Outcome 6 Discontinuation due to adverse events.

9.1. Analysis

Comparison 9 Buspirone versus placebo, Outcome 1 Benzodiazepine discontinuation, end of intervention.

9.2. Analysis

Comparison 9 Buspirone versus placebo, Outcome 2 Anxiety: HAM‐A/Hospital Anxiety Depression Scale, end of intervention.

9.3. Analysis

Comparison 9 Buspirone versus placebo, Outcome 3 Benzodiazepine withdrawal symptoms, end of intervention.

9.4. Analysis

Comparison 9 Buspirone versus placebo, Outcome 4 Benzodiazepine discontinuation, longest follow‐up.

9.5. Analysis

Comparison 9 Buspirone versus placebo, Outcome 5 Benzodiazepine withdrawal symptoms, longest follow‐up.

9.6. Analysis

Comparison 9 Buspirone versus placebo, Outcome 6 Anxiety, Hospital Anxiety Depression Scale, longest follow‐up.

9.7. Analysis

Comparison 9 Buspirone versus placebo, Outcome 7 Discontinuation due to adverse events.

10.1. Analysis

Comparison 10 Melatonin versus placebo, Outcome 1 Benzodiazepine discontinuation, end of intervention.

10.2. Analysis

Comparison 10 Melatonin versus placebo, Outcome 2 Insomnia.

10.3. Analysis

Comparison 10 Melatonin versus placebo, Outcome 3 Discontinuation due to adverse events.

10.4. Analysis

Comparison 10 Melatonin versus placebo, Outcome 4 Benzodiazepine discontinuation, longest follow‐up.

10.5. Analysis

Comparison 10 Melatonin versus placebo, Outcome 5 Adverse events.

10.6. Analysis

Comparison 10 Melatonin versus placebo, Outcome 6 Relapse to benzodiazepine use, longest follow‐up.

11.1. Analysis

Comparison 11 Flumazenil versus placebo, Outcome 1 Benzodiazepine withdrawal symptoms, end of intervention.

11.2. Analysis

Comparison 11 Flumazenil versus placebo, Outcome 2 Anxiety, HAM‐D (Hamilton Depression Rating Scale), end of intervention.

11.3. Analysis

Comparison 11 Flumazenil versus placebo, Outcome 3 Benzodiazepine mean dose, end of intervention.

12.1. Analysis

Comparison 12 Propranolol versus placebo, Outcome 1 Relapse to benzodiazepine use, end of intervention: 2 weeks.

13.1. Analysis

Comparison 13 Progesterone versus placebo, Outcome 1 Benzodiazepine discontinuation, end of intervention.

13.2. Analysis

Comparison 13 Progesterone versus placebo, Outcome 2 Non‐serious adverse events.

14.1. Analysis

Comparison 14 Magnesium aspartate versus placebo, Outcome 1 Benzodiazepine discontinuation.

14.2. Analysis

Comparison 14 Magnesium aspartate versus placebo, Outcome 2 Anxiety.

14.3. Analysis

Comparison 14 Magnesium aspartate versus placebo, Outcome 3 Relapse to benzodiazepine use.

14.4. Analysis

Comparison 14 Magnesium aspartate versus placebo, Outcome 4 Non‐serious adverse events.

14.5. Analysis

Comparison 14 Magnesium aspartate versus placebo, Outcome 5 Discontinuation due to adverse events.

15.1. Analysis

Comparison 15 Homéogène 46/Sedatif PC (homeopathic drugs) versus placebo, Outcome 1 Benzodiazepine discontinuation.

16.1. Analysis

Comparison 16 Carbamazepine versus tricyclic antidepressant, Outcome 1 Benzodiazepine discontinuation, end of intervention.

16.2. Analysis

Comparison 16 Carbamazepine versus tricyclic antidepressant, Outcome 2 Relapse to benzodiazepine use.

16.3. Analysis

Comparison 16 Carbamazepine versus tricyclic antidepressant, Outcome 3 Serious adverse events.

17.1. Analysis

Comparison 17 Cyamemazine versus bromazepam, Outcome 1 Relapse to benzodiazepine use, longest follow‐up.

17.2. Analysis

Comparison 17 Cyamemazine versus bromazepam, Outcome 2 Anxiety: Maximum amplitude of rebound (HAM‐A), end of intervention.

17.3. Analysis

Comparison 17 Cyamemazine versus bromazepam, Outcome 3 Discontinuation due to adverse events.

17.4. Analysis

Comparison 17 Cyamemazine versus bromazepam, Outcome 4 Non‐serious adverse events.

18.1. Analysis

Comparison 18 Zopiclone versus flunitrazepam, Outcome 1 Relapse to benzodiazepine use, longest follow‐up.