Medications for discontinuation of long-term benzodiazepine use

Background

Benzodiazepines are widely prescribed for long-term use despite recommendations of only short-term use. It is often difficult to discontinue benzodiazepines after more than a few weeks of treatment due to the development of physical and psychological dependence. This review aimed to assess the effect and safety of medications to facilitate benzodiazepine discontinuation in chronic benzodiazepine users.

Search date

The evidence is current to October 2017.

Study characteristics

We identified 38 randomised controlled trials involving 2543 participants who had either been treated for more than two months with benzodiazepines, or who had been diagnosed with benzodiazepine dependence. We included studies irrespective of whether benzodiazepines were prescribed for anxiety, insomnia, or any other condition.

The average age of participants was around 50 years, and the majority of participants were women in most studies. Twenty-four trials were conducted in Europe; eight trials in the US or Canada; and six trials in Asia. The trials involved a wide range of medications to facilitate reduction or discontinuation of benzodiazepine use. Fourteen of the 38 included studies were partly funded by the drug manufacturer; nine studies were funded by government agencies; and 15 studies did not state the source of funding. The duration of the trials ranged between 1 and 24 weeks; the average trial duration was 9 weeks.

Key results

We extracted data on 18 different comparisons in a total of 2295 participants. We are uncertain whether valproate and tricyclic antidepressants increase the chance of discontinuing benzodiazepines, and whether benzodiazepine withdrawal symptoms are reduced by pregabalin, captodiame, paroxetine, tricyclic antidepressants, and flumazenil, as we assessed the quality of the evidence as very low. We are uncertain as to whether symptoms of anxiety after withdrawal of benzodiazepines are reduced by carbamazepine, pregabalin, captodiame, paroxetine, and flumazenil, as we assessed the quality of the evidence as very low. The effects of the evaluated medications were too uncertain to inform clinical practice due to risk of bias (systematic errors with overestimation of benefits and underestimation of harms) and risk of chance occurrence (random errors giving any result). Tolerability and safety were poorly reported across the included studies, making it impossible to assess the balance between possible benefits and adverse effects. Consequently, no conclusions can be drawn about the effectiveness of the interventions.

Quality of the evidence

The quality of the evidence was generally low or very low due to the small number of trials including a limited number of participants for each comparison; dissimilar results across studies; poor study design; and pronounced financial involvement of the pharmaceutical industry. Randomised controlled trials are therefore needed without risk of bias and random significant results involving long-term assessments of participants conducted without involvement of industry.

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.

Read the full 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 strategy: 

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.

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