Benzodiazepine anxiolytics
| Type | Recommendation |
|---|---|
| When to deprescribe | |
| CBR |
Given the risk of dependence and other potential harm (e.g. falls, dependence, sedation) generally outweighs the potential benefits, we suggest deprescribing be offered to older people taking long-term (beyond four weeks) benzodiazepines, except in special circumstances, including but not limited to significant alcohol withdrawal or palliative care. |
| Ongoing treatment | |
| CBR | If deprescribing is unsuccessful despite multiple attempts with considerations for non-pharmacological options (e.g. action plan for recurrence of anxiety symptoms), intermittent or “as-required” dosing, we suggest maintaining the lowest effective dose; however, we suggest reassessing the need for long-term therapy periodically. |
| How to deprescribe | |
| CBR |
We suggest individualising the tapering schedule and adjusting it according to the individual's response. In general, we suggest reducing the dose by 25% to 50% every one to four weeks, ensuring the absence of withdrawal symptoms and/or symptoms indicative of relapse before initiating further tapering. Once half the lowest standard dose formulation is reached, we suggest ceasing completely. However, smaller dose reductions may be appropriate or preferred by some individuals, particularly as lower doses are approached. |
| GPS |
Healthcare providers should consider and offer adequate non-pharmacological management options (e.g. psychological interventions for psychiatric disorders such as cognitive-behavioural therapy and relaxation techniques) during and after deprescribing (ungraded good practice statement). |
| GPS |
Healthcare providers should consider and offer appropriate management strategies to the individual’s families and care providers (e.g. verbal de-escalation, psychological intervention, increased staff-to-patient ratio, increased staff training in behaviour management (ungraded good practice statement). |
| Monitoring | |
| CBR |
We suggest closely monitoring for changes in anxiety symptoms, changes in psychological or physical health status, and quality of life every one to two weeks following each dose adjustment until at least four weeks after the medicine is fully ceased if practical. After this initial period, we suggest monthly monitoring for at least three months, followed by monitoring every six months thereafter. However, this should be tailored based on individual factors such as their preferences, responses and tolerance to deprescribing. If in-person visits are impractical, we suggest advising people to report symptoms as needed during monitoring. |
CBR, consensus-based recommendation; GPS, good practice statement
Benzodiazepines are prescribed for a wide range of conditions, with the choice of benzodiazepines depending on the desired duration of action. Long-acting benzodiazepines, such as diazepam, are used for short-term management of anxiety and agitation, typically in severe or treatment-resistant cases [177]. In contrast, temazepam, with its rapid onset and short half-life, is preferred for short-term treatment of insomnia [177]. Benzodiazepines are also used in managing alcohol withdrawal, mania/hypomania, epilepsy, acute seizures, restless legs syndrome, agitation in inpatient settings, musculoskeletal disorders, and palliative care [177].
Refer to the narrative evidence summary, the GRADE Summary of Findings table in the guidelines, and the Technical Report for a complete presentation of the deprescribing evidence based on the GRADE framework (including other factors considered in developing the recommendations).
In practice, benzodiazepines are most commonly prescribed for insomnia and anxiety disorders. While they can provide symptom relief, they are not recommended as first-line treatment for anxiety, particularly in older people, due to limited evidence of long-term benefits and a high risk of harm [648]. Prolonged use is associated with physical and psychological dependence, tolerance, and misuse [177]. Older people are particularly vulnerable to adverse effects of benzodiazepines, including oversedation, falls, confusion, impaired memory, and respiratory depression [648]. Despite these risks, long-term benzodiazepine use remains prevalent in older people [649].
Given the risk of potential harm and dependence with long-term use (e.g. beyond four weeks) generally outweigh the benefits, deprescribing should generally be considered in older people [650]. However, there may be special circumstances where the benefits could potentially outweigh the risks (e.g. palliative care, alcohol withdrawal management). If psychological and behavioural interventions are proven ineffective, trial on-demand or intermittent use of benzodiazepines at the lowest effective dose may be considered if appropriate. The limitations of benzodiazepines, potential benefits, and harms should be thoroughly communicated to the patient so they can make an informed decision about their treatment choice.
When benzodiazepine therapy is identified as suitable for deprescribing, the tapering plan should be individualised, ensuring the absence of physical or neuropsychiatric withdrawal symptoms before initiating further tapering. The common general approach to tapering involves approximately reducing the dose by 25% of the original dose every 1 to 4 weeks [627]. A slower taper may be necessary for the final dose reductions or if withdrawal symptoms arise [627]. The Maudsley deprescribing guidelines recommend a hyperbolic tapering strategy for psychotropic medications, including benzodiazepines, to minimize relapse and withdrawal effects [43]. This strategy involves progressively smaller dose reductions at lower doses, which may be preferred by some individuals.
We identified 16 studies (five RCTs, two cohort studies, and nine before-and-after studies) related to anxiolytic deprescribing from the systematic review and meta-analysis [635, 643, 651-663].
Overall, the current evidence for benzodiazepine deprescribing is derived from studies of low and very low certainty. While deprescribing was shown to lead to a significant improvement in daily functioning in an RCT and improved memory in a cohort study, these outcomes are low and very low in certainty respectively. Single-arm studies suggest that approximately three to eight people in every ten were able to either reduce the dose or discontinue their benzodiazepine completely. Common withdrawal symptoms were anxiety and insomnia. There is no direct evidence indicating that the duration of withdrawal symptoms varies between the different types of benzodiazepines. Furthermore, the evidence to date is from studies with small sample sizes and generally have serious methodological limitations. The majority of the studies have very short follow-up periods (one to 12 months) so it may be possible that severe and persistent withdrawal syndromes, if occurred, were not captured. There was also a lack of clear differentiation between withdrawal effects and relapse of the initial condition in many studies. The evidence at this stage is insufficient to inform evidence-based recommendations.
If benzodiazepines are considered appropriate to deprescribe, closely monitoring for any withdrawal symptoms and/or symptoms indicative of relapse, including worsening in anxiety symptoms, changes in psychological or physical health status, and quality of life may be appropriate.
Key study characteristics and results
A narrative summary of each study is provided below, highlighting key characteristics and main findings.
Habraken 1997 randomised 55 nursing residents who had been taking stable doses of benzodiazepines for more than 12 months to discontinuation (n=27) or continuation (n=28). Participants were excluded if they had dementia, serious psychological problems, or had a recent psycho-traumatic experience (e.g. hospitalisation, death of a relative). At 12 months, it was reported that daily functioning (measured using the Geriatrics Behavioural Observational scale) had significantly improved for participants who discontinued benzodiazepines compared to those who continued (MD -7.60, 95% CI -14.28, -0.92). However, there was no significant difference in mortality at 12 months (OR 0.10, 95% CI 0.01 to 1.93).
Cohen Mansfield 1999 reported a double-blind crossover RCT that included 58 nursing home residents who were taking either haloperidol, thioridazine or lorazepam (antipsychotics or benzodiazepines) for agitation [635]. Participants were excluded if they were taking other antipsychotics or anxiolytics concurrently (except for low-dose trazodone hydrochloride for sleep), had uncontrolled blood glucose, or had a diagnosis of major affective disorder of schizophrenia. There were no significant differences between the discontinuation and continuation period in terms of psychiatric symptoms measured using the Brief Psychiatric Rating Scale, global clinical status measured using the Clinical Global Impression Scale, or cognition measured using the Mini-Mental Status Exam.
Navy 2018 reported an RCT that included 346 community-dwelling patients who were taking alprazolam for at least 90 days in the previous 12 months [660]. In this educational outreach study, 153 patients were randomised to receive a deprescribing educational letter (intervention group) and 173 patients received usual care (control group). At month six, there were no significant differences between the two groups in terms of alprazolam discontinued (OR 0.57, 95% CI 0.27, 1.17) or achieved >50% alprazolam dose reduction (OR 1.21, 95% CI 0.58, 2.55).
Gnjidic 2019 randomised 42 inpatients who were prescribed at least one benzodiazepine to a control group (usual care) or an educational intervention where a patient-empowerment booklet was provided (n=20) during hospitalisation [656]. The study revealed a similar proportion of participants had discussed with their doctor or pharmacist about stopping the benzodiazepine (33% in intervention vs 36% in control). Among the 22 participants discharged on benzodiazepine, 6/11 (55%) intervention group participants and 7/11 (64%) control group participants discontinued benzodiazepines one month following discharge (OR 1.46, 95% CI 0.26 to 8.05).
Tannenbaum 2014 conducted a cluster RCT that involved direct-to-consumer education and tapering intervention [662]. The study randomised 303 community-dwelling patients who were taking at least five active medicines (one being a benzodiazepine for at least three consecutive months) to the intervention group (n=148) and control group consisting of usual care (n=155). Participants who had a severe mental illness, or dementia, or who were taking antipsychotics were excluded. At six months, complete discontinuation was achieved in 40/148 participants (27%) receiving the patient empowerment intervention and a stepwise tapering protocol compared with 7/155 (5%) participants in the control group (OR 0.13, 95% CI 0.06, 0.30).
Salzman 1992 conducted a prospective cohort study that included 25 nursing home residents who were taking benzodiazepines and complained of mild forgetfulness [661]. Participants with moderate-to-severe dementia were excluded. In 13 residents, benzodiazepines were deemed clinically appropriate to deprescribe by the healthcare providers whereas benzodiazepines were continued in 12 residents. Compared to the continuation group, participants who discontinued benzodiazepines had a significant memory improvement (measured using WAIS-R digit span test, MD -1.90, 95% CI -3.40, -0.40) at two to three weeks follow-up. At 12 months, 10 participants were available for follow-up interviews and only 4/10 (40%) restarted on a different benzodiazepine for insomnia, daytime agitation, or behavioural control.
Del Giorno 2018 reported a before-and-after study that involved prescription monitoring, benchmarking, and educational interventions to reduce benzodiazepine prescriptions among internal medicine inpatients [654]. The study revealed a 1.70% reduction in the monthly initiation of new benzodiazepine prescriptions (p< 0.001) during the 18-month intervention period.
Benzodiazepines were either completely withdrawn or reduced in dose in 35-85% of participants in the following seven single-arm studies [643, 651-653, 655, 658, 659].
Mendes 2018 reported two studies (one retrospective cohort study and one before-and-after study) using a direct-to-consumer educational brochure to reduce the use of benzodiazepines[659]. In the retrospective cohort study, it was reported that participants who received an educational brochure had a higher likelihood of benzodiazepine deprescribing was more likely within 24 months (OR 0.70, 95% CI 0.61 to 0.81). Of the 3,896 veterans who received educational brochures in the before-and-after study, benzodiazepine dose was reduced in 1,847 (47%), tapered and then discontinued in 458 (12%), and discontinued immediately without tapering in 455 (12%). The remaining 607 veterans (15%) had a dose increase and 529 (14%) remained on the same dose.
Da Silva 2022 conducted a before-and-after study that included 35 primary care patients who had been taking clonazepam for at least three months [653]. Following an educational intervention involving the patients and the primary care physicians, of the 27 who were available for follow-up after 10 weeks, 22 (81%) had their dose successfully reduced (n=16) or withdrawn completely (n=6).
Westbury 2018 conducted a before-and-after study using a multi-component intervention to reduce the use of antipsychotics and benzodiazepines in aged care facilities [643]. Participants who were receiving respite or end-stage palliative care and those who were prescribed antipsychotics or benzodiazepines for severe psychiatric disorders were excluded. At six months, 39% who were prescribed antipsychotics or benzodiazepines had their dose either reduced or ceased. There was a significant reduction in the mean diazepam equivalent dose at four months (5.1 ± 5.5 mg to 4.3 ± 6.1, p< 0.001) and six months (1.4 ± 5.6 mg to 1.1 ± 8.4, p< 0.001). However, there was no significant change in BPSD, social withdrawal, quality of life, agitation or aggression following the discontinuation of benzodiazepine.
Javelot 2018 reported a before-and-after study that included 31 nursing home residents who were treated with one or more benzodiazepines without the diagnosis of alcoholism and epilepsy [658]. At month six, benzodiazepines were completely withdrawn in 11/31 (35%) residents, and the mean number of falls per resident was significantly reduced from 2.3 ± 0.6 to 0.5 ± 0.2 (p = 0.01) among these 11 residents.
Fernandes 2022 conducted a before-and-after study that included 66 primary care patients who were using benzodiazepines daily use for at least three months with benzodiazepine dependence [655]. The study reported 38/66 (59%) participants successfully discontinued their benzodiazepine. Of these participants, 31/38 (82%) had at least one withdrawal symptom during deprescribing (most frequently insomnia and anxiety). Of the 39 who had at least an 80% reduction in the initial dose and were available for follow-up at 12 months, 33 (85%) maintained the state.
Chae 2024 reported a before-and-after study that included a patient educational outreach program targeting primary care patients who were prescribed at least one long-term benzodiazepine [652]. Patients with a single prescription for less than 15 tablets were excluded. Among the 25 patients who initiated a deprescribing discussion with their primary care physician, seven (28%) had their benzodiazepine discontinued and nine (36%) had a dose reduction.
Carr 2019 conducted a before-and-after study that included inpatients who were taking one or more regular benzodiazepines on hospital admission [651]. Patients with severe anxiety were excluded, although this was not formally assessed. Of the 11 patients who initiated benzodiazepine deprescribing, 6 (55%) had their benzodiazepines ceased completely, whereas the remaining five patients (45%) had a dose reduction of greater than 50%. Among the 11 patients, six (55%) experienced at least one withdrawal symptom including anxiety and sleep problems.
Allary 2024 reported the long-term effects of benzodiazepine and Z-drugs discontinuation among 45 participants enrolled in a previous RCT with available follow-up data at 12 months [663]. Participants were included in the original RCT if they had taken a benzodiazepine or Z-drug for the past two years and were wanting to stop. Participants were excluded if they were experiencing a crisis (e.g. suicidal ideation), having an alcohol or drug dependence disorder, or other indications for use (e.g. epilepsy). At 12 months after discontinuation, depressive symptoms intensity measured using the Beck Depression Inventory–II reduced with reduced use of benzodiazepine or Z-drug (unstandardised regression coefficient, 0.879, p < .01). However, there was no statistically significant association between the change of benzodiazepine or Z-drug use and worry intensity measured using the Penn State Worry Questionnaire or sleep quality measured using the Pittsburgh Sleep Quality Index.
Various methods were used for deprescribing in the included studies and tapering was the most common method. While there was no direct evidence that any particular method was associated with the greatest benefits and harms, dose tapering is likely more acceptable than abrupt cessation and helpful in determining the lowest effective dose for some patients requiring dose reduction rather than complete cessation. Deprescribing benzodiazepines can be particularly challenging, especially among long-term users, those taking higher doses or high-potency benzodiazepines due to the risk of withdrawal symptoms. We acknowledge that the duration of successful tapering can vary substantially between individuals. While one single-arm study of a very small sample size (n=64) switched to diazepam (a long-acting benzodiazepine) prior to initiating gradual tapering, the evidence is very low in certainty and therefore, does not support its effectiveness in improving cessation success rates or reducing the incidence and severity of withdrawal symptoms.
Benzodiazepine was reduced by 25% per week for the first three weeks, then 12.5% reduction for the final two weeks (study=1, n=55, low certainty) [657], titrated over 21 weeks (study=1, n=303, low certainty) [662]. In drug-specific studies, alprazolam was tapered based on an individualised alprazolam tapering plan (n=314, very low certainty) [660] whereas lorazepam was tapered over three weeks before complete withdrawal (n=58, very low certainty) [635]. The method was not described in one study (n=42) [656].
For the two cohort studies (very low certainty), benzodiazepines were gradually tapering over two weeks based on individual response in one study (n=25) whereas in another study (n=2632) benzodiazepines were either tapered for up to 12 weeks or ceased abruptly [659].
In the nine non-controlled trials (all very low certainty), benzodiazepines were gradually tapered in other non-controlled trials, as summarised below, with the method not described in two studies (n=45,715) [643, 654]:
- Individualised (study=1, n=12) [651]
- All benzodiazepines switched to diazepam prior to initiating gradual tapering (study=1, n=64) [655]
- Initial dose reduced by 25% in the first week, then continue reducing over four to ten weeks (study=1, n=31) [658]
- Tapering plan based on previously published clinical guidelines (study=1, n=25) [652]
- Dose reduced by 25% every two weeks (study=1, n=129) [653]
- Either tapered for up to 12 weeks or ceased abruptly (n=3,896) [659]
- Gradual dose reduction for up to 16 weeks (study=1, n=45 very low certainty) [663]