Comparative safety of chronic versus intermittent benzodiazepine prescribing in older adults

Introduction

Benzodiazepines (neuroscience-based nomenclature (NbN): positive allosteric modulators (GABA-A receptor, benzodiazepine site)) are a treatment for anxiety disorders (Baldwin et al., 2014^; Katzman et al., 2014) and insomnia (Buscemi et al., 2007^; Wilson et al., 2019) but are no longer considered the first-line treatment for either indication. However, benzodiazepine use remains widespread (Davies et al., 2018^; Iaboni et al., 2016^; Lader, 2011), especially in older adults (Davies et al., 2018^; Iaboni et al., 2016^; Olfson et al., 2015). In recent data from Ontario, the prevalence of benzodiazepine use in community-dwelling older adults was 11% (Iaboni et al., 2016), with 60% using low doses (50% or less than the World Health Organization defined daily dose (DDD)), 25% using moderate doses (51–100% of the DDD) and 15% using high doses (greater than the DDD).

Regular benzodiazepine use over prolonged periods is controversial due to concerns of tolerance (leading to progressive elevation of dose), dependence, risk of difficult withdrawal and other adverse events (Baldwin et al., 2013). While older adults are susceptible to anxiety disorders and sleep problems, the potential for adverse consequences associated with the use of benzodiazepines appears to be greater than in younger people, particularly in terms of increased risk of falls, fractures (Cumming and Le Couteur, 2003^; Poly et al., 2020), cognitive impairment (Crowe and Stranks, 2018^; Foy et al., 1995) and mortality (Saarelainen et al., 2018). Older adults are more likely to adopt a chronic pattern of use (Fang et al., 2009^; Kurko et al., 2015^; Lader, 2011^; Olfson et al., 2015^; Takeshima et al., 2016), with one Canadian study reporting a mean duration of use of 75.5 days in new benzodiazepine users aged >66 years (Bartlett et al., 2004). Other studies have suggested that the duration of use may be even longer, especially in older adults with comorbid dementia where a mean duration of 2 years has been reported (Taipale et al., 2015).

The issues of whether benzodiazepines should be prescribed to older adults and if so whether treatment should be restricted to a maximum duration have been addressed by numerous national and international guidelines and position statements. However, the controversy (Hood and Davies, 2019^; Lader, 2011) is unresolved, and the guidelines have adopted contrasting positions. Some guidelines (American Geriatrics Society Beers Criteria, Update Expert Panel, 2019^; Wilson et al., 2019) take the view that benzodiazepines should be avoided entirely in older adults. A second group, comprising both guidelines for adults and those specific to older adults (Andrews et al., 2018^; Bandelow et al., 2015^; Conn et al., 2020^; Katzman et al., 2014^; National Institute for Health and Clinical Excellence, 2011), states that short-term benzodiazepine use may be acceptable for some indications. ‘Short-term use’ is often not defined but at least one guideline suggests a maximum duration of around 4 weeks. A further group of guidelines (Baldwin et al., 2013^; Baldwin et al., 2014^; Bandelow et al., 2008^; Canadian Psychiatric Association, 2006) acknowledge that time-limited use is preferable, but allow for long-term use in circumstances where the benefits outweigh the risks.

Various approaches have been used to characterize benzodiazepine adverse outcomes in both short- and long-term use. Randomized controlled trials have demonstrated the efficacy of certain anxiolytic benzodiazepines for anxiety disorders (Baldwin et al., 2014^; Katzman et al., 2014); however, these trials have less utility for examining rarer adverse outcomes or outcomes that emerge after prolonged periods of exposure beyond the duration of the trial. In particular, randomized trials examining outcomes of long-term benzodiazepine use are uncommon; those that exist, such as a 3-year study of clonazepam versus paroxetine in panic disorder (Nardi et al., 2012), have a weaker design than the more numerous short-term trials. We are not aware of any randomized trials that specifically compare chronic and intermittent benzodiazepine use.

An alternative approach to characterizing benzodiazepine outcomes is the use of observational methods such as cohort studies. Most previous observational studies have not been derived from population-based data; rather, they have been derived from clinical settings, which affect their generalizability. A few recent population-based studies have focussed on a single outcome in relation to benzodiazepine exposure, such as those reporting the association of benzodiazepine use with hip fractures (Requena et al., 2016), poor outcome after total hip replacement in arthritis (Beziz et al., 2016) and Alzheimer’s disease (Billioti de Gage et al., 2014). A further study of this type found no association between benzodiazepine use and dementia/cognitive decline (Gray et al., 2016).

Confounding by indication, whereby confounders are associated with both selection of treatment (such as a drug, dose level or indeed pattern of prescribing) and outcomes of interest, is a common problem in observational studies (Joffe, 2000^; McMahon, 2003). Propensity score matching (Austin, 2011) may be used to reduce the impact of this phenomenon. However, the existing studies described above did not employ propensity score matching, instead controlling only for a more limited number of covariates. They may therefore be more susceptible to the effects of measured and unmeasured confounding, especially where characteristics present at baseline may feasibly be associated with both the choice of drug or prescribing pattern and adverse outcomes.

In this study, our aim was to characterize the risks associated with chronic versus intermittent benzodiazepine use in older adults after a new benzodiazepine prescription, with a follow-up period of up to 360 days using population-based administrative health care data. To achieve this, we compared a cohort of chronic benzodiazepine users with a propensity score matched cohort of intermittent benzodiazepine users. The primary outcome was falls resulting in hospital or emergency department (ED) visits, while the secondary outcomes included hip and wrist fractures, hospital/ED visits, long-term care (LTC) admission and mortality. We hypothesized that the risk of adverse outcomes is increased in chronic benzodiazepine users relative to intermittent users, and that this elevated risk would persist after adjustment for benzodiazepine dose.

Methods

The study was approved by the Research Ethics Board at the Centre for Addiction and Mental Health, Toronto.

Propensity matching

The propensity score matching technique (Austin, 2011) addresses confounding by indication by matching subjects on a combined score generated from variables that may be linked to the likelihood that an individual will receive a certain exposure, in this case the pattern of benzodiazepine prescribing. Propensity scores for chronic versus intermittent benzodiazepine prescribing were estimated using 24 covariates ascertained on cohort entry, across six domains as listed in Table 1.

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One-to-two matching was conducted between the chronic and intermittent benzodiazepine users using nearest-neighbour matching on the basis of age (±1 year), sex, and propensity score within a calliper ±0.20 standard deviations of the score. Any chronic user who could not be matched to two intermittent users but could be matched to one was accepted along with their one matched intermittent user. There was no subsequent replacement. A C-statistic was calculated to evaluate the goodness of fit. Standardized differences were used to compare the prevalence of characteristics between the two groups, with an absolute standardized difference of >10% signifying a meaningful imbalance (Nguyen et al., 2017).

Results

In total, we identified 57,072 chronic benzodiazepine users for matching in a 1:2 ratio to a pool of 312,468 intermittent benzodiazepine users. In the matching process, 56,798 chronic users were matched to two intermittent users, and a further 243 could be matched to only one intermittent user, for a total of 113,989 intermittent users included. This left 31 chronic users (0.05%) who could not be matched to an intermittent user were therefore not included in the analysis. The demographic characteristics of the two cohorts were similar and are presented in Table 2. The two groups were well-matched on all variables used in calculating propensity scores (C-statistic for goodness of fit = 0.603) with weighted standard difference of means between 0.00 and 0.03 in every case (Table 2).

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Exposure period

During the 180-day exposure period (Table 3) used to define cohort membership, total benzodiazepine quantity prescribed in LoDEq was greater in the chronic user group (243.5 ± 208.1 mg vs 50.2 ± 63.7 mg, weighted standardized difference of mean = 1.3). Chronic users had benzodiazepines supplied for 140.8 ± 29.9 days compared with 33.0 ± 24.2 days in intermittent users (Table 3). The mean daily benzodiazepine dose (total prescribed divided by days supplied) was similar between the two groups (1.7 ± 1.4 mg LoDEq vs 1.6 ± 1.6 mg LoDEq, weighted standardized difference of mean = 0.07). In both cohorts, lorazepam was the most frequently prescribed benzodiazepine, with 52.1% of chronic users and 59.6% of intermittent users being prescribed this drug.

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Outcomes

The primary outcome of hospitalization/ED visits due to falls occurred during the follow-up period in 2606 (4.6%) chronic users and 3592 (3.2%) intermittent users, representing a HR of 1.13 (95% CI: 1.08 to 1.19; p < 0.0001) (Table 4). When stratifying by sex (Table 4), the excess risk associated with chronic use was observed in both men (HR = 1.18, 95% CI: 1.08 to 1.29; p < 0.001) and women (HR = 1.12, 95% CI: 1.05 to 1.19; p < 0.001). When stratifying by age group (Supplementary Table 2), increased risk in chronic users was observed in both the groups aged 66–75 years (HR = 1.10, 95% CI: 1.02 to 1.20; p = 0.020) and 76–85 years (HR = 1.18, 95% CI: 1.09 to 1.28; p < 0.0001), but not in the oldest group aged 86 years or more (HR = 1.08, 95% CI: 0.96 to 1.22; p = 0.200).

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For most of the secondary outcomes, with the one exception of wrist fractures, chronic benzodiazepine use again conferred significantly greater risk than intermittent use. Chronic users were at elevated risk for hip fracture (HR = 1.27, 95% CI: 1.10 to 1.48; p = 0.002), LTC admission (HR = 1.36, 95% CI: 1.25 to 1.47; p < 0.0001), hospital/ED visits for any reason (HR = 1.12, 95% CI: 1.10 to 1.14; p < 0.0001) and mortality (HR = 1.30, 95% CI: 1.19 to 1.43; p < 0.0001). There was no significant effect of sex in the stratified analyses. Stratification by age yielded a difference between groups only for hip fractures whereby people aged 76–85 years at entry were the only age-band at a significantly excess risk (Supplementary Table 2).

The proportional hazard assumption held for all primary and secondary outcomes.

Discussion

A pattern of chronic benzodiazepine use in the 180 days after incident use, compared to intermittent benzodiazepine use, was associated with significantly greater risk for the primary outcome of hospital/ED visits due to falls, and for the secondary outcomes, hip fractures, hospitalizations/ED visits, LTC admission and death, but not for wrist fractures. The excess risk held true once the models were adjusted for mean daily benzodiazepine dose. This latter finding is important because we found that the mean daily benzodiazepines during the follow-up period was several-fold higher in the chronic use group. The fact that the significantly increased risk remained after adjustment for mean daily dose suggests that the pattern of chronic use of benzodiazepines carries risks relative to intermittent use which are independent of its association with greater drug exposure, assuming that the propensity score matching was able to encompass variables that explain any baseline difference between the groups.

These findings raise the question as to whether there might be a neurobiological explanation for excess risk of adverse outcomes in chronic relative to intermittent users. Benzodiazepine use over time is associated with biological changes in key chemical systems with which benzodiazepines interact. Suggested mechanisms (Bateson, 2002) include downregulation in the number of GABA-A benzodiazepine receptors with prolonged use, uncoupling of receptor binding and the subsequent impact on GABA, regulation of protein degradation, internalization and synthesis, which might result in switching of specific subunits in the GABA-A benzodiazepine receptor over time (Lorenz-Guertin et al., 2019^; Tanay et al., 2001) and effects on mRNA synthesis or degradation. Any of these changes may be associated with increased propensity for adverse effects. It is possible that such changes occur more readily when benzodiazepine exposure is chronic and regular, than when exposure is intermittent and sporadic. Drug accumulation may be a factor contributing to adverse outcomes associated with chronic benzodiazepine use. Older adults are at risk of experiencing benzodiazepine accumulation if age-related pharmacokinetic changes which prolong drug half-life, such as increased volume of distribution, co-occur with reduced clearance of hepatically metabolized long-acting benzodiazepines including diazepam (Greenblatt et al., 2020) and nitrazepam. Accumulation is more likely to occur with chronic rather than intermittent drug use.

A second interesting finding of this study is that chronic benzodiazepine use appears to confer markedly greater risk of adverse outcomes relative to intermittent use in men than is the case in women. This was true for the primary endpoint of hospital/ED visits due to falls and also for three of the five secondary outcomes (hip fractures, hospital/ED visits for any reason, and mortality). Register-based studies (Davies et al., 2018^; Huerta et al., 2016^; Olfson et al., 2015) report consistently that the population prevalence of benzodiazepine prescribing is 1.5 to 2 times higher in women than in men. There are also systematic differences between men and women who are prescribed benzodiazepines which have been previously described (Morgan et al., 2016) and are observed in our cohort, namely, more chronic health issues including vascular disease in men, and more mental health problems and osteoporosis in women. Sex-specific effects in psychopharmacological systems such as GABA-mediated neurotransmission are receiving increased attention (Bolea-Alamanac et al., 2018). One neuroimaging study has reported that women had greater GABA-A benzodiazepine receptor binding availability than men, a measure that was associated with nicotine craving and pain sensitivity (Esterlis et al., 2013). Genetic polymorphisms relating to GABA-A receptor subunit expression and the phenotype of substance use disorders have been described with associations in women only (Lin et al., 2003). In animal models, literature has developed on sex differences in the expression of certain GABA-A benzodiazepine receptor subunits in specific brain areas such as somatosensory thalamus and cortex in control rats (Li et al., 2007). We are unable to offer a biological link between these observations and the present finding that in older adults chronic compared with intermittent benzodiazepine use carries excess risk of certain outcomes in men only. However, evidence on sex-specific differences in receptor availability or subunit expression and distribution makes it plausible that changes occurring with chronic benzodiazepine use might exacerbate the impact on the GABA-benzodiazepine system, and thereby on adverse outcomes, in one sex preferentially. Future studies can explore the question of sex differences in risks associated with benzodiazepine use by developing cohorts matched on the propensity of both receiving a benzodiazepine and being a male.

Strengths of the study are that it has a large, population-based sample that provides adequate numbers, including supporting the stratified analyses for sex described above. Propensity score matching based on 24 variables in six distinct categories to reduce risk of confounding by indication is a further strength. The study has some potential weaknesses which need to be acknowledged. Most fundamentally, as this is a comparison of two patterns of benzodiazepine use, it cannot elucidate the risks of benzodiazepines versus no treatment and therefore does not allow us to judge the merit of guidelines which advises avoiding benzodiazepines entirely in older adults. In those analyses where we do not find a difference between chronic and intermittent use, we are unable to draw a comparison to no treatment, that is, to say whether these two prescribing patterns are equally safe or equally dangerous compared to no benzodiazepine. While we have accounted for many potential confounding variables through hard matching for age group and sex, and made use of a robust propensity score matching approach, the possibility of residual confounding remains as propensity score matching can only be undertaken on observable variables. The ODB database includes all available benzodiazepines but does not allow the possibility to examine the use of the related class of Z-drugs. In Ontario, only zopiclone is commonly prescribed, but is not reimbursed by the ODB so our analyses cannot take account of this ‘benzodiazepine-like’ drug. A further issue is the criteria we have used to define ‘chronic’ and ‘intermittent’ users. In selecting a cut-off of benzodiazepine prescriptions for at least 120 days during the 180-day exposure period, we believe that we chose a threshold which took account of previous work (Kurko et al., 2015) and has face-validity for chronic use, but we cannot be certain that this cut-off is underpinned biologically in terms of differentiating individuals who are likely to have neurochemical changes resulting from their benzodiazepine use from those who likely will not. Note, however, that the two groups had very different mean exposure to benzodiazepines in the exposure period (140 vs 33 days out of 180 days) so appear to be two fairly distinct cohorts. We also incorporated rules for removing or ‘censoring’ individuals over time when they ceased to meet the criteria for ‘chronic’ or ‘intermittent’ use, but again the extent to which these definitions map on to the biological profiles is open to debate.

It must also be recognized that many individuals who entered the cohort by fulfilling our criteria for chronic or intermittent use were censored before the end of the follow-up period due to changes in their pattern of usage over the course of the study. This applies especially in the intermittent user group where almost three quarters of individuals had no further benzodiazepines in the first 180 days of the follow-up period and were therefore censored at the earliest opportunity. Although censoring individuals reduces power, the methodology has the strength of being naturalistic – it reflects the reality that people often change their benzodiazepine use as time progresses, with some eliminating them entirely. The methodology employed ensured that those who continue to use benzodiazepines with the same pattern that they did in the exposure period will contribute more exposure time in the follow-up period than those who changed their usage pattern. Overall, with the greater rate of censoring in the intermittent user group partially offsetting the initial 1:2 matching, the final ratio of person-days for the observation period was 1:1.55. Nevertheless, there may be a limitation in terms of ascertainment bias if adverse outcomes could be observed more frequently by virtue of proportionally more chronic users than intermittent users remaining in the cohorts as time progresses. However, we believe that this limitation is likely to be small and its impact is outweighed by the need to ensure that exposure patterns continue to reflect actual medication use in a population subject to marked changes in use of benzodiazepines over time. Finally, ODB registers provide data on filled/dispensed benzodiazepine prescriptions which is a proxy for benzodiazepine exposure – therefore, some people may have obtained prescribed medications but not actually taken them. It is possible that differences between chronic and intermittent users in taking their medications after filling prescriptions could be a source of bias.

In illustrating excess risks for chronic use over intermittent use, we have captured an issue with benzodiazepines, which cannot be revealed by studies that simply undertake meta-analysis of side effects in short-term trials. A good example of such a study is the recent meta-analysis of Quagliato et al. (2019), which compared the side effect burden of benzodiazepines in panic disorder treatment trials of up to 12 weeks duration to that of SSRIs, concluding that incidence of adverse effects was slightly lower in people randomized to benzodiazepines. While such a meta-analysis is informative, it cannot address the issue of excess harms of benzodiazepines with chronic use over the longer periods we have examined in this study.

While this study illustrates that chronic benzodiazepine use carries enhanced risks of most of the adverse outcomes relative to intermittent use, especially in older men, it must be recognized that the excess risk described is merely one factor to be taken into consideration when deciding whether ongoing benzodiazepine use is acceptable or unacceptable for a given patient who has been taking these drugs for long periods and is deriving benefit, especially where there has been no evidence of dose escalation or tolerance to the therapeutic effect. Clearly, when discussing the way forward with patients in this situation, the excess risks we have enumerated here must be considered against the risks of withdrawal and rebound of symptoms of their original disorder which may occur if established benzodiazepine treatment is reduced in dose and/or frequency, as well as the potential adverse effects of other medications that might be introduced to allow this to happen.

We call for further research to attempt to replicate these results in other large drug prescription databases. These findings should inform future editions of guidelines, which advise on benzodiazepine prescription, especially if replicated in further studies. In addition, there is potential for further analyses in this and other datasets to examine whether individual benzodiazepines or sub-groups based on pharmacological characteristics differ in terms of excess risk in older adults with chronic relative to intermittent use. This might include comparisons of short-acting versus long-acting benzodiazepines, and of drugs eliminated by conjugation versus those subject to extensive liver metabolism given the increased risk of accumulation with some hepatically metabolized drugs.

Our study provides clear-cut evidence that there are significant excess risks associated with chronic benzodiazepine use compared to intermittent use. Importantly, our study design does not permit us to speculate about the safety or risks of prescribing benzodiazepines compared to no treatment. The excess risks quantified here can be used to help inform decision-making by older adults and clinicians about whether short- or long-term benzodiazepine use is a reasonable option for symptom management, weighing up the risks and benefits on a case-by-case basis, as is advocated by some current guidelines (Baldwin et al., 2013^; Baldwin et al., 2014^; Bandelow et al., 2008^; Canadian Psychiatric Association, 2006).