The overall prevalence of BZD use in 7 European countries involved in our study was almost 15%, with Croatia (36%), Spain (34%) and Serbia (31%) having the highest prevalence. It is of importance to note that in all countries included in this study, BZD availability on the pharmaceutical market is bound to medical prescription. Country of residence was in our study recognized as an independent factor associated with BZD use. Variability in overall BZD prevalence and diverse spectrum of BZDs used in different countries indicates for country-specific differences in prescribing habits and availabilities of BZDs on the pharmaceutical markets, as well as different prescribing policies, and other social, cultural, and behavioral factors that play an important role in BZD use.
Prevalence and patterns of BZD use across countries
In Croatia in 2016, BZDs were prescribed in 23%, 19%, and 16% of patients in 60–69, 70–79 and 80 + years age groups; respectively [
21]. It is assumed that war in Croatia during 1990s was the initiator of higher consumption of BZDs [
21]. Reports on consumption of BZDs in Croatia show constant increase of BZD use [
22] and lately coincidence with Covid-19 pandemic [
23]. According to the recent national data, diazepam, alprazolam and oxazepam were the most frequently used BZDs in Croatia [
21], which corresponds with our study. All BZDs available on the pharmaceutical market in Croatia are listed as essential or supplementary medications covered fully or partially by health insurance by the Croatian Health Insurance Fund (CHIF) [
21]. It is important to mention, that oxazepam is listed as supplementary medication and is not fully cowered by the CHIF. Diazepam, on the other hand, is on the list of essential medications with full coverage. This might be one of the reasons for higher prevalence of diazepam use in our Croatian sample compared to oxazepam, although scientific evidence favours use of the latter in older patients. The only prescription limitation implemented by CHIF was prescription of a drug for a maximum of 30 days and a maximum of 2 packages of the same drug per prescription [
24]. Currently, there are no specific national guidelines for BZD use in older population and national scientific literature offers a various range of recommendations on the length of BZD use depending on dosage, type of BZD and diagnosis [
21].
In Serbia, data for general population show constantly increasing trend in BZD prescription. First noted in 1980s, in former Yugoslavia, and repeatedly confirmed in 1990s, with sudden surge in 1999, the year of NATO air strikes to the country [
25], BZD consumption continued raising in 2000s [
26]. In our study both bromazepam and diazepam were most frequently used BZDs in Serbian sample. Bromazepam users were found almost solely in Serbia (83% of all bromazepam users). Bromazepam, diazepam and lorazepam were the most commonly used BZDs in Serbia in general population between 2014 and 2018 [
27]. A study of patients 65 + years old admitted to the emergency ward due to BZD poisoning showed bromazepam and diazepam as the most frequently prescribed BZDs [
28]. The only restriction of BZD prescription in Serbia is the maximum of 30 days stockpile [
27]. As a matter of fact, no specific restriction of length together with possibility of re-prescribing without need of specialist consultation allow use of BZDs in Serbia for longer period than recommended [
27].
In Spain, the Spanish Agency of Medicines and Sanitary Devices stipulated for BZDs, that their information sheet should state the recommended duration of treatment to be as short as possible and not exceeding 4 weeks for insomnia and 8 weeks for anxiety indications [
29]. Moreover, the Spanish Society of Family and Community Medicine recommends short-term use of BZD just for alleviation of symptoms and for limited periods [
30]. Nevertheless, our study found a prevalence of BZD use in Spanish population of almost 34%. Use of BZDs in Spain in older outpatients was reported to range from 14 to 38% in previous studies [
31,
32]. A study of BZD users in Barcelona showed that 96% of BZDs were prescribed
off label (defined as inappropriate dose, length of use and duplicity), while older patients were the most common group to be exposed to such
off-label use [
33]. In the study of BZD dependence in Spain outpatient population, 47% to 44% of older BZD users were BZD dependent [
34]. Moreover, almost half of the population involved in the referred study were not given any medical advice about the risk of dependence [
34]. In 2019, BZDs belonged to the 15 most frequently prescribed medications in Spain, accounting for retail value of about 98 million euros [
35]. Our study showed that lorazepam was the most prevalent BZD in Spain, followed by lormetazepam, alprazolam and diazepam, which corresponds with recent national findings [
35]. Moreover, lormetazepam was found to be the most frequently prescribed BZD in older patients admitted to the emergency ward due to falls [
36]. A recent qualitative study of barriers and enablers for BZD (de)prescription revealed that the issue of high prevalence of BZD prescription in Spanish general population is strongly related to factors beyond purely clinical ones, such as lack of time and excessive workload, inadequate communication between doctors and patients, and extend of psychosocial skills of doctors [
37].
In light of the above mentioned, the extent of BZD use in the older Croatian, Serbian and Spanish community-dwelling patients identified in our study is alarming. Specific guidelines and effective policy measures for reduction of BZD use should be applied.
In our study, the prevalence of BZD use was low in Bulgaria, the Czech Republic, and Turkey. There is a scarcity of data on the use of BZDs in Bulgaria. The latest national study estimated odds of 2.1 for PIMs prescription (including BZDs) in older population with an expected 31% of those leading to a drug related problem [
38]. According to the referred national study there are no national guidelines established for any kind of medication review in the older population or collection of PIMs [
38]. For the Czech Republic, studies show the prevalence of BZD use about 20% [
39] in older nursing home residents. However, educational strategies in the past decades significantly contributed to reduction in prescribing of BZDs in populations of older adults in other settings of care, particularly in community-dwelling older patients, who present significantly different population regarding cognitive, functional, and overall health status. On the other hand there are no current national guidelines or health care policy regulations in the Czech Republic that would regulate use of BZDs in particular. Prescription of BZDs in the Czech Republic is not bound to any specialization or prescribing conditions. In Turkey, BZDs were prescribed at least once a year in 4% of older patients with psychiatric disorders [
40]. The low prescription rates of BZDs can be associated with low preference of BZD use by physicians due to their addictive potential and unwillingness of patients to use BZDs commonly perceived as “heavy drugs” [
40]. The fact that BZDs are listed as controlled substances and their prescription is strictly regulated in Turkey [
41], can also contribute to low prevalence of BZD use found in our study.
Doses and length of BZD use
Maximal doses for older adults recommended by international PIMs criteria [
18‐
20] were exceeded in all four most frequently prescribed BZDs in our study. Studies confirm that about 14% of older population is prescribed BZDs in higher than recommended doses and suggest association between type of BZD used and propensity of risk of high dose intake [
42,
43]. Regarding the appropriateness of BZD doses, the literature differs in cut-off points (i.e., amount of mg) and in methodology of dose calculation. In our study, a daily dose for each patient and each BZD was calculated separately without any further adjustments. This allows for examination of patterns of use of each BZD individually.
The usual maximum length of BZD therapy is set up to 1 month for treatment of insomnia, anxiety, and initiation of depression treatment [
20]. In our study, 71% of 426 BZD users used these medications for more than 1 year, while 36% were users for more than 5 years. Only 1% of BZD users used BZDs for less than 1 month. Some studies show older patients being more likely to be long-term users and users of higher doses compared to younger patients [
43,
44]. The length of BZD use in older long-term users was proved to be associated with higher risk of hospitalization/emergency department visits due to falls [
45].
The length of BZD use accompanied by the proportion of patients taking higher doses in our study is alarming. Specific interventions are needed emphasizing early deprescribing strategies and intensifying other more rational, safer ways of treatment. Tools like specialized software might help in every day clinical practice to specifically monitor dosing, length of therapy, and risk factors of inappropriate drug treatment in older adults. Although this study did not aim to assess appropriateness of BZD use, the results show the prevalence of long-term BZD use remains high. Up to date a vast number of guidelines and recommendations to reduce inappropriate use of BZDs was developed [
46‐
48]. Numerous screening tools such as Beers criteria [
19], STOPP/START criteria [
20] as well as educational programs or deprescribing tools such as Eliminating Medication Through Patient Ownership of End Results (EMPOWER) study [
49], Reducing Use of Sedatives (RedUSe) project [
50] and Halting Antipsychotic Use in Long-Term (HALT) study [
51] have been introduced in previous decades. Interventions to lower BZD use in older patients mainly consist of establishing a specific deprescribing protocol, education of physicians, pharmacists, nurses and patients with focus on non-pharmacological prevention and management of symptoms for witch BZDs were originally prescribed (such as anxiety, insomnia, etc.).
In most of the countries included in our study there is some kind of BZD prescription regulation present, suggesting there must be other factors influencing the magnitude of BZD prescription. A recent qualitative systematic review of healthcare professionals’, patients’ and family caregivers’ attitudes towards the use of psychotropic medication (including BZDs) in older people, showed that we are dealing with multidimensional problem [
52]. While being aware of existence of international guidelines of BZD use, healthcare professionals identified barriers to following them on individual, team and organizational levels [
52]. The situation with alternative non-pharmacological approaches seems to be complicated as well. Some studies revealed lack of time, training, funding and accessibility as well as resistance of patients to accept psychological interventions, to be main barriers in non-pharmacological strategies incorporation [
52].
Factors associated with BZD use
Factors associated with BZD use described in our study might play a critical role in identifying patients at risk and need of specific interventions to reduce extensive inappropriate use of BZDs.
In our study use of BZDs was statistically significantly associated with female gender which is in line with findings in some other studies [
53]. Higher age, in our study, was significantly associated with BZD use only in the simple (univariable) model, however the adjusted association did not remain statistically significant. This is in contrary to other recent findings suggesting advanced age (85 + years) to be a protective factor of prescribing potentially inappropriate polypharmacy in older population [
54]. Even though the overall research evidence points to awareness of prescribing of PIMs in older patients, findings of our study may suggest that the population of community-dwelling older patients is different compared to other specific populations such as nursing home residents, acute hospital in-patients, etc. Differences in functional, cognitive, and overall health status may lead to different approaches in prescription of PIMs in these unique populations of geriatric patients.
The presence of anxiety disorder, depression, and repetitive anxious complains were positively associated with BZD use in our study. Studies suggest that older patients in primary care are at higher risk of inappropriate BZD prescription coupled with underutilization of antidepressants in geriatric depression [
55,
56]. Association of insomnia with BZD use in our study corresponds with general knowledge of BZD prescription in older patients for insomnia and anxiety [
57], despite their minimal efficacy in these indications [
19]. While the BZD prescription in these indications might be seen as appropriate in middle age population, safer therapeutic options should be considered for older patients. Several interdependent factors leading to difficulties in change of BZD prescription patterns were described. These include for instance physicians’ insufficient recognition of adverse effects, lack of skills and training in BZD tapering management, as well as patients’ resistance to change their medication regime, limited availability of psychotherapists, and absence of regular specialist medication reviews [
58].
In our study, BZD users had significantly higher odds of presence of syncope compared to BZD non-users. BZDs are associated with greater systolic blood pressure reduction after an active stand-up [
59]. It is of importance to emphasize that syncope may be consequent adverse drug event of BZD use, responsible also for falls, fractures and intracranial haemorrhage [
60], resulting in hospitalization, reduced mobility, decline in functional status, and higher risk of long-term care facilities admission [
61]. BZDs are considered one of the major fall-risk-increasing drugs, as they increase the risk of falls by approximately 50% [
62]. Annual costs of treatment for BZD related fall injuries in the European Union were estimated up to 1.8 billion Euros [
63].
Our study showed BZD users had lower odds of reporting loss of appetite. The hyperphagic effect of BZDs was connected to their direct effect on appetite mechanism and enhanced responsiveness to sweet, palatable taste [
64]. Although these findings are linked to research on animal models, interestingly loss of appetite is sometimes identified as one of the symptoms of BZD withdrawal [
65]. On the other hand, loss of appetite can be also linked to presence of anxiety and successful anxiety treatment with BZDs might come hand in hand with appetite regulation.
Strengths and limitations
To the best of our knowledge, this study delivers the first and broadest comparisons of BZD prevalence and prescribing patterns in population of community-dwelling older patients across European countries. Using the same comprehensive methodology at all study sites enabled us to make meaningful comparisons in participating countries.
The main limitation of our study is that the sample was not randomly selected. On the other hand, study sites were selected as general health care facilities- pharmacies, not providing services to specialized psychiatric health-care clinics. Country samples were not intended to be nationally representative, therefor the results of this study need to be interpreted with caution in regards to generalizability. The cross-sectional design of the study did not allow for comparison in a time-dependent manner or to identify causal time relationships between BZD use and factors used in multiple regression models. The focus of this study was to describe specifically BZD use, and as such, other drugs prescribed for similar indications and non-pharmacological treatment strategies were not analysed. The individual appropriateness of BZD use was not assessed, as this study did not focus on implicit medication reviews. We did not control our analyses for all clinical comorbidities (except for number of diagnoses), however, in multiple regression model main comorbidities well known to be associated with BZD use were included.