Prescribing Z-drugs in Greece: an analysis of the national prescription database from 2018 to 2021

Insomnia is a common mental disorder, affecting approximately 7% of the population in Europe and resulting in a significant burden of 94 disability-adjusted life years (DALYs) per 100,000 persons [1]. In Greece, the prevalence is unclear, and estimates of self-reported insomnia have ranged from approximately 25% in 2010 [2] to 40% during the first wave of COVID-19 pandemic in 2020 [3].

Although cognitive-behavioral therapy for insomnia (CBT-I) is the recommended first-line treatment, it is not widely available and may not be effective for all individuals [4]. Thus, pharmacological interventions are frequently used, with a wide range of effective drugs available that are generally divided into two main categories: the benzodiazepine receptor agonists, i.e., benzodiazepines and non-benzodiazepines (Z-drugs), and other drugs, e.g., melatonin, and orexin antagonists [4, 5]. The prescription patterns of Z-drugs are particularly of great importance, as these medications were initially marketed and perceived as safe alternatives to benzodiazepines, yet they can also result in abuse and dependence, among other side-effects [4, 6].

The prevalence of Z-drug prescriptions can vary significantly across different countries and regions [7‐11], which makes it challenging to make generalizations. There are generally only sparse data about the situation in Greece. The implementation of a nationwide electronic prescription system during the 2010s represented a significant shift from paper-based to digital prescriptions for medications. However, it was not mandatory to issue electronic prescriptions for medications with abuse potential, including Z-drugs, until 17.07.2019. As a result, the current study aims to analyze prescriptions for Z-drugs from the Greek nationwide prescription database, with the aim to investigate the prevalence of Z-drug prescriptions, their characteristics and trends.

Our analysis was the first to investigate the prescription characteristics and trends of Z-drugs in Greece. We analyzed 1,229,842 prescriptions for Z-drugs (corresponding to 156,554 unique patients), which were registered to the Greek nationwide prescription database within a three-year time period (2018–2021).

We found that about 1% of the Greek population was prescribed at least once a Z-drug (mostly zolpidem) over the course of a year. The prevalence was higher in females and almost exponentially increased with the age, i.e., about two thirds of the patients were older adults ≥ 65 years old. Patients had often other co-prescribed psychotropic medications (e.g., benzodiazepines in about a third of the patients, antidepressants and antipsychotics in about a tenth and twentieth respectively) and psychiatric disorders were also present, mainly anxiety and depressive disorders. Our analysis also indicated that the prevalence of Z-drug prescriptions increased in 2020, which coincided with the start of the COVID-19 pandemic and an associated increase in insomnia [3, 15]. This increase was particularly notable in younger populations, while a decrease was even observed among those aged over 85 years (eAppendix-3).

Our findings were consistent with previous studies from other countries, reporting similar patterns of Z-drug use and prescription characteristics [7‐11]. A concerning trend was the substantial prescribing of Z-drugs among older adults, despite the potentially elevated risk of side-effects such as cognitive impairment, confusion, falls, fractures, and pneumonia [4, 16]. Although this finding may reflect a higher prevalence of insomnia in older adults, it highlights the importance of regularly evaluating the risk–benefit profile of Z-drugs and considering safer alternative interventions, especially for this vulnerable population [17]. Efforts should be made to increase the implementation of efficacious psychosocial and behavioral interventions, such as CBT-I, although their availability and accessibility are generally poor [4, 18]. Moreover, shared decision-making between patients and physicians should be implemented to evaluate the benefits and harms of currently available medications [4, 5, 19]. However, further research is needed, as there is limited randomized evidence on the efficacy and safety of pharmacological and non-pharmacological interventions for insomnia in older adults [20].

Furthermore, our study found that more than two-thirds of the patients were exclusively prescribed by internists and general practitioners, likely reflecting the higher prevalence of insomnia in primary care settings and the distribution of medical specialists in Greece. However, general practitioners may often encounter challenges in optimally diagnosing and treating insomnia as well as the frequently coexisting major mental disorders [18, 21]. Notably, almost half of the patients with anxiety or depressive disorders did not receive a prescription for an antidepressant or anxiolytic. This situation was more frequently observed in prescriptions by medical specialties other than psychiatrists or neurologists. However, it is worth noting that our study may have underestimated the extent of co-prescription for medications, since we did not have access to data for prescriptions that did not include Z-drugs (e.g., patients may have been prescribed psychotropic medications separately from their Z-drug prescription).

Another interesting finding was the increase of about 10% in the monthly number prescriptions after the electronic prescription mandate (Fig. 2), indicating that a number of prescriptions for Z-drugs may not have been registered in the prescription database before the mandate. Therefore, this finding can provide an additional explanation to the observed increase in the prevalence of Z-drug prescriptions during 2020 compared to 2019, considering that the mandate was only active for approximately half of the 2019 period. Moreover, this policy could facilitate the surveillance of prescriptions for drugs with abuse and dependence potential, which could be further enhanced by building an infrastructure of Addictovigilance [22]. Additional policy changes may also be useful in reducing Z-drugs prescriptions [23], but their potential drawbacks should be taken into consideration, including the increased complexity in clinical practice and the possibility of patients switching from Z-drugs to benzodiazepines or other substances with abuse potential [24, 25].

Our analysis has certain limitations. First, there was insufficient information about the prescribed dose that precluded any further investigation. While the data included the number of Z-drug boxes, there were no further details regarding the prescribed dose. Therefore, a more elaborate analysis considering also estimations of continuous and long-term use of Z-drugs was not possible. The relationship between the prescribed dose and sex would also be important given that women have a lower clearance of zolpidem. Accordingly, an FDA warning recommended the use of lower doses of zolpidem in women in order to avoid residual morning sleepiness and impairments in psychomotor performance [26], yet the evidence basis of this warning has been questioned [27]. Second, data for prescriptions that did not contain Z-drugs were not obtained. Therefore, we could not conduct a more comprehensive analysis of the comorbidities and concomitant medications. Accordingly, although our dataset included information about ICD-10 codes, it was not possible with the current data to differentiate between whether a diagnosis was the reason for prescribing Z-drugs or a comorbidity. Third, it is important to acknowledge that our method of identifying diagnoses based on at least one prescription with the corresponding ICD-10 may have led to an overestimation of the prevalence of certain conditions [28, 29]. Nevertheless, there is no universally accepted approach, and we preferred to prioritize a higher sensitivity given that we did not have access to all the prescriptions of the patients. Fourth, the available data covered a limited timeframe of three years, during which the COVID-19 pandemic and medication shortages occurred, potentially influencing the prescription patterns. However, there were no substantial changes in the monthly number of prescriptions, except during the period of medication shortage. Finally, we acknowledge that we did not register a detailed protocol for this study, which had, however, a descriptive and explorative nature.

In conclusion, this was the first study that utilized the Greek national prescription database in order to explore the Z-drug prescribing. The results indicated suggesting that about 1% of the Greek population were prescribed Z-drugs at least once over the course of a year. The prevalence was higher and substantial in older adults, as well as there were considerable rates of psychiatric comorbidity and concomitant psychotropics. The majority of the prescriptions were conducted by internists and general practitioners. Therefore, our findings underscore the high frequency of Z-drug prescriptions in older adults, emphasizing the importance of regular monitoring of their benefit-risk ratio in this vulnerable population. However, due to the limitations inherent to medical claims databases and the insufficient information about the dose, duration of use and concurrent prescribed medications, further research is warranted to evaluate the potential abuse and misuse of Z-drugs in Greece.