Abstract
Benzodiazepines are among the most widely prescribed treatments for insomnia, and can have positive effects on sleep when used for a maximum of 4 weeks. However, benzodiazepines disrupt sleep architecture, and their long-term use leads to negative outcomes, including impairments in memory and attention, increased risk of falls (particularly in the elderly) and car accidents, dependence, and addiction. In addition, stopping benzodiazepines after long-term use can result in severe withdrawal symptoms. Spain is one of the countries with the most widespread benzodiazepine use. A multidisciplinary approach is crucial for the treatment of insomnia and for preventing benzodiazepine overuse/misuse. The present study provides an updated overview of the epidemiology and use of these drugs in vulnerable populations (adolescents, older adults and people with mental disorders). We also describe deprescribing strategies used in clinical practice and present two case studies to exemplify the complexities of benzodiazepine withdrawal observed in our practice. Finally, proposals are provided for the rational use of benzodiazepines in Spain, targeted to the general population, healthcare professionals, and regulatory authorities, in order to improve the clinical management of insomnia.
1 Introduction
An estimated 6.0%–14.8% of all adults in high-income regions, including Spain, suffer from chronic insomnia (RAND Europe, 2023; de Entrambasaguas et al., 2023), with insomnia symptoms affecting up to 43.4% of the Spanish population (de Entrambasaguas et al., 2023). In the short-term, insomnia has a negative impact on functioning and wellbeing, causing fatigue, attention and memory problems, reduced productivity at work, and mood disturbances (Brownlow et al., 2020; Whiting et al., 2023; Gingerich et al., 2018). In the long-term, insomnia is associated with poor health-related quality of life (HRQoL) and an increased risk of a wide range of diseases, including cardiovascular disorders, mental problems, dementia, arterial hypertension, type 2 diabetes, obesity, cancer, and multimorbidity (RAND Europe, 2023; Zhou et al., 2023; Sofi et al., 2014; Hertenstein et al., 2019; Almondes et al., 2016; Johnson et al., 2021; Wu et al., 2023; Shi et al., 2020; Zheng et al., 2019; Valenzuela et al., 2022). As a result, sleep disturbances pose a high burden on individuals, healthcare systems, and society at large (Rosekind et al., 2010; Hillman et al., 2018). However, despite the severe impact of insomnia, only a small percentage of people seek medical help (Torrens Darder et al., 2021).
Benzodiazepines are a class of psychoactive drugs that have anxiolytic, sedative, hypnotic, muscle relaxant and anticonvulsant effects. They are the most commonly prescribed drugs for treating insomnia in some countries, and are also used for managing other conditions such as anxiety, alcohol withdrawal, or acute muscular pain (Soyka et al., 2023; Bounds and Patel, 2024). Benzodiazepines target GABAA receptors (GABAARs), inhibiting synaptic signaling throughout the central nervous system (CNS). These drugs are effective in the acute treatment of insomnia (De Crescenzo et al., 2022), and the recommended maximum duration of treatment for insomnia is 4 weeks (Brandt et al., 2024; Riemann et al., 2023). Only in some cases may longer treatment (off-label use) be considered individually (Riemann et al., 2023) after re-evaluation of the patient (Spanish Agency of Medicines and Medical Devices, 2000). Despite the indication and recommendation of the ≤4 weeks treatment period, benzodiazepines are frequently prescribed off-label for much longer periods, ranging from several months to years (Soyka et al., 2023; Urru et al., 2015; López-Pelayo et al., 2019; Cañellas Dols et al., 1998). This may be due at least in part to limited access to therapeutic alternatives offering better efficacy and safety profiles in both short- and long-term use.
The long-term use of benzodiazepines is associated with several undesired adverse effects. It can lead to alterations in sleep architecture, with an increased time of stage 2 non-rapid eye movement (NREM) sleep and a decreased time of stages 3 and 4 NREM sleep and rapid eye movement (REM) sleep (de Mendonça Maraucci Ribeiro et al., 2023). The chronic use of benzodiazepines can also impair cognitive functions across all domains (Barker et al., 2004a), with these effects persisting even after discontinuation (Barker et al., 2004b). Additionally, benzodiazepine exposure can alter attention and reaction times, increasing the risk of falls (especially in the elderly population) and traffic accidents (Smink et al., 2010; Barbone et al., 1998), making benzodiazepines the second most frequently involved substances in traffic accidents after alcohol (Alvarez-Freire et al., 2023). The risk of work accidents also increases with prolonged use and following discontinuation (Baudot, 2024). The use of benzodiazepines before a work-related injury may increases the risk of disability after the injury (Nkyekyer et al., 2018). Patients consuming benzodiazepines, especially those with long-time use, commonly report several adverse effects including daytime drowsiness, dizziness, light-headedness, disinhibition, delirium, fatigue, anterograde amnesia, and depression (Holbrook et al., 2000; Del Rio Verduzco et al., 2023). Furthermore, benzodiazepines are known to enhance the misuse of opioid medications (Cragg et al., 2019), and their combination can result in serious risks, including death (US Food and Drug Administration, 2024).
Failure to adhere to the recommended duration of benzodiazepine treatment can result in chronic use, leading to tolerance and dependence within a few weeks (Edinoff et al., 2021). Benzodiazepine misuse is a growing public health problem that can occur for different reasons. Firstly, patients may deviate from the prescribed posology, using the medication for longer periods, at higher doses, or more frequently (Soyka et al., 2023; Urru et al., 2015; López-Pelayo et al., 2019). Secondly, benzodiazepines might be used without a prescription, obtained from friends or family members with a prescription, or from illicit sources (Votaw et al., 2019).
European clinical guidelines recommend cognitive-behavioral therapy for insomnia (CBT-I) as a first-line management option for chronic insomnia. If CBT-I proves ineffective, a pharmacological intervention can be proposed, including benzodiazepines and Z drugs for up to 4 weeks (or longer in some cases; recommendation level B), orexin receptor antagonists for up to 3 months (or longer in some cases; recommendation level A), or prolonged release melatonin in patients >55 years for up to 3 months (recommendation level B) (Riemann et al., 2023). Despite these recommendations, CBT-I is rarely used as initial treatment, and benzodiazepines and Z drugs are often prescribed instead (Torrens Darder et al., 2021; Soyka et al., 2023; Ellis et al., 2023).
The present study describes the current scenario of benzodiazepine use and abuse in Spain, a country with some of the highest rates of use and misuse globally (Ma et al., 2023), despite existing recommendations aimed at preventing misuse (Spanish Agency of Medicines and Medical Devices, 2000). Also, we describe the challenges of benzodiazepine deprescription and present feasible proposals to promote the appropriate use of these drugs for the treatment of insomnia. A multidisciplinary group of healthcare professionals (a psychiatrist, a primary care physician, an occupational medicine physician, a community pharmacist and a neurologist) with experience in the management of benzodiazepines in sleep disorders across different contexts, convened on 6 March 2024 to review the available scientific evidence on benzodiazepine use, misuse and abuse in Spain; to discuss commonly found patient situations in the management of benzodiazepines (presented here as case studies); and to develop the strategic proposals for the rational use of benzodiazepines reported herein. These strategic proposals were subsequently graded for feasibility (“moderate” or “high”) and relevance (“moderate” or “high”) by the authors via an online survey in July 2024.
2 Benzodiazepine use in Spain
2.1 Epidemiology
European countries are among the largest consumers of benzodiazepines in the world (Ma et al., 2023), with Spain ranking among the highest in usage rates (Lukačišinová et al., 2024). Research on volume per class for medicines prescribed for insomnia among European countries in 2022 showed that the sales by volume for benzodiazepines were highest in Spain, accounting for 66.3% of the total (Soyka et al., 2023). The consumption of anxiolytic and hypnotic prescription drugs in Spain has been rising since 2010, peaking in 2021 with 93.3 defined daily doses per 1,000 inhabitants per day (Spanish Agency of Medicines and Medical Devices, 2024).
The pronounced peak recorded in 2020 and 2021 might be related to the COVID-19 pandemic, which witnessed an increase in insomnia, anxiety and depression symptoms in Spain (Zhang et al., 2022; Roncero et al., 2024), with prevalence rates exceeding those of other countries like China (Zhang et al., 2022). A study of 1,673 Spanish adults found that during the lockdown, sleep quality worsened, with increased daytime sleepiness, a higher number of awakenings, and a longer duration of awakenings (Ruiz-Herrera et al., 2023). The rise in sleep problems during the pandemic was accompanied by an increase in benzodiazepine consumption (Sánchez Díaz et al., 2021; Perelló et al., 2023). A study across 75 community pharmacies in the region of Catalonia reported a significant rise in benzodiazepine use during the pandemic compared to the two previous years (Perelló et al., 2023) - a trend mirrored in other countries (Zaki and Brakoulias, 2022; Kurvits et al., 2024).
Along with the impact of the pandemic, the continuous rise in benzodiazepine use in recent years can be attributed to several factors. These include a growing trend towards low tolerance for frustration (Marquina-Márquez et al., 2022). Healthcare professionals often face pressure from patients who demand immediate solutions, which together with the limited time for appointments, underestimation of the associated adverse events, and low access to non-pharmacological resources, results in a higher prescription rate of benzodiazepines (Marquina-Márquez et al., 2022). Therapeutic inertia, a low perception of consumption risks, and a lack of knowledge regarding benzodiazepine withdrawal management might also contribute to the increase in benzodiazepine prescriptions (Vicens et al., 2014; Vázquez Canales and Frutos Fernández, 2023).
In addition to the high use of prescribed benzodiazepines, non-medical use—i.e., the use of benzodiazepines without a corresponding medical prescription—is also prevalent in Spain (Novak et al., 2016). A study conducted in Barcelona revealed that one in 11 citizens used benzodiazepines off-label, with primary care physicians and psychiatrists being the most common off-label prescribers (López-Pelayo et al., 2019). Also, a high prevalence of potentially inappropriate use of benzodiazepines has been detected in community pharmacies and nursing homes across Spain (Díaz Planelles et al., 2023; Perelló et al., 2021).
The use of benzodiazepines among the healthcare population is also important. A recent survey conducted among 1,121 healthcare professionals has found that around 30% of the respondents had sleep problems, and over 25% were using benzodiazepines (Roncero et al., 2025).
Community-based interventions have been launched in some regions to promote benzodiazepine deprescription among long-term users. One of these initiatives was the “benzoletter,” where primary care physicians sent a personalized letter to patients who had been using benzodiazepines for more than 3 months, providing information about the adverse effects of such use and a recommendation to discontinue them (Baza Bueno et al., 2020). These local initiatives have achieved some success in reducing benzodiazepine use within targeted populations (Baza Bueno et al., 2020). Nevertheless, misuse and abuse of these medications continue to be prevalent in Spain. The difficulties in instituting possible therapeutic alternatives (both pharmacological and non-pharmacological) offering better efficacy and safety profiles, and with timely access to them, might have limited the success of such local initiatives.
2.2 Vulnerable populations
2.2.1 Adolescents
Recommendations from experts suggest treating insomnia in children and adolescents with CBT-I, limiting the use of benzodiazepines, among other drugs, as much as possible (Pin et al., 2017). However, the use of benzodiazepines among the younger populations in Spain has increased over the years, with a large part of this consumption being non-medical (Carrasco-Garrido et al., 2021a). In 2023, the prevalence of non-medical hypnosedative use among students aged 14–18 years in the last 12 months was 7.4% (Spanish Ministry of Health, 2023a). Consumption is higher among women than in men (Carrasco-Garrido et al., 2021a; Spanish Ministry of Health, 2023a; Carrasco-Garrido et al., 2021b). Specifically, 26.1% of 14- to 18-year-old females admitted to having used these substances at least once in their lifetime, 12.7% of them without a prescription (Spanish Ministry of Health, 2023a).
These figures are concerning not only due to the adverse effects of benzodiazepines but also because there is a relationship between the use of benzodiazepines and the consumption of other substances, such as alcohol, tobacco and marijuana among adolescents and younger adults (Carrasco-Garrido et al., 2021a; Carrasco-Garrido et al., 2018; Palacios-Ceña et al., 2019). Additionally, a survey of 10,824 individuals aged 15–34 years in Spain revealed that lower awareness of drug use risks and more negative health perceptions are associated with the non-medical use of benzodiazepines and Z-drugs among young people (Carrasco-Garrido et al., 2021b).
2.2.2 Older adults
Benzodiazepine use in Spain, including off-label use, increases with age (López-Pelayo et al., 2019; Herrera-Gómez et al., 2018; Spanish Ministry of Health, 2023b), and is more prevalent among women (Spanish Ministry of Health, 2023b; Torres-Bondia et al., 2020). Approximately one-third of all community-residing older adults use benzodiazepines, which is one of the highest prevalence rates among this population in European countries (Lukačišinová et al., 2024). This prevalence is alarming, given that research indicates that benzodiazepine use in the elderly is associated with several negative outcomes, including dependence, an increased risk of falls resulting in fractures, cognitive impairment, dementia and mortality (Markota et al., 2016; Aldaz et al., 2021). Whether the association between benzodiazepine use and dementia is causal or whether these drugs are more frequently prescribed to patients experiencing prodromal symptoms of dementia remains unclear. However, the stronger association observed between long-term benzodiazepine exposures and the risk of Alzheimer’s disease (Billioti de Gage et al., 2014), as well as the increased risk of dementia associated with the concomitant use of two or more benzodiazepines (Tseng et al., 2020), suggest a direct association, although it does not necessarily imply causality. Also, the use of benzodiazepines has been associated with an accelerated reduction of hippocampal and amygdala volume (Hofe et al., 2024). This is despite the possibility that benzodiazepine use might also be an early indicator of conditions such as sleep problems, that are associated with a higher risk of developing dementia (Bubu et al., 2016; Shi et al., 2018).
Considering the available evidence, the potential benefits of benzodiazepines for older adults may not justify the associated risks, particularly when the patients have additional risk factors for cognitive or psychomotor adverse events (Glass et al., 2005). Clinicians should be very cautious when prescribing these medications to older patients. Some medical societies, such as the American Geriatrics Society, recommend avoiding benzodiazepines and non-benzodiazepine hypnotics in this population (By the 2023 American Geriatrics Society Beers Criteria® Update Expert Panel, 2023).
Given the high prevalence of insomnia among the elderly, and the complications related to benzodiazepine use, a complete clinical evaluation/screening and alternative pharmacological and non-pharmacological options should be considered (Vázquez Canales and Frutos Fernández, 2023). Before initiating any treatment, it is important to conduct an assessment of the medical and psychiatric history, and to evaluate the sleep environment and psychosocial stressors of the patient.
2.2.3 People with mental disorders
Benzodiazepines are prescribed for a variety of mental disorders, including not only anxiety and depressive disorders but also schizophrenia, where they are used to manage acute anxiety and prevent relapse after stabilization. While the short-term use of benzodiazepines for specific symptoms can be appropriate, long-term use and at higher than recommended doses remains common among patients with mental health disorders in Spain (Simal-Aguado et al., 2021). The effectiveness and potential adverse effects of these medications on the symptoms of different mental disorders are subjects of ongoing debate.
Patients with mental disorders also have a higher tendency towards addictive behaviors, a problem that is often under-recognized (Szerman et al., 2022). In turn, this addiction to substances is associated with a worse progression of underlying mental disorders. Abuse of benzodiazepines was correlated with an incomplete remission of other substance use disorders and a higher mortality risk among schizophrenic patients (de la Iglesia-Larrad et al., 2020). Tapering benzodiazepines in these patients was associated with improvements in some cognitive functions (de la Iglesia-Larrad et al., 2020).
Among patients with substance use disorders, the use of benzodiazepines is very high. A study showed that approximately 86% of the individuals with addictions who were admitted to a detoxification unit used benzodiazepines, 75% of them without prescription (Roncero et al., 2012). Treating insomnia in patients with drug addiction while hospitalized for detoxification is crucial, as patients with insomnia before and during admission have a higher risk of relapse after discharge (Grau-López et al., 2014).
3 Benzodiazepine deprescribing in clinical practice
The deprescription of benzodiazepines is a real-world challenge that should be considered in patients on prolonged and unjustified treatments, due to their association with dependence and adverse effects. Key challenges in the deprescription process include managing potential addiction to benzodiazepines, as well as addressing rebound effects and withdrawal syndrome. Withdrawal syndrome is characterized by headache, sleep disturbances, anxiety, depression, difficulty in concentration, confusion, delirium and delusions, among other manifestations (Pétursson, 1994). Long-term users or elderly people with metabolic problems are particularly susceptible to withdrawal syndrome (Jobert et al., 2021). Such long-term users are usually more reluctant to discontinue treatment, due to the anticipated withdrawal symptoms. Primary care physicians, despite their awareness of the risks associated with long-term benzodiazepine use, can find the management of withdrawal difficult. They have expressed concern about patients experiencing distress and a lack of alternatives to offer them (Sirdifield et al., 2013). This mutual hesitation can contribute to the continuation of benzodiazepine treatment. Additionally, the high workload of primary care physicians, limited consultation time, and the low availability of psychotherapy in the public healthcare system or pharmacological alternatives for addressing these barriers, further complicate deprescription management (Lasserre et al., 2010).
Strategies for successful benzodiazepine deprescription include gradual dose reductions, switching to another type of medication, or the adoption of non-pharmacological interventions, including patient education and cognitive-behavioral therapy (Brandt et al., 2024; Soni et al., 2023; Dou et al., 2019; Tannenbaum et al., 2014; Satué de Velasco, 2014). Interventions to discontinue long-term benzodiazepine use have been studied in Spanish clinical practice. Two brief structured educational interview programs delivered by general practitioners, with and without follow-up visits, were found to be more effective than standard of care in stopping long-term benzodiazepine use over 12 months (Trépel et al., 2020). Another study showed that the efficacy of interventions to reduce chronic benzodiazepine use persisted even after 3 years, with the probability of stopping benzodiazepine use being 41% higher in patients in the intervention group versus the control group (Fernandes et al., 2022).
Effective communication among the patient, pharmacist and physician is crucial for the successful prescribing and deprescribing process. The treatment plan should be individualized based on the patient characteristics and socio-environmental context. Shared decision-making with the patient encourages the latter to take responsibility and adhere to the discontinuation program.
We present two case studies that describe the course of complicated processes of benzodiazepine withdrawal observed in our clinical practice (Table 1). These cases represent profiles of patients frequently found in clinical practice. Written informed consent was obtained from the patients to share their anonymized data with research purposes. Case 1 represents a patient with reluctance to CBT-I, citing lack of time due to work commitment, but other factors may have had an influence such as lack of access to CBT-I within the Spanish healthcare system, stigma associated with mental health, a dysfunctional belief regarding benzodiazepine dependence, or a lack of motivation (Zamorano et al., 2023). Case 1 also addresses the initiation of daridorexant, a dual orexin receptor antagonist (DORA), which has a different mechanism of action to support benzodiazepine discontinuation (Álamo et al., 2024). Daridorexant is used as a non-sedative treatment of insomnia disorder with a favorable efficacy/safety profile (Mignot et al., 2022) and grade A recommendation from the European insomnia guide (Riemann et al., 2023). This patient was able to discontinue benzodiazepines after gradually reducing the dose, and improved sleep quality and hyperarousal after daridorexant initiation. Case 2 describes a patient who received CBT-I and a reduced benzodiazepine dose, with improvements in insomnia and anxiety.
TABLE 1
| Case 1: Benzodiazepine withdrawal in a young woman Patient information A 32-year-old female lawyer lives with her husband and has no children. She has had difficulty initiating and maintaining sleep for the past 8 years. She reports generalized pain that interferes with sleep, as well as anxiety and a constant state of hyperarousal. This has led to daytime sleepiness, irritability, and concentration difficulties Medical history Fibromyalgia, anxiety-depressive syndrome (under psychiatric follow-up), and hypothyroidism Medications Levothyroxine, sertraline (50 mg/day), lormetazepam (2 mg/night) Initial sleep assessment ISI: 18/28; PSQI: 14/21 (without treatment) Diagnosis Chronic insomnia and benzodiazepine dependence Treatment approach Initial management HDRS: 6/52. The first intervention was an attempt to reduce lormetazepam from 2 mg to 1 mg per night, together with sleep hygiene. The patient declined a structured CBT-I program due to a lack of time caused by work commitments Follow-up: 1month The dose reduction of lormetazepam to 1 mg was initially successful; however, after 3 weeks, the patient returned to the previous dose due to worsening symptoms. Daridorexant (50 mg/night) was initiated while reducing lormetazepam again to 1 mg Follow-up: 2months A reduction of lormetazepam to 1 mg per night was achieved without apparent relapse and maintained good subjective sleep quality. A complete withdrawal of lormetazepam was then proposed while maintaining daridorexant 50 mg/night Last follow-up: 3.5months The patient reported a reduction in hyperarousal, particularly at bedtime and during nocturnal awakenings. She had an improvement in ISI and PSQI scores at this visit (ISI: 9/28; PSQI: 8/21) No additional changes in her medications were necessary. The withdrawal process of lormetazepam was well-tolerated, with improvements in sleep quality and daytime functioning.with daridorexant 50 mg/night |
| Case 2: Patient with insomnia with an emotional/social component Patient information A 56-year-old man, retired from the civil guard, is divorced and has one child. He had difficulty initiating and maintaining sleep for the past 3 years, with daytime repercussions. These changes coincided with increased work responsibilities and stress while still working, and poor sleep hygiene. Since the onset of the sleep problem, he has been receiving treatment with lormetazepam, which improved both sleep and anxiety Medical history Arterial hypertension, diabetes mellitus, overweight, smoker (10 cigarettes/day) Medications Lormetazepam (1 mg 1-0-1), enalapril, metformina, and simvastatina Initial sleep assessment ISI: 15/28 Laboratory tests were normal Diagnosis Chronic insomnia and anxiety Treatment approach Initial management Gradual withdrawal of lormetazepam together with CBT-I was proposed. CBT-I included not only sleep advice but also lifestyle recommendations, such as doing physical activity and reducing stress Follow-up: 1month The lormetazepam dose at breakfast was stopped and maintained to 1 mg at dinner (0-0-1). There was a considerable improvement in anxiety and insomnia Last follow-up: 2months Lormetazepam 0.5 mg at dinner (0-0-1) was maintained (the patient’s follow-up has been coordinated with the Psychiatry Unit, which decided to continue this dose of lormetazepam) |
Case reports of patients with benzodiazepine treatment for insomnia.
Abbreviations: CBT-I, cognitive behavioral therapy for insomnia; HDRS, hamilton depression rating scale; ISI, insomnia severity index; PSQI, pittsburgh sleep quality index.
Scores: HDRS: higher scores indicate more severe depression (0–7: normal, 8–16: mild depression, 17–23: moderate depression, ≥24: severe depression). ISI: higher scores indicate more severe insomnia (0–7: no clinically significant insomnia, 8–14: subthreshold insomnia, 15–21: moderate insomnia, 22–28: severe insomnia). PSQI: higher scores indicate worse sleep quality (0–4: good sleep quality, >5: poor sleep quality).
4 Strategic proposals for the rational use of benzodiazepines in Spain
Addressing sleep education is important. Enhancing understanding of the appropriate use and the misuse of benzodiazepines can benefit both the general public and healthcare professionals now and long-term in the future. After reviewing the main articles focused on this topic we propose practical and highly relevant initiatives for the rational use of benzodiazepines in our country (Table 2). These include public education and awareness campaigns, for which social media platforms could be used, and updated training for healthcare providers.
TABLE 2
| Proposals | Feasibility | Referencesa |
|---|---|---|
| Education and awareness | ||
| Conduct mass awareness-raising campaigns in society regarding the importance of sleep as a determining factor for good health, together with diet and physical exercise | High | Wakefield et al. (2010) |
| Develop and disseminate materials and tools on sleep hygiene accessible to the general population | High | Ilhan et al. (2022),Seda-Cansu and Seher (2022),Garbers et al. (2024),Irish et al. (2015) |
| Raise awareness among policymakers about the importance of aligning schedules with sleep physiology to encourage changes in communication and digital media | Moderate | Adornetti et al. (2025),Kelley et al. (2015),Gurubhagavatula et al. (2021),Chkhaidze et al. (2024) |
| Create sleep education and benzodiazepine discontinuation programs across healthcare professions, including primary care, pharmacy, nursing, and social work | High | Morbioli and Lugoboni (2021),Bourcier et al. (2018) |
| Implement large-scale sleep hygiene training in companies for both employees and employers | High | Redeker et al. (2019),Olson et al. (2015),Robbins et al. (2019) |
| Educate employers about the importance of digital detox for their employees and the impact of sleep disorders upon productivity and accidents at work | Moderate | Mizrak et al. (2025),Dresp-Langley and Hutt (2022),Ansari et al. (2024) |
| Direct targeted awareness programs in schools and high schools for younger populations | Moderate | Chung et al. (2017),Blunden and Rigney (2015) |
| Include basic aspects of sleep into school and university curricula | Moderate | Meltzer et al. (2009),Salas et al. (2018),Falloon et al. (2024),Meaklim et al. (2023) |
| Address the “culture of immediacy” in the population and raise awareness of its impact on health | Moderate | MacKenzie et al. (2022) |
| Training for healthcare professionals | ||
| Develop specialized training programs in sleep disorders, adapted to all specialties, in short formats and oriented towards problem-solving | High | Wappel et al. (2021) |
| Train in the importance of conducting good diagnostic screening of insomnia to distinguish between physiological and other causes | High | Winkelman (2020) |
| Promote the use of therapeutic alternatives to benzodiazepines to treat sleep disorders, such as CBT-I, as well as pharmacological strategies with a more favorable efficacy/safety balance | Moderate | Riemann et al. (2023),Álamo et al. (2024) |
| Complement training with the development of protocols, consensus and clinical practice guidelines that can be used in daily practice | High | Manber et al. (2012) |
| Raise awareness among healthcare professionals about the importance of recording a complete medical history, including a brief assessment of sleep quality | High | Riemann et al. (2023),Baddam et al. (2024) |
| Remind healthcare professionals of the potential adverse events and risks associated with benzodiazepine use | High | Brandt and Leong (2017),Islam et al. (2016),Poly et al. (2020),Grigoriadis et al. (2020),Sun et al. (2019) |
| Disseminate materials aimed at health professionals on the importance of sleep for their own healthcare | High | Stewart and Arora (2019),Trockel et al. (2020),Matricciani et al. (2025) |
| Regulation and improvements in administration | ||
| Disseminate existing guidelines on the use of benzodiazepines across all specialties to promote adherence | High | Tomasone et al. (2020),Silva et al. (2021) |
| Implement an expiration period for benzodiazepine prescriptions (e.g., 1 month, with reevaluation) and include notifications in the electronic health record/prescription system | High | Riemann et al. (2023),Ellis et al. (2023),Mekonnen et al. (2021) |
| Optimize collaboration between specialties through a shared consultation model, facilitating communication between specialists (psychiatry and neurology), primary care, and community pharmacy | Moderate | Furbish et al. (2017),Edinger et al. (2016) |
| Establish a coordinated, bidirectional communication program between physicians and community pharmacies to monitor benzodiazepine use and abuse, and to improve de-addiction processes | Moderate | Huon et al. (2023),Garcia et al. (2024) |
| Facilitate, from the public and private administration, access to benzodiazepine alternatives such as psychological therapy and drugs with a more favorable efficacy/safety profile, compatible with long-term use if necessary | Moderate | Álamo et al. (2024),Manber et al. (2023),Hughes (2024) |
| Include the collection of sleep-related information in occupational health assessments | High | Morin and Jarrin (2022) |
| Promote regulations that protect employee sleep health by addressing key factors such as digital detox, shift work regulation, and on-call duties | Moderate | Gurubhagavatula et al. (2021),Lerouge and Trujillo Pons (2022),Bumpstead et al. (2025) |
| Evidence generation | ||
| Conduct epidemiological studies to determine the current prevalence of sleep disorders | High | NA |
| Develop social media listening studies to analyze conversations on social platforms regarding sleep problems and the treatments used by the population | High | NA |
Strategic proposals for the rational use of benzodiazepines in Spain.
The proposals are supported by the references provided.
All authors graded the proposals individually. The feasibility and relevance of each proposal were graded as “moderate” or “high”. A majority was considered when three or more authors voted in favor of an option. All proposals were graded as highly relevant, and therefore, a column for “relevance” has not been included in the table.
We also include proposals for regulatory authorities that could contribute to the rational use of benzodiazepines. In Spain, there is a procedure known as “inspection validation of prescriptions,” by which the Health Services Inspection authorizes the prescription of medications and pharmaceutical products that require special control (Orozco et al., 2013). The system could help to promote the appropriate use of benzodiazepines in Spain by enforcing the use of these drugs according to the approved indications in the summary of product characteristics and the recommended use in the clinical practice guidelines (Orozco et al., 2013). Also, the regulatory authorities could facilitate access to CBT-I allowing more consultation time per patient and incorporating more physicians and psychologists to treat insomnia and sleep disorders within the Spanish healthcare system, although we recognize that implementing this will require considerable resources and time. Regulatory authorities could also improve access to new, effective and safe pharmacological treatments with a different mechanism of action, such as DORAs, that are not associated with the risks posed by benzodiazepines (Álamo et al., 2024).
Artificial intelligence (AI) and machine learning (ML) will probably transform how we diagnose and treat insomnia. Incorporating AI into sleep medicine could predict risk for sleep disorders, improve the accuracy of diagnoses and referrals, and personalize treatment (Huang and Huang, 2023; Xu et al., 2022). For instance, ML can analyze a range of sleep and clinical data to detect sleep quantity and quality, that might otherwise go unnoticed, with a view to predicting treatment response (Gabbay et al., 2024). Additionally, AI tools can help monitor the efficacy and safety of treatments, providing valuable information for managing patients. These tools represent innovation, time savings, and equitable healthcare solutions. Supervised machine learning methods, including algorithms such as decision trees and random decision forests, could be used to increase predictive accuracy within monitoring algorithms. Once these tools are validated, healthcare professionals should be trained in their use.
5 Conclusion
The prevalence of benzodiazepine use and misuse in Spain is high, and has been rising in the last years, with noticeable increases among vulnerable populations of both adolescents and older adults. The long-term use of these drugs is associated with adverse effects and dependence, and therefore, their use should be restricted to their approved indications and according to the recommendations of the clinical guides (i.e., less than 4 weeks). We advise avoiding the indiscriminate and long-term use of benzodiazepines, and recommend the adoption of pharmacological or non-pharmacological therapeutic alternatives instead. With this in mind, we propose several strategies that could be implemented in Spain, with variable levels of feasibility. These strategies include education and awareness-raising campaigns for the general population, specialized training for healthcare professionals, structural and organizational changes promoted by public and private administrations, and access to new therapeutic options with a better efficacy/safety profile. We anticipate that the implementation of these proposals would reduce the current unmet needs in the clinical management of insomnia, and improve the management and quality of life of patients.
Statements
Data availability statement
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.
Author contributions
CR: Conceptualization, Writing – review and editing, Writing – original draft. LA: Conceptualization, Writing – review and editing, Writing – original draft. CB-C: Conceptualization, Writing – review and editing, Writing – original draft. AB-G: Conceptualization, Writing – review and editing, Writing – original draft. EG-C: Conceptualization, Writing – review and editing, Writing – original draft.
Funding
The author(s) declare that financial support was received for the research and/or publication of this article. Medical writing assistance was provided by Evidenze Health Spain throughout an unrestricted grant from Idorsia Pharmaceuticals.
Acknowledgments
We would like to express our gratitude to Laura Prieto del Val from Evidenze Health Spain S.L.U. for her support as a scientific advisor and medical writer during the elaboration of this article.
Conflict of interest
CR has received fees to give lectures for Janssen-Cilag, MSD, Exceltis, Abbvie, Takeda, Casein-Recordati, Carnot, Angellini, Camurus, Esteve, Tecno Quimica, Viatris and ADAMED. He has received financial compensation for his participation as a consultant or a board member of Gilead, MSD, Exceltis, Camurus, Abbvie, Idorsia, Rovi and Recordati board. He has carried out the PROTEUS project, which was funded by a grant from Indivior and the COSTEDOPIA project, which was funded by INDIVIOR. He received two medical education grants by Gilead and medical writing support from Abbvie.
The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.
Generative AI statement
The author(s) declare that no Generative AI was used in the creation of this manuscript.
Publisher’s note
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References
1
AdornettiJ. P.WolfsonA. R.BohnertA. M.CrowleyS. J. (2025). Clash between the circadian and school clocks: implications for cognitive functioning and school-related behavior during adolescence. Curr. Sleep. Med. Rep.11, 10. 10.1007/s40675-025-00321-3
2
ÁlamoC.Sáiz RuizJ.Zaragozá ArnáezC. (2024). Orexinergic receptor antagonists as a new therapeutic target to overcome limitations of current pharmacological treatment of insomnia disorder. Actas Esp. Psiquiatr.52, 172–182. 10.62641/aep.v52i2.1659
3
AldazP.GarjónJ.BeitiaG.BeltránI.LibreroJ.IbáñezB.et al (2021). Association between benzodiazepine use and development of dementia. Med. Clínica156, 107–111. 10.1016/j.medcli.2020.02.006
4
AlmondesK. M. D.CostaM. V.Malloy-DinizL. F.DinizB. S. (2016). Insomnia and risk of dementia in older adults: systematic review and meta-analysis. J. Psychiatric Res.77, 109–115. 10.1016/j.jpsychires.2016.02.021
5
Alvarez-FreireI.López-GuarnidoO.Cabarcos-FernándezP.Couce-SánchezM.Bermejo-BarreraA. M.Tabernero-DuqueM. J. (2023). Statistical analysis of toxicological data of victims of traffic accidents in galicia (Spain). Prev. Sci.24, 765–773. 10.1007/s11121-023-01502-8
6
AnsariS.IqbalN.AzeemA.DanyalK. (2024). Improving well-being through digital detoxification among social media users: a systematic review and meta-analysis. Cyberpsychology, Behav. Soc. Netw.27, 753–770. 10.1089/cyber.2023.0742
7
BaddamS. K. R.CanapariC. A.Van de GriftJ.McGirrC.NasserA. Y.CrowleyM. J. (2024). Screening and evaluation of sleep disturbances and sleep disorders in children and adolescents. Psychiatr. Clin.47, 65–84. 10.1016/j.chc.2020.09.005
8
BarboneF.McMahonA. D.DaveyP. G.MorrisA. D.ReidI. C.McDevittD. G.et al (1998). Association of road-traffic accidents with benzodiazepine use. Lancet352, 1331–1336. 10.1016/s0140-6736(98)04087-2
9
BarkerM. J.GreenwoodK. M.JacksonM.CroweS. F. (2004a). Cognitive effects of long-term benzodiazepine use: a meta-analysis. CNS Drugs18, 37–48. 10.2165/00023210-200418010-00004
10
BarkerM. J.GreenwoodK. M.JacksonM.CroweS. F. (2004b). Persistence of cognitive effects after withdrawal from long-term benzodiazepine use: a meta-analysis. Arch. Clin. Neuropsychol.19, 437–454. 10.1016/s0887-6177(03)00096-9
11
BaudotF.-O. (2024). Impact of benzodiazepine use on the risk of occupational accidents. PLOS ONE19, e0302205. 10.1371/journal.pone.0302205
12
Baza BuenoM.Ruiz de Velasco ArtazaE.Fernández UriaJ.Gorroñogoitia IturbeA. (2020). Benzocarta: intervención mínima para la desprescripción de benzodiacepinas en pacientes con insomnio. Gac. Sanit.34, 539–545. 10.1016/j.gaceta.2019.06.012
13
Billioti de GageS.MorideY.DucruetT.KurthT.VerdouxH.TournierM.et al (2014). Benzodiazepine use and risk of Alzheimer’s disease: case-control study. BMJ Br. Med. J.349, g5205. 10.1136/bmj.g5205
14
BlundenS.RigneyG., Lessons learned from sleep education in schools: a review of dos and don'ts. J. Clin. Sleep Med. (2015). 11671–680. 10.5664/jcsm.4782
15
BoundsC. G.PatelP. (2024). Benzodiazepines. StatPearls: Treasure Island, FL.
16
BourcierE.Korb-SavoldelliV.HejblumG.FernandezC.HindletP. (2018). A systematic review of regulatory and educational interventions to reduce the burden associated with the prescriptions of sedative-hypnotics in adults treated for sleep disorders. PLoS One13, e0191211. 10.1371/journal.pone.0191211
17
BrandtJ.BressiJ.LêM.-L.NealD.CadoganC.Witt-DoerringJ.et al (2024). Prescribing and deprescribing guidance for benzodiazepine and benzodiazepine receptor agonist use in adults with depression, anxiety, and insomnia: an international scoping review. eClinicalMedicine70, 102507. 10.1016/j.eclinm.2024.102507
18
BrandtJ.LeongC. (2017). Benzodiazepines and Z-drugs: an updated review of major adverse outcomes reported on in epidemiologic research. Drugs R&D17, 493–507. 10.1007/s40268-017-0207-7
19
BrownlowJ. A.MillerK. E.GehrmanP. R. (2020). Insomnia and cognitive performance. Sleep. Med. Clin.15, 71–76. 10.1016/j.jsmc.2019.10.002
20
BubuO. M.BrannickM.MortimerJ.Umasabor-BubuO.SebastiãoY. V.WenY.et al (2016). Sleep, cognitive impairment, and Alzheimer’s disease: a systematic review and meta-analysis. Sleep40, 40. 10.1093/sleep/zsw032
21
BumpsteadH.KovacK.FergusonS. A.VincentG. E.BachmannA.SignalL.et al (2025). How should we manage fatigue in on-call workers? A review of guidance materials and a systematic review of the evidence-base. Sleep. Med. Rev.79, 102012. 10.1016/j.smrv.2024.102012
22
By the 2023 American Geriatrics Society Beers Criteria® Update Expert Panel (2023). American Geriatrics Society 2023 updated AGS Beers Criteria® for potentially inappropriate medication use in older adults. J. Am. Geriatr. Soc.71, 2052–2081. 10.1111/jgs.18372
23
Cañellas DolsF.Ochogavia CánavesJ.Llobera CánavesJ.Palmer PolA.Castell ColomJ.Iglesias TamargoC. (1998). Sleep disorders and the consumption of hypnotics on the island of Mallorca. Rev. Clin. Esp.198, 719–725.
24
Carrasco-GarridoP.Díaz RodríguezD. R.Jiménez-TrujilloI.Hernández-BarreraV.Lima FlorencioL.Palacios-CeñaD. (2021a). Nonmedical use of benzodiazepines among immigrant and native-born adolescents in Spain: national trends and related factors. Int. J. Environ. Res. Public Health18, 1171. 10.3390/ijerph18031171
25
Carrasco-GarridoP.Jiménez-TrujilloI.Hernández-BarreraV.García-Gómez-HerasS.Alonso-FernándezN.Palacios-CeñaD. (2018). Trends in the misuse of tranquilizers, sedatives, and sleeping pills by adolescents in Spain, 2004-2014. J. Adolesc. Health63, 709–716. 10.1016/j.jadohealth.2018.04.003
26
Carrasco-GarridoP.Jiménez-TrujilloI.Hernández-BarreraV.Lima FlorencioL.Palacios-CeñaD. (2021b). Patterns of non-medical use of benzodiazepines and Z-Drugs among adolescents and young adults: gender differences and related factors. J. Subst. Use26, 190–196. 10.1080/14659891.2020.1800846
27
ChkhaidzeA.MillarB. M.RevensonT. A.MindlisI. (2024). Scrolling your sleep away: the effects of bedtime device use on sleep among young adults with poor sleep. Int. J. Behav. Med.10.1007/s12529-024-10326-x
28
ChungK.-F.ChanM.-S.LamY.-Y.LaiC. S.-Y.YeungW.-F. (2017). School-based sleep education programs for short sleep duration in adolescents: a systematic review and meta-analysis. J. Sch. Health87, 401–408. 10.1111/josh.12509
29
CraggA.HauJ. P.WooS. A.KitchenS. A.LiuC.Doyle-WatersM. M.et al (2019). Risk factors for misuse of prescribed opioids: a systematic review and meta-analysis. Ann. Emerg. Med.74, 634–646. 10.1016/j.annemergmed.2019.04.019
30
De CrescenzoF.D'AlòG. L.OstinelliE. G.CiabattiniM.Di FrancoV.WatanabeN.et al (2022). Comparative effects of pharmacological interventions for the acute and long-term management of insomnia disorder in adults: a systematic review and network meta-analysis. Lancet400, 170–184. 10.1016/S0140-6736(22)00878-9
31
de EntrambasaguasM.RomeroO.GuevaraJ. A. C.deL. A. Á. R.CañellasF.SaludJ. P.et al (2023). The prevalence of insomnia in Spain: a stepwise addition of ICSD-3 diagnostic criteria and notes. Sleep. Epidemiol.3, 100053. 10.1016/j.sleepe.2022.100053
32
de la Iglesia-LarradJ. I.BarralC.Casado-EspadaN. M.de AlarcónR.Maciá-CasasA.VicenteH. B.et al (2020). Benzodiazepine abuse, misuse, dependence, and withdrawal among schizophrenic patients: a review of the literature. Psychiatry Res.284, 112660. 10.1016/j.psychres.2019.112660
33
Del Rio VerduzcoA.SalariA.HaghparastP. (2023). Efficacy and safety of pharmacotherapy in chronic insomnia: a review of clinical guidelines and case reports. Ment. Health Clin.13, 244–254. 10.9740/mhc.2023.10.244
34
de Mendonça Maraucci RibeiroF.de Mendonça Paulo Rossi RibeiroG.Souza CostaL.Galvão PequenoL.Paiva SoaresH.de Azevedo Marques PéricoC.et al (2023). Benzodiazepines and sleep architecture: a systematic review. CNS and Neurological Disord. - Drug Targets22, 172–179. 10.2174/1871527320666210618103344
35
Díaz PlanellesI.Navarro-TapiaE.García-AlgarÓ.Andreu-FernándezV. (2023). Prevalence of potentially inappropriate prescriptions according to the new STOPP/START criteria in nursing homes: a systematic review. Healthcare11, 422. 10.3390/healthcare11030422
36
DouC.RebaneJ.BardalS. (2019). Interventions to improve benzodiazepine tapering success in the elderly: a systematic review. Aging and Ment. Health23, 411–416. 10.1080/13607863.2017.1423030
37
Dresp-LangleyB.HuttA. (2022). Digital addiction and sleep. Int. J. Environ. Res. Public Health19, 6910. 10.3390/ijerph19116910
38
EdingerJ. D.GrubberJ.UlmerC.ZervakisJ.OlsenM. (2016). A collaborative paradigm for improving management of sleep disorders in primary care: a randomized clinical trial. Sleep39, 237–247. 10.5665/sleep.5356
39
EdinoffA. N.NixC. A.HollierJ.SagreraC. E.DelacroixB. M.AbubakarT.et al (2021). Benzodiazepines: uses, dangers, and clinical considerations. Neurol. Int.13, 594–607. 10.3390/neurolint13040059
40
EllisJ.Ferini-StrambiL.García-BorregueroD.HeidbrederA.O'ReganD.ParrinoL.et al (2023). Chronic insomnia disorder across Europe: expert opinion on challenges and opportunities to improve care. Healthc. (Basel), 11. 10.3390/healthcare11050716
41
FalloonK.CamposC.NakatsujiM.MoirF.WearnA.BhoopatkarH. (2024). Sleep education for medical students: a study exploring gaps and opportunities. Sleep. Med.120, 29–33. 10.1016/j.sleep.2024.05.052
42
FernandesM.NevesI.OliveiraJ.SantosO.AguiarP.AtalaiaP.et al (2022). Discontinuation of chronic benzodiazepine use in primary care: a nonrandomized intervention. Fam. Pract.39, 241–248. 10.1093/fampra/cmab143
43
FurbishS. M. L.KroehlM. E.LoebD. F.LamH. M.LewisC. L.NelsonJ.et al (2017). A pharmacist–physician collaboration to optimize benzodiazepine use for anxiety and sleep symptom control in primary care. J. Pharm. Pract.30, 425–433. 10.1177/0897190016660435
44
GabbayF. H. W. G.GeorgM. W.GildeaS. M.KennedyC. J.KingA. J.SampsonN. A.et al (2024). Toward personalized care for insomnia in the US Army: a machine learning model to predict response to cognitive behavioral therapy for insomnia. J. Clin. Sleep. Med.20 (6), 921–931. 10.5664/jcsm.11026
45
GarbersS.AnchetaA. J.GoldM. A.MaierM.BruzzeseJ.-M.HealthyS. (2024). Sleeping healthy, living healthy: using iterative, participatory processes to develop and adapt an integrated sleep hygiene/mind-body integrative health intervention for urban adolescents. Health Promot. Pract.25, 865–875. 10.1177/15248399231184453
46
GarciaB. H.OmmaK. K.SmåbrekkeL.JohansenJ. S.SkjoldF.HalvorsenK. H. (2024). Investigating the impact of a pharmacist intervention on inappropriate prescribing practices at hospital admission and discharge in older patients: a secondary outcome analysis from a randomized controlled trial. Ther. Adv. Drug Saf.15, 20420986241299683. 10.1177/20420986241299683
47
GingerichS. B.SeaversonE. L. D.AndersonD. R. (2018). Association between sleep and productivity loss among 598 676 employees from multiple industries. Am. J. Health Promot.32, 1091–1094. 10.1177/0890117117722517
48
GlassJ.LanctôtK. L.HerrmannN.SprouleB. A.BustoU. E. (2005). Sedative hypnotics in older people with insomnia: meta-analysis of risks and benefits. Bmj331, 1169. 10.1136/bmj.38623.768588.47
49
Grau-LópezL.RonceroC.DaigreC.Rodríguez-CintasL.PallaresY.EgidoA.et al (2014). Factors related to relapse in drug-dependent patients in hospital detoxification: the relevance of insomnia. J. Sleep Disor. Treat. Care3, 3. 10.4172/2325-9639.1000138
50
GrigoriadisS.GravesL.PeerM.MamisashviliL.RuthirakuhanM.ChanP.et al (2020). Pregnancy and delivery outcomes following benzodiazepine exposure: a systematic review and meta-analysis. Can. J. Psychiatry65, 821–834. 10.1177/0706743720904860
51
GurubhagavatulaI.BargerL. K.BarnesC. M.BasnerM.BoivinD. B.DawsonD.et al (2021). Guiding principles for determining work shift duration and addressing the effects of work shift duration on performance, safety, and health: guidance from the American Academy of Sleep Medicine and the Sleep Research Society. Sleep44, zsab161. 10.1093/sleep/zsab161
52
Herrera-GómezF.Gutierrez-AbejónE.Criado-EspegelP.ÁlvarezF. J. (2018). The problem of benzodiazepine use and its extent in the driver population: a population-based registry study. Front. Pharmacol., 9. 10.3389/fphar.2018.00408
53
HertensteinE.FeigeB.GmeinerT.KienzlerC.SpiegelhalderK.JohannA.et al (2019). Insomnia as a predictor of mental disorders: a systematic review and meta-analysis. Sleep. Med. Rev.43, 96–105. 10.1016/j.smrv.2018.10.006
54
HillmanD.MitchellS.StreatfeildJ.BurnsC.BruckD.PezzulloL. (2018). The economic cost of inadequate sleep. Sleep41, 41. 10.1093/sleep/zsy083
55
HofeIvStrickerB. H.VernooijM. W.IkramM. K.IkramM. A.WoltersF. J. (2024). Benzodiazepine use in relation to long-term dementia risk and imaging markers of neurodegeneration: a population-based study. BMC Med.22, 266. 10.1186/s12916-024-03437-5
56
HolbrookA. M.CrowtherR.LotterA.ChengC.KingD. (2000). Meta-analysis of benzodiazepine use in the treatment of insomnia. Can. Med. Assoc. J.162, 225–233.
57
HuangA. A.HuangS. Y. (2023). Use of machine learning to identify risk factors for insomnia. PLoS One18, e0282622. 10.1371/journal.pone.0282622
58
HughesJ. M. (2024). Expanding access to CBT-I for older adults: review and expansion of recent recommendations. Curr. Sleep. Med. Rep.10, 93–101. 10.1007/s40675-023-00271-8
59
HuonJ.-F.NizetP.CailletP.LecompteH.Victorri-VigneauC.FournierJ.-P.et al (2023). Evaluation of the effectiveness of a joint general practitioner-pharmacist intervention on the implementation of benzodiazepine deprescribing in older adults (BESTOPH-MG trial): protocol for a cluster-randomized controlled trial. Front. Med.10, 1228883. 10.3389/fmed.2023.1228883
60
IlhanA. E.SenerB.HacihabibogluH. (2022). Improving sleep-wake behaviors using mobile app gamification. Entertain. Comput.40, 100454. 10.1016/j.entcom.2021.100454
61
IrishL. A.KlineC. E.GunnH. E.BuysseD. J.HallM. H. (2015). The role of sleep hygiene in promoting public health: a review of empirical evidence. Sleep. Med. Rev.22, 23–36. 10.1016/j.smrv.2014.10.001
62
IslamM. M.IqbalU.WaltherB.AtiqueS.DubeyN. K.NguyenP.-A.et al (2016). Benzodiazepine use and risk of dementia in the elderly population: a systematic review and meta-analysis. Neuroepidemiology47, 181–191. 10.1159/000454881
63
JobertA.LaforgueE. J.Grall-BronnecM.RousseletM.PéréM.JollietP.et al (2021). Benzodiazepine withdrawal in older people: what is the prevalence, what are the signs, and which patients?Eur. J. Clin. Pharmacol.77, 171–177. 10.1007/s00228-020-03007-7
64
JohnsonK. A.GordonC. J.ChapmanJ. L.HoyosC. M.MarshallN. S.MillerC. B.et al (2021). The association of insomnia disorder characterised by objective short sleep duration with hypertension, diabetes and body mass index: a systematic review and meta-analysis. Sleep. Med. Rev.59, 101456. 10.1016/j.smrv.2021.101456
65
KelleyP.LockleyW. S.FosterR. G.KelleyJ. (2015). Synchronizing education to adolescent biology: ‘let teens sleep, start school later’. Learn. Media Technol.40, 210–226. 10.1080/17439884.2014.942666
66
KurvitsK.ToompereK.JaansonP.UuskülaA. (2024). The COVID-19 pandemic and the use of benzodiazepines and benzodiazepine-related drugs in Estonia: an interrupted time-series analysis. Child. Adolesc. Psychiatry Ment. Health18, 66. 10.1186/s13034-024-00757-5
67
LasserreA.YounèsN.BlanchonT.Cantegreil-KallenI.PasserieuxC.ThomasG.et al (2010). Psychotropic drug use among older people in general practice: discrepancies between opinion and practice. Br. J. Gen. Pract.60, e156–e162. 10.3399/bjgp10X483922
68
LerougeL.Trujillo PonsF. (2022). Contribution to the study on the ‘right to disconnect’ from work. Are France and Spain examples for other countries and EU law?Eur. Labour Law J.13, 450–465. 10.1177/20319525221105102
69
López-PelayoH.ComaA.GualA.ZaraC.LligoñaA. (2019). Call for action: benzodiazepine prescription prevalence analysis shows off-label prescription in one in eleven citizens. Eur. Addict. Res.25, 320–329. 10.1159/000502518
70
LukačišinováA.ReissigováJ.Ortner-HadžiabdićM.BrkicJ.OkuyanB.VolmerD.et al (2024). Prevalence, country-specific prescribing patterns and determinants of benzodiazepine use in community-residing older adults in 7 European countries. BMC Geriatr.24, 240. 10.1186/s12877-024-04742-7
71
MaT.-T.WangZ.QinX.JuC.LauW. C. Y.ManK. K. C.et al (2023). Global trends in the consumption of benzodiazepines and Z-drugs in 67 countries and regions from 2008 to 2018: a sales data analysis. Sleep46, zsad124. 10.1093/sleep/zsad124
72
MacKenzieM. D.ScottH.ReidK.GardaniM. (2022). Adolescent perspectives of bedtime social media use: a qualitative systematic review and thematic synthesis. Sleep. Med. Rev.63, 101626. 10.1016/j.smrv.2022.101626
73
ManberR.CarneyC.EdingerJ.EpsteinD.FriedmanL.HaynesP. L.et al (2012). Dissemination of CBTI to the non-sleep specialist: protocol development and training issues. J. Clin. Sleep Med.08:209–218. 10.5664/jcsm.1786
74
ManberR.SimpsonN.GumportN. B. (2023). Perspectives on increasing the impact and reach of CBT-I. Sleep46, zsad168. 10.1093/sleep/zsad168
75
MarkotaM.RummansT. A.BostwickJ. M.LapidM. I. (2016). Benzodiazepine use in older adults: dangers, management, and alternative therapies. Mayo Clin. Proc.91, 1632–1639. 10.1016/j.mayocp.2016.07.024
76
Marquina-MárquezA.Olry-de-Labry-LimaA.Bermúdez-TamayoC.FerrerL. I.Marcos-MarcosJ. (2022). Identifying barriers and enablers for benzodiazepine (de)prescription: a qualitative study with patients and healthcare professionals. An Sist Sanit Navar, 45. 10.23938/assn.1005
77
MatriccianiL.ClarkeJ.WileyS.WilliamsA.BaljakG. R.GrahamK.et al (2025). Sleep of nurses: a comprehensive scoping review. J. Adv. Nurs.81, 2333–2344. 10.1111/jan.16603
78
MeaklimH.MeltzerL. J.RehmI. C.JungeM. F.MonfriesM.KennedyG. A.et al (2023). Disseminating sleep education to graduate psychology programs online: a knowledge translation study to improve the management of insomnia. Sleep46, zsad169. 10.1093/sleep/zsad169
79
MekonnenA. B.RedleyB.de CourtenB.ManiasE. (2021). Potentially inappropriate prescribing and its associations with health-related and system-related outcomes in hospitalised older adults: a systematic review and meta-analysis. Br. J. Clin. Pharmacol.87, 4150–4172. 10.1111/bcp.14870
80
MeltzerL. J.PhillipsC.MindellJ. A. (2009). Clinical psychology training in sleep and sleep disorders. J. Clin. Psychol.65, 305–318. 10.1002/jclp.20545
81
MignotE.MaylebenD.FietzeI.LegerD.ZammitG.BassettiC. L. A.et al (2022). Safety and efficacy of daridorexant in patients with insomnia disorder: results from two multicentre, randomised, double-blind, placebo-controlled, phase 3 trials. Lancet Neurology21, 125–139. 10.1016/S1474-4422(21)00436-1
82
MizrakF.DemirelH. G.YaşarO.KarakayaT. (2025). Digital detox: exploring the impact of cybersecurity fatigue on employee productivity and mental health. Discov. Ment. Health5, 25. 10.1007/s44192-025-00149-x
83
MorbioliL.LugoboniF. (2021). High-dose benzodiazepine dependence among health-care professionals: a neglected phenomenon. Med. Sci. Law61, 42–45. 10.1177/0025802420928650
84
MorinC. M.JarrinD. C. (2022). Epidemiology of insomnia: prevalence, course, risk factors, and public health burden. Sleep. Med. Clin.17, 173–191. 10.1016/j.jsmc.2022.03.003
85
NkyekyerE. W.Fulton-KehoeD.SpectorJ.FranklinG. (2018). Opioid and benzodiazepine use before injury among workers in Washington state, 2012 to 2015. J. Occup. Environ. Med.60, 820–826. 10.1097/jom.0000000000001346
86
NovakS. P.HåkanssonA.Martinez-RagaJ.ReimerJ.KrotkiK.VarugheseS. (2016). Nonmedical use of prescription drugs in the European Union. BMC Psychiatry16, 274. 10.1186/s12888-016-0909-3
87
OlsonR.CrainT. L.BodnerT. E.KingR.HammerL. B.KleinL. C.et al (2015). A workplace intervention improves sleep: results from the randomized controlled Work, Family, and Health Study. Sleep. Health1, 55–65. 10.1016/j.sleh.2014.11.003
88
OrozcoD.BasoraJ.GarcíaL.PazS.LizanL. (2013). El visado de inspección de medicamentos en España: situación actual desde la perspectiva de los profesionales sanitarios a partir de la introducción de su modalidad electrónica [Validation inspection of prescription drugs in Spain: current situation from a health professional perspective after its introduction in electronic form]. Atención Primaria45, 74–81. 10.1016/j.aprim.2012.09.002
89
Palacios-CeñaD.Jiménez-TrujilloI.Hernández-BarreraV.Lima FlorencioL.Carrasco-GarridoP. (2019). Time trends in the Co-use of cannabis and the misuse of tranquilizers, sedatives and sleeping pills among young adults in Spain between 2009 and 2015. Int. J. Environ. Res. Public Health, 16. 10.3390/ijerph16183423
90
PerellóM.Rio-AigeK.Guayta-EscoliesR.GascónP.RiusP.JambrinaA. M.et al (2021). Evaluation of medicine abuse trends in community pharmacies: the medicine abuse observatory (MAO) in a region of southern Europe. Int. J. Environ. Res. Public Health18, 7818. 10.3390/ijerph18157818
91
PerellóM.Rio-AigeK.RiusP.BagaríaG.JambrinaA. M.GironèsM.et al (2023). Changes in prescription drug abuse during the COVID-19 pandemic evidenced in the Catalan pharmacies. Front. Public Health11, 1116337. 10.3389/fpubh.2023.1116337
92
PéturssonH. (1994). The benzodiazepine withdrawal syndrome. Addiction89, 1455–1459. 10.1111/j.1360-0443.1994.tb03743.x
93
PinA. G.Soto InsugaV.Jurado LuqueM. J.FernandezG. C.Hidalgo VicarioI.Lluch RoselloA.et al (2017). Insomnio en niños y adolescentes. Documento de consenso. An. Pediatría86, 165. 10.1016/j.anpedi.2016.06.005
94
PolyT. N.IslamM. M.YangH.-C.LiY.-C. (2020). Association between benzodiazepines use and risk of hip fracture in the elderly people: a meta-analysis of observational studies. Jt. Bone Spine87, 241–249. 10.1016/j.jbspin.2019.11.003
95
RAND Europe (2023). The societal and economic burden of insomnia in adults - an international study. Available online at: https://www.rand.org/pubs/research_reports/RRA2166-1.html. (Accessed July 26, 2024).
96
RedekerN. S.CarusoC. C.HashmiS. D.MullingtonJ. M.GrandnerM. (2019). Workplace interventions to promote sleep health and an alert, healthy workforce. J. Clin. Sleep Med.15:649–657. 10.5664/jcsm.7734
97
RiemannD.EspieC. A.AltenaE.ArnardottirE. S.BaglioniC.BassettiC. L. A.et al (2023). The European Insomnia Guideline: an update on the diagnosis and treatment of insomnia 2023. J. Sleep Res.32, e14035. 10.1111/jsr.14035
98
RobbinsR.JacksonC. L.UnderwoodP.VieiraD.Jean-LouisG.BuxtonO. M. (2019). Employee sleep and workplace health promotion: a systematic review. Am. J. Health Promot.33, 1009–1019. 10.1177/0890117119841407
99
RonceroC.Bravo-GrandeJ.Remón-GalloD.Andrés-OliveraP.Payo-RodríguezC.Fernández-ParraA.et al (2025). The relevance of insomnia among healthcare workers: a post-pandemic COVID-19 analysis. J. Clin. Med.14(5), 1663. 10.3390/jcm14051663
100
RonceroC.Díaz-TrejoS.Álvarez-LamasE.García-UllánL.Bersabé-PérezM.Benito-SánchezJ. A.et al (2024). Follow-up of telemedicine mental health interventions amid COVID-19 pandemic. Sci. Rep.14, 14921. 10.1038/s41598-024-65382-w
101
RonceroC.Grau-LópezL.Díaz-MoránS.MiquelL.Martínez-LunaN.CasasM. (2012). Evaluation of sleep disorders in drug dependent inpatients. Med. Clin. Barc.138, 332–335. 10.1016/j.medcli.2011.07.015
102
RosekindM. R.GregoryK. B.MallisM. M.BrandtS. L.SealB.LernerD. (2010). The cost of poor sleep: workplace productivity loss and associated costs. J. Occup. Environ. Med.52, 91–98. 10.1097/JOM.0b013e3181c78c30
103
Ruiz-HerreraN.Díaz-RománA.Guillén-RiquelmeA.Quevedo-BlascoR. (2023). Sleep patterns during the COVID-19 lockdown in Spain. Int. J. Environ. Res. Public Health, 20. 10.3390/ijerph20064841
104
SalasR. M. E.StrowdR. E.AliI.SoniM.SchneiderL.SafdiehJ.et al (2018). Incorporating sleep medicine content into medical school through neuroscience core curricula. Neurology91:597–610. 10.1212/WNL.0000000000006239
105
Sánchez DíazM.Martín-CalvoM. L.Mateos-CamposR. (2021). Trends in the use of anxiolytics in castile and leon, Spain, between 2015–2020: evaluating the impact of COVID-19. Int. J. Environ. Res. Public Health18, 5944. 10.3390/ijerph18115944
106
Satué de VelascoE. (2014). Propuesta de un servicio de cesación benzodiazepínica en la farmacia comunitaria. Farm Comunitarios30, 23–28. 10.5672/FC.2173-9218.(2014/Vol6).001.05
107
Seda-CansuY.SeherÜ. (2022). The use of visual material on sleep hygiene in improving sleep quality in patients prior to colorectal surgery: a randomized controlled study. Turkiye Klinikleri J. Nurs. Sci.14, 1–10. 10.5336/nurses.2021-82360
108
ShiL.ChenS.-J.MaM.-Y.BaoY.-P.HanY.WangY.-M.et al (2018). Sleep disturbances increase the risk of dementia: a systematic review and meta-analysis. Sleep. Med. Rev.40, 4–16. 10.1016/j.smrv.2017.06.010
109
ShiT.MinM.SunC.ZhangY.LiangM.SunY. (2020). Does insomnia predict a high risk of cancer? A systematic review and meta-analysis of cohort studies. J. Sleep. Res.29, e12876. 10.1111/jsr.12876
110
SilvaM. T.GalvaoT. F.ChapmanE.da SilvaE. N.BarretoJ. O. M. (2021). Dissemination interventions to improve healthcare workers’ adherence with infection prevention and control guidelines: a systematic review and meta-analysis. Implement. Sci.16, 92. 10.1186/s13012-021-01164-6
111
Simal-AguadoJ.Campos-NavarroM. P.Valdivia-MuñozF.Galindo-TovarA.García-CarmonaJ. A. (2021). Evaluation of risk factors associated to prescription of benzodiazepines and its patterns in a cohort of patients from mental health: a real world study in Spain. Psychopharmacol. Bull.51, 81–93.
112
SirdifieldC.AnthierensS.CreupelandtH.ChipchaseS. Y.ChristiaensT.SiriwardenaA. N. (2013). General practitioners’ experiences and perceptions of benzodiazepine prescribing: systematic review and meta-synthesis. BMC Fam. Pract.14, 191. 10.1186/1471-2296-14-191
113
SminkB. E.EgbertsA. C. G.LusthofK. J.UgesD. R. A.de GierJ. J. (2010). The relationship between benzodiazepine use and traffic accidents: a systematic literature review. CNS Drugs24, 639–653. 10.2165/11533170-000000000-00000
114
SofiF.CesariF.CasiniA.MacchiC.AbbateR.GensiniG. F. (2014). Insomnia and risk of cardiovascular disease: a meta-analysis. Eur. J. Prev. Cardiol.21, 57–64. 10.1177/2047487312460020
115
SoniA.ThiyagarajanA.ReeveJ. (2023). Feasibility and effectiveness of deprescribing benzodiazepines and Z-drugs: systematic review and meta-analysis. Addiction118, 7–16. 10.1111/add.15997
116
SoykaM.WildI.CauletB.LeontiouC.LugoboniF.HajakG. (2023). Long-term use of benzodiazepines in chronic insomnia: a European perspective. Front. Psychiatry14, 1212028. 10.3389/fpsyt.2023.1212028
117
Spanish Agency of Medicines and Medical Devices (2000). Circular 3/2000. Available online at: https://www.aemps.gob.es/informa/circulares/medicamentosusohumano/seguridad-5/2000/circular-3-2000/# (Accesssed July 30, 2024).
118
Spanish Agency of Medicines and Medical Devices (2024). Use of anxiolytics and hypnotics in Spain. Available online at: https://www.aemps.gob.es/medicamentos-de-uso-humano/observatorio-de-uso-de-medicamentos/informes-ansioliticos-hipnoticos/ (Accessed July 30, 2024).
119
Spanish Ministry of Health (2023a). Survey on drug use in secondary education in Spain (ETUDES) 1994-2023. Available online at: https://pnsd.sanidad.gob.es/profesionales/sistemasInformacion/sistemaInformacion/pdf/ESTUDES_2023_Informe.pdf.
120
Spanish Ministry of Health (2023b). Facts and figures on benzodiazepines and other benzodiazepines anxiolytics and hypnosedatives. Available online at: https://pnsd.sanidad.gob.es/noticiasEventos/agoraDGPNSD/2023/Agora16/231010_XVI_AGORA_Cristina_Teruel.pdf (Accesssed August 1, 2024).
121
StewartN. H.AroraV. M. (2019). The impact of sleep and circadian disorders on physician burnout. Chest156, 1022–1030. 10.1016/j.chest.2019.07.008
122
SunG.-Q.ZhangL.ZhangL.-N.WuZ.HuD.-F. (2019). Benzodiazepines or related drugs and risk of pneumonia: a systematic review and meta-analysis. Int. J. Geriatric Psychiatry34, 513–521. 10.1002/gps.5048
123
SzermanN.TorrensM.MaldonadoR.BalharaY. P. S.SalomC.MaremmaniI.et al (2022). Addictive and other mental disorders: a call for a standardized definition of dual disorders. Transl. Psychiatry12, 446. 10.1038/s41398-022-02212-5
124
TannenbaumC.MartinP.TamblynR.BenedettiA.AhmedS. (2014). Reduction of inappropriate benzodiazepine prescriptions among older adults through direct patient education: the EMPOWER cluster randomized trial. JAMA Intern. Med.174, 890–898. 10.1001/jamainternmed.2014.949
125
TomasoneJ. R.KauffeldtK. D.ChaudharyR.BrouwersM. C. (2020). Effectiveness of guideline dissemination and implementation strategies on health care professionals’ behaviour and patient outcomes in the cancer care context: a systematic review. Implement. Sci.15, 41. 10.1186/s13012-020-0971-6
126
Torrens DarderI.Argüelles-VázquezR.Lorente-MontalvoP.Torrens-DarderM. D. M.EstevaM. (2021). Primary care is the frontline for help-seeking insomnia patients. Eur. J. Gen. Pract.27, 286–293. 10.1080/13814788.2021.1960308
127
Torres-BondiaF.de BatlleJ.GalvánL.ButiM.BarbéF.Piñol-RipollG. (2020). Trends in the consumption rates of benzodiazepines and benzodiazepine-related drugs in the health region of Lleida from 2002 to 2015. BMC Public Health20, 818. 10.1186/s12889-020-08984-z
128
TrépelD.AliS.GilbodyS.LeivaA.McMillanD.BejaranoF.et al (2020). Cost-effectiveness of brief structured interventions to discontinue long-term benzodiazepine use: an economic analysis alongside a randomised controlled trial. HRB Open Res.3, 33. 10.12688/hrbopenres.13049.1
129
TrockelM. T.MenonN. K.RoweS. G.StewartM. T.SmithR.LuM.et al (2020). Assessment of physician sleep and wellness, burnout, and clinically significant medical errors. JAMA Netw. Open3, e2028111. 10.1001/jamanetworkopen.2020.28111
130
TsengL. Y.HuangS. T.PengL. N.ChenL. K.HsiaoF. Y.BenzodiazepinesZ.-H. (2020). Benzodiazepines, z-hypnotics, and risk of dementia: special considerations of half-lives and concomitant use. Neurotherapeutics17, 156–164. 10.1007/s13311-019-00801-9
131
UrruS. A.PasinaL.MinghettiP.GiuaC. (2015). Role of community pharmacists in the detection of potentially inappropriate benzodiazepines prescriptions for insomnia. Int. J. Clin. Pharm.37, 1004–1008. 10.1007/s11096-015-0166-4
132
US Food and Drug Administration (2024). US Food and Drug Administration FDA Drug Safety Communication: FDA warns about serious risks and death when combining opioid pain or cough medicines with benzodiazepines; requires its strongest warning. Available online at: https://www.fda.gov/drugs/information-drug-class/new-safety-measures-announced-opioid-analgesics-prescription-opioid-cough-products-and (Accessed July 26, 2024).
133
ValenzuelaP. L.Santos-LozanoA.Torres-BarránA.MoralesJ. S.Castillo-GarcíaA.RuilopeL. M.et al (2022). Poor self-reported sleep is associated with risk factors for cardiovascular disease: a cross-sectional analysis in half a million adults. Eur. J. Clin. Investigation52, e13738. 10.1111/eci.13738
134
Vázquez CanalesL. M.Frutos FernándezM. (2023). La prevención cuaternaria en el uso de benzodiacepinas y cómo deprescribirlas. Atención Primaria Práctica5, 100183. 10.1016/j.appr.2023.100183
135
VicensC.BejaranoF.SempereE.MateuC.FiolF.SociasI.et al (2014). Comparative efficacy of two interventions to discontinue long-term benzodiazepine use: cluster randomised controlled trial in primary care. Br. J. Psychiatry204, 471–479. 10.1192/bjp.bp.113.134650
136
VotawV. R.GeyerR.RieselbachM. M.McHughR. K. (2019). The epidemiology of benzodiazepine misuse: a systematic review. Drug Alcohol Depend.200, 95–114. 10.1016/j.drugalcdep.2019.02.033
137
WakefieldM. A.LokenB.HornikR. C. (2010). Use of mass media campaigns to change health behaviour. Lancet376, 1261–1271. 10.1016/s0140-6736(10)60809-4
138
WappelS. R.ScharfS. M.CohenL.CollenJ. F.RobertsonB. D.WickwireE. M.et al (2021). Improving sleep medicine education among health professions trainees. J. Clin. Sleep Med.172461–2466. 10.5664/jcsm.9456
139
WhitingC.BellaertN.DeveneyC.TsengW. L. (2023). Associations between sleep quality and irritability: testing the mediating role of emotion regulation. Pers. Individ. Dif.213, 112322. 10.1016/j.paid.2023.112322
140
WinkelmanJ. W. (2020). How to identify and fix sleep problems: better sleep, better mental health. JAMA Psychiatry77, 99–100. 10.1001/jamapsychiatry.2019.3832
141
WuT. T.ZouY. L.XuK. D.JiangX. R.ZhouM. M.ZhangS. B.et al (2023). Insomnia and multiple health outcomes: umbrella review of meta-analyses of prospective cohort studies. Public Health215, 66–74. 10.1016/j.puhe.2022.11.021
142
XuS.FaustO.SeoniS.ChakrabortyS.BaruaP. D.LohH. W.et al (2022). A review of automated sleep disorder detection. Comput. Biol. Med.150, 106100. 10.1016/j.compbiomed.2022.106100
143
ZakiN.BrakouliasV. (2022). The impact of COVID-19 on benzodiazepine usage in psychiatric inpatient units. Australas. Psychiatry30, 334–337. 10.1177/10398562211059090
144
ZamoranoS.Sáez-AlonsoM.González-SanguinoC.MuñozM. (2023). Social stigma towards mental health problems in Spain: a systematic review. Clínica Salud34 (1), 23–34. 10.5093/clysa2023a5
145
ZhangS. X.ChenR. Z.XuW.YinA.DongR. K.ChenB. Z.et al (2022). A systematic review and meta-analysis of symptoms of anxiety, depression, and insomnia in Spain in the COVID-19 crisis. Int. J. Environ. Res. Public Health19, 1018. 10.3390/ijerph19021018
146
ZhengB.YuC.LvJ.GuoY.BianZ.ZhouM.et al (2019). Insomnia symptoms and risk of cardiovascular diseases among 0.5 million adults: a 10-year cohort. Neurology93, e2110–e2120. 10.1212/wnl.0000000000008581
147
ZhouY.JinY.ZhuY.FangW.DaiX.LimC.et al (2023). Sleep problems associate with multimorbidity: a systematic review and meta-analysis. Public Health Rev.44, 1605469. 10.3389/phrs.2023.1605469
Summary
Keywords
sleep, insomnia, benzodiazepines, abuse, responsible use, overuse, misuse
Citation
Roncero C, Armenteros L, Bellido-Cambrón C, Bonilla-Guijarro A and Gómez-Cibeira E (2025) Benzodiazepine use in Spain: risks and perspectives on the current situation and proposals for their rational use. Front. Pharmacol. 16:1547488. doi: 10.3389/fphar.2025.1547488
Received
18 December 2024
Accepted
07 May 2025
Published
20 May 2025
Volume
16 - 2025
Edited by
Donna Platt, University of Mississippi Medical Center, United States
Reviewed by
James K. Rowlett, University of Mississippi Medical Center, United States
Updates
Copyright
© 2025 Roncero, Armenteros, Bellido-Cambrón, Bonilla-Guijarro and Gómez-Cibeira.
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*Correspondence: Carlos Roncero, drcarlosroncero@mail.com
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