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. 2020 Sep 11;15(9):e0238723. doi: 10.1371/journal.pone.0238723

Non-GABA sleep medications, suvorexant as risk factors for falls: Case-control and case-crossover study

Yoshiki Ishibashi 1,2,*,#, Rie Nishitani 2,*,#, Akiyoshi Shimura 3,4, Ayano Takeuchi 2, Mamoru Touko 2, Takashi Kato 5, Sahoko Chiba 2, Keiko Ashidate 2, Nobuo Ishiwata 2, Tomoyasu Ichijo 2, Masataka Sasabe 2
Editor: Amir Radfar6
PMCID: PMC7486134  PMID: 32916693

Abstract

The aim of this study was to examine the risk of falls associated with the use of non-gamma amino butyric acid (GABA) sleep medications, suvorexant and ramelteon. This case-control and case-crossover study was performed at the Kudanzaka Hospital, Chiyoda Ward, Tokyo. A total of 325 patients who had falls and 1295 controls matched by sex and age were included. The inclusion criteria for the case group were hospitalized patients who had their first fall and that for the control were patients who were hospitalized and did not have a fall, between January 2016 and November 2018. The internal sleep medications administered were classified as suvorexant, ramelteon, non-benzodiazepines, benzodiazepines, or kampo. In the case-control study, age, sex, clinical department, the fall down risk score, and hospitalized duration were adjusted in the logistic regression model. In the case-control study, multivariable logistic regression showed that the use of suvorexant (odds ratio [OR]: 2.61, 95% confidence interval [CI]: 1.29–5.28), nonbenzodiazepines (OR: 2.49, 95% CI: 1.73–3.59), and benzodiazepines (OR: 1.65, 95% CI: 1.16–2.34) was significantly associated with an increased OR of falls. However, the use of ramelteon (OR: 1.40, 95% CI: 0.60–3.16) and kampo (OR: 1.55, 95% CI: 0.75–3.19) was not significantly associated with an increased OR of falls. In the case-crossover study, the use of suvorexant (OR: 1.78, 95% CI: 1.05–3.00) and nonbenzodiazepines (OR: 1.63, 95% CI: 1.17–2.27) was significantly associated with an increased OR of falls. Similar patterns were observed in several sensitivity analyses. It was suggested that suvorexant increases the OR of falls. This result is robust in various analyses. This study showed that the risk of falls also exists for non-GABA sleep medication, suvorexant, and thus it is necessary to carefully prescribe hypnotic drugs under appropriate assessment.

Introduction

Falls are a major cause of fractures and accidents and are also associated with reduced activities of daily living (ADL) in elderly people [1–3]. It has been reported that over 70% of hip fractures are caused by falls [1] and some fractures occur in approximately 5–10% of all falls. Hip fractures occur in 1–2% cases of falls [2]. Furthermore, even if patients do not get injured, repeated falling is associated with reduced ADL [3]. When viewed from the perspective of hospital management, 70% of hospital accidents are caused by falls, and therefore prevention of falls is an important issue [4].

Oral intake of sleep medications is a major risk factor for falls. For example, a systematic review found that the use of four or more internal medicines was associated with about 1.7–2.7 times increased risk of falls in the elderly [5]. Particularly, sedatives or hypnotics are the most strongly linked to increased risk of falls among oral medications, and it is suggested that there is an increased risk of falls in internal medicine patients with one or more sedatives or hypnotics [5]. In the past, non-benzodiazepines were not considered to be associated with an increased risk of falls and fractures [6]. In recent years, however, several studies have shown that the risk of falls and fractures associated with non-benzodiazepines intake has increased similarly to that of benzodiazepines and it is apparent that the risk associated with non-benzodiazepines intake is higher compared to benzodiazepines [7, 8]. In a previous study, the prevalence of insomnia was 8–18% in the general population, and the prevalence of insomnia symptoms generally increased with age [9]. Many people with insomnia use sleep medications [10, 11]. There appears to be a trade-off here. Though the elderly are at a high risk of falling due to lack of focus of attention, muscle weakness, and sensory deficits [12], at the same time the prevalence of insomnia also increases [9, 11].

Since the mechanism of the orexin receptor antagonist is different from that of existing sleep medications, suvorexant has been studied as an option for insomnia [13–15]. In randomized control trials (RCTs), suvorexant has not been found to be associated with an increased risk of falls and fractures [16–19]. However, there are no studies that have investigated falls as a main outcome, and in previous research, fall cases were very few in the intervention group and the non-intervention group [15–19]. In addition, research on side effects of suvorexant, including falls and fractures are few [20], so the fact that only results of pre-approved clinical trials are available makes it difficult to estimate the cost-effectiveness of suvorexant [21]. Ramelteon, a melatonin receptor agonist, is increasingly being used in the United States and Japan and has become one of the options for treating insomnia [20]. Nonetheless, there are few reports investigating the risk of falls associated with the use of ramelteon [22]. A study that evaluated the standing balance after oral administration of ramelteon found no adverse effect on balance [23]. However, to our knowledge, there are no real clinical reports that have reviewed falls associated with ramelteon [24, 25]. Suvorexant and ramelteon are non-gamma amino butyric acid (GABA) receptor agonist sleep medications, so they are considered to have little muscle relaxant action and little risk for falls [24–26]. However, the half-life of suvorexant is longer than previous medications like zolpidem [14, 27], and some studies have showed that suvorexant and ramelteon have carry-over effects [14, 23]. Regardless, the risk of falling associated with suvorexant and ramelteon is unclear. Thus, the aim of this study was to examine the risk of falls associated with the use of non-GABA receptor agonist sleep medications. We hypothesized that the use of suvorexant and ramelteon would be associated with increased risk of fall.

Methods

Target population, study design, and strategy for matching

Retrospective case-control and case-crossover studies were conducted at the Kudanzaka Hospital (231 beds) in Chiyoda-ward, Tokyo. The inclusion criteria for the case group were hospitalized patients who had their first fall between January 2016 and November 2018. Second or subsequent falls after hospitalization or outpatient falls were excluded. The clinical departments of Kudanzaka hospital were orthopedic surgery, internal medicine, general surgery, rehabilitation department, psychosomatic medicine, gynecology, urology, and dermatology. Inclusion criteria for the control group were patients who were hospitalized between January 2016 and November 2018 and had not fallen. Control group data were collected from 9,111 patients, and controls were randomly matched, based on age (plus or minus 3 years) and sex with a ratio of case:control = 1:4 (Fig 1). Source population in this study is the group who did not fall but was hospitalized in Kudanzaka hospital; so, we sampled the control from the group randomly [28]. In previous studies, matching was performed using gender and age [29, 30], and to reduce overmatching and bias, this study matched only with gender and age [31, 32]. We confirmed the robustness of the result in the case-crossover analysis to eliminate the risk that the matching is overmatching or limited and to reduce the bias of control selection [33].

Fig 1. Design of case-control study.

Fig 1

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Data collection and definition in the case-control and case-crossover study

Falls

The fall of a patient was defined as the incident in which the body of a patient suddenly or unintentionally hits the ground or another location. Falls in hospitals were registered in incident reports submitted by nurses who found the fallen patients. Incident reports included the department, age of the patient, sex, date and time of the fall, and location. Incident reports were checked by the group leader, and two researchers confirmed the incident via checking the electronic medical records.

Sleep medications

The internal sleep medications administered were classified as suvorexant, ramelteon, non-benzodiazepines, benzodiazepines, or the oriental medicine (called kampo, Yokukansan, or Yi-gan san). Kampo is a traditional and popular herbal drug in Japan and yokukansan is a kind of kampo [34]. Although, there is little medical evidence of its efficacy for insomnia, yokukansan is widely used in Japan [35, 36]. We analyzed these medications as exposure for falls. Adjustment for each medication was performed for patients taking multiple sleep medications, and the risk of fall was analyzed. The medications of the patients were extracted from the electronic medical record.

Other variables

The fall down risk score (it consists of 8 items namely age, medical history, vision or hearing impairment, motor dysfunction, activity, cognitive ability, medication, and excretion and was evaluated at 39 points as full score with 16 points or more considered as high risk of falls) [37, 38] (S1 Table). The fall down risk score was evaluated by nurses at hospitalized day and in every week. Hospitalized duration was defined as the date from hospitalization and discharge. The department of hospitalization, hospitalization duration, the fall down risk score, age, and sex were extracted from the electronic medical record.

Variable measurement date in the case-control and case-crossover study

In the case and control groups, the department was collected at hospitalized day, and hospitalization duration was recorded at discharge date. In the case group, we collected data of internal medicine measured on falling date, and the nearest fall down risk score before falls was collected. In the control group, since there were reports that falls tend to occur in approximately 1 week after hospitalization [39, 40], oral medications used within 1 week after hospitalization were investigated and the score of 1 week after hospitalization was collected. In the case-crossover study, internal medications of hospitalization and that of the middle date between hospitalization and falling were measured as an exposure of controls, and internal medications at falling was measured as an exposure of cases (S1 Fig). We summarized the variable information in the case-control and case-crossover study in the S2 Table.

Ethical review

This study was approved by the Kudanzaka Hospital Ethics Committee. This research is part of a hospital-based quality improvement project, and data were dealt anonymously. The need for written informed consent from patients was waived because this study was conducted as part of a hospital-based quality improvement project and posed no risk to patients or their privacy.

Statistical analysis

Sample size was calculated statistically, we needed approximately 1,000 patients at a significant level = 0.05, power = 0.9. For sensitivity analysis and case-crossover study, we collected data for more than 1,000 patients. Age, hospitalized duration, and the fall down risk score were analyzed as quantitative variables. Other data were analyzed as categorical variables. We conducted a complete-case analysis, so those with missing data were not included in the analysis. In the case-control study, age, sex, clinical department, the fall down risk score, and hospitalized duration were adjusted. In the case-crossover study, age, sex, clinical department, and the fall down risk score were adjusted. The association between sleep medications usage and falls was assessed by conditional logistic regression analysis using odds ratio (OR) and 95% confidence interval (CI).

In the case-control study, there were four analyses for sensitivity analysis. Firstly, since previous studies have shown a high risk of falls in orthopedic patients and those with musculoskeletal problems [5, 41, 42], an analysis excluding orthopedic surgery was conducted. Secondly, to eliminate the influence of multiple oral medications or long hospitalized duration, we excluded patients using multiple sleep medications or had long hospitalization. Thirdly, evaluating the onset of action of benzodiazepines, analysis of benzodiazepines by separating them into long-acting type and short-acting type was carried out. Lastly, considering dose response, the analysis of the fall OR of non-benzodiazepines and benzodiazepines was conducted in the case-control study. We could not conduct the dose response analysis of suvorexant and ramelteon because the adoption of suvorexant in Kudanzaka Hospital was only 15 mg tablets and that of ramelteon was only 8 mg. All patients who were prescribed suvorexant and ramelteon were prescribed those of 15 mg and 8 mg. For multivariate analysis, the models considered the multicollinearity with the variance inflation factor of which the cutoff was 2.5. Statistical analysis was performed with R (http://www.r-project.org/) version 3.4.2. We conducted a two-sided test, and the analysis was at α level 0.05.

Results

Case-control and case-crossover study

There were 455 cases of falls at the Kudanzaka Hospital during the period of study (Fig 1). We excluded nine cases that occurred at outpatient service and 121 cases that occurred after the second time of falls, and 325 patients were assigned as cases of study. Of the 325 patients, 181 (55.7%) were taking sleep medications. Of the 1,295 patients who matched on age and sex, 416 (32.1%) were taking sleep medications and were selected as controls. Two patients, a 100-year-old male and a 102-year-old male, could not be matched to four controls (we chose two and one patients for controls corresponding to these cases).

Details of internal medicine and the number of patients who took sleep medications are shown in Table 1. Non-benzodiazepine medications included zolpidem, eszopiclone, and zopiclone. Benzodiazepine medications included triazolam, etizolam, brotizolam, rilmazafone, alprazolam, lorazepam, quazepam, flutoprazepam, clotiazepam, diazepam, flunitrazepam, nitrazepam, clonazepam, and lormetazepam. Across all sleep medications, the percentage of patients taking a medication was higher in the case group compared to the control group (p<0.001). Table 2 shows the measured background factors of the patients. Significant difference (p<0.001) was observed between the case group and the control group in terms of medical departments (except for general surgery and other departments), hospitalized duration, and the fall risk score. Therefore, the department of medical treatment, hospitalization duration, and the fall risk score were included in the multivariate analysis in the case-control study. Table 3 shows the result of conditional logistic regression analysis for falls. All variables were significant in univariate regression results. When the Bonferroni correction was performed in consideration of the multiple tests, almost the same result as the multivariate regression analysis was obtained. In the multivariate regression analysis, the use of suvorexant (OR: 2.61, 95% CI: 1.29–5.28), non-benzodiazepines (OR: 2.49, 95% CI: 1.73–3.59), and benzodiazepines (OR: 1.65, 95% CI: 1.16–2.34) was significantly associated with an increased OR of falls. However, the use of ramelteon (OR: 1.40, 95% CI: 0.60–3.16) and kampo (OR: 1.55, 95% CI: 0.75–3.19) was not significantly associated with an increased OR of falls. Table 4 shows the results of the case-crossover analysis, which showed that in the multivariate regression analysis, the use of suvorexant (OR: 1.78, 95% CI: 1.05–3.00) and non-benzodiazepines (OR: 1.63, 95% CI: 1.17–2.27) was significantly associated with an increased OR of falls. The use of ramelteon (OR: 1.19, 95% CI: 0.55–2.46), benzodiazepines (OR: 1.09, 95% CI: 0.79–1.50), and kampo (OR: 1.46, 95% CI: 0.75–2.68) was not significantly associated with an increased OR of falls.

Table 1. Medication prescribed to cases and controls.

Medication Cases n (%) controls n (%) P value
Suvorexant 30 (9.2) 20 (1.5) <0.001
Ramelteon 13 (4.0) 22 (1.7) 0.017
Non-benzodiazepines 84 (25.8) 151 (11.6) <0.001
Benzodiazepines 96 (29.5) 255 (19.7) <0.001
Kampo (yokukansan) 21 (6.5) 26 (2.0) <0.001
No sleep medication prescribed 144 (44.3) 879 (67.9) <0.001
Total patients 325 1295
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Non-benzodiazepines include: Zolpidem, Eszopiclone, Zopiclone.

Benzodiazepines include: Triazolam, Etizolam, Brotizolam, Rilmazafone, Alprazolam, Lorazepam, Quazepam, Flutoprazepam, Clotiazepam, Diazepam, Flunitrazepam, Nitrazepam, Clonazepam, Lormetazepam.

Variables are analyzed by Fisher's exact probability test.

Table 2. Patient background variables.

Characteristics Case group Control group P value
Age, mean (±SD) 76.7 (±12.0) 76.1 (±11.7) 0.391
Sex n (%) (male) 155 (47.7) 615 (47.5%) 0.951
Department
Orthopaedic surgery n (%) 199 (61.2) 649 (50.1) <0.001
Internal medicine n (%) 59 (18.2) 414 (32.0) <0.001
General surgery n (%) 21 (6.5) 123 (9.5) 0.101
Rehabilitation n (%) 40 (12.3) 62 (4.8) <0.001
Others(Gynecology, Urology, Dermatology, Psychology) n (%) 6 (1.8) 47 (3.6) 0.118
Hospitalized duration mean (SD) (day) 70.1 (63.5) 21.0 (27.9) <0.001
Fall down risk score mean (SD) (point) 15.7 (4.18) 11.3 (5.6) <0.001
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Continuous variables are analysed by student's t-test.

Percentage variables are analyzed by Fisher's exact probability test.

SD: standard deviation.

Table 3. Logistic regression model for sleep medications and covariances.

Univariate analysis for fall OR (95%CI, P value) Multivariate analysis for fall OR (95%CI, P value)
Sleep medications use
Suvorexant 6.48 (3.66–11.7, <0.001) 2.61 (1.29–5.29, 0.008)
Ramelteon 2.41 (1.17–4.78, 0.013) 1.40 (0.60–3.16, 0.429)
Non-benzodiazepines 2.64 (1.95–3.56, <0.001) 2.49 (1.73–3.59, <0.001)
Benzodiazepines 1.71 (1.30–2.25, <0.001) 1.65 (1.16–2.34, 0.005)
Kampo (yokukansan) 3.37 (1.85–6.06, <0.001) 1.55 (0.75–3.19, 0.233)
Department
Orthopaedic surgery (Reference)
Internal medicine 0.46 (0.34–0.63, <0.001) 1.19 (0.81–1.77, 0.367)
General surgery 0.56 (0.33–0.89, 0.019) 1.75 (0.93–3.17, 0.074)
Rehabilitation 2.10 (1.36–3.21, <0.001) 1.20 (0.69–2.06, 0.510)
Others(Gynecology, Urology, Dermatology, Psychology) 0.42 (0.16–0.92, 0.047) 1.42 (0.48–3.52, 0.481)
Hospitalized duration (per 1day) 1.031 (1.027–1.035, <0.001) 1.024 (1.020–1.029, <0.001)
Fall down risk score (per 1point) 1.18 (1.15–1.21, <0.001) 1.15 (1.11–1.19, <0.001)
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Multiple logistic regression adjusted age, sex, all sleep medications, department, hospitalized duration, fall down risk score.

OR: odds ratio, CI: confidence interval.

Table 4. Case-crossover analysis.

Univariate analysis for fall OR (95%CI, P value) Multivariate analysis for fall OR (95%CI, P value)
Suvorexant 1.84 (1.10–3.07, 0.019) 1.78 (1.05–3.00, 0.031)
Ramelteon 1.14 (0.54–2.33, 0.707) 1.19 (0.55–2.46, 0.640)
Non-benzodiazepines 1.60 (1.16–2.20, 0.004) 1.63 (1.17–2.27, 0.004)
Benzodiazepines 1.13 (0.84–1.51, 0.419) 1.09 (0.79–1.50, 0.585)
Kampo (yokukansan) 1.55 (0.83–2.85, 0.159) 1.46 (0.75–2.68, 0.277)
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Multiple logistic regression adjusted age, sex, hospitalized department, the fall down risk score and all sleep medications.

OR: odds ratio, CI: confidence interval.

Sensitivity analysis

The results of the sensitivity analysis are shown in S3–S5 Tables. In the analysis excluding orthopedic surgery data, consistency of the results was maintained, and an increased OR of falls was observed for suvorexant (OR: 5.43, 95% CI: 1.59–20.1) and non-benzodiazepines (OR: 1.81, 95% CI: 0.92–3.45) (S3 Table). In order to eliminate the influence of multiple oral medications, patients using multiple sleep medications were excluded and there was also an increased OR of falls for suvorexant (OR: 2.48, 95% CI: 0.87–6.85), non-benzodiazepines (OR: 2.32, 95% CI: 1.44–3.70), and benzodiazepines (OR: 1.62, 95% CI: 1.05–2.47) intake (S4 Table). The analysis was performed excluding those whose length of hospital stay was above the median (S5 Table). An increase in the OR of falls was observed for suvorexant (OR: 9.09, 95% CI: 1.05–65.6) and non-benzodiazepines (OR: 2.34, 95% CI: 0.91–5.51). Ramelteon and Kampo could not be analyzed because the data were too sparse. However, the consistency of the results was maintained. The analysis in which benzodiazepines were divided into short-acting type and long-acting type is shown in S6 Table. Based on the adjusted analysis, there was an increased OR for falls for long-acting benzodiazepines (OR: 2.17, 95% CI: 1.30–3.57). Considering dose of medications, the consistency of the results was maintained (S7 Table). The multicollinearity test was performed, and the results are presented in S8 Table.

Discussion

Summary of results and differences in results from previous studies: Risk of falls with non-GABA medications

In the case-control study, the OR of falls was significantly higher in patients who used suvorexant, non-benzodiazepines, and benzodiazepines. The use of ramelteon and kampo was not associated with the significantly increased OR of falls. In the case-crossover study, the significance of benzodiazepines disappeared, but similar results were observed elsewhere. Benzodiazepines and non-benzodiazepines have a muscle relaxant action, for which the α1–3 subunits of the GABA receptor [43, 44] are responsible, and even in previous studies, an increased risk of falls has been shown [6–8].

Suvorexant is a sleep drug released in Japan and the United States in 2014 and has a new mechanism, blocking the orexin receptor that controls arousal [13, 15, 45]. Since it does not act on GABA but acts selectively on the orexin system, it is considered not to have a muscle relaxant action or carry-over effect [26]. In some studies, its association with the risk of adverse events such as falls and fractures was negative [16–19]. However, in this study, an increase in the OR of falls was observed. In previous RCTs [17–19], it was difficult to statistically analyze for falls because the number of patients with falls was extremely small. The study that recorded most falls compared 12 (2.3%) and 8 (3.1%) falls [17], and it is necessary to collect falling patients and to design the case-control study for rare events such as falls. There is a possibility that risk determination is affected by the fact that the average age of the samples in this study is older (case group, mean age: 76.7 years), and the proportion of patients with orthopedic surgery is large. However, because the results did not change even in the analysis excluding orthopedic surgery, influence by the medical department is not anticipated. Analysis focused on elderly people has not been conducted in previous studies, and the risk of falls may be selectively high in elderly people. Clinical trials are performed for outpatients who have insomnia, but this study was performed in hospital settings and patients with comorbidities other than insomnia (no patients hospitalized for insomnia) were the subjects. For hospitalized patients, the risk of falls may be higher than that in outpatients. As far as we know, no research for suvorexant has been conducted on hard outcomes such as hip fracture, and further studies are needed. From the perspective of pharmacology, the reason falls are increased with suvorexant may be due to the half-life of the drug in the blood, which is about 9–13 hours [14]. Additionally, to maintain attention, the cholinergic system centered on the forebrain base plays an important role, and the orexin neural system interacts with it [46, 47]. Inhibition of the orexin receptor may reduce attention, and thus the orexin receptor antagonist, suvorexant, may increase the risk of falls by impairing attention [46]. In the elderly, orexin receptor and cholinergic neuron actions decrease, which may further increase the risk of falls [47]. S9 Table shows when patients fell in the case group. Patients who were prescribed suvorexant did not fall more at night than at daytime. There might be some residual sedation and carry over in the pharmacology of suvorexant [14].

Ramelteon is a melatonin receptor agonist, and it is increasingly being used by medical doctors [20, 22]. This case-control study did not show an increased OR for falls with the use of ramelteon. A similar result was obtained with the case-crossover analysis. Ramelteon might be less sedating, and previous studies have found less sedative adverse effects [23]; similar results were obtained in this study. Because melatonin stimulates daytime arousal and nighttime sleep [48, 49], it might not have raised the risk of falls. The result of this study, which was not significant, however, does not indicate the absence of risk [50]; therefore, attention must be paid to adverse effects such as falls. It is necessary to accumulate further research.

In insomnia guidelines, it is generally recommended to first consider cognitive-behavioral-therapy and psychological behavioral interventions and then consider hypnotic formulation [51, 52]. It is suggested that the risk of falls also exists for the non-GABA sleep medications as per the results in this study, and thus it is necessary to carefully prescribe hypnotic drugs under appropriate assessment.

Evaluation of bias by sensitivity analysis and limitation of this research

In hospital studies, it is common that people with low severity are selected as controls, and the OR may be overestimated. Even in the case-crossover study, the same result as the case-control study indicates that bias by control selection is adjusted and the result is robust [33]. In the multivariate analysis, even if the fall risk score or hospitalized duration was added, the result did not change, and among those who are considered to have the same possibility of falls, the influence of sleep medications remained. Furthermore, conditional logistic regression analysis excluding patients taking two or more kinds of sleep medications was similar, and it was considered that the effect of multiple sleep medications could also be eliminated.

There are several limitations in this research. First, we did not consider if patients were taking other medications, which have an increased risk of falls. This could be the bias of the result for this study. Second, it was impossible to evaluate the state of sleep and comorbidities in individuals. It cannot be denied that people with insomnia or chronic disease (like chronic obstructive pulmonary disease and obstructive sleep apnea) often take sleep medications and fall. However, most of the bias due to each patient's condition is controlled in a case-crossover study because the status of patients who have some chronic diseases is the same in the case-crossover comparison and the hospitalized duration. In future, a more planned prospective study is needed. We plan to conduct a validation study using instrumental variables to control potential confounders in this study. Third, this study might suffer from Berkson's bias due to recruitment from the hospitalized patients. Finally, the measurement and documentation of falls may not be entirely accurate and may be a limiting factor in this study.

In conclusion, sleep medications are associated with an increased OR of falls. This result is robust in various analyses, case-crossover studies, and sensitivity analyses. In this study, it was found that suvorexant was associated with an increased OR of falls. Although ramelteon was not associated with an increased OR of falls, further evaluation of its effect on the risk of falls and fractures in the future are needed. This study showed that the risk of falls also exists for non-GABA sleep medications, and thus it is necessary to carefully prescribe hypnotic drugs under appropriate assessment. The results of this study reaffirmed the importance of guidelines to optimize prescriptions. The preconception that there will be no falls because there is no muscle relaxation is dangerous. Physicians need to be cautious when prescribing sleep medications, even if they are not GABA receptor agonists.

Supporting information

S1 Fig. Design of case-crossover study.

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S1 Table. The fall down risk score.

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S2 Table. Summarized variable information in the case-control and case-crossover study.

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S3 Table. Sensitivity analysis of excluding orthopaedic surgery group.

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S4 Table. Logistic regression model among patients who were prescribed single medication.

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S5 Table. Sensitivity analysis of excluding longer hospitalized duration group.

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S6 Table. Logistic regression model for long and short benzodiazepine.

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S7 Table. Logistic regression model considering dose-response.

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S8 Table. Multicollinearity test in variables.

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S9 Table. Falling time according to sleep medications.

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Acknowledgments

The authors are grateful to Prof. T Takebayashi and Pro. T Okamura for helpful discussions. We also thank M. Abe and Ms. Miura for sharing their dataset with us.

Data Availability

All relevant data are within the manuscript and its Supporting Information files.

Funding Statement

The authors received no specific funding for this work.

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Decision Letter 0

Amir Radfar

24 Jun 2020

PONE-D-20-05046

Non-GABA sleep medications suvorexant and ramelteon as risk factors for falls in elderly hospitalized patients: case-control and case-crossover study

PLOS ONE

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**********

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Reviewer #1: This is a timely and well designed and discussed study. There are a few questions that need to be elucidated

Most important of all is when were these falls? Were these middle of the night falls or falls the next day (due to residual sedation)? Second, ramelteon did not have increased risk of falls, but could that be because ramelteon is not sedating enough and not very effective as a sleep agent in the first place?

Reviewer #2: I read this manuscript with interest. The subject is important as so many people suffer from insomnia and they try multiple medications until they find something that works, and risk of fall is a serious side effect, especially in elderlies.

I would like to point out the following major concerns I have regarding this study design and writeup.

A) study design:

1.Data shows that the risk of side effects with both Z drugs and benzodiazepines is dose related. Higher doses tend to linger longer in the system and lead to fogginess, grogginess, altered postural states which have an increased likelihood of falls. Therefore, analysis without dose related side effects would affect the reliability and validity of the results and conclusion is questionable.

2. Authors did not mention in the limitation section if patients were taking other medications which have an increased risk of falls. This could again bias the results of the study.

3. Authors did not mention in the limitation section other confounders such as COPD and OSA (and how to control potential confounders) which could be exacerbated by benzodiazepines and affect the quality of sleep, hence increasing the risk of falls. Another thing to be taken in consideration is the hepatic and renal function of hospitalized patients which can prolong the drug metabolism, elimination, and action, enhancing the side effects on falls. Again, how were all these confounders controlled?

4. It is very possible that this study suffers from Berkson's bias due to recruitment from the hospitalized patients. This was not mentioned in the limitation section of the manuscript.

5. Inclusion and exclusion criteria are not clearly defined.

6. Pag 11 line 12: Regarding the statement “There were 46 people injured because of falls and this number was considered too small to analyze.”, were these patients with preexisting injury excluded from the study? Were these 46 patients on sleep medications?

7. Pag 14 lines 2-4: “Z” drugs were designed more selectively with the purpose of having less side effects than benzodiazepines. Authors assert that non-benzodiazepines cause more severe motor-impairment than benzodiazepines. This contradicts many other studies which report between 10 to 40 times increase in the myorelaxant effects in benzodiazepines compared to Z drugs. The statement in the paper needs to be revised.

B. Write up: I suggest having an English editing service review the manuscript:

8. Page 9 line 7: please correct “electric medical records”

9. Pag 11 line 2: What does the statement “An analysis of multiple oral patients was added to verify consistency of the results” mean?

10. Please check spelling for “case-crossover” throughout the manuscript. There are instances when the spelling is different.

11. The discussion section needs to be rewritten for cohesion and clarity of the conveyed information.

Reviewer #3: The concept of the research is clinically important, and the findings obtained in this research are also practical. However, the reviewer thinks that the description of methods was insufficient. There is also room for improvement in some statistical analysis designs.

**********

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Reviewer #1: Yes: Hrayr Attarian

Reviewer #2: No

Reviewer #3: No

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PLoS One. 2020 Sep 11;15(9):e0238723. doi: 10.1371/journal.pone.0238723.r002

Author response to Decision Letter 0

8 Aug 2020

August 7, 2020

Academic editor Amir Radfar

PLoS ONE

Dear Professor, Amir Radfar

Thank you for the opportunity to submit a revised version of our manuscript. Please see below our responses to the specific comments from the reviewers.

Response to Reviewers

#Reviewer 1

Most important of all is when were these falls? Were these middle of the night falls or falls the next day (due to residual sedation)?

Response: Thank you for your comments. We showed additional analysis of S Table 6. Patients who were prescribed long acting benzodiazepines fell more at night. Patients who were prescribed no sleep medication fell more at daytime. There was no significant difference of falls between daytime and night in patients who were prescribed other sleep medicines. We have modified the manuscript as per your advice as shown below.

S7 Table showed when patients fell in the case group. Patients who were prescribed suvorexant did not fall more at night than at daytime. There might be some residual sedation and carry over in the pharmacology of suvorexant [14]. (page 14 line10-12)

Second, ramelteon did not have increased risk of falls, but could that be because ramelteon is not sedating enough and not very effective as a sleep agent in the first place?

Response: Thank you for your comments. We agree with your proposal, so we have modified the manuscript as shown below.

Ramelteon might be less sedating, and previous studies have found less sedative adverse effects [23]; similar results were obtained in this study. (page14 line15-17)

#Reviewer 2

1. Data shows that the risk of side effects with both Z drugs and benzodiazepines is dose related. Higher doses tend to linger longer in the system and lead to fogginess, grogginess, altered postural states which have an increased likelihood of falls. Therefore, analysis without dose related side effects would affect the reliability and validity of the results and conclusion is questionable.

Response: Thank you for your comments. We added the analysis considering the dose of sleep medicine in the case-control study. S5 Table shows the results. The consistency of the results was maintained compared to Table 3. We have modified the manuscript as shown below.

Method

Lastly, considering dose response, the analysis of the fall OR of non-benzodiazepines and benzodiazepines was conducted in the case-control study. We could not conduct the dose response analysis of suvorexant and ramelteon because the adoption of suvorexant in Kudanzaka Hospital was only 15 mg tablets and that of ramelteon was only 8 mg. All patients who were prescribed suvorexant and ramelteon were prescribed those of 15 mg and 8 mg. (page10 line7-13)

Result

Considering dose of medications, the consistency of the results was maintained (S Table 5). (page12 line17-18)

2. Authors did not mention in the limitation section if patients were taking other medications which have an increased risk of falls. This could again bias the results of the study.

Response: Thank you for your comments. We have modified the manuscript according to your advice as shown below.

First, we did not consider if patients were taking other medications, which have an increased risk of falls. This could be the bias of the result for this study. (page 15 line14-16)

3. Authors did not mention in the limitation section other confounders such as COPD and OSA (and how to control potential confounders) which could be exacerbated by benzodiazepines and affect the quality of sleep, hence increasing the risk of falls. Another thing to be taken in consideration is the hepatic and renal function of hospitalized patients which can prolong the drug metabolism, elimination, and action, enhancing the side effects on falls. Again, how were all these confounders controlled?

Response: Thank you for your comments. We consider that most of the diseases for confounding were adjusted in the case-crossover study because the status of patients who have COPD, OSA, or some chronic disease is same in the case-crossover comparison. But it is unclear in the manuscript, we have modified it as shown below.

Second, it was impossible to evaluate the state of sleep and comorbidities in individuals. It cannot be denied that people with insomnia or chronic disease (like chronic obstructive pulmonary disease and obstructive sleep apnea) often take sleep medications and fall. However, most of the bias due to each patient's condition is controlled in a case-crossover study because the status of patients who have some chronic diseases is the same in the case-crossover comparison and the hospitalized duration. (page15 line16-21)

We totally agree with your suggestion that we should examine the hepatic and renal function of hospitalized patients. So, we conducted additional analysis in the case and control groups: Table A (below). The case group of albumin was worse compared to the control group.

Table A Comparison of renal and hepatic function between cases and controls. 　

　 Cases Controls P value

Renal function

　eGFR mL/min/1.73 m2 mean (SD) 69.2 (25.8) 65.3 (19.7) 0.013

　Creatinine mean (SD) 0.833 (0.427) 0.832 (0.353) 0.986

Hepatic function

　Total bilirubin mean (SD) 0.752 (0.679) 0.814 (0.415) 0.123

　Platelet (×10000) mean (SD) 22.6 (8.7) 21.6 (7.1) 0.079

　PT% mean (SD) 94.9 (19.1) 95.5 (20.8) 0.679

　Albumin g/dl mean (SD) 3.69 (0.56) 3.93 (0.48) <0.001

Total patients 325 1295 　

We conducted additional sensitivity analysis including albumin in the case-control study (Table B). There was no change in the result compared to Table 3.

Table B Logistic regression model for sleep medications, covariances and albumin. 　

　 Univariate analysis for fall

OR (95%CI, P value) Multivariate analysis for fall

OR (95%CI, P value)

Sleep medications use

　Suvorexant 2.53 (1.26 - 5.12, 0.009)

　Ramelteon 1.48 (0.63 - 3.39, 0.361)

　Non-benzodiazepines 2.53 (1.75 - 3.66, <0.001)

　Benzodiazepines 1.59 (1.11- 2.28, <0.001)

　Kampo (yokukansan) 1.43 (0.68 - 2.97, 0.340)

Department

　Orthopedic surgery (Reference)

　Internal medicine 1.14 (0.76 - 1.69, 0.528)

　General surgery 1.73 (0.86 - 3.30, 0.108)

　Rehabilitation 1.18 (0.67 - 2.03, 0.556)

　Others (Gynecology, Urology, Dermatology, Psychology) 1.59 (0.51 - 4.15, 0.376)

Hospitalized duration (per 1day) 1.023 (1.019 - 1.028, <0.001)

Fall down risk score (per 1point) 1.13 (1.09 - 1.18, <0.001)

Albumin (per g/dl) 0.40 (0.31 - 0.51, <0.001) 0.65 (0.48 - 0.88, <0.006)

Multiple logistic regression adjusted age, sex, all sleep medications, department, hospitalized duration, fall down risk score.

OR: odds ratio, CI: confidence interval.

4. It is very possible that this study suffers from Berkson's bias due to recruitment from the hospitalized patients. This was not mentioned in the limitation section of the manuscript.

Response: Thank you for your comments. We have modified the manuscript as per your advice as shown below.

Third, this study might suffer from Berkson's bias due to recruitment from the hospitalized patients. (page15-16 line22-1)

5. Inclusion and exclusion criteria are not clearly defined.

Response: Thank you for your comments. We have modified the manuscript as per your advice as shown below.

Abstract

The inclusion criteria for the case group were hospitalized patients who had their first fall and that for the control were patients who were hospitalized and did not have a fall, between January 2016 and November 2018. (page3 line5-7)

The inclusion criteria for the case group were hospitalized patients who had their first fall between January 2016 and November 2018. Second or subsequent falls after hospitalization or outpatient falls were excluded. (page7 line3-5)

Inclusion criteria for the control group were patients who were hospitalized between January 2016 and November 2018 and had not fallen. Control group data were collected from 9,111 patients, and controls were randomly matched, based on age (plus or minus 3 years) and sex with a ratio of case:control = 1:4 (Fig 1). Source population in this study is the group who did not fall but was hospitalized in Kudanzaka hospital; so, we sampled the control from the group randomly [28]. (page7 line7-12)

6. Pag 11 line 12: Regarding the statement “There were 46 people injured because of falls and this number was considered too small to analyze.”, were these patients with preexisting injury excluded from the study? Were these 46 patients on sleep medications?

Response: Thank you for your comments. The documents were unclear, so we deleted this description about injury. Injured falling cases were also included in the present analysis. We showed the data for injury and medication in this letter (Table C). This data included injured cases (46 cases) and matched controls (182 controls). According to the manuscript, one case, a 100-year-old male was matched with only 2 controls.

Table C Medication prescribed in injured cases and matched controls. 　

　 　 　

Medication Cases n (%) Controls n (%) P value

Suvorexant 3 (6.5) 4 (2.2) 0.130

Ramelteon 2 (4.3) 2 (2.8) 0.576

Non-benzodiazepines 14 (30.4) 16 (8.8) <0.001

Benzodiazepines 10 (21.7) 255 (20.1) 0.899

Kampo (yokukansan) 4 (8.7) 26 (2.2) 0.032

No sleep medication prescribed 23 (50.0) 124 (68.1) 0.022

Total patients 46 182 　

Non-benzodiazepines include: Zolpidem, Eszopiclone, Zopiclone.

Benzodiazepines include: Triazolam, Etizolam, Brotizolam, Rilmazafone, Alprazolam, Lorazepam, Quazepam, Flutoprazepam, Clotiazepam, Diazepam, Flunitrazepam, Nitrazepam, Clonazepam, Lormetazepam.

Variables are analyzed by Fisher's exact probability test.

7. Pag 14 lines 2-4: “Z” drugs were designed more selectively with the purpose of having less side effects than benzodiazepines. Authors assert that non-benzodiazepines cause more severe motor-impairment than benzodiazepines. This contradicts many other studies which report between 10 to 40 times increase in the myorelaxant effects in benzodiazepines compared to Z drugs. The statement in the paper needs to be revised.

Response: Thank you for your comments. We have modified the manuscript more simply as per your advice as shown below.

In the case-control study, the OR of falls was significantly higher in patients who used suvorexant, non-benzodiazepines, and benzodiazepines. The use of ramelteon and kampo was not associated with the significantly increased OR of falls. In the case-crossover study, the significance of benzodiazepines disappeared, but similar results were observed elsewhere. Benzodiazepines and non-benzodiazepines have a muscle relaxant action, for which the α1-3 subunits of the GABA receptor [43, 44] are responsible, and even in previous studies, an increased risk of falls has been shown [6-8]. (page13 line3-8)

B. Write up: I suggest having an English editing service review the manuscript:

Response: Thank you for your comments. We have modified the manuscript as per your advice.

8. Page 9 line 7: please correct “electric medical records”

Response: Thank you for your comments. We have modified the manuscript as per your advice.

from the electronic medical record.

9. Pag 11 line 2: What does the statement “An analysis of multiple oral patients was added to verify consistency of the results” mean?

Response: Thank you for your comments. We have modified the manuscript more clearly. It means we analyzed the patients excluding those who were prescribed multiple sleep medications. There was no description of the sensitivity analysis of hospitalized duration (S3 Table); we have also added the description.

Secondly, to eliminate the influence of multiple oral medications or long hospitalized duration, we excluded patients using multiple sleep medications or had long hospitalization. (page10 line3-5)

10. Please check spelling for “case-crossover” throughout the manuscript. There are instances when the spelling is different.

Response: Thank you for your comments. We have modified the manuscript as per your advice.

11. The discussion section needs to be rewritten for cohesion and clarity of the conveyed information.

Response: Thank you for your comments. We have modified the manuscript more simply and cohesive as per your advice.

Reviewer #3: The concept of the research is clinically important, and the findings obtained in this research are also practical. However, the reviewer thinks that the description of methods was insufficient. There is also room for improvement in some statistical analysis designs.

Response: Thank you for your comments. We have modified the manuscript totally as per your advice.

Response to the “Comments.”

Major comments

(1) The reviewer thinks that the title “Non-GABA sleep medications suvorexant and ramelteon as risk factors for falls in elderly hospitalized patients: case-control and case-crossover study” needs to be reconsidered because it gives the following misunderstandings and false impression.

Ramelteon increased the risk of falls…? (Although ramelteon did not significantly increase the risk of falls in any analyses.)

The study was intended to target the elderly from the beginning…? In that case, it is necessary to describe the range of target age in Methods.

Response: Thank you for your comments. We have modified the title as per your advice. Since we did not exclude the youth patients, we excluded the expression of “elderly.” We selected the expression that readers could understand that significant fall risk was observed only in patients who were prescribed suvorexant and not in those of ramelteon, as shown below.

“Non-GABA sleep medications, suvorexant as risk factors for falls: case-control and case-crossover study”

(2) The description of the Methods as a whole takes effort to understand. The reviewer thinks that the authors should separate the sections or paragraphs in a little more detail and clarify what is defined or explained. It may be an option to summarize the difference in the method of surveying items for each target group in a table.

Response: Thank you for your comments. We modified the method part totally as per your advice. We made a new S3 Figure summarizing the information of the variables and design.

Regarding statistical analysis, the reviewer thinks the authors should clarify which of the three statistical analyses is explained.

Response: Thank you for your comments. We have modified the statistical part more clearly according to your advice.

In Abstract, the description of Methods is also insufficient. The selection criteria of the target, the types of sleep medications investigated, the statistical analysis methods should be described.

Response: Thank you for your comments. We have added and clarified the method description in accordance with your advice.

(3) In the case-crossover analysis, age, sex and clinical department were adjusted, and 5 types of non-GABA sleep medications were included as independent variables. Since the case-control analysis showed that case-group had significantly higher fall risk scores, the reviewer thinks that the subscores (of 8 items) of the fall risk score (as factors that are likely to contribute to fall risk) should be included in the case-crossover analysis as independent variables.

Response: Thank you for your comments. We have modified the analysis adding the fall down risk score in the case-crossover study. We also modified Table 4 and the result and method description in the manuscript. The result did not change including the fall down risk score in the case-crossover study.

In addition, the reviewer thinks that the correlations between covariates should also be presented to evaluate confounding and to interpret the whole results.

Response: Thank you for your comments. We have added the analysis of the variance inflation factor (VIF) in the case-control study (S6 Table). There is no association in the exposure variables in this study. The variables are independent between each other. The cutoff of the VIF is 2.5 or 1.8 generally. *

*Johnston, R., Jones, K., & Manley, D. (2018). Confounding and collinearity in regression analysis: a cautionary tale and an alternative procedure, illustrated by studies of British voting behaviour. Quality & quantity, 52(4), 1957–1976.

We have added the description as shown below.

The multicollinearity test was performed, and the results are presented in S6 Table. (page12 line18-19)

Minor comments

(1) In Introduction, the authors mentioned attention decline as a cause of falls in the elderly. The reviewer thinks that muscle weakness and sensory deficits are also important factors.

Response: Thank you for your comments. We have added the description and changed the references [12], as shown below.

There appears to be a trade-off here. Though the elderly are at a high risk of falling due to lack of focus of attention, muscle weakness, and sensory deficits [12], at the same time the prevalence of insomnia also increases [9,11]. (page5 line20-22)

Reference

12. Institute of Medicine (US) Division of Health Promotion and Disease Prevention, Berg RL, Cassells JS, eds. The Second Fifty Years: Promoting Health and Preventing Disability. Washington (DC): National Academies Press (US); 1992.

(2) Yokukansan is sometimes written as Yi-gan san. It is better to add it?

Response: Thank you for your comments. We have added the description as shown below.

(called kampo, Yokukansan, or Yi-gan san) (page8 line5-6)

(3) The authors mentioned “the number of patients with falls was extremely small. The study which recorded most falls compared 12 and 18 falls” as limitations of previous studies (p. 14, line 16-17). What is the percentage?

Response: Thank you for your comments. We have added the description as shown below.

The study that recorded most falls compared 12 (2.3%) and 8 (3.1%) falls [17], and it is necessary to collect falling patients and to design the case-control study for rare events such as falls. (page13 line15-17)

(4) The authors hypothesized that falls due to the use of suvorexant might have induced REM sleep behavior disorder and led to falling from beds (p. 15, line 14-17). The reviewer wonders how many, in the authors’ data, fell from beds and what percentage of those were taking suvorexant.

Response: Thank you for your comments. Unfortunately, we have no data about falling from beds. So, we have deleted the description about beds, as shown below.

Additionally, to maintain attention, the cholinergic system centered on the forebrain base plays an important role, and the orexin neural system interacts with it [46, 47]. Inhibition of the orexin receptor may reduce attention, and thus the orexin receptor antagonist, suvorexant, may increase the risk of falls by impairing attention [46]. In the elderly, orexin receptor and cholinergic neuron actions decrease, which may further increase the risk of falls [47]. S7 Table shows when patients fell in the case group. Patients who were prescribed suvorexant did not fall more at night than at daytime. There might be some residual sedation and carry over in the pharmacology of suvorexant [14]. (page14 line5-12)

(5) Missing punctuation and capitalization were found. The reviewer also recommend the authors to proofread English by native speakers.

Response: Thank you for your comments. We have modified the manuscript totally. The new manuscript was checked by native speakers.

Attachment

Submitted filename: Response_to_Reviewers_20200808.docx

Click here for additional data file. (35.2KB, docx)

Decision Letter 1

Amir Radfar

18 Aug 2020

PONE-D-20-05046R1

Non-GABA sleep medications, suvorexant as risk factors for falls: case-control and case-crossover study

PLOS ONE

Dear Dr. Ishibashi,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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Academic Editor

PLOS ONE

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Reviewers' comments:

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Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

Reviewer #3: All comments have been addressed

**********

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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Reviewer #3: All comments have been addressed and the manuscript has been properly revised.

Just one trivial point to be re-checked; S1 and S3 Figures are "Table", not "Figure".

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PLoS One. 2020 Sep 11;15(9):e0238723. doi: 10.1371/journal.pone.0238723.r004

Author response to Decision Letter 1

21 Aug 2020

August 19, 2020

Academic editor

Amir Radfar

PLoS ONE

Dear Professor, Amir Radfar

Thank you for the opportunity to submit a revised version of our manuscript. Please see below our responses to the specific comments from the reviewers.

Response to Reviewers

#Reviewer 3

Just one trivial point to be re-checked; S1 and S3 Figures are "Table", not "Figure".

Response: Thank you for your comments. We modified the manuscript, table, and figure as your suggestion.

Attachment

Submitted filename: Response_to_Reviewers_20200819v2.docx

Click here for additional data file. (15.6KB, docx)

Decision Letter 2

Amir Radfar

24 Aug 2020

Non-GABA sleep medications, suvorexant as risk factors for falls: case-control and case-crossover study

PONE-D-20-05046R2

Dear Dr. Ishibashi,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Amir Radfar, MD,MPH,MSc,DHSc

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Acceptance letter

Amir Radfar

28 Aug 2020

PONE-D-20-05046R2

Non-GABA sleep medications, suvorexant as risk factors for falls: case-control and case-crossover study

Dear Dr. Ishibashi:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

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Kind regards,

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on behalf of

Dr. Amir Radfar

Academic Editor

PLOS ONE

Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 Fig. Design of case-crossover study.

    (PPTX)

    Click here for additional data file. (45.4KB, pptx)
    S1 Table. The fall down risk score.

    (XLSX)

    Click here for additional data file. (10.6KB, xlsx)
    S2 Table. Summarized variable information in the case-control and case-crossover study.

    (XLSX)

    Click here for additional data file. (9.8KB, xlsx)
    S3 Table. Sensitivity analysis of excluding orthopaedic surgery group.

    (XLSX)

    Click here for additional data file. (9.7KB, xlsx)
    S4 Table. Logistic regression model among patients who were prescribed single medication.

    (XLSX)

    Click here for additional data file. (10.1KB, xlsx)
    S5 Table. Sensitivity analysis of excluding longer hospitalized duration group.

    (XLSX)

    Click here for additional data file. (9.9KB, xlsx)
    S6 Table. Logistic regression model for long and short benzodiazepine.

    (XLSX)

    Click here for additional data file. (10.1KB, xlsx)
    S7 Table. Logistic regression model considering dose-response.

    (XLSX)

    Click here for additional data file. (10.6KB, xlsx)
    S8 Table. Multicollinearity test in variables.

    (XLSX)

    Click here for additional data file. (9.8KB, xlsx)
    S9 Table. Falling time according to sleep medications.

    (XLSX)

    Click here for additional data file. (9.9KB, xlsx)
    Attachment

    Submitted filename: Comments.docx

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    Attachment

    Submitted filename: Response_to_Reviewers_20200808.docx

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    Attachment

    Submitted filename: Response_to_Reviewers_20200819v2.docx

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    Data Availability Statement

    All relevant data are within the manuscript and its Supporting Information files.

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