Association between nocturnal falls and hypnotic drug use in older patients at acute care hospitals

Although hypnotic drug use is a known risk factor for falls, few reports have analyzed fall risk associated with individual hypnotic drugs after adjusting for confounding factors. While it is recommended that benzodiazepine receptor agonists not be prescribed for older adults, it is unknown whether melatonin receptor agonists and orexin receptor antagonists are safe in this population. Here, we aimed to assess the influence of various hypnotic drugs on fall risk in older patients admitted to acute care hospitals. We investigated the relationship between nocturnal falls and sleeping pill use in 8,044 hospitalized patients aged > 65 years. We used a propensity score matching method to homogenize characteristics of patients with and without nocturnal falls (n = 145 patients per group) using 24 extracted factors (excluding hypnotic drugs) as covariates. Our analysis of fall risk for each hypnotic drug revealed that benzodiazepine receptor agonists were the only drugs significantly associated with falls, suggesting that use of the drugs is a risk factor for falls in older adults (p = 0.003). In addition, a multivariate analysis of 24 selected factors, excluding hypnotic drugs, revealed that patients with advanced recurrent malignancies were at greatest risk of experiencing falls (OR: 2.62; 95% CI: 1.23–5.60; p = 0.013). Benzodiazepine receptor agonists should be avoided in older hospitalized patients since they increase fall risk, with melatonin receptor agonists and orexin receptor antagonists used instead. Particularly, fall risk associated with hypnotic drugs should be considered in patients with advanced recurrent malignancies.


Introduction
Since falls among hospitalized patients diminish quality of life (QOL) and nursing conditions, they are an important safety problem [1]. Many risk factors for falls in hospitalized patients have been reported, suggesting that they are caused by a complex combination of risk factors [2][3][4]. For example, balance failure and gait disturbance increase a person's risk of tipping over. In addition, dizziness, lightheadedness, and muscle relaxation due to drug side effects are potential risk factors for falls. Therefore, it is important to adjust for multiple confounding factors when performing retrospective studies that aim to identify risk factors for falls.
Hypnotic drugs have been reported as risk factors for falls [5]. Patients taking hypnotic drugs are at increased risk of falling at nighttime, when the blood levels of the drugs are highest. Particularly in older patients with diminished levels of physiological functioning, fall risk must be considered based on our understanding of pharmacokinetics. The incidence of insomnia in older adults is 20-30%, with a frequency and severity higher than those of other age groups [6,7]. Therefore, when prescribing hypnotic drugs to older adults, it is necessary to select drugs with a low associated risk of falling. Recently, melatonin receptor agonists and orexin receptor antagonists have been marketed in Japan as somnifacients. Importantly, these drugs seem to be associated with a low risk of falling given that their pharmacological mechanism differs from those of benzodiazepine receptor 1 3 agonists. However, few reports have analyzed fall risk associated with individual hypnotic drugs after adjusting for multiple confounding factors. While it is recommended that benzodiazepine receptor agonists not be prescribed for older adults, it is still unknown whether melatonin receptor agonists and orexin receptor antagonists are safe in this population. The identification of sleep medications that do not increase nocturnal fall risk in older adults has the potential to reduce the number of hospitalized patients who experience falls. Therefore, we assessed the relationship between night falls and hypnotic drug use among older patients in an acute care hospital.

Study period and subjects
A total of 14,332 individuals aged > 65 years who were inpatients at Matsuyama Shimin Hospital between April 2018 and March 2022 were included in this study. The following exclusion criteria were applied: hospitalization multiple times during the study period (4,985 patients); experiencing multiple falls during the study period (98 patients); use of concomitant hypnotic drugs (709 patients); and incomplete data (496 patients). After exclusion criteria were applied, 8,044 patients were considered (Fig. 1).

Survey items
A total of 27 items including age, sex, body mass index (BMI), assessment of fall risk by nurses at admission, and prescription of hypnotic drugs were extracted from electronic medical records. Benzodiazepine receptor agonists, as addressed in the present study, include both benzodiazepines and non-benzodiazepines. The prescription type of each hypnotic drug was classified as one of the following: benzodiazepine receptor agonist, melatonin receptor agonist, or orexin receptor antagonist. In the study, falls were defined as "an unintentional grounding event on the ground, floor, or a lower surface." Falls that occurred between 9:00 p.m. and 6:00 a.m., which is the timeframe during which lights are turned off, were defined as nighttime falls [8].

Statistical analysis
Chi-squared or Student's t-tests were used to perform betweengroup comparisons regarding the presence or absence of nocturnal falls. For propensity score (PS) matching, a PS was calculated using items other than hypnotic drugs as covariates. Matching was performed using logistic regression analysis (caliper coefficient: 0.2). Thereafter, risk of nocturnal falls for each hypnotic drug was analyzed. For the analysis of risk factors for nocturnal falls, odds ratios for each item were calculated using multivariate logistic regression analysis, with items other than hypnotic drugs considered explanatory variables. The covariate factors selected in the present multivariate logistic analysis were those reflecting clinical symptoms and those thought to be related to falls. After confirming for each factor that the correlation coefficient was < 0.4 and the variance inflation factor was < 10, and after confirming the absence of collinearity, statistical analysis was performed using EZR version 1.54 [9] with the significance level set at < 5%.

Ethical considerations
This study was conducted in accordance with the ethical guidelines for medical research involving human subjects and approved by the ethics committee of this hospital (approval number: 20190731mshe).

Patient characteristics
Patient characteristics are described in Table 1. During the study period, 146 patients experienced a nocturnal fall. Before PS matching, a comparison of the patients who did and did not experience a nocturnal fall revealed significant differences regarding the 10 items including age, falls in the past six months, ability to use the toilet without assistance, and unsteadiness. A total of 145 subjects in each group were matched using the PS matching method, with 24 variables other than hypnotic drugs identified as covariates. A between-group comparison after PS matching revealed no significant differences in any of the parameters considered.

Fall risk associated with hypnotic drug use
Fall risk associated with use of each type of hypnotic drug is shown in

Analysis of risk factors for nocturnal falls
Risk factors for nocturnal falls were identified via a multivariate logistic regression analysis that included 24 extracted factors and excluded hypnotic drug use as explanatory variables. Significant differences regarding the following five items were identified: age, male sex, falls in the past  6 months, patients with advanced recurrent malignancies, and analgesics (Table 3). Among these five items, advanced recurrent malignancy had the highest odds ratio (OR: 2.62, 95% CI: 1.23-5.60, p = 0.013).

Discussion
We retrospectively analyzed nocturnal fall risk associated with individual sleep medications to investigate effects of individual hypnotic drugs on the occurrence of nocturnal falls in older adults. Falls have been reported to occur in patients with various internal and external risk factors [10].
In particular, fall risk significantly increases with age, with fall frequency reported as 27% for those aged ≥ 65 years and > 50% for those aged ≥ 80 years living in long-term care facilities [11][12][13][14]. Therefore, when prescribing hypnotic drugs for older adults, one should consider drugs that are unlikely to increase fall risk.
In this study, we used the PS matching method to homogenize patient backgrounds to analyze effects of specific hypnotic drugs in detail, taking into account the relationships among the multiple risk factors for falls. A comparison between groups of patients who did and did not experience nocturnal falls before PS matching revealed significant differences in 10 factors considered. However, no significant differences were found regarding any items except sleeping pill use after PS matching. Further, between-group comparisons of fall risk associated with each sleeping medication after PS matching revealed significant differences only when benzodiazepine receptor agonists were considered. This finding suggests that benzodiazepine receptor agonists may increase fall risk in older adults.
A meta-analysis of observational studies of older subjects aged ≥ 65 years previously suggested that benzodiazepine receptor agonists significantly increase fall incidence, regardless of the duration of drug action [15]. In older adults, the impairment of renal and hepatic function associated with physiological decline may increase blood levels of drugs, and this likely increases fall risk. The results of the present study are consistent with European STOPP/START criteria indicating that use of benzodiazepine receptor agonists in older adults (those aged > 65 years) is inappropriate because of the increased risk of falls and fractures [16]. However, the present results go further to suggest that melatonin receptor agonists and orexin receptor antagonists are safer than benzodiazepine receptor agonists for use in older adults with regard to fall risk. Melatonin receptor agonists and orexin receptor antagonists have been shown to improve insomnia, reduce balance impairment, and prevent delirium, suggesting that they are safe for use in older adults in terms of fall risk [17][18][19][20][21]. Furthermore, a recent case-crossover study of hospitalized patients aged ≥ 75 years in Japan reported that among hypnotic drugs, benzodiazepine receptor agonists increased risk of falls, whereas melatonin receptor agonists and orexin receptor antagonists did not [22]; these results are consistent with those of the present study.
In the present analysis of fall risk associated with each hypnotic drug, the population was limited to older persons aged ≥ 65 years at high risk of falling, and cases with concomitant use of sleep medications were excluded. In addition, this study homogenized patient backgrounds using PS matching, a method not widely used to assess fall risk in the population considered. Because we adjusted for multiple confounding factors, we believe that our study more carefully assessed fall risk in patients taking hypnotic drugs than did other studies and provides strong support for the previously reported association between falls and hypnotic drug use in older adults.
A multivariate analysis with 24 extraction factors (excluding hypnotic drug use) was performed in this study. Results revealed significant odds ratios for the following five factors: age, male sex, fall in the past 6 months, advanced recurrent malignancies, and analgesic agent use. Age and sex were reported in a previous study. Recently, fall history was reported as a risk factor for recurrent falls [23]. Further, patients with malignant tumors have been reported to be at an increased risk of falling owing to muscle weakness and poor balance due to malignant tumors and treatment such as chemotherapy and surgery [24].
As this was a retrospective study conducted in a single facility, there may be a bias regarding patient background. To more accurately assess the impact of a fall history or prescribed medications on fall risk, this study excluded from analysis those patients who had been hospitalized multiple times; however, these patients are the very ones likely to be at high risk of a fall.
Additionally, sleeping pill dosage was not examined, and this may have been a confounding factor. However, results of this study are consistent with those reporting effects of hypnotic drugs thus far. Further, current data clarify the association between nighttime falls and hypnotic drugs in older adults.
The present study did show that patients with advanced recurrent malignancies were at the highest risk of falls. This finding indicates that when sleep medication is used in these patients, benzodiazepine receptor agonists should be avoided, while orexin receptor antagonists and melatonin receptor agonists, which do not increase risk of falls, should be considered. The results of this study suggest that benzodiazepine receptor agonists are risk factors for falls in older adults. In contrast, orexin receptor antagonists and melatonin receptor agonists can be safely used in older adults in terms of fall risk. In particular, the high risk of falling among older patients, especially those with advanced recurrent malignancies, suggests that the risk of falling should be considered when selecting a hypnotic drug.