Vol 4, Issue 2, 2023 (232-241)
http://journal.unpad.ac.id/idjp
*Corresponding author,
e-mail : tkyaraki@gunma-u.ac.jp (T. Araki)
https://doi.org/10.24198/idjp.v4i2.44186
© 2023 T. Araki et al
Hospitalized patients on orexin receptor antagonists have a lower risk of falls
Yukina Ohshima, M.S.1,2, Takuya Araki, Ph.D.*1,2, Hideaki Yashima, Ph.D.2, Noriyuki
Nakayama, M.S.2,3, Koujirou Yamamoto, Ph.D.1,2
1.Department of Clinical Pharmacology and Therapeutics, Gunma University Graduate
School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan
2.Department of Pharmacy, Gunma University Hospital, 3-39-15 Showa-machi, Maebashi,
Gunma 371-8511, Japan
3.Department of Healthcare Quality and Safety, Gunma University Graduate School of
Medicine, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan
Submitted : 04/01/2023, Revised : 10/01/ 2023, Accepted : 05/02/2022, Published : 03/06/2023
Abstract
Falls and fall-related injuries remain a major safety concern in many hospitals and
nursing homes. Although many studies have examined the relationship between
accidents and sedating medications, further analysis is needed of the association
between falls and individual hypnotics. The aim of this study was to clarify the
association between hypnotics and the risk of falls in hospital. The impact of
hypnotics on fall events was retrospectively evaluated in patients aged 20 years or
older who were admitted to Gunma University Hospital between January 2013 and
March 2022. Logistic regression analysis was performed with age, sex, and drug
prescription status as the independent variables and fall events as the dependent
variable. Of the 54,019 patients included in the study, 1,460 experienced a fall
during hospitalization (incidence, 2.7%). The hypnotics prescribed included orexin
receptor antagonists, melatonin receptor agonists, and benzodiazepine receptor
agonists. Logistic regression analysis showed that age (odds ratio [OR] 1.04), male
sex (OR 1.14), estazolam (OR 2.99), flunitrazepam (OR 2.34), brotizolam (OR
1.65), diazepam (OR 3.34), lorazepam (OR 2.93), alprazolam (OR 1.91), ethyl
loflazepate (OR 2.81), zolpidem (OR 1.40), eszopiclone (OR 1.87), clonazepam
(OR 1.94), and ramelteon (OR 2.15) independently contributed to falls. Short-
acting benzodiazepine receptor agonists tended to have smaller ORs for fall risk.
Orexin receptor antagonists were not associated with falls. Therefore, orexin
receptor antagonists and short-acting benzodiazepine receptor agonists are likely
safer than intermediate-acting and long-acting benzodiazepines.
Keywords: fall risk, hypnotics, acute care hospitals
1. Introductio
Insomnia is a common problem that affects
about 10% of adults [1]. Benzodiazepine
receptor agonists have long been widely
used as a treatment option. However,
benzodiazepines have some well-known
disadvantages, including the potential for
dependence and increased risk of
staggering and falls because of their
T. Araki et al / Indo J Pharm 4 (2023) 232-241
233
muscle-relaxant effects [2–7]. Falls are a
serious clinical problem they occur more
frequently in the elderly [8] and are
associated with fractures, which lead to
prolonged hospitalization, decreased
quality of life, and poor prognosis [9–11].
Therefore, falls are a major problem in
clinical practice. In a retrospective study of
3,683 patients hospitalized during the
fourth quarter of 2007, we found an
association between falls and medication
and concluded that hypnotics increase the
risk of falls but that the actual fall risk
significantly depends on the type of
hypnotic administered [7]. Three more
recently published studies have also
investigated the effect of hypnotics on the
risk of falls [12–14], but the effect of
individual hypnotics on the risk of falls is
not yet clear. The lack of progress in
understanding the effect of each type of
hypnotic on the risk of falls can be
attributed to insufficient case numbers and
variations in the characteristics of target
diseases. A large number of cases under
general conditions is required in order to
accurately assess the impact of hypnotics
on the risk of falls. Recently, orexin
receptor antagonists and melatonin receptor
agonists have become available for the
treatment of insomnia. Unlike
benzodiazepine receptor agonists, these
drugs show less potential for dependence
and have minimal effects on motor function
[15–17]. Thus, the fall risk is considered
negligible. However, the impact of these
medications on the risk of falls varies from
study to study and remains controversial
[12,18–20]. One reason for the inconsistent
findings of these studies is that various
benzodiazepine receptor agonists are
categorized into one group as
“benzodiazepines” when investigating new
hypnotics. Our previous study showed that
the effect of the various benzodiazepine
receptor agonists on the risk of falls varies
widely. Therefore, each hypnotic should be
evaluated individually when assessing the
risk of falls. In this study, we investigated
the impact of different types of hypnotics
on the risk of falls in all patients admitted
to Gunma University Hospital over a 10-
year period.
2. Methods
2.1 Patient cohort
All patients over 20 years of age who were
hospitalized at Gunma University Hospital
between January 2013 and March 2022
were included in the study. Only the first
hospitalization was included for patients
who were hospitalized on multiple
occasions during the study period (cohort
1). Information on all medications
administered during the first hospitalization
was analyzed.
A second group of patients (cohort 2) was
then created with addition of the following
conditions to control for patient
background factors. First, the period of
analysis for patients in whom a fall
occurred was censored on the date of the
fall event in order to exclude hypnotics
taken after the fall occurred. Patients
hospitalized for less than 4 days or longer
than 8 weeks were excluded to control for
variations in medical conditions (e.g.,
patients who were hospitalized for
examination only and those who were
bedridden). Finally, patients who had a
single prescription of a hypnotic for fewer
than 2 days before surgery were
excluded.(fig. 1).
T. Araki et al / Indo J Pharm 4 (2023) 232-241
234
2.2 Study design
The relationship between the drugs
prescribed and occurrence of falls during
the study period was investigated in both
study cohorts. Patients who met the study
eligibility criteria were examined for age,
sex, history of prescriptions for hypnotics,
and history of falls. Inpatient falls are
registered via incident reports submitted by
medical staff. Falls were evaluated
according to a previous report by Gibson
[21], and medical charts were reviewed to
obtain clinical data. All drugs prescribed to
the patients during their hospital stay were
extracted electronically from hospital
charts. The drugs analyzed were those
classified as hypnotics according to the
therapeutic category of drugs defined by the
Japanese Ministry of Health, Labour and
Welfare. Thirty-three hypnotics used
during the study period were included
(estazolam, flurazepam, nitrazepam,
haloxazolam, triazolam, flunitrazepam,
brotizolam, lormetazepam, oxazolam,
cloxazolam, clorazepate dipotassium,
diazepam, fludiazepam, bromazepam,
medazepam, lorazepam, alprazolam,
flutazolam, mexazolam, tofisopam,
chlordiazepoxide, ethyl loflazepate,
quazepam, midazolam, rilmazafone,
zopiclone, tandospirone, zolpidem,
eszopiclone, clonazepam, ramelteon,
suvorexant, and lemborexant).
The study was approved by the Gunma
University Ethics Review Committee for
Medical Research Involving Human
Subjects (study number HS2020-154).
2.3 Statistical analysis
Categorical variables, including sex and
prescriptions for hypnotics, were analyzed
for their association with history of falls
using the chi-squared test. As a continuous
variable, age was analyzed for its
association with history of falls using the t-
test. Multivariate logistic regression
analysis was performed for risk factors for
falls that had a p value of <0.1 in univariate
analysis (age, sex, and hypnotic) for
hypnotics prescribed to at least 100
patients. All statistical analyses were
performed using the IBM SPSS Statistics
28 software package (IBM Corp., Armonk,
NY, USA). A p value of <0.05 was
considered statistically significant.
3. Results
3.1 Cohort 1
In total, 2,007 of the 70,069 patients in
cohort 1 had a fall during their hospital stay,
giving a fall rate of 2.9%. After exclusion
of 17 drugs for which there were fewer than
T. Araki et al / Indo J Pharm 4 (2023) 232-241
235
100 prescriptions (flurazepam,
haloxazolam, lormetazepam, oxazolam,
cloxazolam, clorazepate dipotassium,
fludiazepam, bromazepam, medazepam,
flutazolam, mexazolam, tofisopam,
chlordiazepoxide, quazepam, rilmazafone,
zopiclone, and tandospirone), univariate
analysis showed that age, sex, and 16 drugs
(estazolam, nitrazepam, triazolam,
flunitrazepam, brotizolam, diazepam,
lorazepam, alprazolam, ethyl loflazepate,
midazolam, zolpidem, eszopiclone,
clonazepam, ramelteon, suvorexant, and
lemborexant) were significantly associated
with falls (Table 1).
Table 1. Relationship between type of hypnotic prescribed and risk of falls in study cohort 1
T. Araki et al / Indo J Pharm 4 (2023) 232-241
236
Multivariate analysis showed that all these factors independently contributed to falls (Table 2).
Table 2. Risk factors for falls identified by logistic regression analysis in study cohort 1
3.2 Cohort 2
In cohort 2, 1,460 of the 54,019 patients
enrolled had a fall during hospitalization,
giving a fall rate of 2.7%. Univariate
analysis after exclusion of 18 agents with
fewer than 100 prescriptions (flurazepam,
haloxazolam, lormetazepam, oxazolam,
cloxazolam, clorazepate dipotassium,
fludiazepam, bromazepam, medazepam,
flutazolam, mexazolam, tofisopam,
chlordiazepoxide, quazepam, midazolam,
rilmazafone, zopiclone and tandospirone)
showed that age, sex, and 14 hypnotics
(estazolam, nitrazepam, flunitrazepam,
brotizolam, diazepam, lorazepam,
alprazolam, ethyl loflazepate, zolpidem,
eszopiclone, clonazepam, ramelteon,
suvorexant, and lemborexant) were
significantly associated with falls (Table 3).
T. Araki et al / Indo J Pharm 4 (2023) 232-241
237
Multivariate analysis of these factors
showed that age, sex, estazolam,
flunitrazepam, brotizolam, diazepam,
lorazepam, alprazolam, ethyl loflazepate,
zolpidem, eszopiclone, clonazepam, and
T. Araki et al / Indo J Pharm 4 (2023) 232-241
238
ramelteon independently contributed to
falls (Table 4).
Table 4. Risk factors for falls identified by logistic regression analysis in study cohort 2
4. Discussion
In this study, we retrospectively evaluated
the relationship between medications
prescribed and occurrence of falls in all
patients hospitalized at our facility over a
10-year period. As in previous studies
[7,12–14,22], we found that use of
medications, including many
benzodiazepine receptor agonists, was
associated with falls in cohort 1 (Tables 1
and 2). However, the previous studies had
some drawbacks, including the fact that
hypnotics prescribed after a fall were also
evaluated as a risk factor for falls.
Furthermore, some of the patients included
in the analysis had little risk of falling, such
as those who had been in hospital for more
than one year and were inactive and those
who had been hospitalized for only 2 days
for examination purposes. Therefore, in the
present study, we changed the analysis
period to focus on patients who experienced
falls from hospital admission to the first fall
occurrence. We also limited the length of
hospitalization to 4 days or more and 8
weeks or less for the patients in cohort 2.
Our findings were consistent with those
previously reported, namely, that many
benzodiazepines influenced the risk of falls.
An exception was triazolam, which is rarely
prescribed for the first time during
admission to an acute care hospital such as
ours. Many patients had been prescribed
triazolam before recruitment into the study
and were accustomed to taking it, which
may have masked their actual risk of falls.
Therefore, in order to assess the impact of
these drugs on the risk of falls, it is
necessary to examine patient factors in
detail and include the time interval since the
initial prescription. Another finding in our
study was that the melatonin receptor
T. Araki et al / Indo J Pharm 4 (2023) 232-241
239
agonist ramelteon increased the risk of
falls.
In contrast, we found that prescriptions for
the orexin receptor antagonists suvorexant
and lemborexant had no impact on the fall
risk, similar to the reports by Torii et al. and
Sogawa et al [19–20]. Previous studies of
the impact of orexin receptor antagonists on
falls have yielded inconsistent results
[12,18–20], likely in part because of
inclusion of patients on short-term
medications or those who were long-stay
patients. However, the most significant
factor is thought to be the influence of other
benzodiazepines. In our cohort 2, 144
(24.6%) of the 585 patients taking
suvorexant and 34 (12.2%) of the 279
taking lemborexant had a history of
prescriptions for benzodiazepines.
Moreover, of the 18,761 patients who were
prescribed any hypnotics, 1,339 (7.1%)
were prescribed two or more hypnotics.
These findings suggest that orexin receptor
antagonists were prescribed more often
than other hypnotics and that factors related
to other drugs may have played a
significant role in the risk of falls. In
particular, other medications may have
contributed significantly to the effect of
orexin receptor antagonists on the risk of
falls. We did not group benzodiazepines in
this study and instead analyzed them
individually, which adjusted for the effects
of concomitant medications and allowed
for an accurate assessment of the impact of
orexin receptor antagonists on the risk of
falls.
This study has some limitations, including
failure to control for the effects of
medications other than hypnotics that may
impact falls, to evaluate the effects of
medications that interact with hypnotics, to
determine the dosages at which each
medication was administered, and to
investigate each patient's disease status and
therapeutic interventions in detail. These
limitations are largely the result of the
limited number of factors that can be
incorporated simultaneously when
conducting a multivariate analysis. Further
studies are needed to confirm our present
findings and investigate the relevance of
other potential risk factors in more detail.
5. Conclusions
This study retrospectively investigated the
effect of hypnotics on the risk of falls in
patients hospitalized over a 10-year period.
We found that short-acting
benzodiazepines, even though relatively
safe, were still associated with a
significantly increased risk of falls. We also
found that melatonin receptor antagonists
increased the risk of falls but that orexin
receptor antagonists did not. To our
knowledge, this is the first study to use big
data to determine the impact of individual
hypnotics on the risk of falls. Considering
our relatively large sample size and the fact
that patient background characteristics
were controlled to some extent, including
adjustment for the number of hospital days,
we believe that our results are highly
reliable. Therefore, an orexin receptor
antagonist is recommended when the risk of
falls is the primary consideration.
Furthermore, when using benzodiazepines,
even those that are short-acting and
considered to have a relatively low risk of
falls, the patient's risk factors should be
carefully evaluated and adequate
countermeasures taken as necessary to
prevent falls.
References
1. Itani O, Kaneita Y, Munezawa T,
Mishima K, Jike M, Nakagome S, et al.
Nationwide epidemiological study of
insomnia in Japan. Sleep Med
2016;25:130–8.
2. Nielsen S. Benzodiazepines. Curr Top
Behav Neurosci 2017;34:141–59.
T. Araki et al / Indo J Pharm 4 (2023) 232-241
240
3. Woolcott JC, Richardson KJ, Wiens
MO, Patel B, Marin J, Khan KM, et al.
Meta-analysis of the impact of 9
medication classes on falls in elderly
persons. Arch Intern Med
2009;169:1952–60.
4. Buth S, Holzbach R, Martens M-S,
Neumann-Runde E, Meiners O,
Verthein U. Problematic Medication
With Benzodiazepines, “Z-drugs”, and
Opioid Analgesics. Dtsch Arztebl Int
2019;116:607–14.
5. Valencia Morales DJ, Laporta ML,
Johnson RL, Schroeder DR, Sprung J,
Weingarten TN. A Case-Control Study
of Accidental Falls During Surgical
Hospitalizations. Am Surg 2023;89:61–
8.
6. Seppala LJ, Wermelink AMAT, de
Vries M, Ploegmakers KJ, van de Glind
EMM, Daams JG, et al. Fall-Risk-
Increasing Drugs: A Systematic Review
and Meta-Analysis: II. Psychotropics. J
Am Med Dir Assoc 2018;19:371.e11-
371.e17.
7. Obayashi K, Araki T, Nakamura K,
Kurabayashi M, Nojima Y, Hara K, et
al. Risk of falling and hypnotic drugs:
retrospective study of inpatients. Drugs
R D 2013;13:159–64.
8. Hanson SM, Morlock EV, Satyshur
KA, Czajkowski C. Structural
requirements for eszopiclone and
zolpidem binding to the gamma-
aminobutyric acid type-A (GABAA)
receptor are different. J Med Chem
2008;51:7243–52.
9. Moreland B, Kakara R, Henry A.
Trends in Nonfatal Falls and Fall-
Related Injuries Among Adults Aged
≥65 Years - United States, 2012-2018.
MMWR Morb Mortal Wkly Rep
2020;69:875–81.
10. Court-Brown CM, Clement ND,
Duckworth AD, Biant LC, McQueen
MM. The changing epidemiology of
fall-related fractures in adults. Injury
2017;48:819–24.
11. LeLaurin JH, Shorr RI. Preventing Falls
in Hospitalized Patients: State of the
Science. Clin Geriatr Med
2019;35:273–83.
12. Gammel LB, Leonard M, Wheeler H,
Linh H, Burns B Jr. Controlled
Substance Use and Clinical Outcomes
of Elderly Patients After a Fall. Cureus
2022;14:e22356.
13. Hashida R, Matsuse H, Yokoyama S,
Kawano S, Higashi E, Tajma H, et al.
Balance dysfunction the most
significant cause of in-hospital falls in
patients taking hypnotic drugs: A
retrospective study. PLoS One
2022;17:e0272832.
14. Oren G, Jolkovsky S, Tal S. Falls in
oldest-old adults hospitalized in acute
geriatric ward. Eur Geriatr Med
2022;13:859–66.
15. Noh H-M, Song HJ, Park YS, Han J,
Roh YK. Fall predictors beyond fall
risk assessment tool items for acute
hospitalized older adults: a matched
case-control study. Sci Rep
2021;11:1503.
16. Bland H, Li X, Mangin E, Yee KL,
Lines C, Herring WJ, et al. Effects of
Bedtime Dosing With Suvorexant and
Zolpidem on Balance and Psychomotor
Performance in Healthy Elderly
Participants During the Night and in the
Morning. J Clin Psychopharmacol
2021;41:414–20.
17. Murphy P, Kumar D, Zammit G,
Rosenberg R, Moline M. Safety of
lemborexant versus placebo and
zolpidem: effects on auditory
awakening threshold, postural stability,
and cognitive performance in healthy
older participants in the middle of the
night and upon morning awakening. J
Clin Sleep Med 2020;16:765–73.
18. Zammit G, Wang-Weigand S,
Rosenthal M, Peng X. Effect of
ramelteon on middle-of-the-night
balance in older adults with chronic
insomnia. J Clin Sleep Med 2009;5:34–
40.
19. Ishibashi Y, Nishitani R, Shimura A,
Takeuchi A, Touko M, Kato T, et al.
Non-GABA sleep medications,
T. Araki et al / Indo J Pharm 4 (2023) 232-241
241
suvorexant as risk factors for falls:
Case-control and case-crossover study.
PLoS One 2020;15:e0238723.
20. Torii H, Ando M, Tomita H, Kobaru T,
Tanaka M, Fujimoto K, et al.
Association of Hypnotic Drug Use with
Fall Incidents in Hospitalized Elderly
Patients: A Case-Crossover Study. Biol
Pharm Bull 2020;43:925–31.
21. Sogawa R, Emoto A, Monji A,
Miyamoto Y, Yukawa M, Murakawa-
Hirachi T, et al. Association of orexin
receptor antagonists with falls during
hospitalization. J Clin Pharm Ther
2022;47:809–13.
22. Mj G. Falls in later life. Improving the
Health of Older People A World View
1990:296–315.
23. Kobayashi K, Ando K, Nakashima H,
Suzuki Y, Nagao Y, Imagama S.
Relationship between use of sleep
medication and accidental falls during
hospitalization. Nagoya J Med Sci
2021;83:851–60.
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