Risk of Falls with Benzodiazepine Receptor Agonists in Combination with Novel
hypnotics.
Yuya Higuchi1,2, Yuya Ishikawa, Ph.D.2, Takuya Araki, Ph.D.*1,2, Yukina Ohshima, Ph.D.2,
Hideaki Yashima, Ph.D.1,2, 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
e-mail: tkyaraki@gunma-u.ac.jp
Submitted: 12/01/2024, Revised: 16/01/2024, Accepted: 11/02/2024, Published: 17/04/2024
Abstract
Several risk factors for falls during hospitalization have been reported, of which
hypnotics have a major influence. Insomnia is often intractable, and many cases
are treated with two or more hypnotics; however, there is concern about the
increased risk of falls due to the use of multiple hypnotics. Therefore, we aimed to
clarify the effects of combining conventional and new hypnotics on the risk of
falls. The impact of the concomitant use of hypnotics on the occurrence of fall
events was evaluated retrospectively in patients 20 years of age and older received
acute care medicine in a university hospital between January 2013 and August
2022. The survey items included age, sex, drug prescription status, whether a fall
accident had occurred, and its circumstances. Of the 47,236 eligible patients, 976
experienced a fall accident during hospitalization (fall rate, 2.07%). Logistic
regression analysis of the patient population not taking benzodiazepine receptor
agonists showed that age (odds ratio [OR], 1.04), sex (OR, 0.84), and ramelteon
use (OR, 3.06) independently contributed to falls. In contrast, in the patient
population taking benzodiazepine receptor agonists, logistic regression analysis
showed that only age (OR: 1.03) and sex (OR: 0.76) independently contributed to
falls. This suggests that ramelteon, suvorexant, and lemborexant, in combination
with benzodiazepines, may not increase the risk of falls. Hypnotics with novel
mechanisms of action may not increase the risk of fall when combined with
benzodiazepine receptor agonists. evaluasi.
Keywords: fall risk, hypnotics, acute care hospitals
Vol. 5, Issue 2, 2023 (377-384)
http://journal.unpad.ac.id/IdJP
*Corresponding author,
e-mail: tkyaraki@gunma-u.ac.jp (T. Araki)
https://doi.org/10.24198/idjp.v5i2.52528
© 2023 T. Araki et al
378
1. Introduction
Falls in hospitalized patients,
especially in the elderly, occur at a high
frequency [1], leading to prolonged
hospitalization, decreased quality of life,
and prognosis worsening [2], making falls
a problem for which solutions are
strongly desired in clinical practice [3,4].
Many reports have shown that drugs
affect falls, with hypnotics having a
significant effect on falls [5-10].
Benzodiazepine receptor agonists are
widely used as hypnotics, but the
increased risk of patient falls has become
a clinical concern [11-14]. Additionally,
benzodiazepine receptor agonists are
dependent, making their long-term
continuous use problematic.
In recent years, novel hypnotics with
different mechanisms, melatonin receptor
agonists, and orexin receptor antagonists
have been increasingly used. Due to their
mechanism of action, they are thought to
have a low inhibitory effect on physical
activity, and the effect of taking these
drugs on the risk of falls is considered
small. However, some reports have shown
that novel hypnotics increase the risk of
falls [11], and the effects of novel
hypnotics on the risk of falls are not fully
understood.
In addition, an increasing number of
patients are switching from
benzodiazepine receptor agonists to these
novel hypnotics in view of dependence
and fall risk, or are combining
benzodiazepine receptor agonists with
novel hypnotics due to treatment
refractoriness [15], however, the impact
on fall risk associated with the use of
novel hypnotics in these patients has not
been clarified.
This study aimed to evaluate the risk of
falls associated with the use of a
melatonin receptor agonist or orexin
receptor antagonist in combination with a
benzodiazepine receptor agonist. All
inpatients admitted to the Gunma
University Hospital over the past 10 years
were analyzed.
2. Methods
Patient cohort
All patients aged ≥ 20 years who were
admitted to Gunma University Hospital
between January 2013 and August 2022
were included in this study. For patients
who were hospitalized multiple times
during the study period, only the first
hospitalization was included; the second
and subsequent hospitalizations were
excluded. To control for variations in
patients' medical conditions and other
factors, patients who were hospitalized
for less than 4 days or more than 8 weeks
were excluded. Patients who fell within
three days of admission were also
excluded to exclude the effect of
environmental changes due to
hospitalization.
Study design
The relationship between the type of
medication prescribed and the occurrence
of falls during the period of
hospitalization was analyzed in a cohort
of patients. Patient groups selected
according to the above criteria were
surveyed for sex, age, history of
prescriptions for sleeping pills, and fall
records. Inpatient fall records were
surveyed for sex, age, history of
T. Araki et al / Indo J Pharm 5 (2023) 377-384
379
for sleeping pills, and fall records.
Inpatient fall records were collected from
incident reports submitted by medical
staff, and falls were evaluated according
to a previous report by Gibson [16]. All
drugs prescribed to patients during their
hospital stay were electronically extracted
from medical records.
The drugs analyzed were the following 28
drugs classified as sleeping pills
(Estazolam, Flurazepam, Nitrazepam,
Haloxazolam, Triazolam, Flunitrazepam,
Brotizolam, Lormetazepam, Oxazolam,
Cloxazolam, Diazepam, Fludiazepam,
Bromazepam, Medazepam, Lorazepam,
Alprazolam, Mexazolam, Tofisopam,
Chlordiazepoxide, Ethyl Loflazepate,
Quazepam, Rilmazafone, Zopiclone,
Zolpidem, Eszopiclone, Ramelteon,
Suvorexant, and Lemborexant) by the
therapeutic category of drugs defined by
the Japanese Ministry of Health and
Labor Welfare, which have been used for
inpatients at Gunma University Hospital
in the past. The following 28 sleeping
pills were included in the analysis.
To exclude drugs prescribed as needed
but not actually taken, prescriptions of
two days or less were not considered. In
addition, prescriptions after the
occurrence of a fall were excluded from
the analysis in cases where a fall
occurred. This study was approved by the
Gunma University Ethics Review Board
for Medical Research Involving Human
Subjects (Study No. HS2020-154).
Statistical analysis
Among the sleep medication prescription
cases, risk factors for falls were analyzed
using multivariate logistic regression
analysis, with sex and prescription of
each medication as categorical variables
and age as a continuous variable. The risk
factors for falls for each sleeping
medication were also analyzed using the
same technique. All statistical analyses
were performed using IBM SPSS
Statistics for Windows version 28 (IBM).
The significance level was set at p < 0.05.
3. Results
The analysis included 47,236
inpatients, of whom 976 were included as
falls (fall rate: 2.07%) (Table. 1). In the
subgroup of patients not prescribed
benzodiazepine receptor agonists (37,346
patients), multivariate analysis was
conducted to examine the impact of age,
sex, ramelteon, suvorexant, and
lemborexant on falls. The results showed
that age (odds ratio [OR]: 1.04), sex (OR:
0.84), and ramelteon (OR: 3.06)
independently contributed to falls (Table.
2). In contrast, in patients prescribed
benzodiazepine receptor agonists (9,890
patients), only age (odds ratio [OR]: 1.03)
and gender (OR: 0.76) were identified as
independent factors contributing to falls
(Table. 3).
T. Araki et al / Indo J Pharm 5 (2023) 377-384
380
Table 1
Patient Background for this Study.
T. Araki et al / Indo J Pharm 5 (2023) 377-384
381
Table 2
Effects of the concomitant use of novel
sleep medications on falls in patients not
taking benzodiazepine receptor agonists.
T. Araki et al / Indo J Pharm 5 (2023) 377-384
Table 3
Effects of the concomitant use of novel
sleep medications on falls in patients
taking benzodiazepine receptor agonists.
4. Discussion
The rate of falls in patients who
took hypnotics during the study period
was similar to previous reports [3,10,17].
An analysis of the risk of falls with
ramelteon, suvorexant, and lemvorexant
in a patient population not using
benzodiazepine receptor agonists showed
that ramelteon was associated with a
significantly increased risk of falls. In
contrast, no drugs showed a significant
difference in the patient population
treated with benzodiazepine receptor
agonists. The results suggest that
suvorexant and lemvorexant do not
increase the risk of falls, either alone or in
combination with benzodiazepine
receptor agonists. Some reports have
demonstrated that orexin receptor
antagonists are not associated with the
risk of falls [12,14], and our results
support this finding. Furthermore, these
results show that orexin receptor
antagonists, even when used in
combination with benzodiazepines, do
not increase the risk of falls and can be
used relatively safely.
Although ramelteon was associated with
an increased risk of falls when used
alone, it did not increase the risk of falls
when used in combination with
benzodiazepine receptor agonists.
Ramelteon is known to have fewer
hypnotic effects than benzodiazepine
receptor agonists and orexin receptor
antagonists [18]. When used alone, it does
not provide adequate sleep, which may
have increased the risk of falls due to
increased nocturnal activity. However,
when used in combination with a
benzodiazepine receptor agonist, the
agonists may have produced sufficient
effects to make the risk of falls
comparable to baseline.
This study has some limitations. Firstly,
we were unable to adjust for the impact of
medications other than hypnotics on falls.
Secondly, we could not assess the
influence of the dosage and timing of the
medication. Thirdly, we did not evaluate
the effects of the patient's conditions or
disease status, and other treatment
interventions. To address these
limitations, a more detailed analysis
incorporating additional information is
necessary. Additionally, in the group
using two types of medications during
hospitalization, it has not been confirmed
whether the prescriptions for the two
drugs overlapped in terms of timing.
Therefore, there is a possibility that cases
within the group using two medications
may include instances where the type of
hypnotics was changed during
hospitalization, potentially leading to an
underestimation of the fall risk associated
with co-administration. Verification
through future prospective clinical trials
is deemed necessary to investigate the
potential increase in fall risk associated
with the concurrent use of these
medications.
5. Conclusion
This study evaluated the risk of
falls when benzodiazepine receptor
agonists were combined with melatonin
receptor agonists or orexin receptor
antagonists in all patients aged 20 years
or older admitted to a university hospital
in the past 10 years. Concomitant use of a
melatonin receptor agonist or orexin
receptor antagonist with a benzodiazepine
receptor agonist had no effect on the
increased risk of falls. The results also
suggest that the risk of falls may be high
for ramelteon when used alone. To our
knowledge, this is the first study to use
big data to determine the effect of
individual sleep-inducing drugs and
concomitant medications on the
occurrence of falls. Compared to previous
reports, the sample size of this study was
much larger, and patient background was
controlled to some extent, including
adjustment for hospitalization days;
therefore, we believe that the results are
highly reliable.
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