Abstract
This study evaluated the effect of zolpidem and lemborexant on sleep and morning symptoms in patients undergoing type-1 polysomnography for suspected sleep-disordered breathing based on questionnaires and polysomnography results. We enrolled 127 patients (lemborexant: N = 57, zolpidem: N = 25, without hypnotics: N = 45). Rapid eye movement sleep in patients on lemborexant was higher than that in patients without hypnotics (P = 0.02). Frequency of unsteadiness in the morning was higher in patients on zolpidem than that in patients without hypnotics (P = 0.04), which remained after adjustment for potential confounders (P = 0.03). Low-dose lemborexant might be suitable when administered as a single dose during polysomnography.
Keywords: Polysomnography, Zolpidem, Lemborexant, Unsteadiness
Introduction
Zolpidem is a non-benzodiazepine drug with a short half-life. Thus, it is frequently used in the clinical setting as a single dose in patients suffering from insomnia during admission. However, z-drugs, including zolpidem, have been related to falls [1]. On the other hand, lemborexant, which blocks both orexin-1 and orexin-2 receptors (i.e., dual orexin receptor antagonist [DORA]) and regulates the sleep/wake state, has less potency and therefore less capacity for causing unsteadiness or falls during the night or morning [2]. Nevertheless, some clinical studies have indicated a regular dose of DORAs can lead to unrefreshed feeling on waking, somnolence, and fatigue in addition to improvement in sleep [3]. These studies may indicate the falling risk in patients on DORAs can still be higher than the falling risk in those without hypnotics.
Polysomnography (PSG) is the standard test for diagnosing sleep-disordered breathing (SDB). Owing to the multiple sensors and unaccustomed circumstances, some patients undergoing PSG need a single dose of a nocturnal hypnotic during the sleep study. Since the hypnotics are usually administered late at night and the patients are discharged relatively early in the morning, the hypnotics are expected to quickly induce sleep and have no residual effects in the morning. To reduce residual effects, a low dose of DORAs could be used, particularly in elderly patients. The aim of this study was to evaluate the efficacy and safety of a single, low dose of lemborexant and zolpidem in patients who were suspected to have SDB and were undergoing PSG.
Methods
This observational study included patients who were suspected to have SDB and were undergoing PSG (Neurofax, Nihon Kohden, Japan) in our hospital (asked to sleep at 21:00; wake-up after 5:00). The patients were assigned to receive zolpidem (5.0 mg; from October 2020 to January 2021; three patients who regularly took zolpidem were admitted in March 2021, April 2021, and July 2021) or lemborexant (2.5 mg; from January 2021 to February 2022) to induce sleep during PSG as needed, but the time of administration was limited before midnight. All patients who were willing to take hypnotics when they had insomnia provided their informed consent at the outpatient clinic before PSG. The study protocol was approved by the ethics committee of the faculty of medicine at Kyushu University (#23142-00).
The Epworth Sleepiness Scale (ESS) was completed at the first visit [4]. Subjective sleep onset was reported as "easy" or "difficult" after PSG. If the answer was "neither", we regarded the answer as missing data. "Sleepiness" and "Unsteadiness" were evaluated using the 9-point Likert scale just after PSG. Higher values of "Sleepiness" and "Unsteadiness" indicate a more sleepy and more unstable state, respectively. Sleep studies were conducted as type-1 PSG and the acquired data were scored using the American Academy of Sleep Medicine scoring rule version 2.
The data are shown as mean±standard deviation (SD), number (%), standardized β and 95% confidence interval (95% CI), or odds ratio (OR) and 95% CI. To evaluate the efficacy and safety of hypnotics use, the patients were divided into three groups: lemborexant, zolpidem, and no-hypnotic (those who had no trouble falling asleep). Chi-squared tests were used for comparison of the binary data. Kruskal–Wallis test or analysis of variance were used after evaluation of Gaussian distribution by Shapiro–Wilk test. Dunnett test was used as the post hoc test (control: no-hypnotic). We evaluated the factors associated with the use of hypnotics by multiple and logistic regression analysis. The variables with P < 0.10 were included in multivariate analysis (Table 1), except for the independent variables in the analysis. When the two-sided P value was <0.05, we rejected the null hypothesis. All statistical analyses were conducted using Stata version 15.1 (Stata-Corp, TX, USA).
Table 1.
Characteristics and differences among hypnotic-based groups
| No-hypnotic | Lemborexant | Zolpidem | P value | |
|---|---|---|---|---|
| Number | 45 | 57 | 25 | – |
| Age (years) | 54.6 ± 16.6 | 54.5 ± 11.5 | 60.2 ± 17.7 | 0.23 |
| Male, N (%) | 31 (68.9) | 43 (75.4) | 14 (56.0) | 0.21 |
| BMI (kg/m2) | 27.1 ± 9.6 | 27.2 ± 4.4 | 25.5 ± 5.1 | 0.26 |
| ESS, points | 7.2 ± 5.2 | 7.5 ± 4.3 | 8.2 ± 5.9 | 0.66 |
| Comorbidities, N (%) | ||||
| Periodic limb movement with arousal | 9 (20.0) | 19 (33.3) | 7 (28.0) | 0.33 |
| Epilepsy | 3 (6.7) | 1 (1.8) | 1 (4.0) | 0.45 |
| Depression/anxiety | 3 (6.7) | 2 (3.5) | 1 (4.0) | 0.74 |
| Sleep-related data | ||||
| Total sleep time (min) | 388.9 ± 93.8 | 440.0 ± 46.9** | 450.1 ± 56.5** | 0.0002 |
| Sleep latency (min) | 10.7 ± 14.7 | 16.4 ± 14.5 | 21.9 ± 13.9** | 0.0001 |
| WASO (min) | 116.4 ± 80.0 | 64.4 ± 37.5** | 61.5 ± 34.4** | 0.004 |
| Stage N1 (%) | 36.8 ± 17.9 | 32.8 ± 12.9 | 21.8 ± 9.6** | 0.0005 |
| Stage N2 (%) | 45.0 ± 13.5 | 46.2 ± 9.9 | 55.1 ± 9.2** | 0.001 |
| Stage N1+N2 (%) | 81.8 ± 9.6 | 79.0 ± 8.9 | 76.9 ± 10.0 | 0.09 |
| Slow-wave sleep (%) | 5.9 ± 8.2 | 5.0 ± 5.2 | 8.4 ± 8.3 | 0.48 |
| REM (%) | 12.6 ± 6.8 | 15.7 ± 6.1* | 14.7 ± 4.3 | 0.03 |
| Sleep-disordered breathing related data | ||||
| Apnea–hypopnea index (h) | 38.2 ± 28.7 | 37.8 ± 21.0 | 30.3 ± 18.8 | 0.39 |
| Arousal index (h) | 41.1 ± 22.6 | 40.4 ± 16.6 | 26.3 ± 14.0** | 0.002 |
| Mean SpO2 (%) | 94.0 ± 4.4 | 94.2 ± 2.1 | 94.3 ± 2.0 | 0.78 |
| Nadir SpO2 (%) | 78.0 ± 13.7 | 76.8 ± 13.4 | 80.6 ± 7.5 | 0.66 |
| Questionnaire | ||||
| Easy to fall asleep, N (%)a | 21 (55.3) | 29 (64.4) | 17 (81.0) | 0.14 |
| Morning sleepiness, points | 2.6 ± 1.8 | 3.4 ± 2.0 | 3.4 ± 2.3 | 0.11 |
| Morning unsteadiness, points | 1.7 ± 1.4 | 2.0 ± 1.5 | 2.6 ± 1.8* | 0.04 |
N Number, BMI Body mass index, ESS Epworth Sleepiness Scale, WASO Wake time after sleep onset, REM Rapid eye movement, AHI Apnea-hypopnea index
aTotal number of patients were 104 due to missing value
*P < 0.05; **P < 0.01
Results
One-hundred and twenty-seven patients were enrolled. Among them, 57 and 25 patients were administered lemborexant or zolpidem as a single dose of hypnotic, respectively (Table 1). The mean±SD of age, body mass index (BMI), and ESS of all patients were 55.7±14.8 years, 26.8±6.8 kg/m2, and 7.7±4.8 points, respectively. The most prevalent comorbidity was periodic limb movement with arousal. There were no differences in age, sex, BMI, ESS, and comorbidities among the groups. Lemborexant and zolpidem groups had significantly longer sleep based on total sleeping time and wake time after sleep onset than those in the no-hypnotic group. Rapid eye movement (REM) sleep moderately increased in the lemborexant group when compared to the no-hypnotic group (P = 0.02), while Stage N3 did not differ among the study groups. Although the apnea–hypopnea index was not different among the groups, the zolpidem group had more prolonged sleep latency and less arousal index when compared with the no-hypnotic group (P = 0.005, P = 0.002, respectively). Along with the low value of micro-arousal in zolpidem group, the proportion of sleep stage N1 was lower than that of the no-hypnotic group. Zolpidem group reported more morning unsteadiness than those in the no-hypnotic group (P = 0.04).
Multivariate analysis showed patients with zolpidem experienced more morning unsteadiness than those without hypnotics (P = 0.03) (Table 2). In contrast, there were no differences between the lemborexant group and the no-hypnotic group with regard to REM sleep and morning unsteadiness.
Table 2.
Hypnotics effects on sleep parameters
| REM sleep | Easy to fall asleep | Sleepiness | Unsteadiness | |||||
|---|---|---|---|---|---|---|---|---|
| β | P value | OR (95% CI) | P value | β | P value | β | P value | |
| Hypnotics | ||||||||
| No-hypnotic | (ref.) | – | (ref.) | – | (ref.) | – | (ref.) | – |
| Lemborexant | 0.08 | 0.28 | 0.69 (0.23–2.07) | 0.51 | 0.19 | 0.08 | 0.14 | 0.21 |
| Zolpidem | −0.11 | 0.13 | 1.66 (0.40–7.00) | 0.49 | 0.16 | 0.13 | 0.23 | 0.03 |
The variables with P < 0.10 were included in multivariate analysis, as shown in Table 1, except for the independent variables in the multivariate analysis
REM Rapid eye movement, OR Odds ratio, CI confidence interval
Discussion
This study investigated whether low-dose lemborexant in a single-use regimen is suitable as a hypnotic during PSG. For hypnotics, z-drugs have been widely used but have become unpopular recently as they became with unsteadiness during the night or the next morning, leading to falling incidents. The ideal characteristics of a nocturnal, single-dose hypnotics would be quick induction of sleep, minimum influence on REM sleep, and minimum or no sleepiness and unsteadiness in patients who might drive the following morning.
Zolpidem may independently increase falls, which was consistent with the residual unsteadiness on waking observed in this study [1]. The unsteadiness might be related to the fact that zolpidem, as a promoter of GABAa, leads to muscle relaxation through inhibitory neurotransmission in the central nervous system [5]. Furthermore, the present study showed a low dose of lemborexant slightly increased REM sleep but did not affect sleepiness and unsteadiness, which was consistent with the previous studies [6, 7]. Since lemborexant selectively blocks both orexin-1 and orexin-2 receptors but does not bind to GABAa receptors, these differences could explain why the patients with lemborexant did not show unsteadiness in the morning, which can reduce the risk of falls and traffic accidents [1, 8]. Hypoxemia caused by SDB may lead to a high risk of falling due to damage to the cerebellum, which is responsible for safe motor control [9]. In patients undergoing PSG, the risk of falling during night is higher since they are equipped with various probes/electrodes. A large study reported that 33.6% of patients who fell in hospital experienced minor or major injuries (29.7 and 3.9%, respectively) [10]. Therefore, low-dose lemborexant as a single dose may be useful to prevent falls and injury particularly in this study setting.
The strength of this study is the first study to assess the effects of low-dose lemborexant on sleep and symptoms just after PSG in patients with SDB. This study has some limitations. First, since the number of patients taking zolpidem was small, we only compared the differences between patients without hypnotics and those with hypnotics to avoid distorting results due to the low power of the post hoc test after multiple comparisons. Thus, the comparison of the differences in effects or side effects between zolpidem and lemborexant cannot be conclusive. As we have been using 5 mg of zolpidem as the initial dose for a long time in our institute for patient safety purposes, we did not use the data for 10 mg zolpidem in this study. Therefore, we cannot mention the side effects of 10 mg zolpidem in this study. Second, as we did not randomize or crossover types of hypnotics in this study because of its observational nature, there would remain some confounders. It was also ethically challenging to administer hypnotics to patients who did not need them. There were no significant differences among the hypnotic-based groups according to age, sex, BMI, and ESS. Third, as we had no prior PSG data, some confounders may exist in this study. Finally, we cannot extend our results to the effects of other dosages and hypnotics.
Conclusions
Lemborexant could induce sleep with minimum change in REM sleep and less morning unsteadiness in patients who underwent PSG compared to patients without a hypnotic. These results suggest that low-dose lemborexant might be useful and safe for a single-dose administration during PSG.
Declarations
Conflict of interest
There are no conflicts of interest to declare regarding this paper.
Footnotes
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