Ex) Article Title, Author, Keywords
Ex) Article Title, Author, Keywords
R Clin Pharm 2023; 1(1): 10-21
Published online June 30, 2023 https://doi.org/10.59931/rcp.23.001
Copyright © Asian Conference On Clinical Pharmacy.
Hiroyuki Kamei1,2 
, Tsuyoshi Kitajima2 , Masakazu Hatano1,2,3 , Ippei Takeuchi4 , Manako Hanya1 , Kiyoshi Fujita4, Nakao Iwata2
Correspondence to:Hiroyuki Kamei
E-mail hkamei@meijo-u.ac.jp
ORCID
https://orcid.org/0000-0003-3778-2352
This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/bync/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Background: Benzodiazepines play a central role in treating insomnia with negative effects, including muscle relaxants and other adverse effects, and lead to dependence when used for a long period. The present study examined the psychiatric outpatient status with each type of hypnotic and compared the efficacy and satisfaction among benzodiazepines, nonbenzodiazepines, a melatonin receptor agonist, and an orexin receptor antagonist using subjective patient assessments to provide more effective treatment for patients with insomnia based on their symptoms.
Methods: A total of 158 psychiatric outpatients who had used hypnotics regularly or irregularly for ≥4 weeks were investigated. Pharmacists interviewed them and assessed the severity of their insomnia using the Athens Insomnia Scale. A questionnaire survey was conducted to clarify the patient’s status of using hypnotics.
Results: A positive correlation was observed between drug efficacy and satisfaction. Patients using intermediate- and long-acting benzodiazepine hypnotics demonstrated the highest satisfaction. Representative reasons for being satisfied with their current hypnotic prescriptions included “having achieved a sufficient therapeutic effect from the first day” and “achieving a sense of good sleep.” Therefore, the efficacy of hypnotics was the most frequent reason. Conversely, some patients were distressed by their adverse effects, including sleepiness during the daytime and difficulty waking up in the morning.
Conclusion: The present results highlight the importance of reducing the symptoms of insomnia and monitoring the efficacy of hypnotics to increase the satisfaction levels of patients receiving insomnia treatment.
KeywordsHypnotics; Insomnia; Mental disorders; Medication status; Satisfaction
Sleep disorders are common among individuals with psychiatric diseases [1]. A close relationship has been reported between psychiatric diseases and sleep disorders [2]. The incidence of sleep disorders in patients with schizophrenia ranges between 30 and 80% [3]. Sleep disorders occur in the acute phase of schizophrenia, and patients are unable to fall asleep, which leads to the development of sleep disorders [3]. Furthermore, up to 80% of patients with unipolar depression related to mood disorders have insomnia symptoms [4]. Insomnia is also highly prevalent in disorders such as generalized anxiety disorder [5] and posttraumatic stress disorder [6]. Insomnia in these patients varies and includes difficulty in falling asleep, nocturnal awakening, early morning awakening, and difficulty achieving sound sleep. On the other hand, insomnia was reported in the depressive phase in patients with bipolar disorder [7], similar to those with unipolar depression. Furthermore, difficulty in falling asleep or nocturnal awakening appears even in the manic state, frequently shortening the sleep time. Insomnia is considered to be an initial symptom of psychiatric diseases, an opportunity for recurrence, or a mental state-exacerbating factor; therefore, sleep management is important in the treatment of psychiatric diseases, such as schizophrenia [3] and mood disorders [4,7].
Among help-seeking behaviors in psychiatric patients for sleep disorders [8-10], many patients emphasized the efficacy of hypnotics, namely, the feeling of sound sleep or fast-acting properties. Furthermore, the efficacy of hypnotics markedly influenced the degree of satisfaction [9,10]. To further improve the degree of satisfaction, it is important for clinicians to confirm the presence or absence of adverse reactions, such as carry-over sedation the next morning [11]. Various hypnotics have been developed to ameliorate difficulties falling asleep, nocturnal awakening, early morning awakening, and difficulty in sound sleep; therefore, they must be properly used in consideration of a patient’s state of sleep, age, and underlying conditions [11]. The importance of quantitative and qualitative sleep improvements has been indicated, and a previous study reported that an improvement in the state of sleep contributed to a better quality of life [12].
Benzodiazepines currently play a central role in drug therapy in the field of sleep medicine. Benzodiazepines, which became commercially available in the 1960s, exert various effects, such as hypnotic, anti-anxiety, anti-convulsive, muscle relaxant, and amnesia-inducing effects [13]. Among these, drugs with strong hypnotic effects have been developed as hypnotics. However, there have been limitations, such as adverse reactions, including muscle relaxant effects, long-term use-related dependency, and rebound insomnia. Drugs in which these adverse reactions were attenuated were developed in the 1980s [14]. They act on benzodiazepine receptors, but have a structural formula that differs from those of conventional benzodiazepines; therefore, they have been termed non-benzodiazepines [14]. However, even non-benzodiazepines may induce falling, amnesia, or delirium in elderly patients [15]. To overcome these limitations, drugs that more specifically act on the sleep/awakening system are necessary [15]. Hypnotics with new mechanisms of action, such as ramelteon, a melatonin receptor agonist (2010) [16,17] and suvorexant, an orexin receptor antagonist (2014) [18,19], recently became commercially available in Japan. Based on these findings, neither ramelteon nor suvorexant exerts any muscle relaxant or amnesia-inducing effects, which is in contrast to benzodiazepines; therefore, these drugs may be available for elderly patients. Although surveys regarding various hypnotics have been conducted, patient satisfaction with benzodiazepines, ramelteon, and suvorexant, namely, their self-awareness effects or adverse reactions, remains unclear.
In this study, we investigated the prescription status of various hypnotics and compared efficacy and satisfaction among non-benzodiazepines, different types of benzodiazepines, a melatonin receptor agonist, and an orexin receptor antagonist using subjective assessments of patients.
Subjects consisted of 164 psychiatric disease patients (≥20 years old) taking a single hypnotic (non-benzodiazepines, benzodiazepines, ramelteon, and suvorexant) routinely or as needed for 4 weeks or longer and who had consulted the outpatient clinic of the Department of Psychiatrics, Fujita Health University Hospital and the outpatient clinic of Okehazama Hospital between April and July 2016. Patients with marked cognitive hypofunction or a markedly unstable mental state were excluded. The present study was approved by the Institutional Review Board of Fujita Health University and Okehazama Hospital. After an explanation of the present study to subjects, they provided written informed consent. Since 6 patients did not consent to the questionnaire survey, 158 participated in the present study.
After an examination by the attending physician, pharmacists inquired about sleep at night and functional disturbances during the daytime using the Japanese version of Athens Insomnia Scale [20-22] in an interview room. The Athens Insomnia Scale comprised 8 items measured with a 4-point Likert-type scale (i.e. #1 sleep induction, #2 awakening during the night, #3 awakening in the early morning, #4 total sleep duration insufficiency, #5 sleep quality, #6 well-being during the day, #7 functioning capacity during the day, and #8 sleepiness during the day) [21]. Each item of the AIS is rated on a 4-point scale (i.e., 0=no problem at all, 1=slightly problematic, 2=markedly problematic, and 3=extremely problematic).
The cut-off value of the Athens Insomnia Scale for identifying pathological insomnia was estimated at 6 points or more [21]. A questionnaire survey, as described below, was subsequently conducted. We assessed knowledge (drug names, doses, effects, and adverse reactions) on hypnotics, the reasons why hypnotics were prescribed, the degree of satisfaction with hypnotics and its reasons, the realization of drug efficacy and adverse reactions with hypnotics, and patient-expected characteristics of hypnotics. In assessments of knowledge on “effects” and “adverse reactions”, we asked patients whether they knew of the effects and side effects of hypnotics, which should have been explained by a pharmacist or doctor.
We also investigated the relationships between the Athens Insomnia Scale and degree of satisfaction with prescribed drugs and between the degree of satisfaction and degree of drug-efficacy realization with prescribed drugs. The degree of satisfaction was evaluated using 5 grades; 5: “satisfied”, 4: “slightly satisfied”, 3: “neither”, 2: “somewhat unsatisfied”, and 1: “unsatisfied”. The degree of drug-efficacy realization with prescribed drugs was assessed using 5 grades; 5: “effective”, 4: “slightly effective”, 3: “unclear (neither)”, 2: “did not clearly notice any effectiveness (somewhat ineffective)”, and 1: “did not notice effectiveness (ineffective)”.
In statistical analyses, we used IBM SPSS ver. 22 software. Based on the distribution of data, analyses were adequately performed. With respect to questionnaire items, results were compared between two groups using the Mann-Whitney U test. Regarding multi-group comparisons, the Kruskal-Wallis test was conducted, followed by multiple comparisons using Bonferroni’s method. The relationship with age or severity was examined using Pearson’s correlation coefficient, and items on patient characteristics were analyzed using the chi-square test.
As shown in Table 1, there were more female subjects than male subjects, and most were 40–59 years old. Regarding their occupation, office workers accounted for the majority. Primary diseases consisted of depression, schizophrenia, and bipolar disorder. Thirteen patients had insomnia, but no other disorders (8.2%) (Table 1). As shown in Table 2, currently prescribed hypnotics consisted of non-benzodiazepines, benzodiazepines, the melatonin receptor agonist, ramelteon, and the orexin receptor antagonist, suvorexant. These hypnotics had been routinely prescribed for 127 patients (80.4%) and as needed for 31 (19.6%). The mean duration of hypnotic therapy was 8.1±7.6 years.
Table 1 Patient characteristics (n=158)
| Characteristics | Number (%) |
|---|---|
| Sex | |
| Male | 63 (39.9) |
| Female | 95 (60.1) |
| Average age (mean±SD) | 43.2±13.9 |
| 20–39 years | 47 (29.7) |
| 40–59 years | 92 (58.2) |
| ≥60 years | 19 (12.0) |
| Occupation | |
| Office workers (including part time workers) | 55 (34.8) |
| Housewives/-husbands | 36 (22.8) |
| Public service workers | 4 (2.5) |
| Students | 2 (1.3) |
| Persons without an occupation | 50 (31.6) |
| Others | 11 (7.0) |
| Disorder | |
| Depression | 50 (31.6) |
| Schizophrenia | 45 (28.5) |
| Bipolar disorder | 41 (25.9) |
| Insomnia | 13 (8.2) |
| Mood disorder | 1 (0.6) |
| Adjustment disorder | 1 (0.6) |
| Restless legs syndrome | 1 (0.6) |
| Narcolepsy | 1 (0.6) |
| Alcohol dependency | 1 (0.6) |
| Depressive state | 1 (0.6) |
| Social anxiety disorder | 1 (0.6) |
| Sleep rhythm disorder | 1 (0.6) |
| Developmental disorder | 1 (0.6) |
Table 2 Prescribed hypnotics (n=158)
| Type of hypnotic | Prescribed drug | Number (%) | Groups | |
|---|---|---|---|---|
| Non-benzodiazepine | Zopiclone | 6 (3.8) | Non-benzodiazepine | |
| Zolpidem | 3 (1.9) | |||
| Eszopiclone | 19 (12.0) | |||
| Benzodiazepine | Triazolam | Very short | 1 (0.6) | Very short/short-acting benzodiazepine |
| Brotizolam | Short | 35 (22.2) | ||
| Rilmazafone hydrochloride hydrate | Short | 5 (3.2) | ||
| Flunitrazepam | Intermediate | 30 (19.0) | Intermediate/long-acting benzodiazepine | |
| Nitrazepam | Intermediate | 6 (3.8) | ||
| Estazolam | Intermediate | 2 (1.3) | ||
| Flurazepam | Long | 1 (0.6) | ||
| Melatonin receptor agonist | Ramelteon | 25 (15.8) | Melatonin receptor agonist (ramelteon) | |
| Orexin receptor antagonist | Suvorexant | 25 (15.8) | Orexin receptor antagonist (suvorexant) | |
The mean dose of non-benzodiazepine hypnotics in 28 patients was 2.80±1.52 mg/day (diazepam-converted value). In 41 patients taking short-acting benzodiazepine hypnotics, it was 5.85±2.21 mg/day. In 39 patients taking middle-/long-acting benzodiazepine hypnotics, it was 7.30±2.80 mg/day. In 25 patients taking the melatonin receptor agonist, it was 3.82±3.37 mg/day. In 25 patients taking the orexin receptor antagonist, it was 19.60±1.38 mg/day.
Among 28 patients taking non-benzodiazepine hypnotics, 5 (17.9%) were diagnosed with schizophrenia. Eight (19.5%) out of the 41 patients taking very short/short-acting benzodiazepines, 20 (51.3%) out of the 39 taking intermediate/long-acting benzodiazepines, 5 (20.0%) out of the 25 taking the melatonin receptor agonist, and 7 (28.0%) out of the 25 taking the orexin receptor antagonist were diagnosed with schizophrenia. The rate of schizophrenia was significantly higher in patients taking intermediate/long-acting benzodiazepines than in those taking non-benzodiazepine hypnotics or short-acting benzodiazepines (
As shown in Fig. 1, the most common reasons (multiple responses were acceptable) patients sought hypnotic therapy were as follows: difficulty in falling asleep, non-sound sleep, nocturnal awakening (several times), and early morning awakening.
Figure 1. Reasons patients sought hypnotic therapy.
Concerning the degree of recognition of prescribed drugs, 110 (69.6%) out of 158 subjects knew the names of currently prescribed hypnotics, whereas 48 (30.4%) did not.
Regarding an understanding of the effects and adverse reactions of currently prescribed drugs, 26 (16.5%) out of 158 subjects understood them, 46 (29.1%) had mostly understood them, 44 (27.8%) had not completely understood them despite continuous therapy, 40 (25.3%) had not understood them despite continuous therapy, and 2 (1.3%) selected “unclear”.
The severity of insomnia was evaluated using the Athens Insomnia Scale. The mean score was 5.3±10.7. Sixty-three patients (39.9%) showed a score of ≥6, which suggested insomnia, while 95 (60.1%) had a score of <6. Regarding the severity of insomnia, 20 (12.7%) out of 158 subjects were troubled, 38 (24.1%) were slightly troubled, 13 (8.2%) were not markedly troubled, 84 (53.2%) were not troubled, and 3 (1.9%) selected “neither”.
With respect to the influence of insomnia on daytime activities, 47 patients (29.7%) reported its influence, 56 (35.4%) a slight influence, 11 (7.0%) a negligible influence, 35 (22.2%) no influence, and 9 (5.7%) selected “neither”.
When patients were asked the most important characteristics of hypnotics prescribed by physicians, they selected (in order of reported importance) “sound sleep”, “absence of withdrawal symptoms”, “immediate effects (approximately 15 to 30 minutes)”, “absolute effects”, and “the absence of sleepiness or dullness in the morning or during the daytime” (Fig. 2).
Figure 2. Most important characteristics of hypnotics prescribed by physicians.
Concerning the degree of satisfaction with hypnotics, 61 (38.6%) out of 158 subjects were satisfied, 51 (32.3%) were slightly satisfied, 30 (19.0%) were slightly dissatisfied, 5 (3.2%) were dissatisfied, and 11 (7.0%) selected “neither”.
When the 112 patients who were “satisfied” or “slightly satisfied” were asked the reason for their satisfaction, the most common selections were “because the effects were obtained from the first day of administration”, “because the drug was absolutely effective”, “because sound sleep was achieved”, “because I could sleep soundly until morning”, and “because sleep time was prolonged” (Fig. 3A).
Figure 3. Reasons of satisfaction (A) or dissatisfaction (B) with hypnotic therapy.
When the 35 patients who were “dissatisfied” or “slightly dissatisfied” were asked the reason for their dissatisfaction, the most common selections were “because immediate effects (15 to 30 minutes) were not obtained”, “because the effects were weak”, “because sleepiness was present in the morning or during the daytime”, and “because nocturnal awakening was present” (Fig. 3B). Of the 35 patients “dissatisfied” or “slightly dissatisfied” with hypnotics, 19 (54.3%) consulted the attending physicians with dissatisfaction with hypnotics, 3 (8.6%) consulted them through an inquiry, and 13 (37.1%) had not consulted them.
The doses of hypnotics were assessed as high in 3 (1.9%) out of 158 subjects, slightly high in 9 (5.7%), appropriate in 103 (65.2%), slightly low in 10 (6.3%), low in 5 (3.2%), and unclear in 28 (17.7%).
Concerning the effects of hypnotics, 70 (44.3%) out of 158 subjects felt they were “effective”, 61 (38.6%) “slightly effective”, 6 (3.8%) “not very effective”, 8 (5.1%) “ineffective”, and 13 (8.2%) selected “unclear”.
Regarding the frequency of adverse reactions to hypnotics, 17 (6.6%) out of 158 subjects selected “every day”, 18 (11.4%) “often (once a week or more)”, 13 (14.6%) “sometimes (once a month or more)”, 29 (18.4%) “rarely”, 62 (39.2%) “absent”, and 19 (12.0%) “unclear”.
Among the 48 patients who reported “every day”, “often (once a week or more)”, or “sometimes (once a month or more)”, sleepiness during the daytime was observed in 15 (28.3%), difficulty waking up in 9 (17.0%), malaise in 8 (15.1%), dizziness in 4 (7.5%), a memory disorder in 4 (7.5%), memory reduction in 3 (5.7%), a reduction in concentration in 3 (5.7%), dry mouth in 2 (3.8%), nausea in 2 (3.8%), tremors of the fingers in 1 (1.9%), and abdominal pain in 1 (1.9%) (including duplicated patients). There were no significant differences in the presence or absence of adverse reactions among non-benzodiazepine hypnotics, short-acting benzodiazepines, middle-/long-acting benzodiazepines, the melatonin receptor agonist, and orexin receptor antagonist (
Furthermore, 17 (35.4%) were troubled with these symptoms, 17 (35.4%) were slightly troubled, 6 (12.5%) selected “neither”, 4 (8.3%) were not markedly troubled, and 4 (8.3%) were not troubled.
As shown in Fig. 4, among the 28 patients taking non- benzodiazepine hypnotics, 20 (71.7%) reported that the most important characteristics of hypnotics were “items regarding efficacy”. Furthermore, 27 (65.9%) out of the 41 patients taking short-acting benzodiazepines, 26 (66.7%) out of the 39 taking middle-/long-acting benzodiazepines, and 13 (52.0%) out of the 25 taking the orexin receptor antagonist emphasized the importance of “items regarding efficacy”.
Figure 4. Patient-supported characteristics of hypnotics with respect to prescribed drugs.
Among the 25 patients taking the melatonin receptor agonist, 14 (56.0%) reported the most important characteristics of hypnotics as “items regarding adverse reactions” (Fig. 4).
Concerning the realization of the efficacy of various hypnotics, among the 28 patients taking non-benzodiazepine hypnotics, 23 (82.1%) selected “realized (drug efficacy)” or “slightly realized”. Of the 41 patients taking short-acting benzodiazepines, 36 (87.8%) selected “realized” or “slightly realized”. Among the 39 patients taking middle-/long-acting benzodiazepines, 36 (92.3%) selected “realized” or “slightly realized”. Of the 25 patients taking the melatonin receptor agonist, 17 (68.0%) selected “realized” or “slightly realized”. Of the 25 patients taking the orexin receptor antagonist, 19 (76.0%) selected “realized” or “slightly realized”. There were no significant differences among the 5 types of hypnotics (Fig. 5A).
Figure 5. Realization of efficacy (A) and satisfaction (B) in various hypnotics.
Concerning the realization of satisfaction in various hypnotics, of the 28 patients taking non-benzodiazepine hypnotics, 18 (64.3%) selected “satisfied” or “slightly satisfied”. Among the 41 patients taking short-acting benzodiazepines, 31 (75.6%) selected “satisfied” or “slightly satisfied”. Of the 39 patients taking middle-/long-acting benzodiazepines, 32 (82.1%) selected “satisfied” or “slightly satisfied”. Among the 25 patients taking the melatonin receptor agonist, 14 (56.0%) selected “satisfied” or “slightly satisfied”. Of the 25 patients taking the orexin receptor antagonist, 17 (68.0%) selected “satisfied” or “slightly satisfied”. There were significant differences among the 5 types of hypnotics (
The influence of demographic data on the degree of satisfaction was as follows: no significant difference was observed in the degree of satisfaction between men (4.1±1.1) and women (3.7±1.3) (
We investigated the relationships between the degrees of satisfaction and drug efficacy realization with prescribed drugs. The results obtained revealed a moderately positive correlation between the degrees of satisfaction and drug efficacy realization (correlation coefficient: r=0.441) (Fig. 6).
Figure 6. Correlation between the perceived efficacy of hypnotics and patient satisfaction.
The influence of demographic data on the Athens Insomnia Scale was as follows: no significant difference was observed in the Athens Insomnia Scale between men (4.6±3.1) and women (5.8±3.7) (
Regarding the Athens Insomnia Scale for patients taking various hypnotics, of the 28 patients taking non-benzodiazepine hypnotics, 16 (57.1%) scored 6 or higher, which reflects insomnia (Fig. 7). Furthermore, 12 (29.3%) out of the 41 patients taking very short/short-acting benzodiazepines, 20 (51.3%) out of the 39 taking intermediate/long-acting benzodiazepines, 4 (16.0%) out of the 25 taking the melatonin receptor agonist, and 11 (44.0%) out of the 25 taking the orexin receptor antagonist scored 6 or higher (Fig. 7). A significant difference was observed between patients taking non-benzodiazepine hypnotics and those taking the melatonin receptor agonist (
Figure 7. Athens Insomnia Scale for patients who taking the various hypnotics.
We investigated the relationship between the Athens Insomnia Scale and the degree of satisfaction with the prescribed drugs. The results obtained revealed a moderately negative correlation between the Athens Insomnia Scale, which was established to evaluate the severity of insomnia, and the degree of satisfaction with hypnotics (correlation coefficient: r=–0.422) (Fig. 8).
Figure 8. Correlation between the Athens Insomnia Scale and patient satisfaction with hypnotics.
We also examined the correlation between the Athens Insomnia Scale and degree of drug efficacy realization. The results obtained showed a weakly negative correlation between the Athens Insomnia Scale, which was established to evaluate the severity of insomnia, and the degree of drug efficacy realization (correlation coefficient: r=–0.278).
Concerning adverse reactions, no significant differences were observed between the severity of insomnia (assessment with the Athens Insomnia Scale) and the incidence of adverse reactions (
In the present study, we investigated the status of using each type of hypnotic, the sleep status, and satisfaction with the hypnotic in psychiatric outpatients who received various hypnotics for ≥4 weeks. To the best of our knowledge, this is the first study that focused on comparisons of efficacy and satisfaction among non-benzodiazepines, different types of benzodiazepines, a melatonin receptor agonist, and an orexin receptor antagonist using subjective assessments by patients.
The results obtained showed that patients selecting “satisfied” or “slightly satisfied” with prescribed hypnotics in this survey accounting for 70.1%. The primary reasons included items related to efficacy: “because the effects were obtained from the first day of administration” and “because the drug was absolutely effective”. Among patients selecting “dissatisfied” or “slightly dissatisfied”, the primary reasons also included items related to efficacy: “because immediate effects (15 to 30 minutes) were not obtained” and “because the effects were weak”. In addition, a correlation was observed between the degrees of satisfaction with hypnotics and drug efficacy realization, suggesting that the degree of satisfaction with prescribed hypnotics increases with the degree of hypnotic efficacy realization. Therefore, to improve patient satisfaction with insomnia treatments, it may be important to reduce insomnia and improve the degree of hypnotic efficacy realization.
Based on subjective assessments of patients in the present study, the most important factors for hypnotics included items related to efficacy: “sound sleep” and “immediate effects”, followed by items related to adverse reactions: “absence of withdrawal symptoms” and “absence of sleepiness or dullness in the morning or during the daytime”. This result is supported by previous findings [8] showing that the treatment preference of patients is to improve issues associated with sleep onset and maintenance. Therefore, patients may emphasize efficacy, involving sound sleep or immediate effects, despite their negative impression of hypnotics as dangerous drugs with a high incidence of adverse reactions. A negative correlation was observed between the Athens Insomnia Scale and the degree of satisfaction with prescribed drugs, suggesting that the degree of satisfaction with prescribed drugs is higher in patients with a lower Athens Insomnia Scale score. Likewise, a negative correlation was noted between the Athens Insomnia Scale and the degree of drug efficacy realization. Based on these results, the degrees of satisfaction with hypnotics and drug efficacy realization may both be increased by clarifying factors for nocturnal insomnia or functional disturbance during the daytime in individual patients and reducing the Athens Insomnia Scale score. Satisfaction with treatment is important in investigations of insomnia. Previous studies reported that psychological (behavioral) treatment was more acceptable than hypnotics for chronic insomnia because of the presumption that psychological treatment improved daytime functioning with better long-term effectiveness and included fewer side effects [8,23]. Further research on treatment preferences and patient satisfaction are warranted.
In the present study, significant differences were observed in the degree of satisfaction with prescribed drugs among patients taking non-benzodiazepines, very short/short-acting benzodiazepines, intermediate/long-acting benzodiazepines, the melatonin receptor agonist, and the orexin receptor antagonist. Among patients taking intermediate/long-acting benzodiazepines, the rate of those selecting “satisfied” or “slightly satisfied” was the highest, whereas in patients taking the melatonin receptor agonist, it was the lowest (56.0%). However, in this group, patients reporting satisfaction with prescribed drugs as “unclear” accounted for 28.0%, while those selecting “dissatisfied” or “slightly dissatisfied” accounted for 16%; this percentage was the lowest among the 5 groups. Many patients reported satisfaction with prescribed drugs as “unclear”, possibly because the mean dose (3.8±3.4 mg/day) of the melatonin receptor agonist was lower than the standard dose (8 mg/session), affecting drug efficacy realization; 14 out of 25 patients had taken the melatonin receptor agonist at 1 mg/day, corresponding to 1/8 of the standard dose, under a diagnosis of a sleep rhythm disorder possibly based on the findings of previous studies [24]. When administering low-dose melatonin receptor agonists 5 hours before bedtime as MT2 receptor-mediated actions, the circadian rhythm phase was advanced, suggesting that low-dose therapy is useful for the treatment of a marked circadian rhythm sleep disorder-related delay in sleep hours or day-and-night inversion. Furthermore, the rate of patients scoring 6 or higher, which reflects insomnia according to the Athens Insomnia Scale, was the lowest among the 5 groups, and the rate of patients with a severe status was low; therefore, it may have been difficult to realize symptom improvements.
As the most important characteristics of hypnotics, more than 50% of patients taking the melatonin receptor agonist selected “items regarding adverse reactions”, suggesting that the rate of patients selecting drugs with a low incidence of adverse reactions among those taking the melatonin receptor agonist was higher than that of patients selecting effective drugs. In addition, the incidence of adverse reactions in patients taking the melatonin receptor agonist was the lowest among the 5 groups; this may have contributed to the lowest rate of patients selecting “dissatisfied” or “slightly dissatisfied”. Furthermore, melatonin receptor agonists do not exhibit any anti-anxiety or sedative effects, and are considered to be relatively appropriate for untreated patients with insomnia or those with mild anxiety-related symptoms [17]. Since various hypnotics have different characteristics and the sense of values for sleep differs among individual patients, it may be necessary to understand patient satisfaction with hypnotic/drug properties and select adequate hypnotics.
The present results revealed that the rate of patients with schizophrenia was significantly higher among those taking intermediate/long-acting benzodiazepines than in those taking non-benzodiazepines or very short/short-acting benzodiazepines. This result shows that relatively intermediate/long-acting (long-acting) drugs may be prescribed for schizophrenia patients in our sample to manage nocturnal or early morning awakening rather than difficulty in falling asleep. Among psychiatric patients with poor sleep, several correlates of help-seeking behavior and sleep problem recognition were identified [9]. Psychiatric patients may have attributed their sleep difficulties to their psychiatric conditions [25]. Therefore, clinicians and pharmacists play an important role in detecting these cases during consultations with patients and provide them with the necessary treatment and information [26].
Additionally, the present study showed that patients who did not know the names of currently prescribed hypnotics accounted for 30.4%. Furthermore, patients selecting “do not understand” or “do not clearly understand” the effects of/adverse reactions to hypnotics accounted for 53.1%. Many patients consulting the outpatient clinic of the Department of Psychiatrics tend to take hypnotics regardless of diseases. Precautions are initially explained in detail, but not every time for patients who have consulted an outpatient clinic for a long period. Differing perceptions of insomnia and its treatments between patients and clinicians may contribute to some paradox. Patients typically describe their insomnia in terms of its daytime impairments in everyday life, extending the experience beyond nighttime sleep difficulties. Therefore, patients generally perceive available insomnia treatments as ineffective or unattractive, they are prone to self-medicate, and are more likely to believe that insomnia will spontaneously resolve [27,28]. The present study showed that frequent adverse reactions included carry-over effects, such as sleepiness during the daytime and uncomfortable awakening in the morning. Patients selecting “dissatisfied” or “slightly dissatisfied” with prescribed drugs accounted for 22.0%; among these, 54.3% had consulted physicians when dissatisfied with the efficacy or safety of hypnotics. Furthermore, patients who had experienced adverse reactions accounted for 36.8%; of these, 70.8% selected “troubled” or “slightly troubled” with adverse reactions. The combination of our results and previous findings indicate that clinicians and pharmacists need to explain/confirm effects/adverse reactions regularly to patients for whom hypnotics have been prescribed over a long period. If the characteristics of hypnotics cause dissatisfaction or adverse reactions, it may be important for clinicians to propose a switch to a more appropriate drug to patients.
The present study had multiple strengths, including comparisons of efficacy and satisfaction among various types of hypnotics and the use of subjective assessments of patients and understanding what patients expect from hypnotics. However, there were several limitations. A recent meta-analysis reported that the use of non-benzodiazepines for an average of 10.5 weeks was effective against insomnia in major depressive patients without any risk of side effects [29]. However, the effects of the longer-term use of non-benzodiazepines on the incidence of adverse events remain unclear [29]. Therefore, inclusion criteria for the administration of a hypnotic agent for at least 4 weeks in the present study created a bias towards patients who experienced better efficacy, tolerability, and/or satisfaction. Furthermore, the duration of hypnotic treatment in this psychiatric patient was 8 years on average. Chronic insomnia may be associated with psychiatric comorbidities; however, the relationship between them is complex and includes bidirectional causation. A previous study reported that chronic insomnia that had been treated with hypnotics over a 6-year period was a risk factor for psychiatric disorders, such as schizophrenia, depression, and bipolar disorder [30]. This finding led to the concept that managing sleep disturbances may be a fundamental priority for the prevention of ensuing psychiatric co-morbidities. In addition, the present results showed that patients selecting “satisfied” or “slightly satisfied” with prescribed hypnotics in this survey accounted for 70.1%. This result may reflect patients receiving hypnotic therapy for a very long duration (8 years on average). If they had not been satisfied, they may not have continued therapy for that long. This result may markedly differ if this was a prospective trial. Another limitation is that since we did not pre-test the questionnaire, some patients may not have understood or may have misunderstood the terms used in the questionnaire. Moreover, in assessments of knowledge on “effects” and “adverse reactions”, we asked patients whether they knew the effects and side effects of hypnotics, which should have been explained by a pharmacist or doctor. Since we did not confirm details on the effects and side effects of hypnotics that the patients were taking, it was not possible to assess the level of knowledge on hypnotics more accurately. Furthermore, in the present study, we did not examine the relationship between the presence/absence of insomnia as measured by the Athens Insomnia Scale and adherence with hypnotic therapy. Therefore, the degree of insomnia in patients who are adhering to hypnotics well versus those who are not is unclear.
The degree of satisfaction with prescribed drugs was the highest in patients taking intermediate/long-acting benzodiazepines, whereas it was the lowest in those taking the melatonin receptor agonist. Furthermore, the present results suggest that the degree of satisfaction with hypnotics was higher in patients with a higher degree of drug efficacy realization. To improve the degree of satisfaction with insomnia treatment, it may be important to reduce insomnia and increase the degree of drug efficacy realization. Furthermore, approximately 30% of patients had experienced adverse reactions. Of these, approximately 70% selected “troubled” or “slightly troubled” with adverse reactions. Therefore, it may be necessary to pay attention to the presence or absence of adverse reactions in addition to effects in patients taking hypnotics. Moreover, the characteristics of various hypnotics differ, and the sense of value for sleep varies among individual patients; therefore, it is important to understand the degree of satisfaction with hypnotics/their characteristics and select appropriate hypnotics.
None.
We would like to thank Ms. Erika Manabe for her support.
The present study was not specifically supported by any funding. The authors report no conflicts of interest related to this research. Dr. Kitajima has received research grants from Eisai, Takeda, and MSD, and has received personal fees from Eisai, Tanabe-Mitsubishi, Otsuka, Takeda, Eli Lilly, MSD, Meiji, Yoshitomi, Dainippon-Sumitomo, Fukuda, Shionogi, and Novo Nordisk. Dr. Iwata has received research grants from Otsuka, GSK, Tanabe-Mitsubishi, Dainippon-Sumitomo, Eisai, Daiichisankyo, and Meiji, and has received personal fees from Eli Lilly, Janssen, Otsuka, Shionogi, GSK, Dainippon-Sumitomo, Astellas, Yoshitomi, Meiji, Novartis, and Pfizer. However, none of the above-mentioned companies were associated with this study.
R Clin Pharm 2023; 1(1): 10-21
Published online June 30, 2023 https://doi.org/10.59931/rcp.23.001
Copyright © Asian Conference On Clinical Pharmacy.
Hiroyuki Kamei1,2 , Tsuyoshi Kitajima2 , Masakazu Hatano1,2,3 , Ippei Takeuchi4 , Manako Hanya1 , Kiyoshi Fujita4, Nakao Iwata2
1Office of Clinical Pharmacy Practice and Health Care Management, Faculty of Pharmacy, Meijo University, Nagoya, Japan
2Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Japan
3Department of Pharmacotherapeutics and informatics, Fujita Health University School of Medicine, Toyoake, Japan
4Department of Psychiatry, Okehazama Hospital Fujita Kokoro Care Center, Toyoake, Japan
Correspondence to:Hiroyuki Kamei
E-mail hkamei@meijo-u.ac.jp
ORCID
https://orcid.org/0000-0003-3778-2352
This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/bync/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Background: Benzodiazepines play a central role in treating insomnia with negative effects, including muscle relaxants and other adverse effects, and lead to dependence when used for a long period. The present study examined the psychiatric outpatient status with each type of hypnotic and compared the efficacy and satisfaction among benzodiazepines, nonbenzodiazepines, a melatonin receptor agonist, and an orexin receptor antagonist using subjective patient assessments to provide more effective treatment for patients with insomnia based on their symptoms.
Methods: A total of 158 psychiatric outpatients who had used hypnotics regularly or irregularly for ≥4 weeks were investigated. Pharmacists interviewed them and assessed the severity of their insomnia using the Athens Insomnia Scale. A questionnaire survey was conducted to clarify the patient’s status of using hypnotics.
Results: A positive correlation was observed between drug efficacy and satisfaction. Patients using intermediate- and long-acting benzodiazepine hypnotics demonstrated the highest satisfaction. Representative reasons for being satisfied with their current hypnotic prescriptions included “having achieved a sufficient therapeutic effect from the first day” and “achieving a sense of good sleep.” Therefore, the efficacy of hypnotics was the most frequent reason. Conversely, some patients were distressed by their adverse effects, including sleepiness during the daytime and difficulty waking up in the morning.
Conclusion: The present results highlight the importance of reducing the symptoms of insomnia and monitoring the efficacy of hypnotics to increase the satisfaction levels of patients receiving insomnia treatment.
Keywords: Hypnotics, Insomnia, Mental disorders, Medication status, Satisfaction
Sleep disorders are common among individuals with psychiatric diseases [1]. A close relationship has been reported between psychiatric diseases and sleep disorders [2]. The incidence of sleep disorders in patients with schizophrenia ranges between 30 and 80% [3]. Sleep disorders occur in the acute phase of schizophrenia, and patients are unable to fall asleep, which leads to the development of sleep disorders [3]. Furthermore, up to 80% of patients with unipolar depression related to mood disorders have insomnia symptoms [4]. Insomnia is also highly prevalent in disorders such as generalized anxiety disorder [5] and posttraumatic stress disorder [6]. Insomnia in these patients varies and includes difficulty in falling asleep, nocturnal awakening, early morning awakening, and difficulty achieving sound sleep. On the other hand, insomnia was reported in the depressive phase in patients with bipolar disorder [7], similar to those with unipolar depression. Furthermore, difficulty in falling asleep or nocturnal awakening appears even in the manic state, frequently shortening the sleep time. Insomnia is considered to be an initial symptom of psychiatric diseases, an opportunity for recurrence, or a mental state-exacerbating factor; therefore, sleep management is important in the treatment of psychiatric diseases, such as schizophrenia [3] and mood disorders [4,7].
Among help-seeking behaviors in psychiatric patients for sleep disorders [8-10], many patients emphasized the efficacy of hypnotics, namely, the feeling of sound sleep or fast-acting properties. Furthermore, the efficacy of hypnotics markedly influenced the degree of satisfaction [9,10]. To further improve the degree of satisfaction, it is important for clinicians to confirm the presence or absence of adverse reactions, such as carry-over sedation the next morning [11]. Various hypnotics have been developed to ameliorate difficulties falling asleep, nocturnal awakening, early morning awakening, and difficulty in sound sleep; therefore, they must be properly used in consideration of a patient’s state of sleep, age, and underlying conditions [11]. The importance of quantitative and qualitative sleep improvements has been indicated, and a previous study reported that an improvement in the state of sleep contributed to a better quality of life [12].
Benzodiazepines currently play a central role in drug therapy in the field of sleep medicine. Benzodiazepines, which became commercially available in the 1960s, exert various effects, such as hypnotic, anti-anxiety, anti-convulsive, muscle relaxant, and amnesia-inducing effects [13]. Among these, drugs with strong hypnotic effects have been developed as hypnotics. However, there have been limitations, such as adverse reactions, including muscle relaxant effects, long-term use-related dependency, and rebound insomnia. Drugs in which these adverse reactions were attenuated were developed in the 1980s [14]. They act on benzodiazepine receptors, but have a structural formula that differs from those of conventional benzodiazepines; therefore, they have been termed non-benzodiazepines [14]. However, even non-benzodiazepines may induce falling, amnesia, or delirium in elderly patients [15]. To overcome these limitations, drugs that more specifically act on the sleep/awakening system are necessary [15]. Hypnotics with new mechanisms of action, such as ramelteon, a melatonin receptor agonist (2010) [16,17] and suvorexant, an orexin receptor antagonist (2014) [18,19], recently became commercially available in Japan. Based on these findings, neither ramelteon nor suvorexant exerts any muscle relaxant or amnesia-inducing effects, which is in contrast to benzodiazepines; therefore, these drugs may be available for elderly patients. Although surveys regarding various hypnotics have been conducted, patient satisfaction with benzodiazepines, ramelteon, and suvorexant, namely, their self-awareness effects or adverse reactions, remains unclear.
In this study, we investigated the prescription status of various hypnotics and compared efficacy and satisfaction among non-benzodiazepines, different types of benzodiazepines, a melatonin receptor agonist, and an orexin receptor antagonist using subjective assessments of patients.
Subjects consisted of 164 psychiatric disease patients (≥20 years old) taking a single hypnotic (non-benzodiazepines, benzodiazepines, ramelteon, and suvorexant) routinely or as needed for 4 weeks or longer and who had consulted the outpatient clinic of the Department of Psychiatrics, Fujita Health University Hospital and the outpatient clinic of Okehazama Hospital between April and July 2016. Patients with marked cognitive hypofunction or a markedly unstable mental state were excluded. The present study was approved by the Institutional Review Board of Fujita Health University and Okehazama Hospital. After an explanation of the present study to subjects, they provided written informed consent. Since 6 patients did not consent to the questionnaire survey, 158 participated in the present study.
After an examination by the attending physician, pharmacists inquired about sleep at night and functional disturbances during the daytime using the Japanese version of Athens Insomnia Scale [20-22] in an interview room. The Athens Insomnia Scale comprised 8 items measured with a 4-point Likert-type scale (i.e. #1 sleep induction, #2 awakening during the night, #3 awakening in the early morning, #4 total sleep duration insufficiency, #5 sleep quality, #6 well-being during the day, #7 functioning capacity during the day, and #8 sleepiness during the day) [21]. Each item of the AIS is rated on a 4-point scale (i.e., 0=no problem at all, 1=slightly problematic, 2=markedly problematic, and 3=extremely problematic).
The cut-off value of the Athens Insomnia Scale for identifying pathological insomnia was estimated at 6 points or more [21]. A questionnaire survey, as described below, was subsequently conducted. We assessed knowledge (drug names, doses, effects, and adverse reactions) on hypnotics, the reasons why hypnotics were prescribed, the degree of satisfaction with hypnotics and its reasons, the realization of drug efficacy and adverse reactions with hypnotics, and patient-expected characteristics of hypnotics. In assessments of knowledge on “effects” and “adverse reactions”, we asked patients whether they knew of the effects and side effects of hypnotics, which should have been explained by a pharmacist or doctor.
We also investigated the relationships between the Athens Insomnia Scale and degree of satisfaction with prescribed drugs and between the degree of satisfaction and degree of drug-efficacy realization with prescribed drugs. The degree of satisfaction was evaluated using 5 grades; 5: “satisfied”, 4: “slightly satisfied”, 3: “neither”, 2: “somewhat unsatisfied”, and 1: “unsatisfied”. The degree of drug-efficacy realization with prescribed drugs was assessed using 5 grades; 5: “effective”, 4: “slightly effective”, 3: “unclear (neither)”, 2: “did not clearly notice any effectiveness (somewhat ineffective)”, and 1: “did not notice effectiveness (ineffective)”.
In statistical analyses, we used IBM SPSS ver. 22 software. Based on the distribution of data, analyses were adequately performed. With respect to questionnaire items, results were compared between two groups using the Mann-Whitney U test. Regarding multi-group comparisons, the Kruskal-Wallis test was conducted, followed by multiple comparisons using Bonferroni’s method. The relationship with age or severity was examined using Pearson’s correlation coefficient, and items on patient characteristics were analyzed using the chi-square test.
As shown in Table 1, there were more female subjects than male subjects, and most were 40–59 years old. Regarding their occupation, office workers accounted for the majority. Primary diseases consisted of depression, schizophrenia, and bipolar disorder. Thirteen patients had insomnia, but no other disorders (8.2%) (Table 1). As shown in Table 2, currently prescribed hypnotics consisted of non-benzodiazepines, benzodiazepines, the melatonin receptor agonist, ramelteon, and the orexin receptor antagonist, suvorexant. These hypnotics had been routinely prescribed for 127 patients (80.4%) and as needed for 31 (19.6%). The mean duration of hypnotic therapy was 8.1±7.6 years.
Table 1 . Patient characteristics (n=158).
| Characteristics | Number (%) |
|---|---|
| Sex | |
| Male | 63 (39.9) |
| Female | 95 (60.1) |
| Average age (mean±SD) | 43.2±13.9 |
| 20–39 years | 47 (29.7) |
| 40–59 years | 92 (58.2) |
| ≥60 years | 19 (12.0) |
| Occupation | |
| Office workers (including part time workers) | 55 (34.8) |
| Housewives/-husbands | 36 (22.8) |
| Public service workers | 4 (2.5) |
| Students | 2 (1.3) |
| Persons without an occupation | 50 (31.6) |
| Others | 11 (7.0) |
| Disorder | |
| Depression | 50 (31.6) |
| Schizophrenia | 45 (28.5) |
| Bipolar disorder | 41 (25.9) |
| Insomnia | 13 (8.2) |
| Mood disorder | 1 (0.6) |
| Adjustment disorder | 1 (0.6) |
| Restless legs syndrome | 1 (0.6) |
| Narcolepsy | 1 (0.6) |
| Alcohol dependency | 1 (0.6) |
| Depressive state | 1 (0.6) |
| Social anxiety disorder | 1 (0.6) |
| Sleep rhythm disorder | 1 (0.6) |
| Developmental disorder | 1 (0.6) |
Table 2 . Prescribed hypnotics (n=158).
| Type of hypnotic | Prescribed drug | Number (%) | Groups | |
|---|---|---|---|---|
| Non-benzodiazepine | Zopiclone | 6 (3.8) | Non-benzodiazepine | |
| Zolpidem | 3 (1.9) | |||
| Eszopiclone | 19 (12.0) | |||
| Benzodiazepine | Triazolam | Very short | 1 (0.6) | Very short/short-acting benzodiazepine |
| Brotizolam | Short | 35 (22.2) | ||
| Rilmazafone hydrochloride hydrate | Short | 5 (3.2) | ||
| Flunitrazepam | Intermediate | 30 (19.0) | Intermediate/long-acting benzodiazepine | |
| Nitrazepam | Intermediate | 6 (3.8) | ||
| Estazolam | Intermediate | 2 (1.3) | ||
| Flurazepam | Long | 1 (0.6) | ||
| Melatonin receptor agonist | Ramelteon | 25 (15.8) | Melatonin receptor agonist (ramelteon) | |
| Orexin receptor antagonist | Suvorexant | 25 (15.8) | Orexin receptor antagonist (suvorexant) | |
The mean dose of non-benzodiazepine hypnotics in 28 patients was 2.80±1.52 mg/day (diazepam-converted value). In 41 patients taking short-acting benzodiazepine hypnotics, it was 5.85±2.21 mg/day. In 39 patients taking middle-/long-acting benzodiazepine hypnotics, it was 7.30±2.80 mg/day. In 25 patients taking the melatonin receptor agonist, it was 3.82±3.37 mg/day. In 25 patients taking the orexin receptor antagonist, it was 19.60±1.38 mg/day.
Among 28 patients taking non-benzodiazepine hypnotics, 5 (17.9%) were diagnosed with schizophrenia. Eight (19.5%) out of the 41 patients taking very short/short-acting benzodiazepines, 20 (51.3%) out of the 39 taking intermediate/long-acting benzodiazepines, 5 (20.0%) out of the 25 taking the melatonin receptor agonist, and 7 (28.0%) out of the 25 taking the orexin receptor antagonist were diagnosed with schizophrenia. The rate of schizophrenia was significantly higher in patients taking intermediate/long-acting benzodiazepines than in those taking non-benzodiazepine hypnotics or short-acting benzodiazepines (
As shown in Fig. 1, the most common reasons (multiple responses were acceptable) patients sought hypnotic therapy were as follows: difficulty in falling asleep, non-sound sleep, nocturnal awakening (several times), and early morning awakening.
Figure 1. Reasons patients sought hypnotic therapy.
Concerning the degree of recognition of prescribed drugs, 110 (69.6%) out of 158 subjects knew the names of currently prescribed hypnotics, whereas 48 (30.4%) did not.
Regarding an understanding of the effects and adverse reactions of currently prescribed drugs, 26 (16.5%) out of 158 subjects understood them, 46 (29.1%) had mostly understood them, 44 (27.8%) had not completely understood them despite continuous therapy, 40 (25.3%) had not understood them despite continuous therapy, and 2 (1.3%) selected “unclear”.
The severity of insomnia was evaluated using the Athens Insomnia Scale. The mean score was 5.3±10.7. Sixty-three patients (39.9%) showed a score of ≥6, which suggested insomnia, while 95 (60.1%) had a score of <6. Regarding the severity of insomnia, 20 (12.7%) out of 158 subjects were troubled, 38 (24.1%) were slightly troubled, 13 (8.2%) were not markedly troubled, 84 (53.2%) were not troubled, and 3 (1.9%) selected “neither”.
With respect to the influence of insomnia on daytime activities, 47 patients (29.7%) reported its influence, 56 (35.4%) a slight influence, 11 (7.0%) a negligible influence, 35 (22.2%) no influence, and 9 (5.7%) selected “neither”.
When patients were asked the most important characteristics of hypnotics prescribed by physicians, they selected (in order of reported importance) “sound sleep”, “absence of withdrawal symptoms”, “immediate effects (approximately 15 to 30 minutes)”, “absolute effects”, and “the absence of sleepiness or dullness in the morning or during the daytime” (Fig. 2).
Figure 2. Most important characteristics of hypnotics prescribed by physicians.
Concerning the degree of satisfaction with hypnotics, 61 (38.6%) out of 158 subjects were satisfied, 51 (32.3%) were slightly satisfied, 30 (19.0%) were slightly dissatisfied, 5 (3.2%) were dissatisfied, and 11 (7.0%) selected “neither”.
When the 112 patients who were “satisfied” or “slightly satisfied” were asked the reason for their satisfaction, the most common selections were “because the effects were obtained from the first day of administration”, “because the drug was absolutely effective”, “because sound sleep was achieved”, “because I could sleep soundly until morning”, and “because sleep time was prolonged” (Fig. 3A).
Figure 3. Reasons of satisfaction (A) or dissatisfaction (B) with hypnotic therapy.
When the 35 patients who were “dissatisfied” or “slightly dissatisfied” were asked the reason for their dissatisfaction, the most common selections were “because immediate effects (15 to 30 minutes) were not obtained”, “because the effects were weak”, “because sleepiness was present in the morning or during the daytime”, and “because nocturnal awakening was present” (Fig. 3B). Of the 35 patients “dissatisfied” or “slightly dissatisfied” with hypnotics, 19 (54.3%) consulted the attending physicians with dissatisfaction with hypnotics, 3 (8.6%) consulted them through an inquiry, and 13 (37.1%) had not consulted them.
The doses of hypnotics were assessed as high in 3 (1.9%) out of 158 subjects, slightly high in 9 (5.7%), appropriate in 103 (65.2%), slightly low in 10 (6.3%), low in 5 (3.2%), and unclear in 28 (17.7%).
Concerning the effects of hypnotics, 70 (44.3%) out of 158 subjects felt they were “effective”, 61 (38.6%) “slightly effective”, 6 (3.8%) “not very effective”, 8 (5.1%) “ineffective”, and 13 (8.2%) selected “unclear”.
Regarding the frequency of adverse reactions to hypnotics, 17 (6.6%) out of 158 subjects selected “every day”, 18 (11.4%) “often (once a week or more)”, 13 (14.6%) “sometimes (once a month or more)”, 29 (18.4%) “rarely”, 62 (39.2%) “absent”, and 19 (12.0%) “unclear”.
Among the 48 patients who reported “every day”, “often (once a week or more)”, or “sometimes (once a month or more)”, sleepiness during the daytime was observed in 15 (28.3%), difficulty waking up in 9 (17.0%), malaise in 8 (15.1%), dizziness in 4 (7.5%), a memory disorder in 4 (7.5%), memory reduction in 3 (5.7%), a reduction in concentration in 3 (5.7%), dry mouth in 2 (3.8%), nausea in 2 (3.8%), tremors of the fingers in 1 (1.9%), and abdominal pain in 1 (1.9%) (including duplicated patients). There were no significant differences in the presence or absence of adverse reactions among non-benzodiazepine hypnotics, short-acting benzodiazepines, middle-/long-acting benzodiazepines, the melatonin receptor agonist, and orexin receptor antagonist (
Furthermore, 17 (35.4%) were troubled with these symptoms, 17 (35.4%) were slightly troubled, 6 (12.5%) selected “neither”, 4 (8.3%) were not markedly troubled, and 4 (8.3%) were not troubled.
As shown in Fig. 4, among the 28 patients taking non- benzodiazepine hypnotics, 20 (71.7%) reported that the most important characteristics of hypnotics were “items regarding efficacy”. Furthermore, 27 (65.9%) out of the 41 patients taking short-acting benzodiazepines, 26 (66.7%) out of the 39 taking middle-/long-acting benzodiazepines, and 13 (52.0%) out of the 25 taking the orexin receptor antagonist emphasized the importance of “items regarding efficacy”.
Figure 4. Patient-supported characteristics of hypnotics with respect to prescribed drugs.
Among the 25 patients taking the melatonin receptor agonist, 14 (56.0%) reported the most important characteristics of hypnotics as “items regarding adverse reactions” (Fig. 4).
Concerning the realization of the efficacy of various hypnotics, among the 28 patients taking non-benzodiazepine hypnotics, 23 (82.1%) selected “realized (drug efficacy)” or “slightly realized”. Of the 41 patients taking short-acting benzodiazepines, 36 (87.8%) selected “realized” or “slightly realized”. Among the 39 patients taking middle-/long-acting benzodiazepines, 36 (92.3%) selected “realized” or “slightly realized”. Of the 25 patients taking the melatonin receptor agonist, 17 (68.0%) selected “realized” or “slightly realized”. Of the 25 patients taking the orexin receptor antagonist, 19 (76.0%) selected “realized” or “slightly realized”. There were no significant differences among the 5 types of hypnotics (Fig. 5A).
Figure 5. Realization of efficacy (A) and satisfaction (B) in various hypnotics.
Concerning the realization of satisfaction in various hypnotics, of the 28 patients taking non-benzodiazepine hypnotics, 18 (64.3%) selected “satisfied” or “slightly satisfied”. Among the 41 patients taking short-acting benzodiazepines, 31 (75.6%) selected “satisfied” or “slightly satisfied”. Of the 39 patients taking middle-/long-acting benzodiazepines, 32 (82.1%) selected “satisfied” or “slightly satisfied”. Among the 25 patients taking the melatonin receptor agonist, 14 (56.0%) selected “satisfied” or “slightly satisfied”. Of the 25 patients taking the orexin receptor antagonist, 17 (68.0%) selected “satisfied” or “slightly satisfied”. There were significant differences among the 5 types of hypnotics (
The influence of demographic data on the degree of satisfaction was as follows: no significant difference was observed in the degree of satisfaction between men (4.1±1.1) and women (3.7±1.3) (
We investigated the relationships between the degrees of satisfaction and drug efficacy realization with prescribed drugs. The results obtained revealed a moderately positive correlation between the degrees of satisfaction and drug efficacy realization (correlation coefficient: r=0.441) (Fig. 6).
Figure 6. Correlation between the perceived efficacy of hypnotics and patient satisfaction.
The influence of demographic data on the Athens Insomnia Scale was as follows: no significant difference was observed in the Athens Insomnia Scale between men (4.6±3.1) and women (5.8±3.7) (
Regarding the Athens Insomnia Scale for patients taking various hypnotics, of the 28 patients taking non-benzodiazepine hypnotics, 16 (57.1%) scored 6 or higher, which reflects insomnia (Fig. 7). Furthermore, 12 (29.3%) out of the 41 patients taking very short/short-acting benzodiazepines, 20 (51.3%) out of the 39 taking intermediate/long-acting benzodiazepines, 4 (16.0%) out of the 25 taking the melatonin receptor agonist, and 11 (44.0%) out of the 25 taking the orexin receptor antagonist scored 6 or higher (Fig. 7). A significant difference was observed between patients taking non-benzodiazepine hypnotics and those taking the melatonin receptor agonist (
Figure 7. Athens Insomnia Scale for patients who taking the various hypnotics.
We investigated the relationship between the Athens Insomnia Scale and the degree of satisfaction with the prescribed drugs. The results obtained revealed a moderately negative correlation between the Athens Insomnia Scale, which was established to evaluate the severity of insomnia, and the degree of satisfaction with hypnotics (correlation coefficient: r=–0.422) (Fig. 8).
Figure 8. Correlation between the Athens Insomnia Scale and patient satisfaction with hypnotics.
We also examined the correlation between the Athens Insomnia Scale and degree of drug efficacy realization. The results obtained showed a weakly negative correlation between the Athens Insomnia Scale, which was established to evaluate the severity of insomnia, and the degree of drug efficacy realization (correlation coefficient: r=–0.278).
Concerning adverse reactions, no significant differences were observed between the severity of insomnia (assessment with the Athens Insomnia Scale) and the incidence of adverse reactions (
In the present study, we investigated the status of using each type of hypnotic, the sleep status, and satisfaction with the hypnotic in psychiatric outpatients who received various hypnotics for ≥4 weeks. To the best of our knowledge, this is the first study that focused on comparisons of efficacy and satisfaction among non-benzodiazepines, different types of benzodiazepines, a melatonin receptor agonist, and an orexin receptor antagonist using subjective assessments by patients.
The results obtained showed that patients selecting “satisfied” or “slightly satisfied” with prescribed hypnotics in this survey accounting for 70.1%. The primary reasons included items related to efficacy: “because the effects were obtained from the first day of administration” and “because the drug was absolutely effective”. Among patients selecting “dissatisfied” or “slightly dissatisfied”, the primary reasons also included items related to efficacy: “because immediate effects (15 to 30 minutes) were not obtained” and “because the effects were weak”. In addition, a correlation was observed between the degrees of satisfaction with hypnotics and drug efficacy realization, suggesting that the degree of satisfaction with prescribed hypnotics increases with the degree of hypnotic efficacy realization. Therefore, to improve patient satisfaction with insomnia treatments, it may be important to reduce insomnia and improve the degree of hypnotic efficacy realization.
Based on subjective assessments of patients in the present study, the most important factors for hypnotics included items related to efficacy: “sound sleep” and “immediate effects”, followed by items related to adverse reactions: “absence of withdrawal symptoms” and “absence of sleepiness or dullness in the morning or during the daytime”. This result is supported by previous findings [8] showing that the treatment preference of patients is to improve issues associated with sleep onset and maintenance. Therefore, patients may emphasize efficacy, involving sound sleep or immediate effects, despite their negative impression of hypnotics as dangerous drugs with a high incidence of adverse reactions. A negative correlation was observed between the Athens Insomnia Scale and the degree of satisfaction with prescribed drugs, suggesting that the degree of satisfaction with prescribed drugs is higher in patients with a lower Athens Insomnia Scale score. Likewise, a negative correlation was noted between the Athens Insomnia Scale and the degree of drug efficacy realization. Based on these results, the degrees of satisfaction with hypnotics and drug efficacy realization may both be increased by clarifying factors for nocturnal insomnia or functional disturbance during the daytime in individual patients and reducing the Athens Insomnia Scale score. Satisfaction with treatment is important in investigations of insomnia. Previous studies reported that psychological (behavioral) treatment was more acceptable than hypnotics for chronic insomnia because of the presumption that psychological treatment improved daytime functioning with better long-term effectiveness and included fewer side effects [8,23]. Further research on treatment preferences and patient satisfaction are warranted.
In the present study, significant differences were observed in the degree of satisfaction with prescribed drugs among patients taking non-benzodiazepines, very short/short-acting benzodiazepines, intermediate/long-acting benzodiazepines, the melatonin receptor agonist, and the orexin receptor antagonist. Among patients taking intermediate/long-acting benzodiazepines, the rate of those selecting “satisfied” or “slightly satisfied” was the highest, whereas in patients taking the melatonin receptor agonist, it was the lowest (56.0%). However, in this group, patients reporting satisfaction with prescribed drugs as “unclear” accounted for 28.0%, while those selecting “dissatisfied” or “slightly dissatisfied” accounted for 16%; this percentage was the lowest among the 5 groups. Many patients reported satisfaction with prescribed drugs as “unclear”, possibly because the mean dose (3.8±3.4 mg/day) of the melatonin receptor agonist was lower than the standard dose (8 mg/session), affecting drug efficacy realization; 14 out of 25 patients had taken the melatonin receptor agonist at 1 mg/day, corresponding to 1/8 of the standard dose, under a diagnosis of a sleep rhythm disorder possibly based on the findings of previous studies [24]. When administering low-dose melatonin receptor agonists 5 hours before bedtime as MT2 receptor-mediated actions, the circadian rhythm phase was advanced, suggesting that low-dose therapy is useful for the treatment of a marked circadian rhythm sleep disorder-related delay in sleep hours or day-and-night inversion. Furthermore, the rate of patients scoring 6 or higher, which reflects insomnia according to the Athens Insomnia Scale, was the lowest among the 5 groups, and the rate of patients with a severe status was low; therefore, it may have been difficult to realize symptom improvements.
As the most important characteristics of hypnotics, more than 50% of patients taking the melatonin receptor agonist selected “items regarding adverse reactions”, suggesting that the rate of patients selecting drugs with a low incidence of adverse reactions among those taking the melatonin receptor agonist was higher than that of patients selecting effective drugs. In addition, the incidence of adverse reactions in patients taking the melatonin receptor agonist was the lowest among the 5 groups; this may have contributed to the lowest rate of patients selecting “dissatisfied” or “slightly dissatisfied”. Furthermore, melatonin receptor agonists do not exhibit any anti-anxiety or sedative effects, and are considered to be relatively appropriate for untreated patients with insomnia or those with mild anxiety-related symptoms [17]. Since various hypnotics have different characteristics and the sense of values for sleep differs among individual patients, it may be necessary to understand patient satisfaction with hypnotic/drug properties and select adequate hypnotics.
The present results revealed that the rate of patients with schizophrenia was significantly higher among those taking intermediate/long-acting benzodiazepines than in those taking non-benzodiazepines or very short/short-acting benzodiazepines. This result shows that relatively intermediate/long-acting (long-acting) drugs may be prescribed for schizophrenia patients in our sample to manage nocturnal or early morning awakening rather than difficulty in falling asleep. Among psychiatric patients with poor sleep, several correlates of help-seeking behavior and sleep problem recognition were identified [9]. Psychiatric patients may have attributed their sleep difficulties to their psychiatric conditions [25]. Therefore, clinicians and pharmacists play an important role in detecting these cases during consultations with patients and provide them with the necessary treatment and information [26].
Additionally, the present study showed that patients who did not know the names of currently prescribed hypnotics accounted for 30.4%. Furthermore, patients selecting “do not understand” or “do not clearly understand” the effects of/adverse reactions to hypnotics accounted for 53.1%. Many patients consulting the outpatient clinic of the Department of Psychiatrics tend to take hypnotics regardless of diseases. Precautions are initially explained in detail, but not every time for patients who have consulted an outpatient clinic for a long period. Differing perceptions of insomnia and its treatments between patients and clinicians may contribute to some paradox. Patients typically describe their insomnia in terms of its daytime impairments in everyday life, extending the experience beyond nighttime sleep difficulties. Therefore, patients generally perceive available insomnia treatments as ineffective or unattractive, they are prone to self-medicate, and are more likely to believe that insomnia will spontaneously resolve [27,28]. The present study showed that frequent adverse reactions included carry-over effects, such as sleepiness during the daytime and uncomfortable awakening in the morning. Patients selecting “dissatisfied” or “slightly dissatisfied” with prescribed drugs accounted for 22.0%; among these, 54.3% had consulted physicians when dissatisfied with the efficacy or safety of hypnotics. Furthermore, patients who had experienced adverse reactions accounted for 36.8%; of these, 70.8% selected “troubled” or “slightly troubled” with adverse reactions. The combination of our results and previous findings indicate that clinicians and pharmacists need to explain/confirm effects/adverse reactions regularly to patients for whom hypnotics have been prescribed over a long period. If the characteristics of hypnotics cause dissatisfaction or adverse reactions, it may be important for clinicians to propose a switch to a more appropriate drug to patients.
The present study had multiple strengths, including comparisons of efficacy and satisfaction among various types of hypnotics and the use of subjective assessments of patients and understanding what patients expect from hypnotics. However, there were several limitations. A recent meta-analysis reported that the use of non-benzodiazepines for an average of 10.5 weeks was effective against insomnia in major depressive patients without any risk of side effects [29]. However, the effects of the longer-term use of non-benzodiazepines on the incidence of adverse events remain unclear [29]. Therefore, inclusion criteria for the administration of a hypnotic agent for at least 4 weeks in the present study created a bias towards patients who experienced better efficacy, tolerability, and/or satisfaction. Furthermore, the duration of hypnotic treatment in this psychiatric patient was 8 years on average. Chronic insomnia may be associated with psychiatric comorbidities; however, the relationship between them is complex and includes bidirectional causation. A previous study reported that chronic insomnia that had been treated with hypnotics over a 6-year period was a risk factor for psychiatric disorders, such as schizophrenia, depression, and bipolar disorder [30]. This finding led to the concept that managing sleep disturbances may be a fundamental priority for the prevention of ensuing psychiatric co-morbidities. In addition, the present results showed that patients selecting “satisfied” or “slightly satisfied” with prescribed hypnotics in this survey accounted for 70.1%. This result may reflect patients receiving hypnotic therapy for a very long duration (8 years on average). If they had not been satisfied, they may not have continued therapy for that long. This result may markedly differ if this was a prospective trial. Another limitation is that since we did not pre-test the questionnaire, some patients may not have understood or may have misunderstood the terms used in the questionnaire. Moreover, in assessments of knowledge on “effects” and “adverse reactions”, we asked patients whether they knew the effects and side effects of hypnotics, which should have been explained by a pharmacist or doctor. Since we did not confirm details on the effects and side effects of hypnotics that the patients were taking, it was not possible to assess the level of knowledge on hypnotics more accurately. Furthermore, in the present study, we did not examine the relationship between the presence/absence of insomnia as measured by the Athens Insomnia Scale and adherence with hypnotic therapy. Therefore, the degree of insomnia in patients who are adhering to hypnotics well versus those who are not is unclear.
The degree of satisfaction with prescribed drugs was the highest in patients taking intermediate/long-acting benzodiazepines, whereas it was the lowest in those taking the melatonin receptor agonist. Furthermore, the present results suggest that the degree of satisfaction with hypnotics was higher in patients with a higher degree of drug efficacy realization. To improve the degree of satisfaction with insomnia treatment, it may be important to reduce insomnia and increase the degree of drug efficacy realization. Furthermore, approximately 30% of patients had experienced adverse reactions. Of these, approximately 70% selected “troubled” or “slightly troubled” with adverse reactions. Therefore, it may be necessary to pay attention to the presence or absence of adverse reactions in addition to effects in patients taking hypnotics. Moreover, the characteristics of various hypnotics differ, and the sense of value for sleep varies among individual patients; therefore, it is important to understand the degree of satisfaction with hypnotics/their characteristics and select appropriate hypnotics.
None.
We would like to thank Ms. Erika Manabe for her support.
The present study was not specifically supported by any funding. The authors report no conflicts of interest related to this research. Dr. Kitajima has received research grants from Eisai, Takeda, and MSD, and has received personal fees from Eisai, Tanabe-Mitsubishi, Otsuka, Takeda, Eli Lilly, MSD, Meiji, Yoshitomi, Dainippon-Sumitomo, Fukuda, Shionogi, and Novo Nordisk. Dr. Iwata has received research grants from Otsuka, GSK, Tanabe-Mitsubishi, Dainippon-Sumitomo, Eisai, Daiichisankyo, and Meiji, and has received personal fees from Eli Lilly, Janssen, Otsuka, Shionogi, GSK, Dainippon-Sumitomo, Astellas, Yoshitomi, Meiji, Novartis, and Pfizer. However, none of the above-mentioned companies were associated with this study.
Table 1 Patient characteristics (n=158)
| Characteristics | Number (%) |
|---|---|
| Sex | |
| Male | 63 (39.9) |
| Female | 95 (60.1) |
| Average age (mean±SD) | 43.2±13.9 |
| 20–39 years | 47 (29.7) |
| 40–59 years | 92 (58.2) |
| ≥60 years | 19 (12.0) |
| Occupation | |
| Office workers (including part time workers) | 55 (34.8) |
| Housewives/-husbands | 36 (22.8) |
| Public service workers | 4 (2.5) |
| Students | 2 (1.3) |
| Persons without an occupation | 50 (31.6) |
| Others | 11 (7.0) |
| Disorder | |
| Depression | 50 (31.6) |
| Schizophrenia | 45 (28.5) |
| Bipolar disorder | 41 (25.9) |
| Insomnia | 13 (8.2) |
| Mood disorder | 1 (0.6) |
| Adjustment disorder | 1 (0.6) |
| Restless legs syndrome | 1 (0.6) |
| Narcolepsy | 1 (0.6) |
| Alcohol dependency | 1 (0.6) |
| Depressive state | 1 (0.6) |
| Social anxiety disorder | 1 (0.6) |
| Sleep rhythm disorder | 1 (0.6) |
| Developmental disorder | 1 (0.6) |
Table 2 Prescribed hypnotics (n=158)
| Type of hypnotic | Prescribed drug | Number (%) | Groups | |
|---|---|---|---|---|
| Non-benzodiazepine | Zopiclone | 6 (3.8) | Non-benzodiazepine | |
| Zolpidem | 3 (1.9) | |||
| Eszopiclone | 19 (12.0) | |||
| Benzodiazepine | Triazolam | Very short | 1 (0.6) | Very short/short-acting benzodiazepine |
| Brotizolam | Short | 35 (22.2) | ||
| Rilmazafone hydrochloride hydrate | Short | 5 (3.2) | ||
| Flunitrazepam | Intermediate | 30 (19.0) | Intermediate/long-acting benzodiazepine | |
| Nitrazepam | Intermediate | 6 (3.8) | ||
| Estazolam | Intermediate | 2 (1.3) | ||
| Flurazepam | Long | 1 (0.6) | ||
| Melatonin receptor agonist | Ramelteon | 25 (15.8) | Melatonin receptor agonist (ramelteon) | |
| Orexin receptor antagonist | Suvorexant | 25 (15.8) | Orexin receptor antagonist (suvorexant) | |
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