This study aimed to investigate prescription patterns in patients with insomnia who still met the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria despite having already been taking hypnotics, and to determine which drug(s) and what combination therapies were preferred.
Sixty-three patients were enrolled in this study. Patients were selected from participants registered at six university hospitals for a prospective study to evaluate the efficacy of melatonin (Circadin).
The prescribed hypnotics were clonazepam (n=33), trazodone (n=23), zolpidem (n=22), quetiapine (n=14), mirtazapine (n=12), lorazepam (n=10), alprazolam (n=7), triazolam (n=5), doxepin (n=5), diazepam (n=3), etizolam (n=2), and flunitrazepam (n=1). There were five types of monotherapies (benzodiazepine, zolpidem, trazodone, mirtazapine, and doxepin) and 18 types of combination therapies. The total number of hypnotics used ranged from one to six. The frequency of benzodiazepine use was quite high, at 51/63.
This study showed that insomnia can be treated in a wide variety of ways. In particular, 63% of the insomnia treatments in this study used combination therapy. This means that the gap between evidence-based pharmacotherapy and pharmacotherapy used in clinical practice is substantial. This also means that insomnia is still not fully understood and is a heterogeneous condition. In the future, more studies are needed to deepen our understanding of the pathophysiology of insomnia.
Insomnia is a common and painful condition. One study found that 29.9% of the general population had symptoms of insomnia [
This study analyzed the prescription patterns of 63 patients who were already receiving pharmacotherapy for insomnia but showed insufficient responses to existing hypnotic(s), among subjects registered at six university hospitals, for a prospective and multi-institutional study to evaluate the efficacy of melatonin (Circadin), a common insomnia treatment. The six university hospitals were the Pusan National University Hospital, Inje University Ilsan Paik Hospital, Gachon University Gil Hospital, Eulji University Hospital, Korea University Ansan Hospital, and Gyeongsang National University Hospital. The selection criteria were patients over the age of 55 years who satisfied the DSM-5 diagnostic classification criteria for insomnia disorder. Patients with sleep and mental disorders other than insomnia were excluded from the study; however, patients with mild depression (<15 points) with Hamilton Depression Rating Scale (HAMD) were included. For the purposes of this study, hypnotics were defined as including zolpidem, benzodiazepine (BDZ), doxepin, trazodone, mirtazapine, and quetiapine, which are all commonly used in patients with clinical insomnia. The study protocol was approved by the Ethics Committees of each University Hospital, and informed consent was obtained from the participants.
Participants were divided into two groups according to their number of prescribed hypnotics: monotherapy and combination therapy. Statistical tests such as t-tests and chi-square tests were conducted for data analysis. All tests were two-tailed, and the cut-off p-value for statistical significance was set at p<0.05. Statistical analyses were performed using SPSS software (version 25, IBM Corp., Armonk, NY, USA).
The demographic and clinical characteristics of the 63 participants in this study are described in
There were five types of monotherapies (BZD, zolpidem, trazodone, mirtazapine, and doxepin) and 18 types of combination therapies used by our patients (
This study revealed that various types of pharmacotherapies are used to treat patients with insomnia. In our patients, insomnia was more commonly treated with combination therapy than with monotherapy. Among the hypnotics we reviewed, BZDs were prescribed most frequently as both monotherapies and in combination therapies. Eighteen types of combination therapies were prescribed.
In this study, BZD use was very high; 51/63 people in our patient pool had used BZD. In a previous 5-year sleep medication prescription analysis study conducted in China, the most common treatment for insomnia was BZD, although the prescription of BZD declined year over year [
The non-BZD receptor agonist Z-drugs included in this study were zopiclone, eszopiclone, zolpidem, and zaleplon. Among them, only zopiclone and zolpidem are available in South Korea. None of the participants in this study was prescribed zopiclone or eszopiclone. Zolpidem was the third most commonly prescribed hypnotic, after clonazepam and trazodone. A total of 22 patients were being treated with these drugs, six as monotherapy and 16 as part of combination therapies. Zolpidem has been proven to be effective for sleep onset and maintenance [
In this study, trazodone was administered to 23 patients and was prescribed at the highest frequency after clonazepam. One study found that among 357,380 patients with insomnia in the United States, 17.7% were prescribed trazodone, 60.7% were prescribed antidepressants, and 37% were prescribed BZD [
Quetiapine is an atypical antipsychotic drug that is often used as an off-label hypnotic drug because of its strong calming effect. In this study, 14 patients were prescribed quetiapine, making it the fourth most used drug in our patient group. Unlike the other drugs that we investigated, quetiapine was never used as a monotherapy. In one previous study, quetiapine ranked fourth among the most frequently prescribed medications, followed by Z-drugs, trazodone, and BZDs [
Mirtazapine is an antidepressant, but is also used as an off-label hypnotic because of its strong sedative effect. In this study, it was the fifth most commonly used drug in 12 patients, two patients used it as a monotherapy, and 10 patients used it in combination therapies. In a recent study, mirtazapine improved total sleep time and decreased wakefulness after sleep onset in depressed patients, although this study did not include a control group [
Doxepin is also an antidepressant, but unlike trazodone and mirtazapine, it has been FDA-approved at low doses such as 3 and 6 mg. In this study, it was used in five patients: as a monotherapy in one case, with the rest using it in some form of combination therapy. Current American guidelines do recommend the use of doxepin for sleep maintenance [
This study had several limitations. First, it is part of another larger study; therefore, it is difficult to generalize these results. However, unlike evidence-based pharmacotherapy, these results reflect pharmacotherapy for insomnia in a real clinical setting. Second, the sample size was fairly small. Thus, future studies involving larger samples are required.
In conclusion, this study revealed that insomnia can be treated in a wide variety of ways. In particular, 63% of the insomnia treatments in this study used combination therapies. This means that the gap between evidence-based pharmacotherapy and pharmacotherapy used in actual clinical practice is quite substantial. This also means that insomnia is still not fully understood and is a heterogeneous condition. In the future, more studies are needed to fully understand the pathophysiology of insomnia.
This study was funded by Kuhnil Pharmaceutical Co., Ltd.
The authors have no potential conflicts of interest to disclose.
The datasets generated or analyzed during the study are not publicly available due to the privacy or ethical restrictions but are available from the corresponding author on reasonable request.
Conceptualization: Young-Min Park. Data curation: all authors. Formal analysis: all authors. Funding acquisition: all authors. Investigation: all authors. Methodology: Young-Min Park. Project administration: Young-Min Park. Resources: Young-Min Park. Software: Young-Min Park. Supervision: Young-Min Park. Validation: all authors. Visualization: all authors. Writing—original draft: all authors. Writing—review & editing: all authors.
Demographic and clinical variables in patients with insomnia
Variables | Patients with insomnia (n=63) |
---|---|
Age (yr) | 67.18±8.14 |
Sex (male/female) | 21/42 |
HAMD | 8.65±3.82 |
Sleep latency (min) | 83.16±70.61 |
Total sleep time (hr) | 4.33±2.14 |
Sleep efficiency (%) | 56.98±25.72 |
PSQI | 14.40±3.40 |
WHO-5 | 7.73±5.74 |
Data are shown as mean±standard deviation or numbers only. HAMD, Hamilton Depression Rating Scale; PSQI, Pittsburgh Sleep Quality Index; WHO-5, WHO-5 well-being index
Comparison between monotherapy and combination therapy groups
Variables | Monotherapy group (n=23) | Combination therapy group (n=40) | t | p-value |
---|---|---|---|---|
Age (yr) | 66.30±7.99 | 67.68±8.29 | -0.64 | 0.52 |
Sex (male/female) | 7/16 | 14/26 | 0.14 | 0.71* |
HAMD | 8.00±3.72 | 9.03±3.87 | -1.03 | 0.31 |
Sleep latency (min) | 83.48±74.63 | 82.97±69.14 | 0.03 | 0.98 |
Total sleep time (hr) | 4.00±1.71 | 4.53±2.36 | -0.93 | 0.36 |
Sleep efficiency (%) | 58.35±23.33 | 56.2±27.25 | 0.32 | 0.75 |
PSQI | 14.48±3.23 | 14.35±3.53 | 0.14 | 0.89 |
WHO-5 | 8.57±4.95 | 7.25±6.15 | 0.87 | 0.39 |
Data are shown as mean±standard deviation or numbers only. *chi-square test. HAMD, Hamilton Depression Rating Scale; PSQI, Pittsburgh Sleep Quality Index; WHO-5, WHO-5 well-being index
Frequencies of monotherapy and combination therapy
Types of therapy | Frequency of prescription |
---|---|
Monotherapy | n=23 |
BZD | 13 |
ZOL | 6 |
MIR | 2 |
TRZ | 1 |
DOX | 1 |
Combination therapy | n=40 |
BZD+BZD | 2 |
BZD+DOX | 2 |
BZD+MIR | 3 |
BZD+QTP | 3 |
BZD+TRZ | 6 |
BZD+ZOL | 2 |
ZOL+TRZ | 2 |
BZD+ZOL+DOX | 1 |
BZD+ZOL+QTP | 1 |
BZD+ZOL+TRZ | 4 |
BZD+TRZ+DOX | 1 |
BZD+TRZ+MIR | 3 |
BZD+TRZ+QTP | 1 |
BZD+QTP+DOX | 1 |
BZD+QTP+MIR | 2 |
BZD+ZOL+QTP+MIR | 1 |
BZD+ZOL+TRZ+QTP | 4 |
BZD+ZOL+TRZ+QTP+MIR | 1 |
BZD, benzodiazepine; DOX, doxepin; MIR, mirtazapine; QTP, quetiapine; TRZ, trazodone; ZOL, zolpidem