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Volume 14 No. 10
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Scientific Investigations

Use of Sedative-Hypnotics and Mortality: A Population-Based Retrospective Cohort Study

Jae-Won Choi1; Joonki Lee2; Sun Jae Jung3,4; Aesun Shin, MD, PhD2; Yu Jin Lee, MD, PhD5
1Department of Neuropsychiatry, Eulji University School of Medicine, Eulji General Hospital, Seoul, Republic of Korea; 2Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea; 3Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts; 4Department of Preventive Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea; 5Department of Psychiatry and Center for Sleep and Chronobiology, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea

ABSTRACT

Study Objectives:

Researchers have previously reported a possible association between sedative-hypnotics and increased mortality. However, the relationship remains controversial. We investigated the association between sedative-hypnotics and mortality using a large population-based database from the Republic of Korea.

Methods:

We used a National Health Insurance Service database. The study population was a 5% random sample of the database from the years 2002–2015. Individuals who were age 40 years and older were included in the analysis. The sedative-hypnotic users were defined as individuals prescribed 30 or more defined daily doses of sedative-hypnotics per year since January 2004. Sedative-hypnotics were classified based on type and total amount. We estimated the risk of mortality (death from January 2004 to December 2015) using time-dependent Cox regression model adjusted for age, sex, Charlson Comorbidity Index, and psychiatric comorbidity.

Results:

We identified 180,823 study participants who used sedative-hypnotics and 320,136 nonusers. In a multivariate model, study participants who used sedative-hypnotics had significantly higher mortality risk than nonusers (hazard ratio [HR] 1.14, 95% confidence interval [CI] 1.12–1.16). Specifically, study participants who used zolpidem had a higher mortality risk (HR 1.59, 95% CI 1.52–1.67) than nonusers.

Conclusions:

Based on the current study results, sedative-hypnotics were associated with an increased risk of mortality, especially in study participants who used zolpidem.

Citation:

Choi JW, Lee J, Jung SJ, Shin A, Lee YJ. Use of sedative-hypnotics and mortality: a population-based retrospective cohort study. J Clin Sleep Med. 2018;14(10):1669–1677.


BRIEF SUMMARY

Current Knowledge/Study Rationale: Previous studies on the association of sedative-hypnotics with mortality risk have produced controversial results. Several studies found no significant associations between sedative-hypnotics and mortality risk, but others reported a high mortality risk associated with the use of these agents. This study was designed to produce a more accurate estimate of the mortality risks associated with sedative-hypnotics use by analyzing data collected by the National Health Insurance Service over a long follow-up period, while controlling for the following confounding factors: sociodemographic characteristics, physical health, and psychiatric comorbidities.

Study Impact: Individuals prescribed 30 or more defined daily doses of zolpidem per year had a significantly higher risk of mortality than that of nonusers, with a clear dose-dependent relationship.

INTRODUCTION

Benzodiazepines (BZD), Z-drugs, and small doses of anti-depressants and antipsychotics have been prescribed to treat insomnia. In the general population, the overall use of BZD and other hypnotics was reported to range between 2.6% and 9.1%14 and was highest, at up to 11.9%, among 80-year-old women.5 Based on several studies, primary physicians rather than licensed psychiatrists prescribed most BZD in the Republic of Korea.6,7 One-year BZD prescription prevalence was 23.7% for more than one defined daily dose (DDD) and 7.9% for more than 30 DDDs. The total number of prescriptions tended to be four times higher in the elderly (age 65 years or older) than among those age 64 years and younger.8

Previous studies have shown that when sedative-hypnotics are prescribed for a long time, serious adverse effects, including psychomotor impairments (daytime sleepiness, poor physical function, car accidents, increased falls and fractures), cancer, and dementia, can occur.916 Although several recent studies focused on the association of sedative-hypnotics with mortality risk, their results have been controversial.1725 Whereas several studies found no significant associations between sedative-hypnotic use and all-cause mortality,1719 other studies found a high mortality risk associated with the use of both BZD and Z-drugs.2025 However, a study performed in Taiwan found that patients for whom zolpidem was prescribed had a lower mortality risk, but those for whom BZD was prescribed has a higher mortality risk.26 In a population-based cohort study in Japan, study participants of both sexes who used sleeping pills tended to have increased risk of mortality, although not significantly. In another prospective study in the United States, after controlling for covariates, neither insomnia complaints nor the use of hypnotics was associated with an increased risk of mortality.17,18 By contrast, other studies have evaluated the association of sedative-hypnotics with increased risk of mortality.2025 However, most of the previous studies had several limitations, including small numbers of participants, older age distribution, limited information on medication, short follow-up period, and lack of control for confounding factors (medical and psychiatric comorbidities, socioeconomic status, etc.). These limitations appear important; increased crude mortality associated with sedative-hypnotics in an elderly population was reported in two studies; however, after controlling for potential confounding factors such as medical and psychiatric disorders, the risk of mortality was not significantly associated with sedative-hypnotics.27,28

The current study was designed to examine the mortality associated with sedative-hypnotics using the database from the National Health Insurance Service (NHIS) of the Republic of Korea. More than 97% of people in the Republic of Korea are registered with the NHIS, which collects all claims data for medical treatment, such as disease diagnosis, prescriptions provided, and procedures performed. The current study included a sufficient number of participants from the NHIS data to be representative of the Korean population, as well as a long follow-up period, and it controlled for potential confounding factors such as sociodemographic characteristics (age, sex, and economic status), physical health, and psychiatric comorbidity. The primary hypothesis of the current study was that sedative-hypnotics would be associated with increased mortality after adjusting for several confounding factors.

METHODS

Data Source and Study Population

A retrospective cohort study was conducted using the data from the NHIS database of the Republic of Korea from January 2002 to December 2015. The study included a randomly selected sample of 5% of NHIS beneficiaries age 40 years and older.29 We excluded individuals who were younger than 40 years, those who had died or were lost to follow-up, and those who were prescribed any sedative-hypnotics between January 2002 and December 2003. Patients were followed up until time of death, loss of follow-up, or December 31, 2015.

Exposure Definition

The sedative-hypnotics evaluated in this study included BZD, zolpidem (the only Z-drug that can be prescribed in the Republic of Korea), antidepressants, and low-dose antipsychotics, which are often prescribed for the treatment of insomnia in the Republic of Korea. The prescribed dosage of sedative-hypnotics was standardized using the defined daily dose (DDD) suggested by the World Health Organization.30 We evaluated the prescription of sedative-hypnotics from January 2004 and cumulated the prescribed dosage of sedative-hypnotics over time. Exposure (index date) was defined when the cumulative dose of sedative-hypnotics reached 30 DDDs.

The sedative-hypnotics were classified based on their pharmacological mechanisms and total amount of prescription. First, based on pharmacological mechanisms, the hypnotics were classified as BZD, zolpidem, or other drugs (antidepressants and low-dose antipsychotics). While cumulating each type of hypnotic separately, we defined exposure as a cumulative dose exceeding 30 DDDs and nonexposure as a cumulative dose less than 30 DDDs. In addition, when study participants were exposed to more than two types of hypnotics, each combination was analyzed to compare the risks between combinations. Second, we classified the study participants into three subgroups based on the total amount of prescribed hypnotics, 30–179 DDDs, 180–359 DDDs, and ≥ 360 DDDs.

Covariates

In addition to age and sex, insurance premiums based on individuals' income levels were extracted from the NHIS database. The Charlson Comorbidity Index (CCI) is a predictive score of 1-year mortality of a patient having comorbidities, including myocardial infarction, congestive heart failure, peripheral vascular disease, cerebrovascular disease, dementia, chronic pulmonary disease, rheumatic disease, peptic ulcer disease, mild liver disease, diabetes, hemiplegia or paraplegia, renal disease, malignancy, moderate to severe liver disease, metastatic solid tumor, and AIDS/HIV.31 These diseases were extracted using the International Statistical Classification of Diseases and Related Health Problems, 10th revision (ICD-10). The disease diagnostic codes for CCI and the validity are described elsewhere.32 Patients were defined as having the disease if they had at least two claims of diagnosis per 1 year between January 2002 and December 2015. We also extracted psychiatric disorders, including anxiety disorders (F4x), depression (F32, F33), insomnia (F510, G470), and psychotic disorders (F2x), which were possible confounding factors for death or prescription of sedative-hypnotics. Patients were defined as having these psychiatric diseases if they had at least two claims of diagnosis per 1 year between January 2004 and December 2015.

Statistical Analysis

Characteristics were compared between exposure and nonexposure to sedative-hypnotics using the chi-square test and t test. Exposure to sedative-hypnotics was considered as a time-varying covariate; therefore, if a study participant was exposed to sedative-hypnotics in the middle of the study, he or she was considered as having been exposed after the index date. The mortality risk of sedative-hypnotics was analyzed using a time-dependent Cox regression model for multivariate analysis to compute the hazard ratio (HR) and 95% confidence interval (CI) after adjusting for the possible confounding factors (age, sex, insurance premium, CCI score, anxiety disorders, depression, insomnia, and psychotic disorders). Kaplan–Meier survival analysis was used to compare survival rates among the groups classified based on the total amount or type of prescribed sedative-hypnotics. Statistical analysis was performed using the statistical software SAS 9.4 (SAS Institute Inc., Cary, North Carolina, United States).

Sensitivity Analysis

The sedative-hypnotics evaluated in this study were prescribed not only for insomnia but also for other psychological or somatic symptoms. When considering hypnotics as treatment in patients with insomnia, we counted the sedative-hypnotics prescribed only for patients with insomnia; sedative-hypnotics without the diagnostic code of insomnia were not considered. However, we included additional parameters consisting of sedative-hypnotics prescribed for anxiety, mood disorders, and psychosis to compare the risks between these groups.

RESULTS

We identified 827,100 study participants age 40 years or older over the study period; 18,100 study participants were excluded due to death or loss to follow-up before 2004, and 308,041 study participants for whom sedative-hypnotics were prescribed before 2004 were also excluded. The remaining 500,959 study participants were followed for an average of 10.98 years and 68,049 study participants died during the study period (Figure 1).

Flow diagram.

We randomly selected 827,100 participants representing 5% of Korean NHIS beneficiaries between January 2002 and December 2015 who were 40 years of age or older. Among the selected participants, 18,100 were excluded due to death or loss to follow-up before January 2004. Of the remaining sample, 308,041 participants prescribed any sedative-hypnotics before January 2004 were excluded. Finally, a total of 500,959 participants were included for analysis and followed-up for 13 years. Of these, 68,049 participants died during the study period. NHIS = National Health Insurance Service.

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Figure 1

Flow diagram.

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A total of 180,823 study participants were exposed to sedative-hypnotics during the study period; the sedative-hypnotics exposure group had a higher proportion of females and older individuals than the nonexposure group. The exposure group had lower insurance premiums and higher rates of psychiatric morbidities than the nonexposure group. The sedative-hypnotics exposure group had higher CCI scores than the nonexposure group (Table 1).

Characteristics of the study population based on sedative-hypnotic use.

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Table 1

Characteristics of the study population based on sedative-hypnotic use.

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Table 2 shows the HR of covariates on mortality. Age and male sex were significantly associated with increased mortality. Study participants in middle income levels showed the greatest risk of mortality. The risk of mortality was increased by 25% when CCI score increased by one. Study participants who had anxiety, depression, or insomnia had decreased risk of mortality after adjustment, whereas patients with psychotic disorders showed increased risk.

Hazard ratios of mortality for potential confounders.

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Table 2

Hazard ratios of mortality for potential confounders.

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The HR of sedative-hypnotics on mortality after adjusting for age, sex, CCI, insurance premium, and psychiatric disorders is presented in Table 3. Study participants in the sedative-hypnotics exposure group showed a higher risk of mortality (HR 1.14, 95% CI 1.12–1.16) than those in the nonexposure group. Regarding the association between dosage of sedative-hypnotics and mortality, study participants for whom less than 180 DDDs of any sedative-hypnotics was prescribed showed no statistical association with mortality. However, the risk of mortality was significantly increased in study participants for whom 180–359 DDDs (HR 1.05, 95% CI 1.01–1.09) or more than 360 DDDs of any sedative-hypnotics (HR 1.36, 95% CI 1.32–1.39) were prescribed. Study participants exposed to less than 180 DDDs of BZD showed a decreased risk of mortality (HR 0.93, 95% CI 0.91–0.95). Conversely, study participants exposed to ≥ 360 DDDs of BZD had a significantly increased risk of mortality (HR 1.26, 95% CI 1.22–1.29).

Hazard ratios of mortality for sedative-hypnotics according to type and dose.

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Table 3

Hazard ratios of mortality for sedative-hypnotics according to type and dose.

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The risk of mortality was significantly increased in study participants exposed to any dose range of zolpidem. A clear dose-dependent relationship was found for each of the three groups classified based on zolpidem dose (HR of 1.43, 1.62, and 1.65 in the 30–179, 180–359, and ≥ 360 DDDs groups, respectively; all P < .0001). The risk of mortality was also increased in study participants exposed to more than two types of sedative-hypnotics. Moreover, the study participants prescribed both zolpidem and other drugs had the highest risk of mortality (HR 1.81, 95% CI 1.61–2.04).

Table 4 shows the HR of sedative-hypnotics for mortality only in patients with insomnia after adjusting for age, sex, CCI, insurance premium, and psychiatric disorders. Based on sensitivity analysis, the trend of mortality risk was similar to the main analysis except for BZD. The HR of patients with insomnia exposed to ≥ 30 DDDs of BZD was higher than that of patients with insomnia exposed to < 30 DDDs of BZD (HR 1.62, 95% CI 1.44–1.82). Patients with insomnia exposed to > 30 DDDs of three types of sedative-hypnotics had the highest risk of mortality (HR 3.57, 95% CI 3.16–4.02). Sedative-hypnotics were dose-dependently associated with mortality in patients with insomnia (HR of 1.69, 1.87, and 2.56 in the 30–179, 180–359, and ≥ 360 DDDs groups, respectively; all P < .0001). The risk of mortality in patients with insomnia for whom zolpidem was prescribed was increased more than twofold, even when exposed to less than 180 DDDs (HR 2.16, 95% CI 1.92–2.43).

Hazard ratios of mortality among insomnia patients for sedative-hypnotics according to type and dose.

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Table 4

Hazard ratios of mortality among insomnia patients for sedative-hypnotics according to type and dose.

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The survival rate for mortality according to sedative-hypnotics dose was estimated using the Kaplan-Meier method. The survival rate was dose-dependent; study participants for whom more sedative-hypnotics were prescribed died earlier (Figure 2). When mortality was calculated using the Kaplan– Meier survival curve based on type of sedative-hypnotics, almost 80% of study participants for whom only zolpidem was prescribed survived the 11-year observation period compared with approximately 90% of study participants for whom only BZD was prescribed. Approximately 60% of study participants for whom all types of study drugs were prescribed survived the 11-year observation period (Figure 3).

Kaplan-Meier survival curves of sedative-hypnotics for mortality classified based on sedative-hypnotics dose.

Nonexposure = < 30 DDDs, low-dose = 30–179 DDDs, medium-dose = 180–359 DDDs, high-dose = ≥ 360 DDDs. Kaplan–Meier-estimated survival rate and mortality based on sedative-hypnotics dose. The sedative-hypnotics exposure groups had a significantly lower survival rate than the nonexposure group (P < .0001). The survival rate was proportionally lower as doses of sedative-hypnotics increased (P < .0001). DDD = defined daily dose.

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Figure 2

Kaplan-Meier survival curves of sedative-hypnotics for mortality classified based on sedative-hypnotics dose.

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Kaplan-Meier survival curves of sedative-hypnotics for mortality classified based on type of sedative-hypnotics.

Nonexposure = < 30 DDDs, other groups = ≥ 30 DDDs. Kaplan– Meier-estimated survival rate for mortality based on type of sedative-hypnotics. The survival rate of the groups prescribed two or more types of sedative-hypnotics was lower than those of the groups prescribed only one type of sedative-hypnotics. The group prescribed all types of study drugs had the lowest survival rate (P < .0001). DDD = defined daily dose.

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Figure 3

Kaplan-Meier survival curves of sedative-hypnotics for mortality classified based on type of sedative-hypnotics.

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DISCUSSION

In this study, the association between prescription of sedative-hypnotics and increased mortality was examined using NHIS data over a 13-year period among more than 500,000 study participants representing a large sample of the general population. Study participants for whom sedative-hypnotics were prescribed had significantly increased risk of mortality (HR 1.20, 95% CI 1.18–1.22) after adjusting for age and sex. This association remained significant after adjusting for several potential confounding factors (HR 1.14, 95% CI 1.12–1.1.6), including medical and psychiatric comorbidities and socioeconomic status. These results confirmed the hypothesis that use of sedative-hypnotics is associated with increased mortality after adjusting for several confounding factors.

Our HR estimates between sedative-hypnotics and mortality were similar to those of a previous meta-analysis (pooled HR 1.21, 95% CI 1.15–1.28).24 Specifically, study participants for whom ≥ 30 DDDs of zolpidem were prescribed had the most increased HR (HR 1.59, 95% CI 1.52–1.67). In the sensitivity analysis limited to study participants with a diagnosis of insomnia for whom sedative-hypnotics were prescribed, the HRs of all study participants and of the subgroup classified based on the total number or type of sedative-hypnotics prescribed increased more than the HRs in the main analysis.

Inconsistent results have been reported in previous studies; a significant relationship between sedative-hypnotics and mortality has been observed in some studies2025 but not in others.1719 Similarly, in the current study, study participants prescribed only BZD had decreased HR of mortality (HR 0.94, 95% CI 0.92–0.96). However, in the subgroup analysis, only the low-dose BZD subgroup (30–179 DDDs) had decreased HR (HR 0.93, 95% CI 0.91–0.95), whereas the high-dose BZD subgroup (≥ 360 DDDs) had increased HR (HR 1.26, 95% CI 1.22–1.29). It is possible that study participants prescribed low-dose BZD had mild anxiety symptoms, somatic symptoms, or insomnia symptoms, and received more medical care, thus resulting in higher disease detection than in nonusers. Based on a study focusing on the BZD prescription prevalence in the Republic of Korea, 87.7% of patients were prescribed BZD at nonpsychiatric departments; the most frequent prescription indication was gastrointestinal-related disease.8 Similarly, the HR of study participants who had anxiety disorder (HR 0.74, 95% CI 0.72– 0.77) and insomnia (HR 0.93, 95% CI 0.90–0.97) may be lower in this study. However, in sensitivity analysis, patients with insomnia for whom only low-dose BZD was prescribed (30–179 DDDs) also had a higher HR than patients with insomnia for whom < 30 DDDs of BZD was prescribed (HR 1.53, 95% CI 1.37–1.72). More than 40% of patients with obstructive sleep apnea (OSA) have at least one insomnia symptom33; patients with comorbid OSA and insomnia who take BZD may experience a depressant effect on the respiratory system that may aggravate OSA.34 Patients in whom insomnia has been diagnosed and BZD prescribed may self-medicate with other drugs or drink alcohol, which can aggravate the side effects of BZD.35 There are several possible explanations regarding the relationship between sedative-hypnotics use and increased risk of mortality. First, the sedative side effect of sedative-hypnotics is associated with psychomotor impairments, thus increasing the risk of accidents, falls, and fractures, which are associated with cognitive impairment.912,15,16 Second, the depressant effect of sedative-hypnotics on the respiratory system may aggravate sleep-related breathing disorders, especially in patients with pulmonary and cardiac diseases.34 Furthermore, previous studies found increased risks of infection, pneumonia, and cancer associated with suppression of the immune system.13,14,21,36,37 Moreover, disinhibition is a frequent side effect during the peak drug effect of some sedative-hypnotics. According to the FDA Adverse Event Reporting System, amnesia, confusion, hallucination, and parasomnia due to the disinhibitory effect of sedative-hypnotics have been associated with suicide.38

The mortality risk associated with Z-drug use was reported in five studies. The pooled analysis showed a 73% increased risk of mortality among study participants who used Z-drugs compared with nonusers; however, the pooled HR was not statistically significant (HR 1.73, 95% CI 0.95–3.16).24 Unlike this meta-analysis, a matched cohort study performed in the United States found that patients for whom more than 60 pills of zolpidem per year were prescribed had an increased HR for mortality (HR 3.93, 95% CI 2.98–5.17),21 and a retrospective cohort study performed in the United Kingdom found that patients for whom any DDD of Z-drugs were prescribed were more likely than nonusers to have a higher HR for mortality (HR 3.19, 95% CI 2.95–3.45).25 In contrast, a retrospective cohort study performed in Taiwan found that the HR for mortality was high in a BZD group (HR 2.22, 95% CI 2.18–2.26) and low in a zolpidem group (HR 0.85, 95% CI 0.83–0.87).26 Unlike the Taiwanese study, our study results showed that study participants for whom ≥ 30 DDDs of zolpidem was prescribed had a 59% higher risk of mortality than that of study participants not exposed to zolpidem (HR 1.59, 95% CI 1.52–1.67). Our findings are in line with those of most studies suggesting that Z-drugs are associated with increased mortality. Unlike BZD, a clear dose–response relationship was found in study participants using zolpidem, with fully-adjusted HR of mortality ranging from 1.38 to 1.65 among study participants for whom 30–179 DDDs, 180–359 DDDs, and ≥ 360 DDDs of zolpidem was prescribed. Additionally, zolpidem showed a synergistic effect when prescribed with other drugs, including small doses of antidepressants and antipsychotic drugs, to increase the HR of mortality. Several explanations are possible. According to two studies focusing on the adverse effects of zolpidem, performed in Australia and the United States, study participants taking zolpidem showed increased adverse effects of parasomnia, amnesia, hallucination, and suicidality compared with study participants taking BZD or other hypnotics.39,40 It has also been reported that patients taking Z-drugs had an increased risk— over twice that of unexposed patients—of motor vehicle accidents.41 In a Korean insurance registry study, zolpidem use increased the risk of hip fractures and was associated with a higher risk of such fractures than was BZD use.42 Patients with depression or anxiety along with insomnia may seek treatment for only their insomnia because of the stigma of psychiatric treatment. Although several BZDs have been reported to have therapeutic effects on anxiety and depressed mood,43 zolpidem did not. It is possible that patients with underlying depression may report only their insomnia symptoms, resulting in the exclusive prescription of zolpidem. Conversely, patients for whom zolpidem is prescribed may be experience more depression, possibly leading to increased mortality.44

Data on the cause of death were unavailable; therefore, associations between prescription of sedative-hypnotics and specific causes of mortality could not be explained. Also, we could not use information on lifestyle (eg, alcohol consumption or smoking), education, employment status, or marital status that may affect mortality. Another limitation of this study is that the use of sedative-hypnotics may have been overestimated because only data on prescriptions were available; data regarding whether people actually used sedative-hypnotics were absent.

Despite the limitations, the large sample size representative of the general population, its completeness, and the long follow-up period of the NHIS data are strengths of the current study. Objective data on sedative-hypnotics use based on computed prescription data rather than self-reported use were also a strength. Several confounding factors were obtained from NHIS data; specifically, we adjusted for physical health based on CCI and psychiatric comorbidities. Unlike previous studies, we controlled for most mental disorders, such as depressive, anxiety, and psychotic disorders, in addition to insomnia. DDD was used to quantify cumulative doses of sedative-hypnotics, which allowed evaluation of the effects of different drug types. Cohort studies are likely to have immortal time bias.45 In this study, we used time-dependent modeling analysis to overcome this bias.

In conclusion, the use of sedative-hypnotics was associated with an increased risk of mortality. Specifically, this association followed a dose–response relationship for study participants for whom zolpidem was prescribed. The risk of mortality was higher in those prescribed zolpidem, two or more sedative-hypnotics, or high doses. However, because information regarding causes of death was unavailable, the mechanism between sedative-hypnotics use and mortality could not be investigated. Further well-designed, prospective studies are warranted to evaluate the underlying mechanism responsible for increased mortality associated with sedative-hypnotics.

DISCLOSURE STATEMENT

This study was supported by the research fund of the Mental Health Technology Development Project (Project No. HM15C1197). The authors report no conflicts of interest.

ABBREVIATIONS

BZD

benzodiazepines

CCI

Charlson Comorbidity Index

CI

confidence interval

DDD

defined daily dose

HR

hazard ratio

ICD

International Statistical Classification of Diseases and Related Health Problems

NHIS

National Health Insurance Service

OSA

obstructive sleep apnea

ACKNOWLEDGMENTS

Author contributions: Dr. Lee and Dr. Shin developed the study concepts and collected the data. Dr. Choi, Dr. Joonki Lee, and Dr. Jung analyzed the data and wrote the manuscript. All authors provided important information on data and contributed to the final version of the manuscript. The English in this document has been checked by at least two professional editors, both native speakers of English. For a certificate, please see: http://www.textcheck.com/certificate/uqxDPI.

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