Journal of Psychiatric Research 54 (2014) 116e120 Contents lists available at ScienceDirect Journal of Psychiatric Research journal homepage: www.elsevier.com/locate/psychires The association between zolpidem and infection in patients with sleep disturbance Chih-Yuan Huang a,m,1, Frank Hunag-Chih Chou b,c,1, Yung-Sung Huang d,1, Chang-Jen Yang e, Yu-Chieh Su k,f,g, Shiun-Yang Juang h, Pin-Fan Chen i, Pesus Chou j, Ching-An Lee k, Ching-Chih Lee g,j,l,m,* a Division of Nephrology, Department of Internal Medicine, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi, Taiwan b Department of Community Psychiatry, Kai-Syuan Psychiatric Hospital, Kaohsiung City, Taiwan c Graduate Institute of Health Care and Department of Nursing, Meiho University, Ping-Tong County, Taiwan d Division of Neurology, Department of Internal Medicine, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi, Taiwan e Department of Orthopedics, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi, Taiwan f Division of Hematology-Oncology, Department of Internal Medicine, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi, Taiwan g Cancer Center, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi, Taiwan h Department of Research, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi, Taiwan i Division of Metabolism and Endocrinology, Department of Internal Medicine, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi, Taiwan j Community Medicine Research Center and Institute of Public Health, National Yang-Ming University, Taipei, Taiwan k Department of Pharmacy, Chiayi Branch, Taichung Veterans General Hospital, Chiayi, Taiwan l Department of Otolaryngology, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi, Taiwan m School of Medicine, Tzu Chi University, Hualian, Taiwan article info abstract Article history: Objective: Recent case reports suggest that zolpidem usage may be associated with infection events. The Received 14 November 2013 aim of this study was to determine the risk of infection events in patients with sleep disturbance taking Received in revised form zolpidem in a full 3-year follow-up study. 8 March 2014 Methods: A total of 17474 subjects with a diagnosis of sleep disturbance in 2002 and 2003 were Accepted 8 March 2014 identified, of whom 5882 had used zolpidem after recruitment. A Cox proportional hazard model was used to estimate the 3-year infection event-free rates for the patients using zolpidem and those not Keywords: using zolpidem after adjusting for confounding factors. To maximize case ascertainment, only patients Zolpidem Infection hospitalized for infection events were included. Mean daily dose Results: A total of 646 patients had had infection events, 331 (5.63%) of whom had been taking zolpidem Immunity and 315 (2.71%) had not. Zolpidem usage increased the risk of infection events. After adjustments for gender, age, co-morbidities, and other medications, patients using zolpidem with cDDD 1-28, 29-84, and >84 had hazard ratios of 1.67 (95% CI, 1.32e2.11), 1.91 (95% CI, 1.47e2.49) and 1.62 (95% CI, 1.32e1.98) respectively, compared with patients who did not use zolpidem. Conclusions: Zolpidem increased the risk of infection events in sleep disturbance patients. This increased risk of infection should be explained to sleep disturbance patients, and prescriptions of zolpidem to chronic insomnia patients should be restricted. Ó 2014 Elsevier Ltd. All rights reserved. 1. Introduction The clinical use of sedatives and hypnotics has gradually * Corresponding author. Center for Clinical Epidemiology and Biostatistics, increased, and a 53% growth in prescriptions over 5 years was Department of Otolaryngology, Buddhist Tzu Chi Medical Foundation, No. 2, Ming- reported in 2006 (Jon, 2007). The most commonly prescribed Sheng Road, Dalin Town, Chiayi, 622, Taiwan.Tel.: þ886 5 2648000x5919; fax: þ886 medications are benzodiazepines, non-benzodiazepines, gamma- 5 2648006. E-mail address: [email protected] (C.-C. Lee). aminobutyric acid (GABA) agonists, melatonin receptor agonists, 1 These authors contributed equally to this manuscript. sedating antidepressants, antihistamines and wake-promoting http://dx.doi.org/10.1016/j.jpsychires.2014.03.017 0022-3956/Ó 2014 Elsevier Ltd. All rights reserved. C.-Y. Huang et al. / Journal of Psychiatric Research 54 (2014) 116e120 117 drugs (Kryger MH, 2010). However, the potential side effects outcomes including any type of infectious disease. To maximize of hypnotics, such as infection, cancer and death have been case ascertainment, only patients hospitalized for infection events overlooked. were included. These patients were then linked to the adminis- Zolpidem, an imidazopyridine developed in 1980, has been trative data to calculate infection event-free rates, with cases increasingly used in patients with sleep disturbance because of its censored for those who drew back guarantees from the National effectiveness, good tolerance and a short half-life of 2.5 h (Drover, Health Insurance Program or were still robust without defined 2004; Rhodes et al., 1990) Only a few studies have explored the events at the end of follow-up. relationship between zolpidem usage and infection events (Malloy et al., 2006; Obiora et al., 2013). According to detailed information 2.3.1. Definition of exposure and covariate adjustment fi available on the Sano -Aventis website, the incidence of sinusitis in The main exposure of interest was zolpidem use after recruit- individuals taking zolpidem is 4% (placebo 2%), the incidence of ment. The dosage, date of prescription, duration, and total number upper respiratory tract infections 5% (placebo 6%), and pharyngitis of pills dispensed from the outpatient pharmacy prescription 3% (placebo 1%) (aventis). Recently, an increased risk of infection database were recorded. The defined daily doses (DDD) was 10 mg with zolpidem use was reported in a meta-analysis study (Joya each day for zolpidem. The cumulative DDD was calculated ac- et al., 2009). However, the heterogeneity between studies, lack of cording to the following formula: (total amount of drug/amount of infection details, small number of infections in individual trials, and drug in a DDD). To examine the doseeeffect relationship, we cate- short follow-up duration may raise potential bias. gorized zolpidem use into four groups in our series (0,1e28, 29e84, Zolpidem-induced adverse effects, such as hallucinations, and >84 cDDDs). Other medications were included for analysis sleepwalking, and nocturnal eating, have recently been reported including antihypertensives (i.e. propranolol, terazosin, doxazosin, in the literature (Inagaki et al., 2010). Nevertheless, the impact prazosin, atenolol, furosemide, nifedipine, verapamil, diltiazem, of zolpidem on infection events in patients with sleep disturbance isosorbide dinitrate, lisinopril, amitriptyline, chlorpromazine, and has not been clearly explored. The aim of the current study was procholorperazine), psychotropic agents (i.e. diazepam, alprazolam, to determine the relative risk of infection events with zolpidem and haloperidol), oral hypoglycemic agents and insulin use. The usage in sleep disturbance patients using a population-based patients’ age, gender, comorbidities, and monthly income level as a dataset. proxy of socioeconomic status were also recorded. The comorbid- ities of each patient were based on the modified Charlson comor- 2. Materials and methods bidity index score, which has been widely used in recent years for risk adjustment in administrative claims data sets (Deyo et al.,1992). 2.1. Ethics statement This study was initiated after approval by the Institutional 2.4. Statistical analysis Review Board of Buddhist Dalin Tzu Chi General Hospital, Taiwan. Since all identifying personal information was stripped from the The SPSS version 15 (SPSS Inc., Chicago, IL) were used for data ’ secondary files before analysis, the review board waived the analysis. Pearson s chi-square test was used for categorical vari- requirement for written informed consent from the patients ables, demographic characteristics (age group and gender), Charl- involved. son Comorbidities Index Score and medications. The 3-year infection event-free survival rate was estimated us- e 2.2. Database ing the Kaplan Meier method. The cumulative risk of an infection event was estimated as a function of time from initial treatment. A The National Health Insurance program, which provides Cox proportional hazard regression model was used to calculate the compulsory universal health insurance, was implemented in Taiwan risk of an infection event for patients with sleep disturbance with in 1995. It enrolls up to 99% of the Taiwanese population and has zolpidem versus those without, after adjustments for age, gender, contracts with 97% of all medical providers. The database contains comorbidities, urbanization and region of residence, socioeconomic comprehensive information on insured subjects, including dates of status, and medication. A p value less than 0.05 was considered fi clinical visits, diagnostic codes, details of prescriptions and expen- statistically signi cant in the regression models. diture. This study used the Longitudinal Health Insurance Dataset for 2002e2003 released by the Taiwan Nation Health Research Institute. 3. Results The patients in this dataset did not statistically significantly differ from the larger cohort in age, gender or health care costs, as reported The