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      Association Between Benzodiazepine Use and Epilepsy Occurrence : A Nationwide Population-Based Case–Control Study

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      , MD, PhD, , MSc, , MD
      Medicine
      Wolters Kluwer Health

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          Abstract

          We conducted a retrospective case–control study to evaluate the association between the risk of benzodiazepine (BZD) use and epilepsy occurrence by using data from the Taiwan National Health Insurance Research Database.

          We recruited 1065 participants who ages 20 years or older and newly diagnosed with epilepsy (International Classification of Diseases, Ninth Revision, Clinical Modification 345) between 2004 and 2011 and assigned them to the epilepsy group. We subsequently frequency-matched them with participants in a control group (n = 4260) according to sex, age, and index year at a 1:4 ratio. A logistic regression model was employed to calculate the odds ratio (OR) for association of epilepsy with BZD exposure. Multivariate logistic regression was conducted to estimate the dose–response relationship between BZD levels and epilepsy risk.

          The adjusted OR (aOR) for the association of epilepsy with BZD exposure was 2.02 (95% confidence interval [CI] = 1.68–2.42). The aOR for an average BZD dose increased to 1.26 for the participants on <0.01 defined daily dose (DDD), and increased to 4.32 for those on ≥1.50 DDD. On average, when the DDD of BZD exposure increased by 100 units, the epilepsy risk increase by 1.03-fold (95% CI = 1.01–1.04, P = 0.003). The annual BZD exposure day ranges were significantly associated with epilepsy (2–7 days: aOR = 1.67; 8–35 days: aOR = 3.16; and ≥35 days: aOR = 5.60). Whenever the annual BZD exposure increased by 30 days, the risk of epilepsy notably increased by 1.03-fold (95% CI = 1.01–1.04, P < 0.001). In addition, users who quit BZD for more than 6 months still exhibited a higher risk of epilepsy than did the non-BZD users.

          A considerable increase in epilepsy occurrence was observed in ones with BZD use, particularly in those with prolonged use, multiple exposure, and high-dose consumption.

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          Most cited references22

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          GABA actions and ionic plasticity in epilepsy.

          Concepts of epilepsy, based on a simple change in neuronal excitation/inhibition balance, have subsided in face of recent insights into the large diversity and context-dependence of signaling mechanisms at the molecular, cellular and neuronal network level. GABAergic transmission exerts both seizure-suppressing and seizure-promoting actions. These two roles are prone to short-term and long-term alterations, evident both during epileptogenesis and during individual epileptiform events. The driving force of GABAergic currents is controlled by ion-regulatory molecules such as the neuronal K-Cl cotransporter KCC2 and cytosolic carbonic anhydrases. Accumulating evidence suggests that neuronal ion regulation is highly plastic, thereby contributing to the multiple roles ascribed to GABAergic signaling during epileptogenesis and epilepsy. Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.
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            Regulation of GABA(A) receptor subunit expression by pharmacological agents.

            The gamma-aminobutyric acid (GABA) type A receptor system, the main fast-acting inhibitory neurotransmitter system in the brain, is the pharmacological target for many drugs used clinically to treat, for example, anxiety disorders and epilepsy, and to induce and maintain sedation, sleep, and anesthesia. These drugs facilitate the function of pentameric GABA(A) receptors that exhibit widespread expression in all brain regions and large structural and pharmacological heterogeneity as a result of composition from a repertoire of 19 subunit variants. One of the main problems in clinical use of GABA(A) receptor agonists is the development of tolerance. Most drugs, in long-term use and during withdrawal, have been associated with important modulations of the receptor subunit expression in brain-region-specific manner, participating in the mechanisms of tolerance and dependence. In most cases, the molecular mechanisms of regulation of subunit expression are poorly known, partly as a result of neurobiological adaptation to altered neuronal function. More knowledge has been obtained on the mechanisms of GABA(A) receptor trafficking and cell surface expression and the processes that may contribute to tolerance, although their possible pharmacological regulation is not known. Drug development for neuropsychiatric disorders, including epilepsy, alcoholism, schizophrenia, and anxiety, has been ongoing for several years. One key step to extend drug development related to GABA(A) receptors is likely to require deeper understanding of the adaptational mechanisms of neurons, receptors themselves with interacting proteins, and finally receptor subunits during drug action and in neuropsychiatric disease processes.
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              Safety of benzodiazepines in the geriatric population.

              Benzodiazepines are the most frequently prescribed antianxiety drugs in the elderly. Despite their usefulness and safety in the younger population, there is concern about the rationale for their use in the elderly. Studies of the therapeutic use of benzodiazepines in the elderly are rare. Elderly females with co-morbid medical and psychiatric conditions and who are taking multiple medications form the group most frequently prescribed benzodiazepines among the elderly, and the group most likely to experience side effects. Age-related pharmacokinetic and pharmacodynamic changes increase the potential for certain side effects in the elderly. Significant adverse effects that may be associated with benzodiazepine use in the elderly include falls, cognitive impairment, sedation, and impairment of driving skills, all of which are particularly related to the long half-life of benzodiazepines. Long-term use of benzodiazepines should be discouraged because of the risk of dependence, which is a serious problem in the elderly. Unrecognised and untreated benzodiazepine dependence can lead to serious medical complications.
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                Author and article information

                Journal
                Medicine (Baltimore)
                Medicine (Baltimore)
                MEDI
                Medicine
                Wolters Kluwer Health
                0025-7974
                1536-5964
                September 2015
                18 September 2015
                : 94
                : 37
                : e1571
                Affiliations
                From the Department of Neurosurgery, Hualien Tzu Chi General Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan (TH); College of Medicine, Tzu Chi University, Hualien, Taiwan (TH); Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan (Y-CW); College of Medicine, China Medical University, Taichung, Taiwan (Y-CW); Graduate Institute of Clinical Medical Science and School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan (C-HK); and Department of Nuclear Medicine and PET Center, China Medical University Hospital, Taichung, Taiwan (C-HK).
                Author notes
                Correspondence: Chia-Hung Kao, Graduate Institute of Clinical Medical Science and School of Medicine, College of Medicine, China Medical University, No. 2, Yuh-Der Road, Taichung 404, Taiwan (e-mail: d10040@ 123456mail.cmuh.org.tw).
                Article
                01571
                10.1097/MD.0000000000001571
                4635822
                26376408
                497fa8d3-bfbe-4d74-be8c-47c3ab0f4c15
                Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

                This is an open access article distributed under the Creative Commons Attribution-NoDerivatives License 4.0, which allows for redistribution, commercial and non-commercial, as long as it is passed along unchanged and in whole, with credit to the author. http://creativecommons.org/licenses/by-nd/4.0

                History
                : 7 April 2015
                : 17 August 2015
                : 19 August 2015
                Categories
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                Research Article
                Observational Study
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