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

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.