Abstract
BackgroundAlthough long-term use of benzodiazepines and benzodiazepine receptor agonists (BZDs) has been associated with an increased risk of dependence, the incidence, details of clinical manifestations, and triggering factors of withdrawal symptoms associated with long-term BZD use at common clinical doses remain unclear.MethodsIn a multicenter, open-label study of 123 Japanese patients with insomnia, patients were given a common clinical dose of eszopiclone (2 mg) for 24 weeks, and then treatment was abruptly discontinued. Withdrawal symptoms were evaluated using the Benzodiazepine Hypnotics Withdrawal Symptom Scale (BHWSS). The Insomnia Severity Index (ISI) was used to rate insomnia severity during treatment and 2 weeks after discontinuation. Dependence and poor compliance during treatment without strict medication controls were evaluated with the Benzodiazepine Dependence Self Report Questionnaire short version (Bendep-SRQ SV) subscale sum scores for problematic use, preoccupation, and lack of compliance. Associations between the presence of clinically relevant withdrawal symptoms (BHWSS≥7) and demographic measures, ISI scores at Week 24, and Bendep-SRQ SV subscale sum scores were evaluated by multivariable stepwise logistic regression analyses.ResultsSeventy-six patients completed treatment and 2 weeks of withdrawal; eight (10.5%) had clinically relevant withdrawal symptoms. On multiple logistic regression analysis, Bendep-SRQ SV subscale sum scores were correlated with withdrawal symptoms (odds ratio, 1.650; 95% confidence interval, 1.105–2.464; p = 0.014). Exacerbation of post-discontinuation insomnia was not significantly different between patients who showed clinically relevant withdrawal symptoms and those who did not (p = 0.245).ConclusionsDependence and poor compliance may contribute to withdrawal symptoms with long-term BZD use. Providing guidance to ensure proper compliance is thought to be the best way to mitigate withdrawal symptoms.Trial registrationUMIN000024462 (18/10/2016).
Highlights
Long-term use of benzodiazepines and benzodiazepine receptor agonists (BZDs) has been associated with an increased risk of dependence, the incidence, details of clinical manifestations, and triggering factors of withdrawal symptoms associated with long-term Benzodiazepine receptor agonist (BZD) use at common clinical doses remain unclear
A study associated with the United States National Health and Nutrition Examination Survey (NHANES) found that a growing proportion of patients received long-term prescriptions of BZDs, with about 3% receiving a prescription for 6 months or longer [1]
Of even greater concern is the lack of research on the relationship between daytime withdrawal symptoms and the worsening of insomnia often occurring in patients who discontinue a hypnotic medication at a common clinical dose [7,8,9,10]
Summary
Long-term use of benzodiazepines and benzodiazepine receptor agonists (BZDs) has been associated with an increased risk of dependence, the incidence, details of clinical manifestations, and triggering factors of withdrawal symptoms associated with long-term BZD use at common clinical doses remain unclear. Long-term BZD use may lead to increasing individuals’ need for higher doses, BZD dependence and its associated withdrawal symptoms, including seizures, hallucinations [3, 4], did not occur in randomized clinical trials with the continuous use of BZDs at common clinical doses for 6 months or 1 year [5, 6]. In these studies, patients were strictly instructed to take their allocated treatment regularly, which, differ widely from daily clinical practice, where the medication administration is left mainly to patients. Of even greater concern is the lack of research on the relationship between daytime withdrawal symptoms and the worsening of insomnia often occurring in patients who discontinue a hypnotic medication at a common clinical dose [7,8,9,10]
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