Original Title: Long-term use of sedative-hypnotic drugs in patients with primary chronic insomnia disorder

Authors' objectives: BACKGROUND: Sedative-hypnotic drugs are used to reduce tension and anxiety and to induce calm (sedative effect) or sleep (hypnotic effect). Following clinical guidelines and product information, these drugs should not be prescribed for longer than four weeks for primary chronic insomnia disorder. The current total costs of these drugs have a large impact on the national healthcare budget. Despite the high costs, potential harms and clear discouraging guideline recommendations for long-term sedative-hypnotic drug treatment, the rates of sedative-hypnotic drugs use have not changed meaningfully over time. OBJECTIVE: The aim of the HTA is to investigate the clinical efficacy, effectiveness, safety, and cost-effectiveness of intermediate (1-6 months) and long-term (≥6 months) use of sedative-hypnotic drugs of ATC categories N05BA (benzodiazepine derivatives), N05CD (benzodiazepine derivatives), or N05CF (Z-drugs/benzodiazepine related drugs) listed in the Swiss speciality list to treat primary chronic insomnia disorder compared to placebo, no treatment, or other non-pharmacological treatment, or compared to the short-term use (≤ one month) of sedative-hypnotic drugs.

Authors' results and conclusions: RESULTS: Evidence from eight RCTs was evaluated to inform efficacy and safety outcomes of intermediate-term (1-6 months) and long-term (≥6 months) use of Z-drugs compared to placebo, no treatment, other non-pharmacological treatment for the treatment of primary chronic insomnia disorder. Only RCTs on Z-drugs were found; RCTs on benzodiazepine derivatives did not fulfil our inclusion criteria. No RCTs were found comparing intermediate- and long-term sedative-hypnotic drug use to short-term (≤1 month) use. Three RCTs compared intermediate-term use of Z-drugs with behaviour therapy. No studies were found on the efficacy of long-term use of Z-drugs compared with behaviour therapy. Three RCTs compared intermediate-term and three RCTs compared long-term use of Z-drugs with a placebo group. Compared to placebo, use of Z-drugs seemed efficacious, while intermediate-term treatment results were inconclusive. In the RCT studies, no major safety issues, nor symptoms of tolerance to Z-drugs were observed. Withdrawal from treatment due to adverse events was found to be significantly higher in long-term Z-drug users compared to placebo users. However, the underlying adverse events were mild, and the serious adverse events were not related to the study medication. Results from a de novo economic model showed that the long-term use of Z-drugs is associated with more costs and less QALYs than short-term use of Z-drugs alone, short-term use of Z-drugs followed by cognitive behavioural therapy for insomnia (CBT-I), CBT-I alone or no treatment. The sensitivity analyses showed that the results were sensitive to the benefit derived from Z-drugs, as well as the baseline quality of life. In most scenario analyses, incremental costs and a reduction of effects with long-term use of Z-drugs were dominated as a strategy by all the comparators in our model. The PSA of each PICO yielded stable incremental costs with little variance, while incremental QALYs were more sensitive to variation in the model. The budget impact analysis results showed that no treatment or short-term use of Z-drugs could save more than 130 million Swiss francs, while CBT-I alone or short-term use of Z-drugs in combination with CBT-I could save around 30 million Swiss francs. Relevant ethical, legal, social, and organisational issues were informed by 20 reports, including observational studies, literature reviews, and guidelines. The included literature suggests that dependency and dosage increase are associated with Z-drug use. Long-term use of Z-drugs in the elderly may be accompanied with polypharmacy related side effects. Observational studies show that Z-drug use is associated with an increased risk of road traffic accidents and fractures. CONCLUSION: Sparse, clinical evidence based on only two RCTs suggests that compared to placebo, long-term (≥6 months) use of Z-drugs is efficacious for the treatment of primary chronic insomnia disorders. No major safety issues, nor symptoms of tolerance to Z-drugs were observed. No RCTs on long-term use of benzodiazepine derivatives were found. From a health economic perspective, long-term use of Z-drugs most likely increases costs and reduces effects in terms of QALYs relative to short-term use of Z-drugs alone, short-term use of Z-drugs followed by CBT-I, CBT-I alone or no treatment. Further, literature found Z-drugs to be associated with increased risk of road traffic accidents and fractures.

Authors' methods: METHODS: Clinical and economic evidence was retrieved from systematic literature searches conducted in PubMed (MEDLINE) and Embase.com, as well as other sources (NHS EED and CRD). A de novo individual state transition cost-effectiveness model was developed to determine the cost-effectiveness of long-term use of sedative-hypnotic drugs (Z-drugs specifically due to lack of evidence for the other ATC groups of interest) to treat primary chronic insomnia disorder against no treatment, other non-pharmacological treatment, or short-term use (≤ 1 month) of sedative-hypnotic drugs applying a 10-year time horizon, and a 3% discounting of costs and effects. Although the systematic literature searches included the three ATC categories, the model was built only for N05CF (Z-drugs) due to data scarcity. Many of the effectiveness components were sourced from observational studies, as RTC outcomes sourced in the clinical effectiveness systematic literature search do not easily translate to quality-adjusted life years (QALY) and did not cover all effectiveness elements included in the cost-effectiveness model. The uncertainty around input parameters was explored in sensitivity and scenario analyses. In addition, a budget impact analysis was conducted.

Project Status: Completed

URL for project: https://www.bag.admin.ch/bag/en/home/versicherungen/krankenversicherung/krankenversicherung-leistungen-tarife/hta/hta-projekte/sedativa.html

Year Published: 2022

URL for published report: https://www.bag.admin.ch/dam/bag/en/dokumente/kuv-leistungen/leistungen-und-tarife/hta/berichte/h0045sdtv-hta-report.pdf.download.pdf/h0045sdtv-hta-report.pdf

URL for additional information: https://www.bag.admin.ch/bag/en/home/versicherungen/krankenversicherung/krankenversicherung-leistungen-tarife/hta/hta-programm.html

English language abstract: An English language summary is available

Publication Type: Full HTA

Country: Switzerland

Organisation Name: Swiss Federal Office of Public Health (FOPH)

Contact Address: Federal Office of Public Health, Schwarzenburgstrasse 157, CH-3003 Berne, Switzerland

Contact Name: Stephanie Vollenweider

Contact Email: hta@bag.admin.ch

Copyright: Swiss Federal Office of Public Health