Drug Class Review Newer Drugs for Insomnia Final Update 2 Report October 2008 The Agency for Healthcare Research and Quality has not yet seen or approved this report. The purpose of Drug Effectiveness Review Project reports is to make available information regarding the comparative clinical effectiveness and harms of different drugs. Reports are not usage guidelines, nor should they be read as an endorsement of or recommendation for any particular drug, use, or approach. Oregon Health & Science University does not recommend or endorse any guideline or recommendation developed by users of these reports. Update 1: July 2006 Original: December 2005 Susan Carson, MPH Marian S. McDonagh, PharmD Sujata Thakurta, MPA:HA Po-Yin Yen, MS Drug Effectiveness Review Project Marian McDonagh, PharmD, Principal Investigator Oregon Evidence-based Practice Center Mark Helfand, MD, MPH, Director Copyright © 2008 by Oregon Health & Science University Portland, Oregon 97239. All rights reserved. Final Report Update 2 Drug Effectiveness Review Project The medical literature relating to the topic is scanned periodically (see http://www.ohsu.edu/xd/research/centers-institutes/evidence-based-policy- center/derp/documents/methods.cfm for scanning process description). Upon review of the last scan, the Drug Effectiveness Review Project governance group elected not to proceed with another full update of this report based on the information contained in the scan. Some portions of the report may not be up to date. Prior versions of this report can be accessed at the DERP website. Insomnia Page 2 of 87 Final Report Update 2 Drug Effectiveness Review Project TABLE OF CONTENTS INTRODUCTION ............................................................................................................. 6 Scope and Key Questions ....................................................................................................................... 6 METHODS ...................................................................................................................... 9 Literature Search ..................................................................................................................................... 9 Study Selection ........................................................................................................................................ 9 Data Abstraction ...................................................................................................................................... 9 Validity Assessment ................................................................................................................................. 9 Data Synthesis ....................................................................................................................................... 10 RESULTS ..................................................................................................................... 11 Overview of included studies ................................................................................................................. 11 Key Question 1. What is the comparative effectiveness of newer drugs in treating adults and children with insomnia? ....................................................................................................................................... 14 Summary of the Evidence................................................................................................................. 14 Detailed Assessment ........................................................................................................................ 15 Key Question 2. What is the comparative tolerability and safety of Newer Drugs for Insomnia when used to treat patients with insomnia? .................................................................................................... 31 Summary of the Evidence................................................................................................................. 31 Detailed Assessment ........................................................................................................................ 32 Key Question 3. Are there subgroups of patients for which one Newer Drug for Insomnia is more effective or associated with fewer adverse events? .............................................................................. 39 Summary of the Evidence................................................................................................................. 39 Detailed Assessment ........................................................................................................................ 40 SUMMARY .................................................................................................................... 44 REFERENCES .............................................................................................................. 47 FIGURES Figure 1. Newer drugs for insomnia: Results of literature search.......................................................... 12 Figure 2. Subjective sleep latency in placebo-controlled trials of newer insomnia drugs ..................... 23 Figure 3. Subjective sleep duration in placebo-controlled trials of newer insomnia drugs .................... 24 Figure 4. Subjective wake time after sleep onset in placebo-controlled trials of newer insomnia drugs ...................................................................................................................................................... 25 Figure 5. Subjective number of awakenings in placebo-controlled trials of newer insomnia drugs ...... 26 Figure 6. Withdrawals due to adverse events reported in placebo-controlled trials of newer drugs for insomnia ................................................................................................................................................. 34 TABLES Table 1. Newer drugs for insomnia .......................................................................................................... 8 Table 2. Total numbers of head-to-head trials of newer drugs for insomnia ......................................... 13 Table 3. Head-to-head trials of newer insomnia drugs: Study design and patient characteristics ........ 16 Table 4. Head-to-head comparison of eszopiclone compared with zolpidem on polysomnography- measured outcomes .............................................................................................................................. 17 Table 5. Placebo-controlled trials included in meta-analysis of subjective sleep outcomes ................. 20 Table 6. Adjusted indirect meta-analysis: Summary of results .............................................................. 27 Table 7. Subgroup analysis by elderly and non-elderly adult patients .................................................. 28 Table 8. Placebo-controlled trials of zolpidem extended-release .......................................................... 30 Table 9. Adverse events in head-to-head studies of zaleplon compared with zolpidem ....................... 32 Table 10. Adjusted indirect analysis of placebo-controlled trials: Withdrawals due to adverse events. 35 Table 11. Summary of the evidence by key question ............................................................................ 44 Insomnia Page 3 of 87 Final Report Update 2 Drug Effectiveness Review Project APPENDIXES Appendix A. Literature search strategies ............................................................................................... 60 Appendix B. Quality assessment methods for drug class reviews for the Drug Effectiveness Review Project .................................................................................................................................................... 61 Appendix C. Excluded studies ............................................................................................................... 65 Appendix D. Summary of results of trials comparing newer insomnia drugs compared with benzodiazepines .................................................................................................................................... 84 EVIDENCE TABLES Published in a separate document Insomnia Page 4 of 87 Final Report Update 2 Drug Effectiveness Review Project Suggested citation for this report: Carson S, McDonagh M, Thakurta S, Yen P. Drug class review: Insomnia. 2008. http://www.ohsu.edu/drugeffectiveness/reports/final.cfm Funding: The funding source, the Center for Evidence-based Policy, is supported by 17 organizations, including 15 state Medicaid programs. These organizations selected the topic and had input into the Key Questions of this review. The content and conclusions of the review are entirely determined by the Evidence-based Practice Center researchers. The authors of this report have no financial interest in any company that makes or distributes the products reviewed in this report. Insomnia Page 5 of 87 Final Report Update 2 Drug Effectiveness Review Project INTRODUCTION Insomnia is a serious health problem that affects millions of people. Population surveys have estimated the prevalence of insomnia to be about 30% to 50% of the general population. Variation in estimates depends on different methods of surveying and definitions of insomnia.1 About three-fourths of people who have trouble sleeping say that the problem is “occasional,” averaging about 6 nights per month. The other one-fourth have frequent or chronic insomnia, averaging about 16 nights per month.2