Comparative Efficacy and Safety of Dual Orexin Receptor Antagonists (DORAs) Versus Z-Drugs for Insomnia in Older Adults : A Systematic Review
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Abstract
Introduction
Insomnia affects up to 48% of older adults globally, often treated with Z-drugs that increase the risk of cognitive impairment and falls.1,4 Dual Orexin Receptor Antagonists (DORAs) offer a targeted alternative by specifically suppressing wakefulness-promoting pathways to minimize these adverse effects.7,8
Method
This systematic review of Randomized Controlled Trials was conducted using the PRISMA guideline with references found in multiple online databases including PubMed, ScienceDirect, Proquest and Sage Journals. The search strategy utilized a combination of keywords relevant to this study and the screening process was conducted by implementing exclusion and inclusion criteria developed using the PRISMA guideline.9 The studies recovered were then assessed by the Cochrane RoB 2 risk of bias tool.12
Result
Seven RCTs were evaluated. DORAs demonstrated significantly superior efficacy over Z-drugs, with Least Squares Mean differences of -6.7 and -8.0 minutes for 5 mg and 10 mg doses, respectively.14 Furthermore, safety analyses revealed DORAs had a significantly lower relative incidence of residual effects and cognitive impairment (<5%) compared to Z-drugs (>15%).16
Conclusion
Although both DORAs and Z-drugs help mitigate insomnia symptoms, DORAs have shown lesser adverse side effects in the treatment regimen, most notably in safety, DORAs have also shown lower levels of falls during treatment. Heterogeneity still is a limitation and restricts data power, standardized studies are needed to show a more comprehensive outcome in studies.
Article Details
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References
Miner B, Kryger MH. Sleep in the aging population. Sleep Med Clin. 2020;15(2):311–8. doi:10.1016/j.jsmc.2020.02.016.
Ohayon MM, Reynolds CF 3rd. Epidemiological and clinical relevance of insomnia diagnosis algorithms according to the DSM-IV and the International Classification of Sleep Disorders (ICSD). Sleep Med. 2009;10(9):952–60. doi:10.1016/j.sleep.2009.07.008.
Patel D, Steinberg J, Patel P. Insomnia in the elderly: a review. J Clin Sleep Med. 2018;14(6):1017–24. doi:10.5664/jcsm.7172.
Kementerian Kesehatan Republik Indonesia. Gangguan tidur pada lansia [Internet]. Jakarta: Kementerian Kesehatan RI; [cited 2026 May 16]. Available from: https://keslan.kemkes.go.id/view_artikel/68/gangguan-tidur-pada-lansia
Rahman FF, Lin KY, Lin KH. Sleep disturbance and associated factors in older adults using data from the Indonesian Family Life Survey. Int J Gerontol. 2024;18(3):184–90. doi:10.6890/IJGE.202407_18(3).0009.
Amari DT, Juday T, Frech FH, et al. Falls, healthcare resources and costs in older adults with insomnia treated with zolpidem, trazodone, or benzodiazepines. BMC Geriatr. 2022;22:484. doi:10.1186/s12877-022-03165-6.
Treves N, Perlman A, Geron LK, Asaly A, Matok I. Z-drugs and risk for falls and fractures in older adults: a systematic review and meta-analysis. Age Ageing. 2018;47(2):201–8. doi:10.1093/ageing/afx167.
Young J, Lee E, Lindblad AJ, Falk J. Orexin antagonists for insomnia. Can Fam Physician. 2024;70(3):183–4. doi:10.46747/cfp.7003183.
Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71.
Richardson WS, Wilson MC, Nishikawa J, Hayward RS. The well-built clinical question: a key to evidence-based decisions. ACP J Club. 1995;123(3):A12-A13.
Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71.
Sterne JAC, Savović J, Page MJ, Elbers RG, Blencowe NS, Boutron I, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019;366:l4898.
Rosenberg R, Murphy P, Zammit G, Mayleben D, Kumar D, Dhadda S, et al. Comparison of Lemborexant With Placebo and Zolpidem Tartrate Extended Release for the Treatment of Older Adults With Insomnia Disorder: A Phase 3 Randomized Clinical Trial. JAMA Netw Open. 2019;2(12):e1918254.
Uemura SI, Imanishi A, Terui Y, Park I, Satake M, Han G, et al. Residual effects of low dose of suvorexant, zolpidem, and ramelteon in healthy elderly subjects: A randomized double-blind study. Neuropsychopharmacol Rep. 2022;42(3).
Moline M, Zammit G, Cheng JY, Perdomo C, Kumar D, Mayleben D. Comparison of the effect of lemborexant with placebo and zolpidem tartrate extended release on sleep architecture in older adults with insomnia disorder. J Clin Sleep Med. 2021;17(6):1167–1174.
Murphy P, Kumar D, Zammit G, Rosenberg R, Moline M. Safety of lemborexant versus placebo and zolpidem: effects on auditory awakening threshold, postural stability, and cognitive performance in healthy older participants in the middle of the night and upon morning awakening. J Clin Sleep Med. 2020;16(5):765–773.
Koopmans I, Geerse D, de Ridder L, Roerdink M, Juachon MJ, Muehlan C, et al. The interactive walkway provides fit-for-purpose fall-risk biomarkers in the elderly: Comparison of zolpidem and suvorexant. Clin Transl Sci. 2024.
Sattari N, Dave A, Niknazar H, Chen IY, Neikrug AB, Mander BA, et al. Effects of lemborexant and zolpidem on sleep electroencephalography in older adults with insomnia: a randomized trial. Sleep Adv. 2026;7(1):zpag017.
Inoue Y, Nishida M, Kubota N, Koebis M, Taninaga T, Muramoto K, et al. Comparison of the treatment effectiveness between lemborexant and zolpidem tartrate extended-release for insomnia disorder subtypes defined based on polysomnographic findings. J Clin Sleep Med. 2023;19(3):519–528.