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CNS & Neurological Disorders - Drug Targets


ISSN (Print): 1871-5273
ISSN (Online): 1996-3181

Systematic Review Article

Benzodiazepines and Sleep Architecture: A Systematic Review

Author(s): Felipe Maraucci Ribeiro de Mendonça, Giulia Paulo Rossi Ribeiro de Mendonça, Laura Costa Souza, Lucas Pequeno Galvão, Henrique Soares Paiva, Cintia de Azevedo Marques Périco, Julio Torales, Antonio Ventriglio, João Maurício Castaldelli-Maia and Anderson Sousa Martins Silva*

Volume 22, Issue 2, 2023

Published on: 26 November, 2021

Page: [172 - 179] Pages: 8

DOI: 10.2174/1871527320666210618103344

Price: $65


Background: Insomnia, defined as a difficulty in initiating or maintaining sleep, is a relevant medical issue. Benzodiazepines (BZDs) are commonly prescribed to treat insomnia. Two phases characterize human sleep structure: sleep with Non-Rapid Eye Movement (NREM) and sleep with Rapid Eye Movement (REM). Physiological sleep includes NREM and REM phases in a continuous cycle known as “Sleep Architecture.”

Objective: This systematic review summarizes the studies that have investigated effects of BZDs on Sleep Architecture.

Methods: The articles selection included human clinical trials (in English, Portuguese, or Spanish) only, specifically focused on BZDs effects on sleep architecture. PubMed, BVS, and Google Scholar databases were searched.

Results: Findings on BZDs effects on sleep architecture confirm an increase in stage 2 of NREM sleep and a decrease in time of stages 3 and 4 of NREM sleep with a reduction in time of REM sleep during the nocturnal sleep.

Conclusion: Variations in NREM and REM sleep may lead to deficits in concentration and working memory and weight gain. The increase in stage 2 of NREM sleep may lead to a subjective improvement of sleep quality with no awakenings. BZDz should be prescribed with zeal and professional judgment. These patients should be closely monitored for possible long-term side effects.

Keywords: Benzodiazepines, sleep, sleep architecture, sleep slow-wave, sleep REM, sleep stages.

Graphical Abstract
Antonelli Incalzi R, Marra C, Salvigni BL, et al. Does cognitive dysfunction conform to a distinctive pattern in obstructive sleep apnea syndrome? J Sleep Res 2004; 13(1): 79-86.
[] [PMID: 14996039]
Dauvilliers Y. The major physiological functions during sleep. Sleep. Physiol, Investigat, Med. 2003; pp. 45-60.
Ancoli-Israel S, Cooke JR. Prevalence and comorbidity of insomnia and effect on functioning in elderly populations. J Am Geriatr Soc 2005; 53(7) (Suppl.): S264-71.
[] [PMID: 15982375]
National institutes of health state of the science conference statement on manifestations and management of chronic insomnia in adults. Sleep 2005; 28(9): 1049-57.
Mellinger GD, Balter MB, Uhlenhuth EH. Insomnia and its treatment. Prevalence and correlates. Arch Gen Psychiatry 1985; 42(3): 225-32.
[] [PMID: 2858188]
Keenan, S., & Hirshkowitz, M. Monitoring and staging human sleep: In M.H. Kryger, T. Roth, W.C. Dement. Eds. Principles and practice of sleep medicine. 5th ed. St. Louis: Elsevier Saunders 2011; pp 1602-1609.
Silva RS. Introdução ao estagiamento do sono humano. Braz J Epilepsy Clin Neurophysiol 1996; 3(2): 187-99.
Fernandes RMF. O sono normal. Medicina (Ribeirão Preto) 2006; 39(2): 157-68.
Galduróz JC, Noto AR, Nappo SA, Carlini EA. Use of psychotropic drugs in Brazil: household survey involving the 107 largest cities in the country - 2001. Rev Latino-Am Enfermagem 2005; 13(spe)
Sadock BJ, Sadock VA, Ruiz P. Sono normal e transtorno do sono-vigília. Compêndio de Psiquiatria - Ciências do Comportamento e Psiquiatria Clínica. 11th ed. Porto Alegre: Artes Médicas 2017; pp. 533-63.
Woods JH, Katz JL, Winger G. Benzodiazepines: Use, abuse, and consequences. Pharmacol Rev 1992; 44(2): 151-347.
[PMID: 1356276]
Soldatos CR, Dikeos DG, Whitehead A. Tolerance and rebound insomnia with rapidly eliminated hypnotics: A meta-analysis of sleep laboratory studies. Int Clin Psychopharmacol 1999; 14(5): 287-303.
[] [PMID: 10529072]
Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. PLoS Med 2009; 6(7): e1000097.
[] [PMID: 19621072]
Uchida S, Okudaira N, Nishihara K, Iguchi Y. Flunitrazepam effects on human sleep EEG spectra: Differences in NREM, REM and individual responses. Life Sci 1996; 58(10): PL199-205.
[] [PMID: 8602113]
Kales A, Bixler EO, Soldatos CR, Jacoby JA, Kales JD. Lorazepam: effects on sleep and withdrawal phenomena. Pharmacology 1986; 32(3): 121-30.
[] [PMID: 3960963]
Gaillard JM, Tissot R. EEG sleep studies of insomniacs under flunitrazepam treatment. Int Pharmacopsychiatry 1975; 10(4): 199-207.
[] [PMID: 2563]
Bixler EO, Kales A, Soldatos CR, Kales JD. Flunitrazepam, an investigational hypnotic drug: Sleep laboratory evaluations. J Clin Pharmacol 1977; 17(10 Pt 1): 569-78.
[] [PMID: 21199]
Jovanović UJ. Polygraphic sleep recordings before and after the administration of flunitrazepam. J Int Med Res 1977; 5(2): 77-84.
[] [PMID: 17559]
Aeschbach D, Dijk DJ, Trachsel L, Brunner DP, Borbély AA. Dynamics of slow-wave activity and spindle frequency activity in the human sleep EEG: effect of midazolam and zopiclone. Neuropsychopharmacology 1994; 11(4): 237-44.
[] [PMID: 7857498]
Zarcone VP Jr, Benson KL, Greene KA, Csernansky JG, Faull KF. The effect of chronic alprazolam on sleep and bioamine metabolites in depression. J Clin Psychopharmacol 1994; 14(1): 36-40.
[] [PMID: 7512100]
Vgontzas AN, Kales A, Bixler EO, Myers DC. Temazepam 7.5 mg: Effects on sleep in elderly insomniacs. Eur J Clin Pharmacol 1994; 46(3): 209-13.
[] [PMID: 8070501]
Feinberg I, Fein G, Walker JM, Price LJ, Floyd TC, March JD. Flurazepam effects on slow-wave sleep: Stage 4 suppressed but number of delta waves constant. Science 1977; 198(4319): 847-8.
[] [PMID: 21453]
Grözinger M, Kögel P, Röschke J. Effects of Lorazepam on the automatic online evaluation of sleep EEG data in healthy volunteers. Pharmacopsychiatry 1998; 31(2): 55-9.
[] [PMID: 9562209]
Hemmeter U, Müller M, Bischof R, Annen B, Holsboer-Trachsler E. Effect of zopiclone and temazepam on sleep EEG parameters, psychomotor and memory functions in healthy elderly volunteers. Psychopharmacology (Berl) 2000; 147(4): 384-96.
[] [PMID: 10672632]
Uchimura N, Nakajima T, Hayash K, et al. Effect of zolpidem on sleep architecture and its next-morning residual effect in insomniac patients: A randomized crossover comparative study with brotizolam. Prog Neuropsychopharmacol Biol Psychiatry 2006; 30(1): 22-9.
[] [PMID: 16048734]
Roehrs T, Zorick F, Kaffeman M, Sicklesteel J, Roth T. Flurazepam for short-term treatment of complaints of insomnia. J Clin Pharmacol 1982; 22(7): 290-6.
[] [PMID: 7107976]
Calvo JM. La neurobiología del sueño en animals experimentales y en el hombre. Salud Ment 1996; 19(3): 58-65.
Declerck AC, Ruwe F, O’Hanlon JF, Vermeeren A, Wauquier A. Effects of zolpidem and flunitrazepam on nocturnal sleep of women subjectively complaining of insomnia. Psychopharmacology (Berl) 1992; 106(4): 497-501.
[] [PMID: 1579623]
Feinberg I, Maloney T, Campbell IG. Effects of hypnotics on the sleep EEG of healthy young adults: New data and psychopharmacologic implications. J Psychiatr Res 2000; 34(6): 423-38.
[] [PMID: 11165310]
Freemon FR, Al-Marashi MSH, Lee JCM. The effect of a new benzodiazepine on the polygraphically monitored sleep of normal volunteers. J Clin Pharmacol 1977; 17(7): 398-401.
[] [PMID: 18491]
Nicholson AN, Stone BM, Clarke CH. Effect of diazepam and fosazepam (a soluble derivative of diazepam) on sleep in man. Br J Clin Pharmacol 1976; 3(4): 533-41.
[] [PMID: 22216491]
Risberg AM, Henricsson S, Ingvar DH. Evaulation of the effect of fosazepam (a new benzodiazepine), nitrazepam and placebo on sleep patterns in normal subjects. Eur J Clin Pharmacol 1977; 12(2): 105-9.
[] [PMID: 200435]
Monti JM, Debellis J, Gratadoux E, Alterwain P, Altier H, D’Angelo L. Sleep laboratory study of the effects of midazolam in insomniac patients. Eur J Clin Pharmacol 1982; 21(6): 479-84.
[] [PMID: 7075654]
Tan X, Uchida S, Matsuura M, Nishihara K, Kojima T. Long-, intermediate- and short-acting benzodiazepine effects on human sleep EEG spectra. Psychiatry Clin Neurosci 2003; 57(1): 97-104.
[] [PMID: 12519461]
Peigneux P, Laureys S, Fuchs S, et al. Are spatial memories strengthened in the human hippocampus during slow wave sleep? Neuron 2004; 44(3): 535-45.
[] [PMID: 15504332]
McNamara P, Johnson P, McLaren D, Harris E, Beauharnais C, Auerbach S. REM and NREM sleep mentation. Int Rev Neurobiol 2010; 92: 69-86.
[] [PMID: 20870063]
Roehrs T, Roth T. Drug-related sleep state changes: functional significance and clinical relevance. Sleep Med Clin 2010; 5(4): 559-70.
[] [PMID: 21344068]
Song Y, Blackwell T, Yaffe K, Ancoli-Israel S, Redline S, Stone KL. Relationships between sleep stages and changes in cognitive function in older men: the MrOS Sleep Study. Sleep (Basel) 2015; 38(3): 411-21.
[] [PMID: 25325465]
Martynas Z, Vanda L, Ramune G, Raminta M, Osvaldas R. Arousals and macrostructure of sleep: importance of NREM stage 2 reconsidered. Sleep Sci 2013; 6(3): 91-7.
Madsen PL, Schmidt JF, Holm S, Vorstrup S, Lassen NA, Wildschiødtz G. Cerebral oxygen metabolism and cerebral blood flow in man during light sleep (stage 2). Brain Res 1991; 557(1-2): 217-20.
[] [PMID: 1747754]
Maquet P, Dive D, Salmon E, et al. Cerebral glucose utilization during stage 2 sleep in man. Brain Res 1992; 571(1): 149-53.
[] [PMID: 1611488]
Wulff K, Gatti S, Wettstein JG, Foster RG. Sleep and circadian rhythm disruption in psychiatric and neurodegenerative disease. Nat Rev Neurosci 2010; 11(8): 589-99.
[] [PMID: 20631712]
Wulff K, Porcheret K, Cussans E, Foster RG. Sleep and circadian rhythm disturbances: multiple genes and multiple phenotypes. Curr Opin Genet Dev 2009; 19(3): 237-46.
[] [PMID: 19423332]
Mesrine S, Gusto G, Clavel-Chapelon F, Boutron-Ruault MC, Fournier A. Use of benzodiazepines and cardiovascular mortality in a cohort of women aged over 50years. Eur J Clin Pharmacol 2018; 74(11): 1475-84.
[] [PMID: 29971451]
Billioti de Gage S, Pariente A, Bégaud B. Is there really a link between benzodiazepine use and the risk of dementia? Expert Opin Drug Saf 2015; 14(5): 733-47.
[] [PMID: 25691075]
Patorno E, Glynn RJ, Levin R, Lee MP, Huybrechts KF. Benzodiazepines and the risk of all-cause mortality in older patients. Innov Aging 2018; 2(1): 852-3.
Osler M, Jørgensen MB. Associations of benzodiazepines, z- drugs, and other anxiolytics with subsequent dementia in patients with affective disorders: a nationwide cohort and nested case-control study. Am J Psychiatry 2020; 177(6): 497-505.
[] [PMID: 32252539]
Rasch B, Born J. About sleep’s role in memory. Physiol Rev 2013; 93(2): 681-766.
[] [PMID: 23589831]
Mander BA, Marks SM, Vogel JW, et al. β-amyloid disrupts human NREM slow waves and related hippocampus-dependent memory consolidation. Nat Neurosci 2015; 18(7): 1051-7.
[] [PMID: 26030850]
Aly M, Moscovitch M. The effects of sleep on episodic memory in older and younger adults. Memory 2010; 18(3): 327-34.
[] [PMID: 20182945]
Scullin MK. Sleep, memory, and aging: the link between slow-wave sleep and episodic memory changes from younger to older adults. Psychol Aging 2013; 28(1): 105-14.
[] [PMID: 22708533]
Schneider-Helmert D. Why low-dose benzodiazepine-dependent insomniacs can’t escape their sleeping pills. Acta Psychiatr Scand 1988; 78(6): 706-11.
[] [PMID: 2906215]
Horne JA. Human REM sleep: Influence on feeding behaviour, with clinical implications. Sleep Med 2015; 16(8): 910-6.
[] [PMID: 26122167]
Shechter A, O'Keeffe M, Roberts AL, Zammit GK, RoyChoudhury A. St-Onge MP. Alterations in sleep architecture in response to experimental sleep curtailment are associated with signs of positive energy balance. Am J Physiol - Reg Integ Comp Physiol 2012; 303: R883-9.
Gonnissen HK, Hursel R, Rutters F, Martens EA, Westerterp-Plantenga MS. Effects of sleep fragmentation on appetite and related hormone concentrations over 24 h in healthy men. Br J Nutr 2012; 8: 1-9.
Goldstein AN, Walker MP. The role of sleep in emotional brain function. Annu Rev Clin Psychol 2014; 10: 679-708.
[] [PMID: 24499013]
Wiesner CD, Pulst J, Krause F, et al. The effect of selective REM-sleep deprivation on the consolidation and affective evaluation of emotional memories. Neurobiol Learn Mem 2015; 122: 131-41.
[] [PMID: 25708092]
Gaillard J-M, Auhert C. (1075): Specificity of benzodiazepine action on human sleep confirmed. Another contribution of automatic analysis of polygraph recordings. Biol Psychiatry 10: 185-97.
Jouvet M. Biogenic amines and the states of sleep. Science 1969; 163(3862): 32-41.
[] [PMID: 4303225]
Chen L, Bell JS, Visvanathan R, et al. The association between benzodiazepine use and sleep quality in residential aged care facilities: A cross-sectional study. BMC Geriatr 2016; 16(1): 196.
[] [PMID: 27888835]
Hümpel M, Nieuweboer B, Milius W, Hanke H, Wendt H. Kinetics and biotransformation of lormetazepam. II. Radioimmunologic determinations in plasma and urine of young and elderly subjects: first-pass effect. Clin Pharmacol Ther 1980; 28(5): 673-9.
[PMID: 6108174]
Tanaka E. Clinically significant pharmacokinetic drug interactions with benzodiazepines. J Clin Pharm Ther 1999; 24(5): 347-55.
[] [PMID: 10583697]
Wlaź P, Roliński Z, Kleinrok Z, Czuczwar SJ. Influence of chronic aminophylline on antielectroshock activity of diazepam and aminophylline-induced convulsions in mice. Pharmacol Biochem Behav 1994; 49(3): 609-13.
[] [PMID: 7862714]
Moghadamnia AA, Moudi S, Tamaskani N, Saleki M, Hamidia A, Mouodi M. Effects of alprazolam and clonazepam on blood sugar in patients with panic disorder. Cyprus J Med Sci 2019; 4(3): 195-200.
Martins IJ. Nutrition therapy regulates caffeine metabolism with relevance to nafld and induction of type 3 diabetes. J Diabetes Metab Disord 2017; 4: 019.
Martins IJ. Sirtuin 1, a Diagnostic protein marker and its relevance to chronic disease and therapeutic drug interventions. EC Pharmacology and Toxicology 2018; 6(4): 209-15.

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