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Effects on postural oscillation and memory functions of a single dose of zolpidem 5 mg, zopiclone 3.75 mg and lormetazepam 1 mg in elderly healthy subjects. A randomized, cross-over, double-blind study versus placebo

  • Pharmacodynamics
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Abstract

Objective

In elderly patients, both falls and impaired memory are considerable medical problems. Hypnotics, which are frequently administered to this patient group for the treatment of insomnia, should ideally not impair equilibrium or memory functions. This double-blind, randomised, four-way, cross-over study investigated the effects of frequently prescribed hypnotics from different classes on postural oscillation and memory under real life conditions. Zolpidem 5 mg, zopiclone 3.75 mg, lormetazepam 1 mg (i.e. usual starting doses in elderly) or placebo were administered at night to 48 healthy elderly volunteers aged 65 years or more. The study included four treatment periods separated by wash-out periods of at least 1 week.

Methods

Psychomotor tests up to 9 h or 10 h after drug intake included, for attention and body sway, clinical stabilometric platform (CSP) tests, simple reaction time (SRT), and the critical tracking test (CTT); for memory, the learning memory tasks (LMT) and the Sternberg memory scanning test (mean reaction time [MRT] and percentage of correct answers) were used. For subjective sleep evaluation the Leeds sleep evaluation questionnaire (LSEQ) and for sedation a visual analogue scale (VAS) were used. For safety evaluations, adverse events (AEs) were recorded.

Results

The results demonstrate that compared with placebo, the active drugs increased body sway (area eyes open and closed in the CSP); however, this effect disappeared after 5 h with zolpidem, while it disappeared only after 8 h with lormetazepam and zopiclone. All three drugs did not affect attention assessed by the SRT and CTT. Concerning memory, Sternberg MRT at 9 h was not significantly different up to 5 digits for all groups in comparison with placebo, while for 6 digits it was significantly increased with lormetazepam and zopiclone. In the LMT, an impairment of performance was observed with lormetazepam relative to both zolpidem and placebo.

Conclusion

The safest compared drug with regard to body sway was zolpidem, because of its short-lasting effect. In addition, zolpidem did not show any significant effect on memory functions, in the present dose comparison.

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References

  1. Wittchen HU, Krause P, Höfler M, et al (2001) NISAS-2000—Nationwide Insomnia and Awareness Study. Nervenheilkunde 20:4–16

    Google Scholar 

  2. Gryfe CI, Amies A, Ashley MU (1977) A longitudinal study of falls in an elderly population. I. Incidence and morbidity. Age Ageing 6:201–210

    CAS  PubMed  Google Scholar 

  3. Prudham PW, Evans JG (1981) Factors associated with falls in the elderly: a community study. Age Ageing 10:141–146

    CAS  PubMed  Google Scholar 

  4. Blake AJ, Morgan K, Endall MJ, et al (1998) Falls by elderly people at home: prevalence and associated factors. Age Aging 17:365–372

    Google Scholar 

  5. Campbell AJ (1991) Drug treatment as a cause of falls in old age. A review of the offending agents. Drugs Aging 1:289–302

    CAS  PubMed  Google Scholar 

  6. McClelland GE (1989) Body sway and the effects of psychoactive drugs—a review. Hum Psychopharmacol 4:3–14

    Google Scholar 

  7. Patat A, Fouhoux P (1985) Effects of postural sway of various benzodiazepine tranquillizers. Br J Clin Pharmacol 20:585–592

    Google Scholar 

  8. Patat A, Klein JM, Hucher M, Granier J (1988) Acute effects of amitriptyline on human performance and interactions with diazepam. Eur J Clin Pharmacol 35:585–592

    CAS  PubMed  Google Scholar 

  9. Robin DW, Hasan SS, Lichtenstein MJ, et al (1991) Dose-related effect of triazolam on postural sway. Clin Charmacol Ther 49:582–588

    Google Scholar 

  10. Berlin I, Warot D, Hergueta T, et al (1993) Comparison of the effects of zolpidem and triazolam on memory functions, psychomotor performances and postural sway in healthy subjects. J Clin Psychopharmacol 13:100–106

    CAS  PubMed  Google Scholar 

  11. Tada K, Sato Y, Sakai T, et al (1994) Effects of zopiclone, triazolam and nitrazepam on standing steadiness. Neuropsychobiology 29:17–22

    CAS  PubMed  Google Scholar 

  12. Robin DW, Hasan SS, Lichtenstein MJ, et al (1993) The effects of age on triazolam-induced postural sway. J Am Geriat Soc 41:SA5

    Google Scholar 

  13. Allain H, Patat A, Le Coz F, et al (1995) Comparative study of the effects of zopiclone (7.5 mg), zolpidem, flunitrazepam and a placebo on nocturnal cognitive performance in healthy subjects, in relation to pharmacokinetics. Eur Psychiatry 10:129S–135S

    Article  Google Scholar 

  14. Patat A, Foulhoux P, Klein MJ (1986) Etude des effets résiduels sur l'équilibre de trois hypnotiques (loprazolam, flunitrazepam, triazolam) appréciés par l'analyse spectrale des oscillations posturales. Thérapie 41:443–447

    Google Scholar 

  15. Roth T, Roehrs TA, Stepanski E, et al (1990) Hypnotics and behavior. Am J Med 88:43S–46S

    CAS  PubMed  Google Scholar 

  16. Roth T, Roehrs TA, Vogel GW, et al (1994) Evaluation of hypnotic medications. In: Prien RF, Robinson DS (eds) Clinical evaluation of psychotropic drugs: principles and guidelines. Raven Press Ltd, New York, pp 579–592

    Google Scholar 

  17. Unden M, Roth Schechter B (1996) Next day effects after nighttime with zolpidem. A review. Eur Psychiatry 11[Suppl 1]:21S–30S

    Google Scholar 

  18. Holm KJ, Goa KL (2000) Zolpidem. An update of its pharmacology, therapeutic efficacy and tolerability in the treatment of insomnia. Drugs 59:865–889

    CAS  PubMed  Google Scholar 

  19. Pichart L, Gillet G, Bonfields C, et al (1995) Oxidative metabolism of zolpidem by human liver cytochrome P450. Drug Metab Dispos 23:1253–1262

    PubMed  Google Scholar 

  20. VIDAL (2002) 78ème edn., Editions du Vidal, Paris

  21. Allain H, Monti J (1996) General safety profile of zolpidem: safety in elderly, overdose and rebound effects. Eur Psychiatry 11:465–473

    Google Scholar 

  22. Langer SZ, Arbilla S (1988) Imidazopyridines as a tool for the characterisation of benzodiazepine receptors: a proposal for a pharmacological classification as omega-receptor subtypes. Pharmacol Biochem Behav 29:763–766

    Article  CAS  PubMed  Google Scholar 

  23. Besnard F, Avent P, Itier V, et al (1996) GABAA receptor subtypes and the mechanism of action of zolpidem. In: Freeman H, Puech AJ, Cloth T (eds) Zolpidem: an update of its pharmacological properties and therapeutic place in the management of insomnia. Elsevier, Paris, pp 21–32

    Google Scholar 

  24. Im HK, Im WB, Hammeltron BJ, et al (1993) Potentiation of gamma-aminobutyric acid-induced chloride currents by various benzodiazepine site-agonists with an alpha 1 gamma 2, beta 2 gamma 2 and alpha 1 beta 2 gamma 2 subtypes of cloned gamma-aminobutyric acid type A receptor. Mol Pharmacol 44:866–870

    CAS  PubMed  Google Scholar 

  25. Lillsunde P, Seppälä T (1990) Simultaneous screening and quantitative analysis of benzodiazepines by dual-channel gas chromatrography using electron-capture and nitrogen-phosphorus detection. J Chromatogr 533:97–110

    Article  CAS  PubMed  Google Scholar 

  26. Benavides J, Abadie P, Baron JC, Scatton B (1996) In vivo interaction of zolpidem with ω (benzodiazepine) site subtypes. In: Freeman H, Puech A, Roth T (eds) Zolpidem: an update of its pharmacological properties and therapeutic place in the management of insomnia. Elsevier, Paris, pp 33–44

    Google Scholar 

  27. Goa KL, Heel RC (1986) Zopiclone—a review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy as a hypnotic. Drugs 32:48–65

    CAS  PubMed  Google Scholar 

  28. Wadworth AN, McTavish D (1993) Zopiclone—a review of its pharmacological properties and therapeutic efficacy as a hypnotic. Drugs Aging 3:441–459

    CAS  PubMed  Google Scholar 

  29. Laska EM, Klein DF, Lavori PW, et al (1994) Design issues for the clinical evaluation of psychotropic drugs. In: Prien RF, Robinson DS (eds) Clinical evaluation of psychotropic drugs: principles and guidelines. Raven Press Ltd., New York, pp 29–67

    Google Scholar 

  30. Kapteyn TS, Bles W, Njiokiktjein CJ, et al (1983) Standardisation in platform stabilometry being part of posturography. Agressologie 24:321–326

    CAS  PubMed  Google Scholar 

  31. Allain H, Lieury A, Gandon JM (1993) Psychopharmacology of memory components. Hum Psychopharmacol 4:143–164

    Google Scholar 

  32. Sternberg S (1969) Memory scanning: memory processes revealed by reaction time experiments. Am Sci 57:421–457

    CAS  PubMed  Google Scholar 

  33. Parrott AC, Hindmarch I (1978) Factor analysis of a sleep evaluation questionnaire. Psychol Med 8:325–329

    PubMed  Google Scholar 

  34. Parrott AC, Hindmarch I (1980) The Leeds sleep evaluation questionnaire in psychological investigations—a review. Psychopharmacology 71:173–179

    CAS  PubMed  Google Scholar 

  35. Mattila MJ, Vanakoski J, Kalska H, et al (1998) Effects of alcohol, zolpidem, and some other sedatives and hypnotics on human performance and memory. Pharmacol Biochem Behav 59:917–923

    Article  CAS  PubMed  Google Scholar 

  36. Langtry HD, Benfield P (1990) Zolpidem. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential. Drugs 40:291–313

    CAS  PubMed  Google Scholar 

  37. Vermeeren A, O'Hanlon JF, Declerck AC, et al (1995) Acute effects of zolpidem and flunitrazepam on sleep, memory and driving performance, compared to those of partial sleep deprivation and placebo. Acta Ther 21:47–64

    Google Scholar 

  38. Dujardin K, Guieu JD, Leconte-Lambert C, et al (1998) Comparison of the effects of zolpidem and flunitrazepam on sleep structure and daytime cognitive functions. A study of untreated insomniacs. Pharmacopsychiatry 31:14–18

    CAS  PubMed  Google Scholar 

  39. Fairweather DB, Kerr JS, Hindmarch I (1992) The effects of acute and repeated doses of zolpidem on subjective sleep, psychomotor performance and cognitive function in elderly volunteers. Eur J Pharmacol 43:597–601

    Google Scholar 

  40. Wesensten NJ, Balkin TJ, Belenky GL (1995) Effects of daytime administration of zolpidem versus triazolam on memory. Eur J Clin Pharmacol 48:115–122

    CAS  PubMed  Google Scholar 

  41. Mintzer MZ, Griffiths RR (1999) Selective effects of zolpidem on human memory functions. J Psychopharmacol 13:18–31

    CAS  PubMed  Google Scholar 

  42. Greenblatt DJ, Harmatz JS, Wright CE, et al (1996) Does zolpidem have unique clinical properties? A pharmacodynamic comparison with triazolam and placebo (abstract). Clin Pharmacol Ther 59:178

    Google Scholar 

  43. Balkin TJ, Wesensten NJ, Belenky GL (1994) Triazolam versus zolpidem I: effects on memory (abstract). Sleep Res 23:64

    Google Scholar 

  44. Unden M, Roth Schechter B (1996) Next day effects after nighttime treatment with zolpidem: a review. Eur Psychiatry 11[Suppl 1]:21S–30S

  45. Warot D, Bensimon G, Danjou P, Puech AJ (1987) Comparative effects of zopiclone, triazolam and placebo on memory and psychomotor performance in healthy volunteers. Fundam Clin Pharmacol 1:145–152

    CAS  PubMed  Google Scholar 

  46. Saano V, Hansen PP, Paronen P (1992) Interactions and comparative effects of zopiclone, diazepam and lorazepam on psychomotor performance and on elimination pharmacokinetics in healthy volunteers. Pharmacol Toxicol 70:135–139

    CAS  PubMed  Google Scholar 

  47. Hergueta T, Molinier P, Olivieri AN, et al (1996) Effects of loprazolam, zolpidem and zopiclone on memory, vigilance and postural control during nocturnal and morning awakenings in healthy subjects (abstract). J Methods Find Exp Clin Pharmacol 18[Suppl B]:203

  48. Fossen A, Godlibsen OB, Loyning Y, Dreyfus JF (1983) Effects of hypnotics on memory. Pharmacology 27[Suppl 2]:116–126

  49. Bhatti JZ, Alford CA, Hindmarch I (1988) Lormetazepam, memory and information processing: a review. Psychopharmacol Ser 6:169–179

    CAS  PubMed  Google Scholar 

  50. Deijen JB, Heemstra ML, Orlebeke JF (1991) Residual effects of lormetazepam on mood and performance in healthy elderly volunteers. Eur J Clin Pharmacol 40:267–271

    CAS  PubMed  Google Scholar 

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Acknowledgements

The authors wish to thank D. Gérard, MD, for his collaboration to the study, and D. Pittrow, MD, Institute of Clinical Pharmacology, Technical University of Dresden, Germany, for valuable input to various sections of the manuscript.

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Authors and Affiliations

  1. Laboratoire de Pharmacologie Expérimentale et Clinique, Université de Rennes 1, Faculté de Médecine, 2 rue du Pr Léon Bernard, CS 34317, 35043 , Rennes, Cedex, France

    Hervé Allain & Danièle Bentué-Ferrer

  2. Biotrial SA, Technopôle Rennes-Atalante, Rue Jean-Louis Bertrand, 35000 , Rennes, France

    Antoine Tarral & Jean-Marc Gandon

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  1. Hervé Allain
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  2. Danièle Bentué-Ferrer
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  3. Antoine Tarral
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  4. Jean-Marc Gandon
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Correspondence to Hervé Allain.

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Allain, H., Bentué-Ferrer, D., Tarral, A. et al. Effects on postural oscillation and memory functions of a single dose of zolpidem 5 mg, zopiclone 3.75 mg and lormetazepam 1 mg in elderly healthy subjects. A randomized, cross-over, double-blind study versus placebo. Eur J Clin Pharmacol 59, 179–188 (2003). https://doi.org/10.1007/s00228-003-0591-5

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