Skip to main content
SpringerLink
Log in

Randomised, Double-Blind Study of the Effects of Oxybutynin, Tolterodine, Trospium Chloride and Placebo on Sleep in Healthy Young Volunteers

  • Original Research Article
  • Published:
Clinical Drug Investigation Aims and scope Submit manuscript

Abstract

Objective: Central nervous effects of oral anticholinergics may limit the success of incontinence therapy and patient compliance. Only a few studies investigating this topic are available. This study was conducted to determine whether oral anticholinergics alter sleep and psychometric test parameters.

Design: Randomised, double-blind, crossover, placebo-controlled study.

Study participants: 24 healthy volunteers (age 22–36 years) without sleeprelated problems.

Interventions: Polysomnographic recordings, sleep questionnaires and psychometric tests (the number combination test [Zahlen-Verbindungs Test; ZVT] and the d2 attention test) were performed following single doses of oxybutynin 15mg, tolterodine 4mg, trospium chloride 45mg or placebo, each separated by an 8-day washout period.

Results: Rapid eye movement (REM) sleep (relative to total sleep time) was the primary parameter of polysomnography. The REM sleep for oxybutynin was significantly lower than that for trospium chloride (18.4% vs 20.2%; p < 0.05) and lower than that for placebo (20.1%; ns). The number combination test (ZVT), the primary parameter of cognitive function, and the d2 test did not reveal any differences in reaction time. With regard to the other sleep parameters, the REM latency for oxybutynin was clearly higher than that for placebo, trospium chloride and tolterodine. Effects on non-REM sleep were observed only after administration of oxybutynin compared with placebo.

Conclusions: Oxybutynin influenced sleep structure, as was reflected by REM suppression and mild sedation, while subjective parameters and psychometric tests remained unaffected. The sleep and psychometric test values for tolterodine and trospium chloride were comparable to those of placebo. The clinical relevance of these effects is small in healthy young volunteers, but these results cannot be extended to the elderly.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Table I
Fig. 1
Fig. 2
Table II

Similar content being viewed by others

Notes

  1. 1The use of tradenames is for product identification only and does not imply endorsement.

References

  1. McGrother C, Resnick M, Yalla SV, et al. Epidemiology and etiology of urinary incontinence in the elderly. World J Urol 1998; 16 Suppl. 1: S3–9

    Article  PubMed  Google Scholar 

  2. Schwantes U, Topfmeier P. Importance of pharmacological and physiochemical properties for tolerance of antimuscarinic drugs in the treatment of detrusor instability and detrusor hyperreflexia: chances for improvement of therapy. Int J Clin Pharmacol Ther 1999; 37(5): 209–18

    CAS  PubMed  Google Scholar 

  3. Fiisgen I, Hauri D. Trospium chloride: an effective option for medical treatment of bladder overactivity. Int J Clin Pharmacol Ther 2000; 38(5): 223–34

    Article  Google Scholar 

  4. Nies AS, Spielberg SP. Principle of therapeutics. In: Hardman JG et al., editors. Goodman & Gilman’s The pharmacological basis of therapeutics. 9th ed. New York: McGraw-Hill, 1996: 43–62

    Google Scholar 

  5. Katz IR, Sands LP, Bilker W, et al. Identification of medications that cause cognitive impairment in older people: the case of oxybutynin chloride. J Am Geriatr Soc 1998; 46(1): 8–13

    CAS  PubMed  Google Scholar 

  6. Herberg KW. Alltags-und Verkehrssicherheit unter Inkontinenz-Medikation: Neue Untersuchungen zum Sicherheitspotential urologischer Anticholinergika. Med Welt 1999; 50: 217–22

    Google Scholar 

  7. British Medical Association, Royal Pharmaceutical Society of Great Britain. British National Formulary. No. 34. London: BMA.RPS, 1997

  8. Pietzko A, Dimpfel W, Schwantes U, et al. Influences of trospium chloride and oxybutynin on quantitative EEG in healthy volunteers. Eur J Clin Pharmacol 1994; 47: 337–43

    Article  CAS  PubMed  Google Scholar 

  9. Donnellan CA, Fook L, McDonald P, et al. Oxybutynin and cognitive dysfunction. BMJ 1997; 315(7119): 1363–4

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. InT’Veld BA, Kwee-Zuiderwijk WJM, Van Puijenbroek EP, et al. Neuropsychiatrische bijwerkingen toegeschreven aan her gebruik van oxybutynin. Ned Tijschr Geneeskd 1998; 142(11): 590–2

    Google Scholar 

  11. Valsecia ME, Malgor LA, Espindola JH, et al. New adverse effect of oxybutynin: “night terror” [letter]. Ann Pharmacother 1998; 32(4): 506

    Article  CAS  PubMed  Google Scholar 

  12. Appell R. Clinical efficacy and safety of tolterodine in the treatment of overactive bladder: a pooled analysis. Urology 1997; 50(6A Suppl. ): 90–9

    Article  CAS  PubMed  Google Scholar 

  13. Guay DRP. Tolterodine, a new antimuscarinic drag for treatment of bladder overactivity. Pharmacotherapy 1999; 19(3): 267–80

    Article  CAS  PubMed  Google Scholar 

  14. Benet LZ, Kroetz DL, Sheiner LB. Pharmacokinetics: the dynamics of drag absorption, distribution, and elimination: principle of therapeutics. In: Hardman JG et al., editors. Goodman & Gilman’s The pharmacological basis of therapeutics. 9th ed. New York: McGraw-Hill, 1996: 3–28

    Google Scholar 

  15. Bradbury MW. History and physiology of the blood-brain barrier in relation to delivery of drugs to the brain. In: Begley DJ, Bradbury MW, Kreuter J, editors. The blood-brain barrier and drug delivery to the CNS. New York: Marcel Dekker, 2000: 1–8

    Google Scholar 

  16. Eglen RM, Choppin A, Watson N. Therapeutic opportunities from muscarinic receptor research. Trends Pharmacol Sci 2001; 22(8): 409–14

    Article  CAS  PubMed  Google Scholar 

  17. Chappie CR. Muscarinic receptor antagonists in the treatment of overactive bladder. Urology 2000; 55(5A Suppl. ): 33–46

    Article  Google Scholar 

  18. Shiromani PJ, Gillin JC, Henriksen S. Acetylcholine and the regulation of REM sleep: basic mechanisms and clinical implications for affective illness and narcolepsy. Annu Rev Pharmacol Toxicol 1987; 27: 137–56

    Article  CAS  PubMed  Google Scholar 

  19. Velazquez-Moctezuma J, Shalauta M, Gillin JC, et al. Cholinergic antagonists and REM sleep generation. Brain Res 1991; 541: 175–9

    Article  Google Scholar 

  20. Hohagen F, Lis S, Riemann D, et al. Influence of biperiden and bomaprine on sleep in healthy subjects. Neuropsychopharmacology 1994; 11(1): 29–32

    Article  CAS  PubMed  Google Scholar 

  21. Vorderholzer U, Hornyak M, Berger M, et al. Antidepressiva. In: Schulz H, editor. DGSM. Ecomed, Landsberg/Lech. Kompendium Schlafmedizin. 1997: XI-2.3

  22. Sagales T, Erill S, Domino EF. Effects of repeated doses of scopolamine on the electroencephalographic stages of sleep in normal volunteers. Clin Pharmacol Ther 1975; 18(6): 727–32

    CAS  PubMed  Google Scholar 

  23. Sitaram N, Moore AM, Gillin JC. Experimental acceleration and slowing of REM sleep ultradian rhythm by cholinergic agonist and antagonist. Nature 1978; 274: 490–2

    Article  CAS  PubMed  Google Scholar 

  24. Poland RE, Tondo L, Rubin RT, et al. Differential effects of scopolamine on nocturnal cortisol secretion, sleep architecture, and REM latency in normal volunteers: relation to sleep and cortisol in depression. Biol Psychiatry 1989; 25: 403–12

    Article  CAS  PubMed  Google Scholar 

  25. McCracken JT, Poland RE, Lutchmansingh P, et al. Sleep electroencephalographic abnormalities in adolescent depressives: effects of scopolamine. Biol Psychiatry 1997; 42: 577–84

    Article  CAS  PubMed  Google Scholar 

  26. Fachinformationsverzeichnis Deutschland. BPI Service GmbH, Frankfurt, Internet: http://www.fachinfo.de

  27. Rechtschaffen A, Kales A. A manual of standardized terminology, techniques and scoring system for sleep stages of human sleep subjects. Washington (DC): US Government Printing Office, 1968

    Google Scholar 

  28. Oswald WD, Roth E. Der Zahlen-Verbindungs-Test. In: Testkatalog 2000/2001. Testzentrale, Göttingen, Bern: Hogrefe-Verlag, 2000: 35

    Google Scholar 

  29. Brickenkamp R, Zillner E. The d2 Test of Attention (d2). In: Testkatalog 2000/2001. Testzentrale, Göttingen, Bern: Hogrefe-Verlag, 2000: 60

    Google Scholar 

  30. Hiller E. Über den statistischen Vergleich mehrerer abhängiger Stichproben: Friedman-Test und dij —Test von Wilcoxon und Wilcox. Z Ärztl Fortbild 1988; 82: 885–6

    CAS  Google Scholar 

  31. Wemecke KD. Abhängige Stichproben: Friedman-Test. In: Angewandte Statistik für die Praxis. Bonn: Addison-Wesley, 1995: 107–8

  32. Fleiss JL. Statistical methods for rates and proportions. 2nd ed. New York: John Wiley & Sons, 1981: 212–36

    Google Scholar 

  33. Riemann D, Hohagen F, Bahro M, et al. Sleep in depression: the influence of age, gender and diagnostic subtype on baseline sleep and the cholinergic REM induction test with RS 86. Em Arch Psychiatry Clin Neurosci 1994; 243: 279–90

    Article  CAS  Google Scholar 

  34. Alloussi S, Laval K-U, Eckert R, et al. Trospium chloride in patients with motor urge syndrome (detrusor instability): a double-blind, randomised, multicentre, placebo-controlled study. J Clin Res 1998; 1: 439–1

    Google Scholar 

  35. Cardozo L, Chappie CR, Tooz-Hobson P, et al. Efficacy of trospium chloride in patients with detrusor instability: a placebo-controlled, randomised, double-blind, multicentre clinical trial. Br J Urol Intern 2000; 85: 659–64

    Article  CAS  Google Scholar 

  36. Tapp AJS, Cardozo LD, Versi E, et al. The treatment of detrusor instability in post-menopausal women with oxybutynin chloride: a double blind placebo controlled study. Br J Obstet Gynaecol 1990; 97: 521–6

    Article  CAS  PubMed  Google Scholar 

  37. Thüroff JW, Bunke B, Ebner A, et al. Randomized, double-blind multicenter trial on treatment of frequency, urgency and incontinence related to detrusor hyperactivity: Oxybutynin versus propantheline versus placebo. J Urol 1991; 145: 813–7

    PubMed  Google Scholar 

  38. Ulshöfer B, Bihr AM, Bödeker R-H, et al. Randomised, double-blind, placebo-controlled study on the efficacy and tolerance of trospium chloride in patients with motor urge incontinence. Clin Drug Invest 2001; 21: 563–9

    Article  Google Scholar 

Download references

Acknowledgements

The authors are grateful to Suzyon O’Neal Wandrey, Berlin for proofreading the manuscript. This trial was funded by the Dr R. Pfleger GmbH as part of its clinical development programme for trospium chloride.

Dr Haselmann and Dr Schwantes are with Dr R Pfleger GmbH working on concept, planning, administrative and organisational matters and monitoring of clinical trials.

Author information

Authors and Affiliations

  1. Institute of Clinical Pharmacology, Charité University Medical Centre, Humboldt University of Berlin, Berlin, Germany

    Konstanze Diefenbach, Frank Donath, Agathe Maurer, Sabine Quispe Bravo & Ivar Roots

  2. Institute of Medical Biometry, Charité University Medical Centre, Humboldt University of Berlin, Berlin, Germany

    Klaus-Dieter Wernecke

  3. Department of Medical Science/Clinical Research, Dr R. Pfleger GmbH, Bamberg, D-96045, Germany

    Ulrich Schwantes (Head of Department Clinical Research/Medical Science) & Jutta Haselmann

Authors
  1. Konstanze Diefenbach
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Frank Donath
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Agathe Maurer
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sabine Quispe Bravo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Klaus-Dieter Wernecke
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ulrich Schwantes
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jutta Haselmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ivar Roots
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Diefenbach, K., Donath, F., Maurer, A. et al. Randomised, Double-Blind Study of the Effects of Oxybutynin, Tolterodine, Trospium Chloride and Placebo on Sleep in Healthy Young Volunteers. Clin. Drug Investig. 23, 395–404 (2003). https://doi.org/10.2165/00044011-200323060-00003

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00044011-200323060-00003

Keywords

Search

Navigation