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Effect of withdrawal from long-term use of temazepam, zopiclone or zolpidem as hypnotic agents on cognition in older adults

European Journal of Clinical Pharmacology volume 70, pages 319–329 (2014)Cite this article

Abstract

Purpose

The aim of this study was to assess the effect of withdrawal from the long-term use of temazepam, zopiclone or zolpidem as hypnotics drugs (here referred to as BZD) on cognitive performance.

Methods

Ninety-two adults (age ≥55 years) with primary insomnia and who were long-term daily users of BZD volunteered to participate in a 1-month medically supported withdrawal attempt from BZD use, with a subsequent 5-month follow-up. Withdrawal was based on plasma BZD measurements at baseline, at 1 month and during subsequent regular clinical appointments. Attention and psychomotor performance were measured using the CogniSpeed® at baseline and at 1, 2 and 6 months. Reaction times were determined in the Simple Reaction Time (SRT), Two-Choice Reaction Time (2-CRT) and Vigilance tests, and errors were measured by the 2-CRT and Vigilance tests. The cognition data of the withdrawal group were also compared with a cohort of BZD non-users.

Results

Eighty-nine (97 %) participants (59 women, 30 men) were followed-up for a maximum of 6 months. During the follow-up period, changes in reaction times and errors did not differ between short-term withdrawers (no residual BZD at 1 month; N = 69), non-withdrawers (residual BZD at 1 month; N = 20) or long-term withdrawers (N = 34). Compared to the reaction times of the BZD-free cohort, those of BZD users were slower at baseline. The reaction times of BZD withdrawers based on the results of the SRT or 2-CRT tests during follow-up did not reach those of the BZD-free cohort, but there was no difference between these groups in the Vigilance test.

Conclusions

Long-term use of BDZ as hypnotic drugs by older adults is related to prolonged impairment of attentional and psychomotor cognitive functioning that persists for at least 6 months after withdrawal.

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References

  1. Barker MJ, Greenwood KM, Crowe SF (2003) Cognitive effects of benzodiazepine use: a review. Aust Psychol 38(3):12

    Article  Google Scholar 

  2. Stewart SA (2005) The effects of benzodiazepines on cognition. J Clin Psychiatry 66[Suppl 2]:9–13

    CAS  PubMed  Google Scholar 

  3. Glass J, Lanctot KL, Herrmann N, Sproule BA, Busto UE (2005) Sedative hypnotics in older people with insomnia: meta-analysis of risks and benefits. BMJ 331(7526):1169

    Article  PubMed  Google Scholar 

  4. Bierman EJ, Comijs HC, Gundy CM, Sonnenberg C, Jonker C, Beekman AT (2007) The effect of chronic benzodiazepine use on cognitive functioning in older persons: good, bad or indifferent? Int J Geriatr Psychiatry 22(12):1194–1200

    Article  CAS  PubMed  Google Scholar 

  5. Hanlon JT, Horner RD, Schmader KE, Fillenbaum GG, Lewis IK, Wall WE Jr, Landerman LR, Pieper CF, Blazer DG, Cohen HJ (1998) Benzodiazepine use and cognitive function among community-dwelling elderly. Clin Pharmacol Ther 64(6):684–692

    Article  CAS  PubMed  Google Scholar 

  6. Paterniti S, Dufouil C, Alperovitch A (2002) Long-term benzodiazepine use and cognitive decline in the elderly: the Epidemiology of Vascular Aging Study. J Clin Psychopharmacol 22(3):285–293

    Article  CAS  PubMed  Google Scholar 

  7. Gallacher J, Elwood P, Pickering J, Bayer A, Fish M, Ben-Shlomo Y (2012) Benzodiazepine use and risk of dementia: evidence from the Caerphilly Prospective Study (CaPS). J Epidemiol Community Health 66(10):869–873. doi:10.1136/jech-2011-200314

    Article  PubMed  Google Scholar 

  8. Billioti de Gage S, Bégaud B, Bazin F, Vermeeren A, Dartigues JF, Pèrés K, Kurth T, Pariente A (2012) Benzodiazepine use and risk of dementia: prospective population based study. BMJ 345:e6231. doi:10.1136/bmj.e6231

  9. Puustinen J, Nurminen J, Lopponen M, Vahlberg T, Isoaho R, Raiha I, Kivela SL (2011) Use of CNS medications and cognitive decline in the aged: a longitudinal population-based study. BMC Geriatr 11:70. doi:10.1186/1471-2318-11-70

    Article  PubMed Central  PubMed  Google Scholar 

  10. Folstein MF, Folstein SE, McHugh PR (1975) Mini-mental state. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12(3):189–198

    Article  CAS  PubMed  Google Scholar 

  11. Puustinen J, Nurminen J, Vahlberg T, Lyles A, Isoaho R, Raiha I, Kivelä SL (2012) CNS Medications as predictors of precipitous cognitive decline in the cognitively disabled aged: a longitudinal population-based study. Dement Geriatr Cogn Disord Extra 2:57–68. doi:10.1159/000336710

    Article  Google Scholar 

  12. Barker MJ, Greenwood KM, Jackson M, Crowe SF (2004) Cognitive effects of long-term benzodiazepine use: a meta-analysis. CNS Drugs 18(1):37–48

    Article  CAS  PubMed  Google Scholar 

  13. McAndrews MP, Weiss RT, Sandor P, Taylor A, Carlen PL, Shapiro CM (2003) Cognitive effects of long-term benzodiazepine use in older adults. Hum Psychopharmacol 18(1):51–57. doi:10.1002/hup.453

    Article  CAS  Google Scholar 

  14. Rummans TA, Davis LJ Jr, Morse RM, Ivnik RJ (1993) Learning and memory impairment in older, detoxified, benzodiazepine-dependent patients. Mayo Clin Proc 68(8):731–737

    Article  CAS  PubMed  Google Scholar 

  15. Curran HV, Collins R, Fletcher S, Kee SC, Woods B, Iliffe S (2003) Older adults and withdrawal from benzodiazepine hypnotics in general practice: effects on cognitive function, sleep, mood and quality of life. Psychol Med 33(7):1223–1237

    Article  CAS  PubMed  Google Scholar 

  16. Salzman CF, Nobel K, Glassman R, Wolfson A, Kelley M (1992) Cognitive improvement following benzodiazepine discontinuation in elderly nursing home residents. Int J Geriatr Psychiatry 7:89–93

    Article  Google Scholar 

  17. Tsunoda K, Uchida H, Suzuki T, Watanabe K, Yamashima T, Kashima H (2010) Effects of discontinuing benzodiazepine-derivative hypnotics on postural sway and cognitive functions in the elderly. Int J Geriatr Psychiatry 25(12):1259–1265. doi:10.1002/gps.2465

    Article  PubMed  Google Scholar 

  18. Barker MJ, Greenwood KM, Jackson M, Crowe SF (2004) Persistence of cognitive effects after withdrawal from long-term benzodiazepine use: a meta-analysis. Arch Clin Neuropsychol: Off J Natl Acad Neuropsychol 19(3):437–454. doi:10.1016/S0887-6177(03)00096-9

    Article  Google Scholar 

  19. Barker MJ, Greenwood KM, Jackson M, Crowe SF (2005) An evaluation of persisting cognitive effects after withdrawal from long-term benzodiazepine use. J Int Neuropsychol Soc 11(3):281–289. doi:10.1017/S1355617705050332

    Article  CAS  PubMed  Google Scholar 

  20. Lähteenmäki R, Puustinen J, Vahlberg T, Lyles A, Neuvonen PJ, Partinen M, Räihä I, Kivelä S-L (2013) Melatonin for sedative withdrawal in older patients with primary insomnia: a randomised double-blind placebo-controlled trial. Br J Clin Pharmacol. doi:10.1111/bcp.12294

  21. Alhola P, Polo-Kantola P, Erkkola R, Portin R (2006) Estrogen therapy and cognition: a 6-year single-blind follow-up study in postmenopausal women. Neurology 67(4):706–709. doi:10.1212/01.wnl.0000230135.10179.86

    Article  CAS  PubMed  Google Scholar 

  22. Alhola P, Tuomisto H, Saarinen R, Portin R, Kalleinen N, Polo-Kantola P (2010) Estrogen + progestin therapy and cognition: a randomized placebo-controlled double-blind study. J Obstet Gynaecol Res 36(4):796–802. doi:10.1111/j.1447-0756.2010.01214.x

    Article  CAS  PubMed  Google Scholar 

  23. Karakorpi M, Alhola P, Urrila AS, Kylmala M, Portin R, Kalleinen N, Polo-Kantola P (2006) Hormone treatment gives no benefit against cognitive changes caused by acute sleep deprivation in postmenopausal women. Neuropsychopharmacology 31(9):2079–2088. doi:10.1038/sj.npp.1301056

    Article  CAS  PubMed  Google Scholar 

  24. American Psychiatric Association (1994) Diagnostic and statistical manual of mental disorders, 4th edn. American Psychiatric Association, Washington, DC

  25. Otmani S, Demazieres A, Staner C, Jacob N, Nir T, Zisapel N, Staner L (2008) Effects of prolonged-release melatonin, zolpidem, and their combination on psychomotor functions, memory recall, and driving skills in healthy middle aged and elderly volunteers. Hum Psychopharmacol 23(8):693–705. doi:10.1002/hup.980

    Article  CAS  PubMed  Google Scholar 

  26. Almeida OP, Almeida SA (1999) Short versions of the geriatric depression scale: a study of their validity for the diagnosis of a major depressive episode according to ICD-10 and DSM-IV. Int J Geriatr Psychiatry 14(10):858–865

    Article  CAS  PubMed  Google Scholar 

  27. Kujala P, Portin R, Revonsuo A, Ruutiainen J (1994) Automatic and controlled information processing in multiple sclerosis. Brain 117(Pt 5):1115–1126

    Article  PubMed  Google Scholar 

  28. Kujala P, Portin R, Revonsuo A, Ruutiainen J (1995) Attention related performance in two cognitively different subgroups of patients with multiple sclerosis. J Neurol Neurosurg Psychiatry 59(1):77–82

    Article  CAS  PubMed  Google Scholar 

  29. Revonsuo A, Portin R, Koivikko L, Rinne JO, Rinne UK (1993) Slowing of information processing in Parkinson’s disease. Brain Cognition 21(1):87–110. doi:10.1006/brcg.1993.1007

    Article  CAS  PubMed  Google Scholar 

  30. Lilja AM, Portin RI, Hamalainen PI, Salminen EK (2001) Short-term effects of radiotherapy on attention and memory performances in patients with brain tumors. Cancer 91(12):2361–2368

    Article  CAS  PubMed  Google Scholar 

  31. Ashton H (1991) Protracted withdrawal syndromes from benzodiazepines. J Subst Abuse Treat 8(1–2):19–28

    Article  CAS  PubMed  Google Scholar 

  32. Roy-Byrne PP (2005) The GABA-benzodiazepine receptor complex: structure, function, and role in anxiety. J Clin Psychiatry 66[Suppl 2]:14–20

    CAS  PubMed  Google Scholar 

  33. Lopez-Munoz F, Alamo C, Garcia-Garcia P (2011) The discovery of chlordiazepoxide and the clinical introduction of benzodiazepines: half a century of anxiolytic drugs. J Anxiety Disord 25(4):554–562. doi:10.1016/j.janxdis.2011.01.002

    Article  PubMed  Google Scholar 

  34. Portin R, Polo-Kantola P, Polo O, Koskinen T, Revonsuo A, Irjala K, Erkkola R (1999) Serum estrogen level, attention, memory and other cognitive functions in middle-aged women. Climacteric 2(2):115–123

    Article  CAS  PubMed  Google Scholar 

  35. Portin R, Revonsuo A, Koivikko L, Rinne J (1992) Kognitiivinen hitaus ja vanheneminen [Cognitive slowness and ageing]. Gerontologia [Gerontology] 6(3):196–210

    Google Scholar 

  36. Fortier-Brochu E, Beaulieu-Bonneau S, Ivers H, Morin CM (2012) Insomnia and daytime cognitive performance: a meta-analysis. Sleep Med Rev 16(1):83–94. doi:10.1016/j.smrv.2011.03.008

    Article  PubMed  Google Scholar 

  37. Chavez EL, Trautt GM, Brandon A, Steyaert J (1983) Effects of test anxiety and sex of subject on neuropsychological test performance: finger tapping, trail making, digit span and digit symbol tests. Percep Motor Skills 56(3):923–929

    Article  CAS  Google Scholar 

  38. Gladsjo JA, Rapaport MH, McKinney R, Lucas JA, Rabin A, Oliver T, Davis J, Auerbach M, Judd LL (1998) A neuropsychological study of panic disorder: negative findings. J Affect Disord 49(2):123–131

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments, author contributions and competing financial interests

See ESM Acknowledgments.

Author information

Authors and Affiliations

  1. Department of Family Medicine, University of Turku, Lemminkäisenkatu 1, 20014, Turku, Finland

    Juha Puustinen, Ritva Lähteenmäki, Ismo Räihä & Sirkka-Liisa Kivelä

  2. Medical Teaching and Research Health Centre, University Consortium of Pori, Pori, Finland

    Juha Puustinen & Ritva Lähteenmäki

  3. Department of Neurology, University of Turku, Turku, Finland

    Juha Puustinen

  4. Division of Clinical Neurosciences, Turku University Hospital, Turku, Finland

    Juha Puustinen

  5. Department of Obstetrics and Gynecology, Turku University Hospital, Turku, Finland

    Päivi Polo-Kantola

  6. University of Turku, Turku, Finland

    Päivi Polo-Kantola

  7. Sleep Research Unit, University of Turku, Turku, Finland

    Päivi Polo-Kantola

  8. Department of Psychology, University of Turku, Turku, Finland

    Paula Salo

  9. Research Unit for Psychosocial Factors, Finnish Institute of Occupational Health, Turku, Finland

    Paula Salo

  10. Department of Biostatistics, University of Turku, Turku, Finland

    Tero Vahlberg

  11. College of Public Affairs, University of Baltimore, Baltimore, MD, USA

    Alan Lyles

  12. Division of Social Pharmacy, University of Helsinki, Helsinki, Finland

    Alan Lyles & Sirkka-Liisa Kivelä

  13. Härkätie Health Centre, Lieto, Finland

    Alan Lyles

  14. Clinical Pharmacology, University of Helsinki, Helsinki, Finland

    Pertti J. Neuvonen

  15. HUSLAB, Helsinki University Central Hospital, Helsinki, Finland

    Pertti J. Neuvonen

  16. Helsinki Sleep Clinic, Vitalmed Research Center, Helsinki, Finland

    Markku Partinen

  17. Haartman Institute, University of Helsinki, Helsinki, Finland

    Markku Partinen

  18. Turku City Hospital, Turku, Finland

    Ismo Räihä

  19. Satakunta Central Hospital, Hospital District of Satakunta, Pori, Finland

    Sirkka-Liisa Kivelä

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  1. Juha Puustinen
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Correspondence to Juha Puustinen.

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Puustinen, J., Lähteenmäki, R., Polo-Kantola, P. et al. Effect of withdrawal from long-term use of temazepam, zopiclone or zolpidem as hypnotic agents on cognition in older adults. Eur J Clin Pharmacol 70, 319–329 (2014). https://doi.org/10.1007/s00228-013-1613-6

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  • DOI: https://doi.org/10.1007/s00228-013-1613-6

Keywords

  • Temazepam
  • Zopiclone
  • Zolpidem
  • Withdrawal
  • Cognition
  • Long-term effects