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European Journal of Clinical Pharmacology

, Volume 70, Issue 3, pp 319–329 | Cite as

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

  • Juha PuustinenEmail author
  • Ritva Lähteenmäki
  • Päivi Polo-Kantola
  • Paula Salo
  • Tero Vahlberg
  • Alan Lyles
  • Pertti J. Neuvonen
  • Markku Partinen
  • Ismo Räihä
  • Sirkka-Liisa Kivelä
Pharmacoepidemiology and Prescription

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.

Keywords

Temazepam Zopiclone Zolpidem Withdrawal Cognition Long-term effects 

Notes

Acknowledgments, author contributions and competing financial interests

See ESM Acknowledgments.

Supplementary material

228_2013_1613_MOESM1_ESM.docx (31 kb)
ESM 1 (DOCX 30.6 kb)

References

  1. 1.
    Barker MJ, Greenwood KM, Crowe SF (2003) Cognitive effects of benzodiazepine use: a review. Aust Psychol 38(3):12CrossRefGoogle Scholar
  2. 2.
    Stewart SA (2005) The effects of benzodiazepines on cognition. J Clin Psychiatry 66[Suppl 2]:9–13PubMedGoogle Scholar
  3. 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):1169PubMedCrossRefGoogle Scholar
  4. 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):1194–1200PubMedCrossRefGoogle Scholar
  5. 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):684–692PubMedCrossRefGoogle Scholar
  6. 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):285–293PubMedCrossRefGoogle Scholar
  7. 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 PubMedCrossRefGoogle Scholar
  8. 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. 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 PubMedCentralPubMedCrossRefGoogle Scholar
  10. 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):189–198PubMedCrossRefGoogle Scholar
  11. 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 CrossRefGoogle Scholar
  12. 12.
    Barker MJ, Greenwood KM, Jackson M, Crowe SF (2004) Cognitive effects of long-term benzodiazepine use: a meta-analysis. CNS Drugs 18(1):37–48PubMedCrossRefGoogle Scholar
  13. 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 CrossRefGoogle Scholar
  14. 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):731–737PubMedCrossRefGoogle Scholar
  15. 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):1223–1237PubMedCrossRefGoogle Scholar
  16. 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 7:89–93CrossRefGoogle Scholar
  17. 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 PubMedCrossRefGoogle Scholar
  18. 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 CrossRefGoogle Scholar
  19. 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 PubMedCrossRefGoogle Scholar
  20. 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. 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 PubMedCrossRefGoogle Scholar
  22. 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 PubMedCrossRefGoogle Scholar
  23. 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 PubMedCrossRefGoogle Scholar
  24. 24.
    American Psychiatric Association (1994) Diagnostic and statistical manual of mental disorders, 4th edn. American Psychiatric Association, Washington, DCGoogle Scholar
  25. 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 PubMedCrossRefGoogle Scholar
  26. 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):858–865PubMedCrossRefGoogle Scholar
  27. 27.
    Kujala P, Portin R, Revonsuo A, Ruutiainen J (1994) Automatic and controlled information processing in multiple sclerosis. Brain 117(Pt 5):1115–1126PubMedCrossRefGoogle Scholar
  28. 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):77–82PubMedCrossRefGoogle Scholar
  29. 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 PubMedCrossRefGoogle Scholar
  30. 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):2361–2368PubMedCrossRefGoogle Scholar
  31. 31.
    Ashton H (1991) Protracted withdrawal syndromes from benzodiazepines. J Subst Abuse Treat 8(1–2):19–28PubMedCrossRefGoogle Scholar
  32. 32.
    Roy-Byrne PP (2005) The GABA-benzodiazepine receptor complex: structure, function, and role in anxiety. J Clin Psychiatry 66[Suppl 2]:14–20PubMedGoogle Scholar
  33. 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 PubMedCrossRefGoogle Scholar
  34. 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):115–123PubMedCrossRefGoogle Scholar
  35. 35.
    Portin R, Revonsuo A, Koivikko L, Rinne J (1992) Kognitiivinen hitaus ja vanheneminen [Cognitive slowness and ageing]. Gerontologia [Gerontology] 6(3):196–210Google Scholar
  36. 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 PubMedCrossRefGoogle Scholar
  37. 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):923–929CrossRefGoogle Scholar
  38. 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):123–131PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Juha Puustinen
    • 1
    • 2
    • 3
    • 4
    Email author
  • Ritva Lähteenmäki
    • 1
    • 2
  • Päivi Polo-Kantola
    • 5
    • 6
    • 7
  • Paula Salo
    • 8
    • 9
  • Tero Vahlberg
    • 10
  • Alan Lyles
    • 11
    • 12
    • 13
  • Pertti J. Neuvonen
    • 14
    • 15
  • Markku Partinen
    • 16
    • 17
  • Ismo Räihä
    • 1
    • 18
  • Sirkka-Liisa Kivelä
    • 1
    • 12
    • 19
  1. 1.Department of Family MedicineUniversity of TurkuTurkuFinland
  2. 2.Medical Teaching and Research Health CentreUniversity Consortium of PoriPoriFinland
  3. 3.Department of NeurologyUniversity of TurkuTurkuFinland
  4. 4.Division of Clinical NeurosciencesTurku University HospitalTurkuFinland
  5. 5.Department of Obstetrics and GynecologyTurku University HospitalTurkuFinland
  6. 6.University of TurkuTurkuFinland
  7. 7.Sleep Research UnitUniversity of TurkuTurkuFinland
  8. 8.Department of PsychologyUniversity of TurkuTurkuFinland
  9. 9.Research Unit for Psychosocial FactorsFinnish Institute of Occupational HealthTurkuFinland
  10. 10.Department of BiostatisticsUniversity of TurkuTurkuFinland
  11. 11.College of Public AffairsUniversity of BaltimoreBaltimoreUSA
  12. 12.Division of Social PharmacyUniversity of HelsinkiHelsinkiFinland
  13. 13.Härkätie Health CentreLietoFinland
  14. 14.Clinical PharmacologyUniversity of HelsinkiHelsinkiFinland
  15. 15.HUSLABHelsinki University Central HospitalHelsinkiFinland
  16. 16.Helsinki Sleep ClinicVitalmed Research CenterHelsinkiFinland
  17. 17.Haartman InstituteUniversity of HelsinkiHelsinkiFinland
  18. 18.Turku City HospitalTurkuFinland
  19. 19.Satakunta Central HospitalHospital District of SatakuntaPoriFinland

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