Skip to main content
SpringerLink
Log in
Book cover

Pharmacovigilance in Psychiatry pp 191–207Cite as

Safety and Tolerability of Anxiolytics/Sedative-Hypnotics

  • Chapter
  • First Online:

Abstract

A variety of pharmacological agents are currently available for the treatment of anxiety disorders and insomnia. The adverse event profile of selective serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs), first-line drugs for the treatment of many anxiety conditions, is discussed in Chap. 8. Benzodiazepines are still valuable in the management of anxiety disorders and transient insomnia. Tolerability and safety issued associated with benzodiazepines includes sedation, memory and psychomotor impairment and reduced driving performance. As stated in international guidelines, benzodiazepine treatment should be of short duration not exceeding 3 months, as continuous use of benzodiazepines can lead to abuse and dependence. In addition, recent findings suggest that long-term use of benzodiazepines in the elderly may increase the risk of developing Alzheimer’s disease. Moreover, warnings released by European Medicines Agency (EMA) and Food and Drug Administration (FDA) advised that two benzodiazepines, tetrazepam and clobazam, may cause serious skin events, including Stevens-Johnson syndrome and toxic epidermal necrolysis. Emerging evidence indicates that pregabalin, a pharmacological agent approved for the treatment of generalized anxiety disorder, also has the potential to lead to abuse and dependence. Recent data in elderly patients has highlighted potential safety concerns of non-benzodiazepine hypnotics, the so-called Z-drugs, including zolpidem, specifically with regard to effects on balance and memory and on fracture risk.

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

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   99.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   129.00
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   119.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  • Allard J, Artero S, Ritchie K (2003) Consumption of psychotropic medication in the elderly: a re-evaluation of its effect on cognitive performance. Int J Geriatr Psychiatry 18:874–878

    Article  PubMed  Google Scholar 

  • Amieva H, Le Goff M, Millet X, Orgogozo JM, Peres K, Barberger-Gateau P, Jacqmin-Gadda H, Dartigues JF (2008) Prodromal Alzheimer’s disease: successive emergence of the clinical symptoms. Ann Neurol 64:492–498

    Article  PubMed  Google Scholar 

  • Ashton H (2005) The diagnosis and management of benzodiazepine dependence. Curr Opin Psychiatry 18:249–255

    Article  PubMed  Google Scholar 

  • Baldwin DS, Ajel K, Masdrakis VG, Nowak M, Rafiq R (2013) Pregabalin for the treatment of generalized anxiety disorder: an update. Neuropsychiatr Dis Treat 9:883–892

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Baldwin DS, Anderson IM, Nutt DJ, Allgulander C, Bandelow B, den Boer JA, Christmas DM, Davies S, Fineberg N, Lidbetter N, Malizia A, McCrone P, Nabarro D, O’Neill C, Scott J, van der Wee N, Wittchen HU (2014) Evidence-based pharmacological treatment of anxiety disorders, post-traumatic stress disorder and obsessive-compulsive disorder: a revision of the 2005 guidelines from the British Association for Psychopharmacology. J Psychopharmacol 28:403–439

    Article  PubMed  Google Scholar 

  • Bandelow B, Sher L, Bunevicius R, Hollander E, Kasper S, Zohar J, Moller HJ, WFSBP Task Force on Mental Disorders in Primary Care, WFSBP Task Force on Anxiety Disorders, OCD and PTSD (2012) Guidelines for the pharmacological treatment of anxiety disorders, obsessive-compulsive disorder and posttraumatic stress disorder in primary care. Int J Psychiatry Clin Pract 16:77–84

    Article  CAS  PubMed  Google Scholar 

  • Barbone F, McMahon AD, Davey PG, Morris AD, Reid IC, McDevitt DG, MacDonald TM (1998) Association of road-traffic accidents with benzodiazepine use. Lancet 352:1331–1336

    Article  CAS  PubMed  Google Scholar 

  • Barbui C, Gastaldon C, Cipriani A (2013) Benzodiazepines and risk of dementia: true association or reverse causation? Epidemiol Psychiatry Sci 22:307–308

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Berry SD, Lee Y, Cai S, Dore DD (2013) Nonbenzodiazepine sleep medication use and hip fractures in nursing home residents. JAMA Intern Med 173:754–761

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Billioti de Gage S, Bégaud B, Bazin F, Verdoux H, Dartigues JF, Pérès K, Kurth T, Pariente A (2012) Benzodiazepine use and risk of dementia: prospective population based study. BMJ 345:e6231

    Article  PubMed  PubMed Central  Google Scholar 

  • Billioti de Gage S, Moride Y, Ducruet T, Kurth T, Verdoux H, Tournier M, Pariente A, Bégaud B (2014) Benzodiazepine use and risk of Alzheimer’s disease: case-control study. BMJ 349:g5205

    Article  PubMed  PubMed Central  Google Scholar 

  • Boeuf-Cazou O, Bongue B, Ansiau D, Marquie JC, Lapeyre-Mestre M (2011) Impact of long-term benzodiazepine use on cognitive functioning in young adults: the VISAT cohort. Eur J Clin Pharmacol 67:1045–1052

    Article  CAS  PubMed  Google Scholar 

  • Bond AJ (1998) Drug-induced behavioural disinhibition. Incidence, mechanisms and therapeutic implications. CNS Drugs 9:41–57

    Article  CAS  Google Scholar 

  • Bonnet MH, Arand DL (1999) The use of lorazepam TID for chronic insomnia. Int Clin Psychopharmacol 14:81–89

    Article  CAS  PubMed  Google Scholar 

  • Charlson F, Degenhardt L, McLaren J, Hall W, Lynskey M (2009) A systematic review of research examining benzodiazepine-related mortality. Pharmacoepidemiol Drug Saf 18:93–103

    Article  PubMed  Google Scholar 

  • Chessick CA, Allen MH, Thase M, Batista Miralha da Cunha AB, Kapczinski FF, de Lima MS, dos Santos Souza JJ (2006) Azapirones for generalized anxiety disorder. Cochrane Database Syst Rev 3, CD006115

    Google Scholar 

  • Chouinard G (2004) Issues in the clinical use of benzodiazepines: potency, withdrawal, and rebound. J Clin Psychiatry 65(Suppl 5):7–12

    CAS  PubMed  Google Scholar 

  • Cumming RG, Le Couteur DG (2003) Benzodiazepines and risk of hip fractures in older people: a review of the evidence. CNS Drugs 17:825–837

    Article  CAS  PubMed  Google Scholar 

  • Curran HV, Bond A, O’Sullivan G, Bruce M, Marks I, Lelliot P, Shine P, Lader M (1994) Memory functions, alprazolam and exposure therapy: a controlled longitudinal trial of agoraphobia with panic disorder. Psychol Med 24:969–976

    Article  CAS  PubMed  Google Scholar 

  • Curran HV, Collins R, Fletcher S, Kee SCY, 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 33:1223–1227

    Article  CAS  PubMed  Google Scholar 

  • Daderman AM, Lidberg L (1999) Flunitrazepam (rohypnol) abuse in combination with alcohol causes premeditated, grievous violence in male juvenile offenders. J Am Acad Psychiatry Law 27:83–99

    CAS  PubMed  Google Scholar 

  • Dassanayake T, Michie P, Carter G, Jones A (2011) Effects of benzodiazepines, antidepressants and opioids on driving: a systematic review and meta-analysis of epidemiological and experimental evidence. Drug Saf 34:125–156

    Article  CAS  PubMed  Google Scholar 

  • Dealberto MJ, McAvay GJ, Seeman T, Berkman L (1997) Psychotropic drug use and cognitive decline among older men and women. Int J Geriatr Psychiatry 12:567–574

    Article  CAS  PubMed  Google Scholar 

  • European Medicine Agency (EMA). Recommendation to suspend tetrazepam-containing medicines endorsed by CMDh. EMA Drug Safety Communication (29 April 2013). Available from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2013/04/news_detail_001777.jsp&mid=WC0b01ac058004d5c1. Accessed on 19 May 2015

  • Fastbom J, Forsell Y, Winblad B (1998) Benzodiazepines may have protective effects against Alzheimer disease. Alzheimer Dis Assoc Disord 12:14–17

    Article  CAS  PubMed  Google Scholar 

  • Finkle WD, Der JS, Greenland S, Adams JL, Ridgeway G, Blaschke T, Wang Z, Dell RM, VanRiper KB (2011) Risk of fractures requiring hospitalization after an initial prescription for zolpidem, alprazolam, lorazepam, or diazepam in older adults. J Am Geriatr Soc 59:1883–1890

    Article  PubMed  Google Scholar 

  • Food and Drug Administration (FDA) (2013a). FDA warns of serious skin reactions with the anti-seizure drug Onfi (Clobazam) and has approved label changes. FDA Drug Safety Communication (12 Dec 2013). Available from: http://www.fda.gov/Drugs/DrugSafety/ucm377204.htm. Accessed on: 19 May 2015

  • Food and Drug Administration (FDA) (2013b) Risk of next-morning impairment after use of insomnia drugs; FDA requires lower recommended doses for certain drugs containing zolpidem. FDA Drug Safety Communications (10 Jan 2013). Available from: http://www.fda.gov/Drugs/DrugSafety/ucm334033.htm. Accessed on: 19 May 2015

  • Frampton JE (2014) Pregabalin: a review of its use in adults with generalized anxiety disorder. CNS Drugs 28:835–854

    Article  CAS  PubMed  Google Scholar 

  • Frey DJ, Ortega JD, Wiseman C, Farley CT, Wright KP (2011) Influence of zolpidem and sleep inertia on balance and cognition during nighttime awakening: a randomized placebo-controlled trial. J Am Geriatr Soc 59:73–81

    Article  PubMed  Google Scholar 

  • Gahr M, Freudenmann RW, Hiemke C, Kölle MA, Schönfeldt-Lecuona C (2013) Pregabalin abuse and dependence in Germany: results from a database query. Eur J Clin Pharmacol 2013:1335–1342

    Google Scholar 

  • 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 66:869–873

    Article  PubMed  Google Scholar 

  • Gorenstein C, Bernik MA, Pompeia S (1994) Differential acute psychomotor and cognitive effects of diazepam on longterm benzodiazepine users. Int Clin Psychopharmacol 9:145–153

    Article  CAS  PubMed  Google Scholar 

  • Gould RL, Coulson MC, Patel N, Highton-Williamson E, Howard RJ (2014) Interventions for reducing benzodiazepine use in older people: meta-analysis of randomized controlled trials. Br J Psychiatry 204:98–107

    Article  PubMed  Google Scholar 

  • Greenblatt DJ (2011) Psychotropic drug prescribing in the United States: extent, costs, and expenditures. J Clin Psychopharmacol 31:1–3

    Article  PubMed  Google Scholar 

  • Gunja N (2013) The clinical & forensic toxicology of Z-drugs. J Med Toxicol 9:163–171

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 64:684–692

    Article  CAS  PubMed  Google Scholar 

  • Hemmelgarn B, Suissa S, Huang A, Boivin JF, Pinard G (1997) Benzodiazepine use and the risk of motor vehicle crash in the elderly. JAMA 278:27–31

    Article  CAS  PubMed  Google Scholar 

  • Kang DY, Park S, Rhee CW, Kim YJ, Choi NK, Lee J, Park BJ (2012) Zolpidem use and risk of fracture in elderly insomnia patients. J Prev Med Public Health 45:219–226

    Article  PubMed  PubMed Central  Google Scholar 

  • Kasper S, Iglesias-García C, Schweizer E, Wilson J, DuBrava S, Prieto R, Pitman VW, Knapp L (2014) Pregabalin long-term treatment and assessment of discontinuation in patients with generalized anxiety disorder. Int J Neuropsychopharmacol 17:685–695

    Article  CAS  PubMed  Google Scholar 

  • Kmietowicz Z (2014) Benzodiazepines may be linked to Alzheimer’s disease, study finds. BMJ 349:g5555. doi:10.1136/bmj.g5555 (Published 10 September 2014)

    Article  PubMed  Google Scholar 

  • Kripke DF, Langer RD, Kline LE (2012) Hypnotic association with mortality or cancer; a matched cohort study. BMJ Open 2, e000850

    Article  PubMed  PubMed Central  Google Scholar 

  • Lader M (1987) Long-term anxiolytic therapy: the issue of drug withdrawal. J Clin Psychiatry 48:12–16

    PubMed  Google Scholar 

  • Lader M (1998) Withdrawal reactions after stopping hypnotics in patients with insomnia. CNS Drugs 10:425–440

    Article  CAS  Google Scholar 

  • Lader M (2011) Benzodiazepines revisited—will we ever learn? Addiction 106:2086–2109. add_3563

    Article  PubMed  Google Scholar 

  • Lader M (2014) Benzodiazepine harm: how can it be reduced? Br J Clin Pharmacol 77:295–301

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lagnaoui R, Begaud B, Moore N, Chaslerie A, Fourrier A, Letenneur L, Dartigues JF, Moride Y (2002) Benzodiazepine use and risk of dementia: a nested case-control study. J Clin Epidemiol 55:314–318

    Article  PubMed  Google Scholar 

  • Lagnaoui R, Tournier M, Moride Y, Wolfson C, Ducruet T, Begaud B, Moore N (2009) The risk of cognitive impairment in older community-dwelling women after benzodiazepine use. Age Ageing 38:226–228

    Article  PubMed  Google Scholar 

  • Leipzig RM, Cumming RG, Tinetti ME (1999) Drugs and falls in older people: a systematic review and meta-analysis. I: psychotropic drugs. J Am Geriatr Soc 47:30–39

    Article  CAS  PubMed  Google Scholar 

  • Leung SY (2011) Benzodiazepines, opioids and driving: an overview of the experimental research. Drug Alcohol Rev 30:281–286

    Article  PubMed  Google Scholar 

  • Levy HB (2014) Non-benzodiazepine hypnotics and older adults: what are we learning about zolpidem? Expert Rev Clin Pharmacol 7:5–8

    Article  CAS  PubMed  Google Scholar 

  • Loane C, Politis M (2012) Buspirone: what is it all about? Brain Res 1461:111–118

    Article  CAS  PubMed  Google Scholar 

  • Mancuso C, Tanzi MG, Gabay M (2004) Paradoxical reactions to benzodiazepines: literature review and treatment options. Pharmacotherapy 24:1177–1185

    Article  CAS  PubMed  Google Scholar 

  • Maxwell HG, Dubois S, Weaver B, Bédard M (2010) The additive effects of alcohol and benzodiazepines on driving. Can J Public Health 101:353–357

    PubMed  Google Scholar 

  • O’Brien CP (2005) Benzodiazepine use, abuse, and dependence. J Clin Psychiatry 66(suppl 2):28–33

    PubMed  Google Scholar 

  • Orriols L, Philip P, Moore N, Castot A, Gadegbeku B, Delorme B, Mallaret M, Lagarde E (2011) Benzodiazepine-like hypnotics and the associated risk of road traffic accidents. Clin Pharmacol Ther 89:595–601

    Article  CAS  PubMed  Google Scholar 

  • Oulis P, Konstantakopoulos G (2012) Efficacy and safety of pregabalin in the treatment of alcohol and benzodiazepine dependence. Expert Opin Investig Drugs 21:1019–1029

    Article  CAS  PubMed  Google Scholar 

  • Paquin AM, Zimmerman K, Rudolph L (2014) Risk versus risk: a review of benzodiazepine reduction in older adults. Exp Opin Drug Saf 13:919–934

    Article  CAS  Google Scholar 

  • 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 22:285–293

    Article  CAS  PubMed  Google Scholar 

  • Paton C (2002) Benzodiazepines and disinhibition: a review. Psychiatr Bull 26:460–462

    Article  Google Scholar 

  • Proy-Vega B, Aguirre C, de Groot P, Solis-Garcia del Pozo J, Jordan J (2014) On the clinical evidence leading to tetrazepam withdrawal. Exp Opin Drug Saf 13:705–712

    CAS  Google Scholar 

  • Ray WA, Griffin MR, Downey W (1989) Benzodiazepines of long and short elimination half-life and risk of hip fracture. JAMA 262:3303–3307

    Article  CAS  PubMed  Google Scholar 

  • Salzman C, Shader RI (2015) Benzodiazepine use and risk for Alzheimer disease. J Clin Psychopharmacol 35:1–3

    Article  PubMed  Google Scholar 

  • Schifano F (2014) Misuse and abuse of pregabalin and gabapentin: cause for concern? CNS Drugs 28:491–496

    Article  CAS  PubMed  Google Scholar 

  • Schwan S, Sundström A, Stjernberg E, Hallberg E, Hallberg P (2010) A signal for an abuse liability for pregabalin–results from the Swedish spontaneous drug reaction reporting system. Eur J Clin Pharmacol 66:947–953

    Article  PubMed  Google Scholar 

  • Smink BE, Egberts AC, Lusthof KJ, Uges DR, de Gier JJ (2010) The relationship between benzodiazepine use and traffic accidents: a systematic literature review. CNS Drugs 24:639–653

    Article  CAS  PubMed  Google Scholar 

  • Verdoux H, Lagnaoui R, Begaud B (2005) Is benzodiazepine use a risk factor for cognitive decline and dementia? A literature review of epidemiological studies. Psychol Med 35:307–315

    Article  PubMed  Google Scholar 

  • Vikander B, Koechling UM, Borg S, Tönne U, Hiltunen AJ (2010) Benzodiazepine tapering: a prospective study. Nord J Psychiatry 64:273–282

    Article  PubMed  Google Scholar 

  • Wang PS, Bohn RL, Glynn RJ, Mogun H, Avorn J (2001) Zolpidem use and hip fractures in older people. J Am Geriatr Soc 49:1685–1690

    Article  CAS  PubMed  Google Scholar 

  • Woods JH, Katz JL, Winger G (1992) Benzodiazepine use, abuse and consequences. Pharmacol Rev 44:151–347

    CAS  PubMed  Google Scholar 

  • Woolcott JC, Richardson KJ, Wiens MO, Patel B, Marin J, Khan KM, Marra CA (2009) Meta-analysis of the impact of 9 medication classes on falls in elderly persons. Arch Intern Med 169:1952–1960

    Article  PubMed  Google Scholar 

  • Wu CS, Wang SC, Chang IS, Lin KM (2009) The association between dementia and long-term use of benzodiazepine in the elderly: nested case-control study using claims data. Am J Geriatr Psychiatry 17:614–620

    Article  PubMed  Google Scholar 

  • Wu CS, Ting TT, Wang SC, Chang IS, Lin KM (2011) Effect of benzodiazepine discontinuation on dementia risk. Am J Geriatr Psychiatry 19:151–159

    Article  PubMed  Google Scholar 

  • Xing D, Ma XL, Ma JX, Wang J, Yang Y, Chen Y (2014) Association between use of benzodiazepines and risk of fractures: a meta-analysis. Osteoporos Int 25:105–120

    Article  CAS  PubMed  Google Scholar 

  • Zaccara G, Gangemi P, Perucca P, Specchio L (2011) The adverse event profile of pregabalin: a systematic review and meta-analysis of randomized controlled trials. Epilepsia 52:826–836

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy

    Vincenzo Arcoraci & Edoardo Spina

Authors
  1. Vincenzo Arcoraci
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Edoardo Spina
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Edoardo Spina .

Editor information

Editors and Affiliations

  1. University of Messina, Department of Clinical and Experimental Medicine, Messina, Italy

    Edoardo Spina

  2. University of Messina, Department of Clinical and Experimental Medicine, Messina, Italy

    Gianluca Trifirò

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Arcoraci, V., Spina, E. (2016). Safety and Tolerability of Anxiolytics/Sedative-Hypnotics. In: Spina, E., Trifirò, G. (eds) Pharmacovigilance in Psychiatry. Adis, Cham. https://doi.org/10.1007/978-3-319-24741-0_10

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-24741-0_10

  • Published:

  • Publisher Name: Adis, Cham

  • Print ISBN: 978-3-319-24739-7

  • Online ISBN: 978-3-319-24741-0

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation