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benzodiazepine

Epidemiology: - women twice as likely as men to use benzodiazepines [11] - older adults more likely than younger adults to use benzodiazepines [11] - > 25% of older adults prescribed benzodiazepines by non-psychiatrists become chronic users [20] Dosage: Equivalent doses of oral benzodiazepines lorazepam 1 mg oxazepam 15 mg Adverse effects: 1) temporary cognitve effects - confusion, especially in the elderly - amnesia, aggression, delirium - impairment in inferring anger from facial expressions, posture or prosody [22] 2) use of benzodiazepines in the elderly is associated with increased risk of dementia [8], RR=1.7 for >180 days use - benzodiazepine use is not associated with increased risk for dementia or Alzheimer's disease [14,23] - although both benzodiazepines & anxiety disorders increase risk of dementia in the elderly, benzodiazepine use in elderly with anxiety disorder does not increase risk of dementia [26] 3) urinary incontinence 4) increased risk falls & of hip fracture [3] 5) increased risk of community-acquired pneumonia & pneumonia-related death [6] - increased risk of pneumonia in Alzheimer's disease [18] 6) increased mortality - 2-fold increase in 8 year mortality [7] - risk may be smaller than previously reported [19] 7) use in early pregnancy is associated with increased risk for spontaneous abortion (1.4% vs. 0.6%) [21] - highest risk with diazepam, temazepam, alprazolam [21] 8) withdrawal may occur within 24-48 hours after discontinuation* [4,5,24] a) moderate dose 1] agitation, anxiety 2] photophobia, phonophobia 3] paresthesias 4] muscle cramps 5] myoclonic jerks 6] tremor 6] sleep disturbance 8] dizziness 9] tachycardia b) high-dose 1] seizure 2] delirium 9) benzodiazepine-induced neurological dysfunction (BIND) - associated adverse life consequences - may present during benzodiazepine use or tapering - may continue after benzodiazepine discontinuation - not all benzodiazepine users experience BIND [25] * see discontinuation of chronic benzodiazepine use (treatment of benzodiazepine dependence) [17] Drug interactions: 1) disulfiram, nefazodone, fluoxetine, fluvoxamine, cimetidine & grapefruit juice decrease metabolism &/or increase absorption of benzodiazepines 2) CNS depressants in combination increase CNS depression 3) antiepileptic agents, rifampin increase metabolism of benzodiazpines 4) flumazenil antagonizes effects of benzodiazepines 5) peripheral manifestations of benzodiazepine withdrawal may be masked by beta-blockers [5] Laboratory: - benzodiazepine in specimen - benzodiazepine in hair - benzodiazepine in body fluid - benzodiazepine in blood - benzodiazepine in gastric fluid - benzodiazepine in meconium - benzodiazepine in saliva - benzodiazepine in serum/plasma - benzodiazepine in stool - benzodiazepine in urine - benzodiazepine in vitreous fluid Management: - also see discontinuation of chronic benzodiazepine use - also see benzodiazepine toxicity

Interactions

drug interactions drug adverse effects (more general classes)

Related

benzodiazepine toxicity discontinuation of chronic benzodiazepine use; benzodiazepine deprescribing gamma-aminobutyric acid (GABA) A receptor, alpha translocator protein; peripheral-type benzodiazepine receptor; PBR; PKBS; mitochondrial benzodiazepine receptor (TSPO, BZRP, MBR)

Specific

7-aminoclonazepam alprazolam (Xanax, Niravam) chlordiazepoxide (Librium) clobazam (ONFI, Frisium, Urbanol) clonazepam (Klonopin) clorazepate (Tranxene) diazepam (Vallium, Diastat) estazolam (ProSom) flunitrazepam (Rohypnol) flurazepam (Dalmane) halazepam (Paxipam) lorazepam (Ativan) midazolam (Versed, Buccolam) nitrazepam (Benzalin, Mogadon, Remnos, Neozepam, Nitrados) oxazepam (Serax) prazepam (Centrax) quazepam (Doral) remimazolam (Byfavo) temazepam (Restoril) triazolam (Halcion) zolazepam

General

benzazepine sedative/hypnotic (tranquilizer)

References

  1. Goodman & Gilman 1990
  2. Drug Information & Medication Formulary, Veterans Affairs, Central California Health Care System, 1st ed., Ravnan et al eds, 1998
  3. Wang PS et al Hazardous benzodiazepine regimens in the elderly: effects of half-life, dosage, and duration on risk of hip fracture. Am J Psychiatry 158:892 2001 PMID: 11384896
  4. The Pharmacological Basis of Therapeutics, 9th ed. Gilman et al, eds. Permagon Press/McGraw Hill, 1996 pg 564
  5. Geriatric Review Syllabus, 7th edition Parada JT et al (eds) American Geriatrics Society, 2010 - Geriatric Review Syllabus, 8th edition (GRS8) Durso SC and Sullivan GN (eds) American Geriatrics Society, 2013 - Geriatric Review Syllabus, 11th edition (GRS11) Harper GM, Lyons WL, Potter JF (eds) American Geriatrics Society, 2022
  6. Obiora E et al The impact of benzodiazepines on occurrence of pneumonia and mortality from pneumonia: a nested case-control and survival analysis in a population-based cohort. Thorax. 5 December 2012 PMID: 23220867 http://thorax.bmj.com/content/early/2012/11/12/thoraxjnl-2012-202374
  7. Weich S et al Effect of anxiolytic and hypnotic drug prescriptions on mortality hazards: retrospective cohort study. BMJ 2014;348:g1996 PMID: 24647164 http://www.bmj.com/content/348/bmj.g1996
  8. Billioti de Gage S, Begaud B, Bazin F, Verdoux H et al Benzodiazepine use and risk of dementia: prospective population based study. BMJ. 2012 Sep 27;345:e6231. PMID: 23045258 - Billioti de Gage S et al. Benzodiazepine use and risk of Alzheimer's disease: Case- control study. BMJ 2014 Sep 9; 349:g5205 PMID: 25208536
  9. Curran HV, Collins R, Fletcher S, Kee SC, Woods B, Iliffe S. Older adults and withdrawal from benzodiazepine hypnotics in general practice: effects on cognitive function, sleep, mood and quality of life. Psychol Med. 2003 Oct;33(7):1223-37. PMID: 14580077
  10. Mugunthan K1, McGuire T, Glasziou P. Minimal interventions to decrease long-term use of benzodiazepines in primary care: a systematic review and meta-analysis. Br J Gen Pract. 2011 Sep;61(590):e573-8 PMID: 22152740
  11. Olfson M, King M, Schoenbaum M Benzodiazepine Use in the United States. JAMA Psychiatry. Published online December 17, 2014 PMID: 2551722 http://archpsyc.jamanetwork.com/article.aspx?articleid=2019955 - Moore N, Pariente A, Begaud B Why Are Benzodiazepines Not Yet Controlled Substances? JAMA Psychiatry. Published online December 17, 2014 PMID: 25517135 http://archpsyc.jamanetwork.com/article.aspx?articleid=2019953
  12. Gould RL, Coulson MC, Patel N, et al. Interventions for reducing benzodiazepine use in older people: meta-analysis of randomised controlled trials. Br J Psychiatry. 2014;204(2):98-107. PMID: 24493654
  13. Vicens C, Bejarano F, Sempere E, et al. Comparative efficacy of two interventions to discontinue long- term benzodiazepine use: cluster randomised controlled trial in primary care. Br J Psychiatry. 2014;204(6):471-479 PMID: 24526745
  14. Gray SL, Dublin S, Yu O et al Benzodiazepine use and risk of incident dementia or cognitive decline: prospective population based study. BMJ 2016;352:i90 PMID: 26837813 http://www.bmj.com/content/352/bmj.i90
  15. Lader M. Benzodiazepine harm: how can it be reduced? Br J Clin Pharmacol. 2014 Feb;77(2):295-301. Review. PMID: 22882333 Free PMC Article
  16. Paquin AM, Zimmerman K, Rudolph JL. Risk versus risk: a review of benzodiazepine reduction in older adults. Expert Opin Drug Saf. 2014 Jul;13(7):919-34. Review. PMID: 24905348
  17. Soyka M Treatment of Benzodiazepine Dependence. N Engl J Med 2017; 376:1147-1157. March 23, 2017 PMID: 28328330 http://www.nejm.org/doi/full/10.1056/NEJMra1611832
  18. Taipale H, Tolppanen AM, Koponen M et al Risk of pneumonia associated with incident benzodiazepine use among community-dwelling adults with Alzheimer disease. CMAJ April 10, 2017 vol. 189 no. 14 E519-E529 PMID: 28396328 http://www.cmaj.ca/content/189/14/E519 - Rochon PA, Vozoris N, Gill SS. The harms of benzodiazepines for patients with dementia. CMAJ April 10, 2017 189:E517-E518 PMID: 28396327 http://www.cmaj.ca/content/189/14/E517
  19. Orciari Herman A, Sofair A, Chavey WE Link Between Benzodiazepines and Mortality Called into Question Physician's First Watch, July 2017 David G. Fairchild, MD, MPH, Editor-in-Chief Massachusetts Medical Society http://www.jwatch.org - Patorno E et al Benzodiazepines and risk of all cause mortality in adults: cohort study. BMJ 2017;358:j2941 http://www.bmj.com/content/358/bmj.j2941
  20. Gerlach LB, Maust DT, Leong SH et al Factors Associated With Long-term Benzodiazepine Use Among Older Adults. JAMA Intern Med. Published online September 10, 2018. PMID: 30208384 https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2701626
  21. Sheehy O, Zhao JP, Berard A et al Association Between Incident Exposure to Benzodiazepines in Early Pregnancy and Risk of Spontaneous Abortion JAMA Psychiatry. Published online May 15, 2019. PMID: 31090881 https://jamanetwork.com/journals/jamapsychiatry/article-abstract/2733517
  22. Garcez H, Fernandes C, Barbosa F et al. Effects of benzodiazepines administration on identification of facial expressions of emotion: A meta-analysis. Psychopharmacology (Berl) 2019 Nov 18 PMID: 31740993
  23. Osler M, Jorgensen MB. Associations of benzodiazepines, Z-drugs, and other anxiolytics with subsequent dementia in patients with affective disorders: A nationwide cohort and nested case-control study. Am J Psychiatry 2020 Apr 7; PMID: 32252539 https://ajp.psychiatryonline.org/doi/10.1176/appi.ajp.2019.19030315
  24. Jobert A, Laforgue E, Grall-Bronnec M et al. Benzodiazepine withdrawal in older people: what is the prevalence, what are the signs, and which patients? Eur J Clin Pharmacol. 2021;77(2):171-177 PMID: 33006626 https://link.springer.com/article/10.1007/s00228-020-03007-7
  25. Rivito AD, Foster DE, Huff C et al Long-term consequences of benzodiazepine-induced neurological dysfunction: A survey. PLOS One, 2023. Jun 29;18(6):e0285584. PMID: 37384788 PMCID: PMC10309976 Free PMC article
  26. Brieler JA, Salas J, Amick ME et al Anxiety disorders, benzodiazepine prescription, and incident dementia. J Am Geriatr Soc. 2023. Nov 71(11):3376-3389 PMID: 37503956 https://agsjournals.onlinelibrary.wiley.com/doi/abs/10.1111/jgs.18515