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Benzodiazepine use and risk of Alzheimer’s disease: case-control study

BMJ 2014; 349 doi: https://doi.org/10.1136/bmj.g5205 (Published 09 September 2014) Cite this as: BMJ 2014;349:g5205

Benzodiazepines in older adults: definite harms, doubtful benefits.(Re: Benzodiazepine use and risk of Alzheimer’s disease: case-control study)

To the editors:

We applaud the work of Billioti de Gage and colleagues who linked benzodiazepine use in older adults to the subsequent development of dementia.1 However, we disagree with their assertions that “Benzodiazepines are indisputably valuable tools for managing anxiety disorders and transient insomnia” and their suggestion that short duration benzodiazepine exposure is consistent with good practice guidelines. A mass of evidence suggests that the benefits of benzodiazepines in older adults rarely, if ever outweigh their risks.

Benzodiazepine risks, whether short-term or chronic, include cognitive impairment,23, delirium,4 respiratory insufficiency,5 falls,6 fall-related injuries such as hip fractures,7 motor vehicle crashes,8 and death.9 Most patients are not warned of these risks before starting these medications.10 The main risk factor for chronic benzodiazepine use is any previous use, so an intended short-duration prescription of these habit-forming medication is likely to lead to their long-term use.11 Chronic benzodiazepine users are rarely prompted to discontinue, despite good evidence for the safety and tolerability of tapering protocols.12

Benzodiazepines’ benefits for anxiety disorders are questionable, especially as they are commonly used in clinical practice. First, the dose of benzodiazepines necessary to provide a clinical response is far higher than that needed to cause harms in older adults – for example, 6-10mg daily of alprazolam is needed to bring about remission from panic disorder,13, and 30-60mg daily of oxazepam was needed for response in (to our knowledge) the only controlled study of benzodiazepines for anxiety disorder in older adults.14. Second, there is growing evidence in anxiety disorders that benzodiazepine use reduces the efficacy of exposure-based cognitive behavior therapy, probably by interfering with learning and memory and preventing habituation to the anxiety.15 Hence, benzodiazepine use may actually perpetuate (rather than treat) many anxiety disorders by preventing naturalistic recovery from them.16

The evidence for benefits of benzodiazepines in insomnia is equally poor. In a meta-analysis, benzodiazepine use resulted in a mean nightly improvement of 25.2 minutes sleep. The number needed to treat for improvement of insomnia was 13, while the number needed to harm was 6.17

Safer treatments for anxiety disorders and insomnia exist and are effective in older adults, including serotonin reuptake inhibitors (for anxiety) and psychotherapy such as relaxation training or cognitive behavioral therapy (for anxiety and/or insomnia).18. These treatments can also be used effectively in combination for chronic anxiety19 . For occasional insomnia or transient anxiety, watchful waiting or other low-intensity intervention are superior to initiating a dangerous and habit-forming medication.

To conclude, Billioti De Gage and colleagues provide more evidence still that deleterious consequences of benzodiazepines in older adults are a large and growing public health problem, given their high rates of use in this age group.20 It is time for their use to be limited, for example to palliative and hospice care or specific treatment-refractory cases, and as a start we recommend the following:

1. Clinicians prescribing these medications to older adults should warn them that their use is not considered best practice.
2. These medications should come with a warning (like that found on cigarette packages) such as “If you are older than 60, use of this medication will increase your risk of cognitive impairment, falls, hip fractures, and death.”
3. Educate health care providers regarding (a) risks of short-term and long-term benzodiazepine use and (b) safe alternatives for the management of anxiety and insomnia.

Doing so would improve the quality of life, safety, and cognitive health, of the large and growing population of older adults.

Competing interests: none to report

Literature cited:
1. Billioti de Gage S, Moride Y, Ducruet T, Kurth T, Verdoux H, Tournier M, et al. Benzodiazepine use and risk of Alzheimer's disease: case-control study. BMJ 2014;349:g5205.
2. Stewart SA. The effects of benzodiazepines on cognition. J Clin Psychiatry 2005;66 Suppl 2:9-13.
3. Pomara N, Lee SH, Bruno D, Silber T, Greenblatt DJ, Petkova E, et al. Adverse performance effects of acute lorazepam administration in elderly long-term users: Pharmacokinetic and clinical predictors. Progress in neuro-psychopharmacology & biological psychiatry 2014;56C:129-35.
4. Clegg A, Young JB. Which medications to avoid in people at risk of delirium: a systematic review. Age Ageing 2011;40(1):23-9.
5. Vozoris NT, Fischer HD, Wang X, Anderson GM, Bell CM, Gershon AS, et al. Benzodiazepine use among older adults with chronic obstructive pulmonary disease: a population-based cohort study. Drugs & Aging 2013;30(3):183-92.
6. Woolcott JC, Richardson KJ, Wiens MO, Patel B, Marin J, Khan KM, et al. Meta-analysis of the impact of 9 medication classes on falls in elderly persons. Arch Intern Med 2009;169(21):1952-60.
7. Finkle WD, Der JS, Greenland S, Adams JL, Ridgeway G, Blaschke T, et al. Risk of fractures requiring hospitalization after an initial prescription for zolpidem, alprazolam, lorazepam, or diazepam in older adults. J Am Geriatr Soc 2011;59(10):1883-90.
8. Meuleners LB, Duke J, Lee AH, Palamara P, Hildebrand J, Ng JQ. Psychoactive medications and crash involvement requiring hospitalization for older drivers: a population-based study. J Am Geriatr Soc 2011;59(9):1575-80.
9. Weich S, Pearce HL, Croft P, Singh S, Crome I, Bashford J, et al. Effect of anxiolytic and hypnotic drug prescriptions on mortality hazards: retrospective cohort study. BMJ 2014;348:g1996.
10. Iliffe S, Curran HV, Collins R, Yuen Kee SC, Fletcher S, Woods B. Attitudes to long-term use of benzodiazepine hypnotics by older people in general practice: findings from interviews with service users and providers. Aging Ment Health 2004;8(3):242-8.
11. Neutel CI. The epidemiology of long-term benzodiazepine use. International review of psychiatry 2005;17(3):189-97.
12. Paquin AM, Zimmerman K, Rudolph JL. Risk versus risk: a review of benzodiazepine reduction in older adults. Expert Opin Drug Saf 2014;13(7):919-34.
13. Ballenger JC, Burrows GD, DuPont RL, Jr., Lesser IM, Noyes R, Jr., Pecknold JC, et al. Alprazolam in panic disorder and agoraphobia: results from a multicenter trial. I. Efficacy in short-term treatment. Arch Gen Psychiatry 1988;45(5):413-22.
14. Koepke HH, Gold RL, Linden ME, Lion JR, Rickels K. Multicenter controlled study of oxazepam in anxious elderly outpatients. Psychosomatics 1982;23(6):641-5.
15. Rothbaum BO, Price M, Jovanovic T, Norrholm SD, Gerardi M, Dunlop B, et al. A randomized, double-blind evaluation of D-cycloserine or alprazolam combined with virtual reality exposure therapy for posttraumatic stress disorder in Iraq and Afghanistan War veterans. The American journal of psychiatry 2014;171(6):640-8.
16. Birk L. Pharmacotherapy for performance anxiety disorders: occasionally useful but typically contraindicated. J Clin Psychol 2004;60(8):867-79.
17. Glass J, Lanctot KL, Herrmann N, Sproule BA, Busto UE. Sedative hypnotics in older people with insomnia: meta-analysis of risks and benefits. BMJ 2005;331(7526):1169.
18. Sivertsen B, Omvik S, Pallesen S, Bjorvatn B, Havik OE, Kvale G, et al. Cognitive behavioral therapy vs zopiclone for treatment of chronic primary insomnia in older adults: a randomized controlled trial. JAMA 2006;295(24):2851-8.
19. Wetherell JL, Petkus AJ, White KS, Nguyen H, Kornblith S, Andreescu C, et al. Antidepressant medication augmented with cognitive-behavioral therapy for generalized anxiety disorder in older adults. Am J Psychiatry 2013;170(7):782-9.
20. Jackson G, Gerard C, Minko N, Parsotam N. Variation in benzodiazepine and antipsychotic use in people aged 65 years and over in New Zealand. N Z Med J 2014;127(1396):67-78.

Competing interests: No competing interests

09 October 2014
Eric J Lenze
geriatric psychiatrist
Andrea Iaboni, MD, and Julie Wetherell, PhD
Washington University School of Medicine
660 S Euclid, ST Louis MO 63110
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