Examining the Risks and Benefits Benzodiazepine Landscape in the from Benzodiazepines United States Rakesh Jain, MD, MPH Saundra Jain, MA, PsyD, LPC Clinical Professor Adjunct Clinical Affiliate Department of Psychiatry University of Texas at Austin Texas Tech Health Sciences Center School of Nursing School of Medicine Austin, Texas Midland, Texas Is Benzodiazepine (and “Z” Sedative Drug) Use Answer – These Agents are Utilized Rare in America? Very Frequently in the United States Top 10 Prescriptions for Psychotropics Written in America (2013 Medical Expenditure Panel Survey) In 2013: • There were 5,259,000 prescriptions for Alprazolam • There were 4,865,000 prescriptions for Zolpidem • There were 3,273,000 prescriptions for Clonazepam • There were 3,165,000 prescriptions for Lorazepam SSRI = selective serotonin reuptake inhibitor; SARI = serotonin antagonist and reuptake inhibitor; SNRI = serotonin norepinephrine reuptake inhibitor. Brand names are included in this table for participant clarification purposes only. Moore TJ, et al. JAMA Intern Med . 2017;177(2):274-275. No product promotion should be inferred. Moore TJ, et al. JAMA Intern Med . 2017;177(2):274-275. Who Exactly is Receiving the Anxiolytic/ Sedative/Hypnotic Class of Medications? US Adult Population Exposed to Psychiatric Drugs (%) Is There a Problem with the Use of All Numbers are high, but Benzodiazepines? highest risk is associated with: 1. Female gender 2. Older age 3. White race Moore TJ, et al. JAMA Intern Med . 2017;177(2):274-275.
BZD Link with Accidental Falls BZD Use and Risk of Hip Fracture Register-based Medication Use and Alzheimer’s disease (MEDALZ) study, including all community-dwelling persons diagnosed with AD in Finland during 2005–2011 (n = • In a questionnaire survey 70,718) and their matched comparison persons without AD. of 8000 people in 2 districts of Wales, BZD use was associated with injuries outside work and cognitive failures In a recent Finnish study of patients with • The risk of hip fractures or without AD, BZDR use was associated in older adults can be Duration with an increased risk of hip fracture in of Use increased by as much as persons: in Days 50% • With AD – HR increase is 1.4 • Without AD – HR increase is 1.6 BZDR use was associated with an increased risk of hip fracture in persons with and without AD = Alzheimer’s disease; BZD = benzodiazepine; BZDR = BZD and related drug; HR = hazard ratio. AD (adjusted HR 1.4 [95% CI 1.2–1.7] and 1.6 [95% CI 1.3–1.9], respectively) Wadsworth EJ, et al. Hum Psychopharmacol . 2005;20(6):391-400. Cumming RG, et al. CNS Drugs . CI = confidence interval. 2003;17(11):825-837. Lader M. Addiction . 2011;106(12):2086-2109. Saarelainen L, et al. J Am Med Dir Assoc . 2017;18(1):87.e15-e87.e21. Saarelainen L, et al. J Am Med Dir Assoc . 2017;18(1):87.e15-e87.e21. The Ugly Side of BZDs: It Plays an Important A Publication from VA Clinicians Part in Drug Overdose Deaths • BZDs have been linked to falls, fractures, cognitive Oklahoma State Drug Overdoses 1994–2006 decline, amnesia, impaired psychomotor speed (eg, A total of 2112 fatal unintentional medication overdoses motor vehicle accidents), and nursing home placement were identified • Such risks above are of greatest concern among older Methadone 30.9% adults, who are more sensitive to medicines and most Hydrocodone 19.3% vulnerable to their consequences Individual drugs contributing Alprazolam 15.2% most frequently • The pharmacokinetic and pharmacodynamic changes in Oxycodone 14.7% the aging body and brain make older patients vulnerable Diazepam 4.5% • As a result, all BZDs are on the list of Potentially 0.0% 10.0% 20.0% 30.0% 40.0% Inappropriate Medications in the 2012 Beers Criteria Crude overdose death rates increased 7-fold during the investigation period in 2006 VA = Veterans Affairs. Paquin AM, et al. Expert Opin Drug Saf . 2014;13(7):919-934. Piercefield E, et al. Am J Prev Med . 2010;39(4):357-363. BZD Use and Dementia Risk – The World’s Latest and Largest Meta-Analysis of Dementia Risk with BZDs Reveals... Case Control Studies Also Show Heightened Risk Meta-analysis pooled data from 8 studies. These 8 studies included Independent German analysis: 66,177 participants and 30,914 cases of dementia • The regular use of BZDRs was associated with a significant increased risk of incident dementia for patients aged ≥ 60 years • Adjusted OR 1.21, 95% CI 1.13–1.29 • The association was slightly stronger for long-acting substances than for short-acting ones • A trend for increased risk for dementia with higher exposure was observed Conc lusion: The restricted use of BZDRs may contribute to dementia prevention in the elderly Odds of dementia were 78% higher in those who used BZDs compared with those who did not use BZDs (OR 1.78; 95% CI 1.33–2.38) BZDR = BZD and related z-substance; OR = odds ratio. Gomm W, et al. J Alzheimers Dis . 2016;54(2):801-808. Islam MM, et al. Neuroepidemiology . 2016;47(3-4):181-191.
BZD Use and Association with AD – Another Set of Very Large Databases – FDA and Emerging Data is Concerning Canadian Pharmacovigilance Data Set, Reveals… • Dose-effect relationship between BZD use and increased risk of AD in older people treated previously for > 3 months • Higher risk for long-acting formulations • Nature of the link cannot be definitively established US / FDA database revealed BZD use increased OR of • BZD use may be an early marker of a condition dementia risk by 1.63 associated with an increased risk of dementia (n = 1,971,750) • Recommend shortest duration and short half-life formulations Billioti de Gage S, et al. BMJ . 2014;349:g5205. Takada M, et al. Int J Med Sci . 2016;13(11):825-834. The Famous BMJ Gray Study from 2016 Does Cognition Improve after Withdrawal from Long-Term BZD Use? Are the Conclusions Corrrect? • Over a mean follow-up of 7.3 years, 797 participants (23.2%) developed dementia, of whom 637 developed AD • For dementia, the adjusted HRs associated with cumulative BZD use compared with nonuse were 1.25 (95% CI 1.03–1.51) for 1–30 Does cognitive Are previous long- TSDDs; 1.31 (1.00–1.71) for 31–120 TSDDs; and 1.07 (0.82–1.39) for ≥ 121 TSDDs function of long-term term BZD users still BZD users improve impaired at 6-month Conclusion: The risk of dementia is slightly higher in people with minimal post-withdrawal? follow-up? exposure to BZDs but not with the highest level of exposure. These results do not support a causal association between BZD use and dementia. “…given the mixed evidence regarding benzodiazepines and risk of dementia and that these drugs are associated with many adverse events, healthcare META-ANALYSIS OF 10 STUDIES providers are still advised to avoid benzodiazepines…” TSSD = total standardized daily doses. Gray SL, et al. BMJ . 2016;352:i90. Barker MJ, et al. Arch Clin Neuropsychol . 2004;19(3):437-454. Overdose Situations with BZDs: Does Cognition Improve after Withdrawal from Long-Term BZD Use? (cont’d) Where Did These Medications Come From? N = 297 N = 284 Interviews were conducted with 31 patients who attended the ED following a medication overdose and typical stories regarding the acquisition of medications reported. • Improvement in cognitive function does occur following withdrawal from long-term BZD use Recreational Use, 16% • Patients withdrawn from long-term BZD use continued to Treatment perform more poorly than controls across all cognitive Purposes, 77% categories, except sensory processing Overdose, • As age increased post-withdrawal cognitive recovery 7% decreased on tasks of attention/concentration Conclusion: We are the main suppliers of BZDs that are ultimately used in overdoses ! ED = emergency department. Barker MJ, et al. Arch Clin Neuropsychol . 2004;19(3):437-454. Buykx P, et al. Aust N Z J Public Health . 2010;34(4):401-404.
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