2. New users of benzodiazepines: implications for elder patient safety G. Bartlett, PhD Family Medicine McGill University

3. Outline  Benzodiazepine use in the elderly  Objectives of study  Methods  Population & data sources  Results – new users vs non-users  Results – predictors of new use  Conclusions, Limitations  Future Directions

4. Benzodiazepines - review  Sedative/hypnotics:  hypnotic, anxiolytic, anticonvulsant, muscular relaxant, amnesic  high efficacy, rapid onset of action, low toxicity  unique among psychotropics for multiple indications and relative safety compared with other sedative/hypnotics

5. Concerns about Benzodiazepines  psychomotor impairment  paradoxical excitement  tolerance, dependence and withdrawal effects with long term use  injuries from falls

6. Concerns about Benzodiazepines for the Elderly Due to changes that occur with normal aging, elderly demonstrate increased sensitivity to: psychomotor impairment memory impairment rebound or withdrawal effects interactions with other medications/conditions

7. Use of Benzodiazepines: Why the Elderly?  insomnia can be a “pathological” feature associated with age  anxiety due to other illnesses  more likely to suffer acute grief reactions  fewer complications with benzodiazepines than with tricyclic anti-depressants and anti-psychotics

8.  Risk from injuries from falls for benzodiazepines still in dispute  Physicians may be prescribing benzodiazepines perceived to be safer to higher risk patients  Pre-existing risk factors may be cause confounding in published studies What risk factors for falls are present before a benzodiazepine is prescribed? Why are we still discussing benzodiazepine safety?

9. Methods  All patients >65 years with no benzodiazepine script in baseline year  Risk factors for falls assessed in baseline year: age & sex clinical characteristics disabilities & impairments prior hospitalizations prior health care use use of other prescription medication.  5 years of follow-up until first benzodiazepine script dispensed – product name identified

10. Benzodiazepines available in QC  Triazolam (Halcion)  Midazolam (Versed) – IV only  Alprazolam (Xanax)  Bromazepam (Lectopam)  Lorazepam (Ativan)  Oxazepam (Serax)  Nitrazepam (Mogadon)  Temazepam (Restoril)  Clobazam (Frisium)  Clonazepam (Rivotril)  Diazepam (Valium)  Flurazepam (Dalmane)  Chlordiazepoxide (Librium)  Clorazepate* (Traxene)

11. Data Sources: The Quebec Health Care Databases  Beneficiary Database: all Quebec residents, age, sex, date of death, address  Pharmaceutical Database: all claims for prescriptions dispensed to elderly and welfare recipients in Quebec  Medical Services Claims: all medical services provided on a fee-for-service basis (90%) to Quebec residents  Hospitalization Database: all discharges from Quebec hospitals - dates for hospitalization

12. Study Sample

13. Study Overview Jan. 1989Jan. 1990Dec. 1994 BaselineFollow-up

14. Results - general  average age 73.4 years with 52% women  78,367 (31%) new benzodiazepine users  New users had an almost two-fold increase in use of anti-depressants and sedatives, cardiac medications, anti-hypertensive agents, vasodilators and diuretics  9.5% of new users versus 5.6% of non-users filled at least one prescription for another psychotropic medication  44% of new users vs 38% of non-users filled at least one prescription for medications that affect motor stability  New users were more likely to have depression and arthritis, and used more health care services than non-users

15. H.R.95% CI Sex - Men vs Women0.870.86-0.89 No. Prescribing Drs.1.091.09-1.10 No. Hospital Stays0.950.94-0.97

16. H.R.95% CI Any Injury (1989) 0.960.93-0.99 Visual Impairment 0.970.95-0.99 Stroke 0.950.91-0.99 Depression 1.351.30-1.41 Neurological Disorders 1.101.05-1.15 Arthritis 1.081.06-1.10 Seizure 0.960.91-1.02 Osteoporosis 0.990.90-1.10 Misc. Impairments 1.010.98-1.05 Alcohol Abuse 1.351.18-1.54 Drug Abuse 1.181.03-1.37 Charlson Co-morbidity Index 1.021.02-1.03

17. H.R.95% CI Anti-Depressants1.671.61-1.74 Anti-Psychotics1.231.16-1.31 Sedatives1.271.23-1.32 Lithium, L-tryptophan1.261.09-1.46 Cardiac Drugs1.051.03-1.07 Anti–Hypertensive Agents1.061.04-1.08 Vasodilators1.171.15-1.20 Opiod Agonists1.141.06-1.23 Opiod Mixed Partial Agonists/Antagonists 1.110.91-1.34 Non-Thiazide Diuretics1.081.06-1.11

18. Results – product specific  decreased risk of starting oxazepam and flurazepam for older ages  women were more to be new users of the majority of the benzodiazepines except temazepam and flurazepam  each additional prescribing physician seen increased by risk of new use by 5-15%  having an fall injury decreased risk for lorazepam (HR=0.93, p=0.01) and diazepam (HR=0.86, p=0.04) and an increased probability for chlordiazepoxide (HR=1.34, p=0.04)

19. Results – disabilities and impairments  depression was strongly associated with new use except triazolam and temazepam -particularly strong for alprazolam (HR=1.98, p<0.0001) and clonazepam (HR=2.46, p<0.0001)  weaker but consistently positive increased risk for arthritis  neurological disorders (including dementia and Parkinson’s disease) and clonazepam (HR=2.24, p<0.0001);  alcohol abuse and both oxazepam (HR=1.55 p=0.001) and chlordiazepoxide (HR=12.1, p<0.0001)  drug abuse with bromazepam (HR=2.34, p=0.0008).

20. Results – disabilities and impairments  strongest and most consistent associations were seen for use of anti-depressants as well as other psychotropic medications (anti-psychotics and non-benzodiazepine sedatives, lithium or l-tryptophan)  filling a prescription for an anti-depressant significantly increased risk varying from a 23% increase for diazepam (HR=1.23) to more than tripling the hazard for clonazepam (HR=3.13)  use of anti-psychotics, other sedatives, and lithium or l-tryptophan increased risk by more than double for new clonazepam and flurazepam use and over five times for clonazepam (HR=5.19, p<0.0001).

21. Conclusions  Factors associated with new benzodiazepine use vary considerably among the individual products  Physicians appear to be “channeling” new users based on own criteria – not necessarily evidence based  Any research on risk needs to account for these factors by individual products

22. Limitations  under-diagnosis and under-reporting of the treatment of certain diseases  anxiety and insomnia were often not coded in the database making it difficult to assess the association between these diagnoses and benzodiazepine use  proxy measure of use (dispensed prescription)  no prescription information available during hospitalization

23. Future Directions  Why benzodiazepines are chosen by physicians – are other risk factors accounted for?  Role of risk in guidelines recommendations…  Methods to reduce risk of falls – smart alerts?  Investigations of risk from falls – are other risk factors accounted for?  Is dose adjusted for in high risk patients?

24. Questions & Comments gillian.bartlett@mcgill.ca