1. Long Term Use of Sedative-Hypnotics
Yates Brown, MD
Medical Director / Tenderloin Outpatient Clinic

2. Disclosure Statement
No relevant financial relationships with commercial interests to disclose

3. Definitions “Sedative-Hypnotics” =
Benzodiazepines + BZD-like Hypnotics (‘Z drugs’)
Clonazepam (Klonopin), Diazepam (Valium), Lorazepam (Ativan),
Alprazolam (Xanax), Temazepam (Restoril), Chlordiazepoxide (Librium)
Zolpidem (Ambien), Zaleplon (Sonata), Eszopiclone (Lunesta)
“Long Term” ?

4. Risks vs. Benefits Benefits Risks Rapid Anxiety Relief (transient)
Rapid Insomnia Relief (transient)
Detox (transient)
Neuro (RLS, RBD, myoclonus)
Risks
Sedation
Misuse/Dependence/Diversion
Interactions/Overdose
Falls/Accidents
Sleep-related behaviors
All-cause Mortality
Cognitive

5. Risks Upfront Overdose deaths Motor vehicle accidents Injurious Falls
30% of OD deaths involve BZDs, as well as 30% of opioid ODs (SAMSHA DAWN 2010)
Motor vehicle accidents
40-60% increased risk with BZDs and Z drugs (n=20,000 UK, Lancet 1998) (n=70,000 France, Clin Pharm Ther 2011)
Injurious Falls
20,000 injurious falls (with 1800 fatal) per year attributable to BZDs in France per case control 10 yr database review & population estimate (Pariente et al, Drugs Aging 2008)
Sleep related behaviors

7. Mortality 2014 retrospective cohort study
35,000 adults (any age) taking BZD or Z drug vs. 70,000 matched controls
Average length of follow-up = 7.6 years
Age-adjusted hazard ratio for all cause mortality = 3.32
“4 excess deaths linked to sedative-hypnotic use for every 100 people followed”
Clear dose-response association: hazard ratio up to 4.5 among those who received more than 90 daily doses of any sedative-hypnotic
Weich et al, BMJ 2014

8. Cognition

9. Cognition
Long term BZD use negatively affects multiple measures of cognitive functioning
2004 meta-analysis of 13 studies
neuropsych testing for a mean of 34 patients taking BZDs for an average length of 9.9 years
large, consistent and significant impairments in all tested categories:
sensory processing problem solving psychomotor speed concentration motor control verbal reasoning processing speed verbal memory nonverbal memory working memory visuospatial general intelligence
Barker et al, CNS Drugs 2004

10. Cognition Memory impairment persists even after tolerance…
Tolerance develops to sedative and attention effects in first few weeks
Long-term memory (implicit & explicit) impairment persists
Difficulty encoding new information (anterograde amnesia) (Buffett-Jerrott & Stewart, Curr Pharm Des 2002)
…and may not come back completely
Follow-up to same 2004 meta-analysis, looking at clients taken off BZDs
Cognitive function improved in all domains
6 months out still had not attained the cognitive performance of non-BZD using controls (Barker et al, Arch Clin Neuropsychol 2004)

11. Cognition Benzodiazepines linked to Alzheimer’s risk
2014 case control study in Quebec
2000 elderly clients with recent AD diagnosis compared to 7000 controls
50% increased risk of Alzheimer’s diagnosis if used BZDs in the 5 years prior
Strong dose-effect relationship (PDD = “prescribed daily doses”):
<90 PDDs (<3 months) – no risk difference from controls
PDDs (3-6 months) – 32% increased risk of Alzheimer’s
>180 PDDs (>6 months) – 84% increased risk of Alzheimer’s
Theory: beyond 3 months use, BZDs reduce cognitive reserve capacity so that dementia is more apparent with the same level of early brain changes Billoti et al, BMJ 2014

13. Long term benefits?

14. “You see, they work.”
“For their main indications of insomnia and anxiety, benzodiazepines fare little better than placebos after a few weeks of treatment. After an initial improvement, the effect wears off and tends to disappear. At that point, when patients try to stop taking benzodiazepines they experience withdrawal insomnia and anxiety. The usual conclusion is ‘you see, they work. When I stop them, I get worse.’ After a few weeks of treatment, patients are actually worse off (or at at least not better) and cannot stop taking the drug.”
Drs. Moore, Pariente, & Begaud
JAMA Psychiatry Feb 2015

15. Long term use in trauma May increase PTSD risk after trauma
Recent trauma victims followed for 6 months
Half treated with BZDs, half not
69% in benzo group developed PTSD vs 15% in the non-benzo group
J Clin Psychiatry 1996
“Harmful in PTSD”
VA/DOD 2010 Evidence Based Clinical Guidelines for PTSD
BZDs moved from “No Benefit” to “Harmful” category

16. Long term use in anxiety
Increased healthcare costs in GAD
866 patients with GAD on different treatments followed for 6 months
Those on BZDs >90 days incurred $2334 more in healthcare costs
More than half due to falls, accidents, and cognitive impairment
BMC Psychiatry 2012
General anxiety & mood ratings
2004 meta-analysis, clients on BZDs an average of 10 years
6 months after stopping BZDs, ratings on HAM-A, HAM-D, and BDI either did not change (5 studies) or improved (3 studies)
Arch Clin Neuropsychol 2004

17. Long term use in psychosis
Increased mortality in schizophrenia
2588 schizophrenia patients followed 4 years after 1st hospitalization
Significant increase in risk of all-cause mortality for those on BZDs, including suicides (vs no increased risk for APs or ADMs)
90% had early BZD refill or other treatment contract violation
Arch Gen Psychiatry 2012
Increased BZD use in adolescents with psychosis
In 7000 adolescents taking BZDs > 1 year, psychosis was one predictor of going on to chronic or accelerated use
Psychiatr Serv 2011

18. Long term use in substance use
No help for remission rates
203 dually diagnosed clients followed for 6 years, 50% on BZDs
No difference in remission rates
BZDs: worse on BPRS, BPRS-A, and general life satisfaction scales
Psychiatr Serv 2003
Worse methadone maintenance outcomes
172 methadone maintenance clients followed for 3 years
Those on BZDs:
More ODs
More likely to start prescription opioids
More likely to test positive for cocaine or opioids on urine screens
J Addict Dis 2008