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

Disclosure Statement No relevant financial relationships with commercial interests to disclose

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” ?

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

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

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

Cognition

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

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)

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 91-180 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

Long term benefits?

“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

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

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

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

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