Download - Long Term Use of Sedative-Hypnotics Yates Brown, MD Medical Director / Tenderloin Outpatient Clinic
Long Term Use of Sedative-Hypnotics
Yates Brown, MDMedical 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
o Rapid Anxiety Relief (transient)o Rapid Insomnia Relief
(transient)o Detox (transient)o Neuro (RLS, RBD, myoclonus)
• Riskso Sedationo Misuse/Dependence/Diversiono Interactions/Overdoseo Falls/Accidentso Sleep-related behaviorso All-cause Mortalityo Cognitive
Risks Upfront• Overdose deaths
o 30% of OD deaths involve BZDs, as well as 30% of opioid ODs(SAMSHA DAWN 2010)
• Motor vehicle accidentso 40-60% increased risk with BZDs and Z drugs
(n=20,000 UK, Lancet 1998)(n=70,000 France, Clin Pharm Ther 2011)
• Injurious Fallso 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
o 35,000 adults (any age) taking BZD or Z drug vs. 70,000 matched controls
o Average length of follow-up = 7.6 yearso Age-adjusted hazard ratio for all cause mortality = 3.32o “4 excess deaths linked to sedative-hypnotic use
for every 100 people followed”o 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 o 2004 meta-analysis of 13 studies o neuropsych testing for a mean of 34 patients taking BZDs for an
average length of 9.9 yearso large, consistent and significant impairments in all tested
categories:
sensory processing problem solvingpsychomotor speed concentrationmotor control verbal reasoningprocessing speed verbal memorynonverbal memory working memoryvisuospatial general intelligence
Barker et al, CNS Drugs 2004
Cognition• Memory impairment persists even after tolerance…
o Tolerance develops to sedative and attention effects in first few weekso Long-term memory (implicit & explicit) impairment persistso Difficulty encoding new information (anterograde amnesia)
(Buffett-Jerrott & Stewart, Curr Pharm Des 2002)
• …and may not come back completely
o Follow-up to same 2004 meta-analysis, looking at clients taken off BZDso Cognitive function improved in all domainso 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
o 2014 case control study in Quebeco 2000 elderly clients with recent AD diagnosis compared to 7000
controlso 50% increased risk of Alzheimer’s diagnosis if used BZDs in the 5
years prior
o 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
o 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 traumao Recent trauma victims followed for 6 monthso Half treated with BZDs, half noto 69% in benzo group developed PTSD vs 15% in the non-benzo
group
J Clin Psychiatry 1996
• “Harmful in PTSD”o VA/DOD 2010 Evidence Based Clinical Guidelines for PTSDo BZDs moved from “No Benefit” to “Harmful” category
Long term use in anxiety
• Increased healthcare costs in GADo 866 patients with GAD on different treatments followed for 6
monthso Those on BZDs >90 days incurred $2334 more in healthcare
costso More than half due to falls, accidents, and cognitive impairment
BMC Psychiatry 2012
• General anxiety & mood ratingso 2004 meta-analysis, clients on BZDs an average of 10 yearso 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 schizophreniao 2588 schizophrenia patients followed 4 years after 1st
hospitalizationo Significant increase in risk of all-cause mortality for those on
BZDs,including suicides (vs no increased risk for APs or ADMs)
o 90% had early BZD refill or other treatment contract violation
Arch Gen Psychiatry 2012
• Increased BZD use in adolescents with psychosiso 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 rateso 203 dually diagnosed clients followed for 6 years, 50% on BZDso No difference in remission rateso BZDs: worse on BPRS, BPRS-A, and general life satisfaction scales
Psychiatr Serv 2003
• Worse methadone maintenance outcomeso 172 methadone maintenance clients followed for 3 yearso 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