Drugs in Delirium Helpful or Harmful? - PowerPoint Presentation

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Drugs in DeliriumHelpful or Harmful?

Amie Jo Digatono, PharmD, BCPP

October 26, 2017

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Objectives

Describe the impact and pathophysiology of delirium

Identify patients who are at increased risk for delirium

Review the current evidence for medication use in the prevention and treatment of delirium

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Disclosure Statement

Neither I nor my spouse have any relevant financial or non-financial relationships to disclose.

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Key Questions

What role do medications play in the treatment of delirium?

What role

do medications

play in the prevention of delirium in patients hospitalized for illness or surgery?

What medications should we avoid in vulnerable patients to reduce the risk of delirium?

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Patient Case: Introduction

M.S. 56 year old female

PMH: schizoaffective disorder, depression, history of cocaine use disorder (in remission), history of stroke, personality disorder NOS, obesity, hyperlipidemia, and urinary incontinence (neurogenic bladder)

CC: Evening staff report poor cooperation with cares, at times striking out toward staff, mood lability (tearfulness), and increased hallucinations

Current medications: olanzapine 15 mg bid, divalproex EC 750 mg bid, sertraline 50 mg daily, simvastatin 40 mg

qhs

, oxybutynin XL 10 mg daily and diphenhydramine 50 mg q4h PRN anxiety or sleep

M.S. was seen in morning rounds and haloperidol 5 mg bid started for hallucinations

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What is delirium?1

Disturbance in attention

Reduced attention, focus, and ability to shift focus

Disturbance in cognition

Impaired memory, language, orientation or perception

Acute change from baseline

Develops over a short time and may fluctuate over time

Different than dementia

Caused by illness, substance intoxication or withdrawal, or medication

Other features

Hyperactive, hypoactive, and mixed

Mood lability, sleep cycle disruption

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Where is Delirium found?1

HospitalSevere illnessSepsis, infectionsSurgical unitsCardiovascular surgeryAIDS-relatedCancer-relatedICUAIDS: Acquired immunodeficiency syndromeICU: Intensive care unit

Long-term care facilities

Emergency department

Palliative care

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Impact of Delirium1-4

Affects many patients30% older medical patients11-42% patients hospitalized on medical units10-50% older post-surgical patients70% ICU patients42% hospice patients85% terminally ill cancer patientsLonger hospital stays and increased healthcare costsAdd $16,303 to $64,421/delirious patient/year$38-152 billion/year in the U.S.

Results in significant distress for patients and caregivers

Less likely to return to baseline functioning

More long-term care facility placements

Increased rate of decline in patients with dementia

Poorer outcomes

Associated with an increased rate of death

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Pathogenesis2,5

Mechanism unknown, likely multiple mechanisms involved

Neurotransmitter imbalances

Decreased acetylcholine

Excessive dopamine

Endorphins

Serotonin

Norepinephrine

GABA (gamma-aminobutyric acid)

Proinflammatory cytokines

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Risk Factors1,6

Older age (>65 years)

Cognitive impairment

Underlying brain disease

Dementia

Parkinson disease

Stroke

Sensory impairment

Previous episode of delirium

Femoral neck fractures

Severe illness

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Precipitating Factors1,7

InfectionDehydrationElectrolyte imbalancesHypercalcemiaImmobilityUse of restraintsMalnutritionThiamine deficiencyUse of bladder catheters

Pain

Renal failure

Hepatic failure

Respiratory failure

Hypoxia

Hypoglycemia

Substance intoxication or withdrawal

Polypharmacy

Psychoactive drugs

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Patient Case: Review of Risk Factors

M.S. continues to have mood lability and difficulty participating in her cares. Despite escalating doses of haloperidol (up to 30 mg/day), she continues to talk to shadow-people in her room and has been lowering herself to the ground to access the pool.

Evaluated by the evening medical team and diagnosed with delirium

Difficulty following staff directions -> Disturbance in attention

Hallucinations -> Disturbance in cognition (perception)

Acute change, fluctuated over a 24 hour period

Increased irritability and mood lability

What are M.S.’s risk factors for delirium?

History of stroke

Possible previous episode of delirium?

Polypharmacy with psychoactive medications?

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Delirium Treatment Goals7,8

Identify and treat any underlying medical condition or toxicity

Provide supportive cares

Manage agitation

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Non-Pharmacologic Interventions6,8

Provide orientation when neededFacilitate family visits, orientation to date and timeEnsure adequate hydrationProvide adequate nutritionConsider thiamine supplementation in patientsEncourage activity to maintain mobilityMeals up in chair to decrease risk of aspiration

Treat pain

Minimize nighttime disruptions to facilitate sleep

Use planned toileting to reduce incontinence

Assess and treat constipation

Verbal De-escalation

Mild to moderate agitation

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Pharmacologic Agents6,8

No medication that is FDA-approved for treatment of delirium or agitation associated with delirium

Pharmacologic agents may be considered for severe agitation

When verbal de-escalation has failed

What role is there for the following agents in the treatment of delirium?

Antipsychotics

Benzodiazepines

Cholinesterase inhibitors

FDA: Food & Drug Administration

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Cholinesterase inhibitors5,8,9

Uses: Alzheimer disease, Parkinson disease dementia (rivastigmine), Lewy body dementia (off-label)

Mechanism: Increase acetylcholine in the CNS

Examples: rivastigmine, donepezil, galantamine

No role in the treatment of delirium

RCT by van

Eijk

, et al. (2010) studying rivastigmine as add-on to haloperidol in ICU was stopped early due to increased mortality in the rivastigmine group

CNS: central nervous system

RCT: randomized controlled trial

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Antipsychotic Agents2,8,10

Uses: schizophrenia, psychosis, mania, bipolar disorder, depression (adjunct)

Mechanism: block the activity of dopamine at the D2 receptor. Second generation antipsychotics also antagonize serotonin 2A receptors

Examples: haloperidol, risperidone, olanzapine, quetiapine, and aripiprazole

No clear evidence supporting use in literature

Meta-analysis by Neufeld, et al. (2016) found no improvement in outcomes with antipsychotics in either prevention or treatment of delirium.

No difference in 30-day mortality, length of stay, severity or duration of delirium

Outcomes such as patient distress not measured

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Antipsychotic Agents2,6-8,10

Consensus statements and guidelines (e.g. APA, NICE) do support use of antipsychotic medications in certain instances for short duration (≤7 days)

Indications: patients with significant distress due to delirium, who may be at risk of harm to self or others, or whose symptoms interfere with treatment of underlying cause; when verbal de-escalation and non-pharmacologic interventions have failed

Choice of agent

Haloperidol historically has had the most use

Olanzapine, risperidone, chlorpromazine, ziprasidone, & quetiapine have also been studied

Abbreviations

APA: American Psychiatric Association

NICE: National Institute for Health and Care Excellence (U.K.)

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Antipsychotic Agents: Preferred2,6

Haloperidol

Formulations: tablet, oral solution, IM/IV solutionInitial dose: 0.5-1 mgDaily max: 5-10 mg/dayAdverse effects: dystonia, akathisia, parkinsonismAdvantages: minimal anticholinergic side effects and hypotensionDisadvantages: QTc prolongation, avoid in Parkinson diseaseIM: intramuscular IV: intravascular

Olanzapine

Formulations: tablet, orally disintegrating tablet, IM injection

Initial dose: 2.5-5 mg

Daily max: 10 mg

Adverse effects: hypotension, parkinsonism, sedation

Advantages: less dystonia

Disadvantages: more anticholinergic side effects

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Antipsychotic Agents2

Risperidone

Formulations: tablet, oral disintegrating tabletInitial dose: 0.5 mgDaily max: 1 mg/dayAdverse effects: parkinsonism, hypotension, sedationAdvantages: less anticholinergic adverse effects Disadvantages: may cause orthostatic hypotension, not available in a short-acting injection

Quetiapine

Formulations: tablet

Initial dose: 12.5-25 mg

Daily max: 50 mg/day

Adverse effects: hypotension, sedation, agitation

Advantages: may be considered in Parkinson disease

Disadvantages: may cause orthostatic hypotension, injection not available

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Benzodiazepines5,6-8

Uses: anxiety disorders, seizure disorders, sedation, catatonia (off-label), panic disorder (off-label)

Mechanism: increases activity of GABA in CNS to provide anxiolysis and sedation

Examples: lorazepam, diazepam, clonazepam, and midazolam

Limited role in treating delirium

Few studies, less effective or no different from antipsychotic agents in treatment of delirium

May worsen confusion and sedation

Preferred for delirium due to alcohol or benzodiazepine withdrawal

May be considered if antipsychotics are contraindicated, or side effects limit use

Starting dose: lorazepam 0.5-1 mg

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Summary: Medication use in the Treatment of Delirium

Non-pharmacologic interventions are first-line

Consider thiamine supplementation in nearly all patients

Pharmacologic therapy may be considered in severe agitation

Haloperidol is the most studied and most frequently used, but avoid in patients with prolonged QTc

Olanzapine may also be considered as a first line agent

Avoid antipsychotics in patients with Parkinson disease or Lewy Body dementia

Increased sensitivity to movement adverse effects

Use of quetiapine or benzodiazepines may be appropriate

Avoid benzodiazepines in most patients

Preferred for delirium associated with alcohol or benzodiazepine withdrawal

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Patient Case: Treatment

M.S. continued on haloperidol while delirium work-up progressed. She received fluids for slight dehydration. Urinalysis was negative for UTI. Work-up eventually revealed fungal skin infection. Nystatin powder topically to affected areas TID initiated.

Delirium resolved after a few days and M.S. returned to the behavioral health unit. After a few more days, haloperidol was tapered and discontinued.

Was M.S.’s delirium treated appropriately?

Identified and treated underlying condition

Provided supportive care

Antipsychotic medication for delirium tapered

The End ??

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Prevention of Delirium6,8,11

Focused on modifying risk factors and reducing precipitating events

Non-pharmacologic interventions are preferred

Same interventions as for treatment

Geriatric order set

What role is there for pharmacologic agents in the prevention of delirium?

Systematic review by Tremblay and Gold (2016) summarizes evidence for various pharmacological interventions for the prevention of post-operative delirium

Antipsychotics, cholinesterase inhibitors, statins, steroids, gabapentin, benzodiazepines, and melatonin, tryptophan, and ramelteon

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Drugs to prevent delirium: Antipsychotics11

Haloperidol

Most evidence, mix of positive and negative trials

Non-cardiac surgeries

5 mg IV x5 days, IV infusion +/- bolus, 1.5 mg orally x3 days

Risperidone

Two trials in cardiac patients

1 mg orally post-op, 0.5 mg bid

Limited positive outcomes noted

Olanzapine

One trial showed reduced incidence, but increased severity of delirium

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Drugs to prevent delirium8,11,12

GabapentinSmaller, pilot clinical trial900 mg daily x4 daysReduction in post-op delirium & reduction in PCA useBenzodiazepinesOne trial, focused on improvement in sleepDiazepam IM, flunitrazepam IV infusion, and pethidine (meperidine) IV infusionLess delirium, but significant “morning lethargy”

Cholinesterase inhibitors

Donepezil: three trials, no difference found

Rivastigmine: two trials, no difference found

Statins

Observational studies only

Results mixed, possible difference in relation to presence/absence of sepsis

Steroids

One trial in cardiac patients

Dexamethasone 8 mg IV pre- & post-op

Reduction seen post-op day 1 only

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Drugs to prevent Delirium: Melatonin8,11

Melatonin

Hormone produced in pineal gland that plays a role in sleep-wake cycle

Synthesized from tryptophan (via serotonin)

Available over-the-counter as a dietary supplement (not FDA-regulated)

One positive, one negative trial: 3 or 5 mg/day

Minimal adverse effects

Ramelteon

Melatonin agonist approved by FDA for insomnia

No difference seen in post-op patients, trials in patients with medical illness have shown better results

Tryptophan

1 g orally

tid

x9 days studied with no difference seen

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SUMMARY: Medication use in the PREVENTION of Delirium

Despite continued investigation, there is still insufficient evidence to recommend the routine use of any pharmacologic agent for the prevention of delirium in acute medical illness, peri-operative patients, or the ICU

Non-pharmacologic interventions are still first-line

Consider changes to modify risk factors and reduce precipitating events

Polypharmacy in general patient population

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Drugs that may cause or prolong delirium1

Anticholinergics

Antibiotics and antivirals

Steroids

Herbal Medications

Over-the-Counter (OTC) preparations

Hypnotics and Sedatives

Muscle relaxants

Opioids

Antiepileptic agents

Antidepressants

Antihypertensive agents

Dopamine agonists

Antihistamines

Hypoglycemic agents

Non-steroidal anti-inflammatory drugs (NSAIDs)

Psychotropic agents

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Drugs that may cause or prolong delirium1,5

Category

Example

Mechanism

Anticholinergics

Benztropine, scopolamine, tolterodine

Reduced cholinergic activity

Dopamine agonists

Amantadine, levodopa, pramipexole, ropinirole

Increased dopamine activity

Antibiotics

Cefepime, quinolones

GABA antagonism

Linezolid

Serotonergic dysfunction

Antidepressants

Serotonin reuptake inhibitors

Serotonergic dysfunction

Analgesics

NSAIDs

Anticholinergic activity

Fentanyl, hydromorphone, morphine

GABA antagonism

Steroids

Dexamethasone, methylprednisolone

Anticholinergic activity

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Anticholinergic Medications1,5,13

Anticholinergic medications

Primary mechanism of action is blocking effects of acetylcholine

Examples: atropine, benztropine, trihexyphenidyl, scopolamine, tolterodine

More commonly accepted as potentially inappropriate in vulnerable populations (age >65 years)

Medications with anticholinergic side effects

Primary mechanism of action is something else

Anticholinergic properties are considered adverse effects

Examples: amitriptyline, diphenhydramine, hydroxyzine, olanzapine, paroxetine

Still potentially inappropriate, but more difficult to determine risk

Anticholinergic Burden

Seven different expert-based rating scales with high variability, probably oversimplified

Higher anticholinergic burden is associated with cognitive and physical impairment in vulnerable populations

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Anticholinergic Cognitive Burden (ACB) Scale

Available at www.agingbraincare.orgMedications are given a score of 1, 2, or 3Score of 1: In vitro evidenceScore of 2: Evidence of anticholinergic effects from literature, package insert, or expert opinionScore of 3: Evidence of possible delirium from literature, package insert, or expert opinionPotentially unexpected inclusions (Score of 1)Atenolol, digoxin, nifedipine, triamtereneCimetidine, ranitidineBupropion, haloperidol, trazodoneWarfarin

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Drugs to Avoid14

Systematic review by Clegg and Young (2011) identified three classes of medications to avoid in people at risk of delirium

Opioids: moderate quality evidence indicating 2-fold increased risk

Benzodiazepines: moderate quality evidence of increased risk, worse with longer acting agents

Dihydropyridines: low quality evidence, specifically for nifedipine

Additional findings

Digoxin: low quality evidence suggesting no association

Haloperidol: high quality evidence suggesting no association, evidence not as clear for other neuroleptics

Antihistamines: moderate quality evidence showed trend, but not significant, to increased risk

Low quality evidence, uncertain risk: H2-receptor blockers, tricyclic antidepressants, steroids, drugs for Parkinson disease, NSAIDs, and oxybutynin

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Analgesics15

Analgesia and Delirium

Pain can precipitate delirium

Acetaminophen is often not sufficient

NSAIDs carry risk for elderly patients including renal failure and cardiovascular effects

Opioids may have serotonergic, anticholinergic, and GABA antagonistic properties

Comparative Risk of Delirium with Opioids

Swart

, et al. (2017) conducted a systematic review evaluating use in older patients

Compared to no opioid, meperidine and tramadol were associated with increased risk of delirium

Compared to other opioids, only meperidine was associated with increased risk

Morphine, fentanyl, oxycodone, and codeine

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Summary: Medication use in vulnerable populations

Assess risk versus benefit in each case

Use a resource, such as the Anticholinergic Cognitive Burden Scale, to screen medications for anticholinergic activity

Reduce or eliminate (if possible) medications with anticholinergic properties

Risk appears to be more established with benzodiazepines and opioids

Reduce or eliminate (if possible) benzodiazepine and opioids; use tapers

If benzodiazepines or opioids are used, use cautiously and avoid long-acting agents, those with active metabolites, or with serotonergic properties (meperidine, tramadol)

Avoid nifedipine, but not necessarily other calcium channel blockers

More evidence needed to identify other precipitant or protective agents

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Reducing Inappropriate Benzodiazepine use in older patients (EMPOWER Trial)16

Tannenbaum, et al (2014) conducted a cluster randomized trial to test the effects of a direct-to-consumer intervention versus usual care on rates of benzodiazepine use in older adults

65-95 years old, minimum of 5 active prescriptions, benzodiazepine dispensed monthly x3 months

Mean duration of use 9.6 years (intervention group) vs. 11.2 years (control)

Excluded patients with mental illness or dementia, or living in long term care facility

Just less than half of patients had previously attempted tapering

In the intervention group, 62% talked to their physician or pharmacist about stopping benzodiazepine therapy

At 6 months, 27% patients in the intervention group had discontinued use vs. 5% in control group. Dose reduction happened in another 11%

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Patient Case wrap-up

After her second episode(!) of delirium resolved, M.S.’s medications were reviewed. Although reluctant to stop oxybutynin, she agreed to a trial off after a discussion regarding increased risk of delirium. Diphenhydramine was also discontinued and melatonin 3 mg nightly was started.

Nursing staff increased frequency of skin monitoring and the next discovery of infection was not accompanied by delirium.

What strategies for delirium prevention were employed?

Engaged patient in decision making

Increased monitoring for infection (avoid precipitating factor)

Decreased anticholinergic burden

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Questions?

amie.digatono@allina.com

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references

Francis J, Jr, and Young GB. Diagnosis of delirium and confusional states.

Wilterdink

JL, ed. UpToDate. Waltham, Ma: UpToDate Inc.

http://www.uptodate.com

Accessed Sept 21, 2017.

Thom RP, Mock CK,

Teslyar

P. Delirium in hospitalized patients: Risks and benefits of antipsychotics. Cleveland Clinic J Med 2017; 84(8):616-622.

Fong TG, Davis D,

Growdon

ME, Albuquerque A, Inouye SK. The Interface of delirium and dementia in older persons. Lancet

Neurol

2015; 14(8):823-832.

Breitbart W and

Alici

Y. Evidence-based treatment of delirium in patients with cancer. J

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Devlin JW (2016). Delirium in Critically Ill Adults. In: B.

Erstad

(Ed.),

Critical Care Pharmacotherapy

(pp. 186-197). Lenexa, KS: American College of Clinical Pharmacy.

National Institute for Health and Care Excellence (NICE). Delirium: prevention, diagnosis, and management.

www.nice.org.uk/guidance/cg103

. Accessed Sept 23, 2017.

Trzepacz

P, Breitbart W, Franklin J, Levenson J, Martini DR, Wang P; American Psychiatric Association (APA). Practice guideline for the treatment of patients with delirium.

http://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/delirium.pdf

Accessed Sept 23, 2017.

Francis J, Jr. Delirium and acute confusional states: Prevention, treatment, and prognosis.

Wilterdink

JL, ed. UpToDate. Waltham, Ma: UpToDate Inc.

http://www.uptodate.com

Accessed Sept 21, 2017.

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Refences (continued)

van

Eijk

MMJ, Roes KCB, Honing MLH, Kuiper MA,

Karakus

A, van der

Jagt

M,

Spronk

PE,

Gool

WA, van der Mast RC,

Kesecioglu

J,

Slooter

AJ. Effect of rivastigmine as an

adjunt

to usual care with haloperidol on duration of delirium and mortality in critically ill patients: a multicenter, double-blind, placebo-controlled randomized trial. Lancet 2010; 36:1829.

Neufeld KJ, Yue J, Robinson TN, Inouye SK, Needham DM. Antipsychotics for prevention and treatment of delirium in hospitalized adults: a systematic review and meta-analysis. J Am

Geriatr

Soc

2026; 64(4):705-714.

Tremblay P and Gold S. Prevention of post-operative delirium in the elderly using pharmacological agents. Can

Geriatr

J 2016; 19(3):113-126.

Tsuruta

R and Oda Y. A Clinical perspective of sepsis-associated delirium. J

Intens

Care 2016; 4:18. DOI 10.1186/s40560-016-0145-4

Salahudeen

MS,

Duffull

SB,

Nishtala

PS. Anticholinergic burden quantified by anticholinergic risk scales and adverse outcomes in older people: a systematic review. BMC Geriatric 2015; 15:31. DOI 10.1186/s12877-015-0029-9

Clegg A and Young JB. Which medications to avoid in people at risk of delirium: a systematic review. Age Aging 2011; 40:23-29.

Swart

LM, van der

Zanden

V, Spies PE, de

Rooij

SE, van Munster BC. The Comparative risk of delirium with different opioids: a systematic review. Drugs Aging 2017; 34:437-443.

Tannenbaum C, Martin P, Tamblyn R, Benedetti A, Ahmed S. Reduction of inappropriate benzodiazepine prescriptions among older adults through direct patient education: the EMPOWER cluster randomized trial. JAMA Intern Med 2014; 174(6):890-898.

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