“When Sleep Plays Coy”

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“When Sleep Plays Coy”*

The Management of Insomnia in Hospice CareBy: Joelle Potts, PharmD, BCGP

July 9th & 10th, 2019

*From “Insomniac” by Maya Angelou

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The planners and presenters (spouse/domestic partner) of this educational activity have disclosed no healthcare related conflicts of interest, commercial interest, or have any related financial relationships/support.

The material in this presentation is for informational and educational purposes only and is not a substitute for medical advice, diagnosis, or treatment provided by a qualified health care provider. All information contained in this presentation is protected by copyright and remains the property of ProCare HospiceCare. All rights are reserved.

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Objectives

Review the physiology of sleep vs. wakefulness and “normal” sleep aswell as the types of sleep disorders

Identify common causes of insomnia and/or disrupted sleep, focusingon those most relevant to the elderly and hospice populations

Describe non-pharmacologic measures to improve sleep, including“sleep hygiene” practices

Evaluate pharmacologic therapies that can be used for sleep,emphasizing those most commonly used and/or appropriate forhospice patients

The Physiology of Sleep vs. Wakefulness: Homeostatic System

Homeostasis = balance, equilibrium

AKA sleep/wake restorative process – balances sleep and wakefulness

Appears to control NREM (non-rapid eye movement) and slow wave sleep(stages 3 and 4)

Sleep is a primary drive

Adenosine

Induces sleepiness; levels accumulate the longer you’re awake

Effects blocked by caffeine

Winter WC. Kryger M, Kryger E. Mystakidou K, et al.


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The Physiology of Sleep vs. Wakefulness: Circadian System

AKA day-night cycle, sleep-wake rhythm – regulates timing of sleepand wakefulness

Affects the distribution of REM sleep

Suprachiasmatic Nucleus (SCN) = biological clock, circadianpacemaker of the brain

SCN wakefulness drive counteracts the homeostatic drive’s dip inalertness in the afternoon

Affected by light and dark; synchronized by light

Melatonin induces sleepiness

Produced in conditions of darkness… darkness signals retinal cells suprachiasmatic nucleus (SCN) pineal gland releases melatonin

Dopp JM, Phillips BG. Kryger M, Kryger E. Mystakidou K, et al. Winter WC.

Stages of Sleep

Dopp JM, Phillips BG. Mystakidou K, et al. Bubble diagram from Winter WC. Hypnogram from Neubauer DN.

Awake

Dream

Sleep

Dream (REM) Sleep

DeepSleep

Light Sleep

REM (rapid eye movement) vs. NREM (non-rapid eye movement)

4 Stages of NREM sleep

Stage 1: Stage between wakefulness and asleep

Stage 3 and 4: Metabolic activity and brain waves slow, AKA delta sleep orslow-wave sleep


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Other Neurochemistry Involved

NREM sleep: Mediated by GABA and adenosine

REM sleep

Turned on by cholinergic cells

Turned off by dorsal raphe nucleus, locus coeruleus, and nucleusparabrachialis lateralis (the latter two are primarily noradrenergic)

Dopamine has an alerting effect; decreases in dopamine promotesleepiness

Wakefulness

Norepinephrine and acetylcholine

Histamine and neuropeptides (e.g. substance P) and corticotropin-releasing factor

Dopp JM, Phillips BG.

Changes in the Elderly that Contribute to Insomnia

Measurable changes in sleep/sleepcycle

Decrease in total sleep time, sleepefficiency, REM sleep, NREM slow-wave sleep

Increase in time awake after sleeponset (time awake in bed), Stage 1and Stage 2 NREM sleep

Roth T, Saffel D. Hypnogram from Neubauer DN.


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Changes in the Elderly that Contribute to Insomnia, continued

Physiological/chemical changes

Age-related changes in the Suprachiasmatic Nucleus (SCN), the circadianpacemaker

Increase in Orexin A as we age – wakefulness transmitter

Older people tend to go to sleep and wake earlier (Advanced Sleep-Phase Syndrome)

Increased prevalence in insomnia-causing conditions (e.g. prostate, hipimpairment, pulmonary disease/obstructive sleep apnea,depression/late-life stressors)

Do we need less sleep as we age?

National Sleep Foundation recommends 7-9 hours of sleep for young adults(18-25) and adults (26-64), and 7-8 hours of sleep for older adults (65+)

Roth T, Saffel D. Kryger M, Kryger E.

Sleep Disorders Per DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, 5th Edition)

Insomnia disorder

Hypersomnolence disorder

Narcolepsy

Breathing-related sleep disorders (e.g. central sleep apnea, obstructive sleepapnea)

Circadian rhythm sleep disorders (e.g. jet lag, shift work sleep disorder)

Non-REM sleep arousal disorders

Nightmare disorder

REM sleep behavior disorder

Restless legs syndrome (RLS)

Substance- or medication-induced sleep disorder



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Insomnia

Defined as difficulty falling asleep, difficulty staying asleep, and/orhaving non-restorative sleep

Is subjective

Primary insomnia vs. secondary/comorbid insomnia

Prevalence:

Approx. 30% of adults report one or more of these symptoms above

In chronically ill non-cancer patients: more common in women and olderadults

In cancer patients: more common in younger patients; those with breastand lung cancer have higher rates of sleep disturbances

Other chronic diseases associated with sleep disturbances: HIV/AIDS,COPD, liver disease, degenerative brain diseases (e.g. Alzheimer’s)

Dopp JM, Phillips BG. Mystakidou K, et al.

Common Etiologies of Insomnia

Situational

Work/financialstress, major lifeevents, interpersonalconflict

Jet lag, shift work

Medical

Cardiovascular(arrhythmias,angina, heart failure)

Respiratory (asthma,sleep apnea)

Chronic pain

Endocrine disorders(diabetes,hyperthyroidism)

GI (GERD, ulcers)

Neurologic (delirium,epilepsy, Parkinson’s)

Pregnancy

Psychiatric

Mood disorders(depression, mania)

Anxiety disorders(e.g. GAD, OCD)

Substance abuse(alcohol or sedative-hypnotic withdrawal)



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Common Etiologies of Insomnia, continued: Pharmacologically Induced

Anticonvulsant – e.g. lamotrigine

Central adrenergic blocker – e.g. beta-blockers: metroprolol, propranolol,sotalol

Diuretics

SSRI antidepressant – e.g. citalopram, fluoxetine, fluvoxamine,venlafaxine, paroxetine

Steroids

Stimulants – e.g. methylphenidate, theophylline, caffeine

Others: donepezil, clonidine, pseudoephedrine, ciprofloxacin, levofloxacin

Dopp JM, Phillips BG. Foral P, Knezevich J, Dewan N, Malesker M. LexiComp drug monographs.

Non-Pharmacologic Measures: Stimulus Control

Establish regular sleep and wake times (including weekends)

Sleep only as much as needed to feel rested

Use the bed only for sleep or intimacy

Go to bed only when sleepy, avoid long periods of wakefulness in bed

Do not read or watch TV in bed; don’t use the bed for working or lounging

Dopp JM, Phillips BG. Winter WC. Patel D, et al.


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Non-Pharmacologic Measures: Stimulus Control, continued Avoid trying to force sleep

If you do not fall asleep within 20-30 minutes, get up and perform arelaxing activity until drowsy. Repeat as often as necessary.

But… Note that the 20-30 minute rule is somewhat arbitrary and cancause stress/anxiety; there are benefits to simply “resting” in bed, key isnot becoming anxious about not sleeping. If it is consistently taking youlonger than 20-30 minutes to fall asleep, you’re likely going to bed tooearly and should go to bed later.

Avoid blue spectrum light from devices (including television)

Avoid daytime naps; may take a brief (20-30 minute) nap, early inthe day

Schedule worry time during the day; do not take your troubles tobed


Non-Pharmacologic Measures: Sleep Hygiene Exercise routinely

3-4 times weekly, but at least 6 hours before bedtime

Create comfortable sleep environment

Avoid temperature extremes, loud noises, illuminated (and/or ticking) clocks inthe bedroom

Cooler environmental temperatures typically contribute to higher-quality sleep

Discontinue or reduce use of alcohol, caffeine, and nicotine

Avoid drinking large amounts of liquid in the evening, to prevent overnighttrips to the bathroom

Do something relaxing and enjoyable before bedtime



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Other Non-Pharmacologic Measures

Hot bath or shower before bed improved sleep quality

Exposure to green spaces and nature – found to improve sleep,especially in men

Sleep restriction

Restrict time in bed to the number of hours of actual sleep (i.e. to theamount of sleep needed), until sleep efficiency improves

If sleep efficiency remains lower than 85% after 10 days, restrict sleeptime in bed by 15-30 minutes until sleep efficiency improves; time in bedis gradually increased by 15-30 minutes when time asleep exceeds 85% oftotal time in bed

Winter WC. Roth T, Saffel D. Patel D, et al.

Other Non-Pharmacologic Measures, continued

Relaxation techniques

E.g. progressive muscle tensing/relaxing, guided imagery, paceddiaphragmatic breathing, meditation

Appropriate use of light vs. dark…

To combat Advanced Sleep-Phase Syndrome (ASPS)… Many elderly peoplesit in darkened houses/rooms in the evening; encourage them to sit inlight in the evening as appropriate

If getting to sleep is a problem… Keep environment dim at the end of theday

Once in bed, make room as dark as possible/safe/appropriate; ifnightlights are needed, keep them out of line of vision

Winter WC. Roth T, Saffel D. Patel D, et al.


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Non-Pharmacologic Measures: Cognitive Behavioral Therapy for Insomnia (CBT-I or CBTI)

Targets factors that perpetuate insomnia over time (e.g. dysregulationof sleep drive, sleep-related anxiety, sleep-interfering behaviors)

Based on elements of sleep hygiene and behavior modification

vs. sleep hygiene alone… which has been found to be less effective thanCBT-I in studies

First-line therapy for all forms of insomnia, for all patients

Per the Guidelines of the Agency for Healthcare Research and Quality(2014) and American College of Physicians (ACP) (2016), and the AmericanAcademy of Sleep Medicine (AASM)

ACP cautiously recommends adding pharmacologic therapy when CBT-I isunsuccessful

Schroeck JL, et al. Mitchell MD, et al. Chung KF, et al. Sateia MJ, et al.

Non-Pharmacologic Measures: CBT-I Data Overall: CBT-I is at least as effective when compared to sleep medications,

and effects may be more durable than medications

Can improve time to sleep onset and time awake after sleep onset

CBT-I has greater effect on subjective measures of sleep than on objectivemeasures (e.g. polysomnography, actigraphy) – but insomnia can be a highlysubjective problem

Studies demonstrate the long-term effectiveness of CBT-I and itssuperiority over medications (benzodiazepines and non-benzodiazepines);appears to be more effective than medications at 6-12 months aftertreatment is complete

The downside:

Conflicting data re: short-term effectiveness of CBT-I vs. medications(benzodiazepines, zolpidem, zopiclone) at 4 to 8 weeks; more research needed

Improvements typically not seen until 3-4 weeks into treatment

Schroeck JL, et al. Mitchell MD, et al.


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Drug Treatments

Terminology/Measures of Sleep Quality

Sleep-onset latency (or sleep latency) = the length of time it takes totransition from full wakefulness to sleep (following bedtime)

Sleep maintenance = the ability to stay asleep, measured by totalsleep time

Total sleep time = the total time asleep after sleep onset

Quality of sleep = subjective, patient-reported measure; definitioncan vary by measurement tool and patient perceptions

Schroeck JL, et al. Sateia MJ, et al.


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Benzodiazepines

FDA-approved for treatment of short-term insomnia:

temazepam (Restoril®)

triazolam (Halcion®)

flurazepam

quazepam (Doral®)

estazolam

Mechanism of action: Bind to GABA receptors in CNS, inhibitingneuronal excitation

Generally: Reduce time to REM sleep, shorten sleep-onset latency, anddecrease nocturnal awakenings

Schroeck JL, et al. PL Detail-Document.

Benzodiazepines, continued Elderly have increased sensitivity to benzodiazepines d/t changes in the

GABA neurotransmitter system, and d/t age-related changes inpharmacokinetics and pharmacodynamics

Elderly are more predisposed to ataxia, sedation, and cognitive impairment

All except temazepam have prolonged elimination half-life in elderly

Flurazepam and quazepam have long half-life and active metabolites – avoid inelderly

Triazolam, estazolam, and temazepam do not have clinically significant activemetabolites

“LOT” drugs are preferred in elderly: Lorazepam, Oxazepam, Temazepam

Can develop physical dependence, and/or have rebound/withdrawalsymptoms with discontinuation, especially with high doses; increased riskof falls

2019 AGS Beers Criteria® Update: Generally avoid in elderly

Schroeck JL, et al. PL Detail-Document. 2019 Beers Criteria® Update. Kryger M, Kryger E.


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Benzodiazepines, FDA-Approved for Insomnia, continued

Temazepam (Restoril®)

Onset of action: approx. 1 hour

Duration: 6-10 hours

Improves sleep onset and maintenance

Triazolam (Halcion®)

Onset of action: within 30 minutes

Duration: 2-5 hours

Improves sleep-onset latency

Not first-line d/t potential for rebound insomnia, anterograde amnesia,psychological dependence, anxiety


Benzodiazepines, FDA-Approved for Insomnia, continued

Estazolam

Onset of action: 1-2 hours


Specific use: Sleep onset and maintenance

Flurazepam and Quazepam (Doral®)

Onset of action: 1-2 hours


Specific use: Sleep onset and maintenance

Long half-life and active metabolites, avoid in elderly



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Benzodiazepines Used Off-Label for Insomnia: Lorazepam (Ativan®), Oxazepam

Lorazepam

Onset of action: approx. 30 minutes

Typically used for secondary insomnia (e.g. d/t anxiety)

Improves sleep maintenance, not sleep onset

Oxazepam

Onset of action: 30-60 minutes

May be effective for sleep-onset insomnia

Duration of effect for insomnia: unclear

PL Detail-Document.

Nonbenzodiazepine GABAA Agonists (non-BzRAs, a.k.a. “Z” Drugs) Zolpidem (Ambien®), zaleplon (Sonata®), eszopiclone (Lunesta®)

GABA receptor complex = multicomponent, transmembranereceptor with multiple binding sites

GABAA complex is the major inhibitory receptor in the CNS; isassociated with sedation, anxiolysis, muscle relaxation,amnesia, and other cognitive effects

Lexicomp drug monographs. Schroeck JL, et al. Image from: Jacob TC, Moss SJ, Jurd R. GABAA receptor trafficking and its role in the dynamic modulation of neuronal inhibition. Nature Reviews Neuroscience. May 1, 2008; 9: 331-343.

Is composed of 5 subunits (α, β, and γ), with each subunit appearing toproduce a drug’s unique pharmacologic effects…. The α1 subunit mediates sedation/hypnotic effects; α2, α3, and α5 subunits mediate anxiolyticpathways; several different receptors control anticonvulsant, ataxic, muscle-relaxing effects

Benzodiazepines bind nonselectively to GABAA α subunits; the non-BzRAsbind more selectively to the α1 subunits


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Non-BzRAs: FDA Adds Boxed Warning

April, 2019 -- For zolpidem, zaleplon, and eszopiclone

Can cause complex sleep behaviors, including sleepwalking, sleepdriving, and engaging in other activities while not fully awake – hasresulted in serious injuries and fatalities

Incidents can occur after first dose or after longer period of use, inpatients without any prior history of these behaviors, and even at thelowest recommended doses

Adding contraindication against use of these drugs in patients whohave experienced such an episode after taking them

Brooks M.

Non-BzRAs: Zolpidem (Ambien®)

Mechanism of action: Short-acting, GABAA α1-selective, with lesseraffinity for α2 and α3 receptors

Decreases sleep-onset latency and improves total sleep time in elderly

Dosage forms: IR tablet, ER tablet, SL tablet, oral spray

Maximum recommended dose of 5mg in females or elderly

Onset: 30 minutes

Duration (for IR, ER, oral spray, Edluar® SL tab): approx. 8 hours

Intermezzo® SL tab: approx. 4 hours

2019 Beers Criteria® Update: Avoid in elderly

Cost: Average for generic zolpidem IR tablets is approx. $2.60 per tablet,although can vary widely; other dosage forms can be significantly higher

Lexicomp zolpidem monograph. Schroeck JL et al. PL Detail-Document. 2019 Beers Criteria® Update.


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Non-BzRAs: Zaleplon (Sonata®)

Mechanism of action: Binds selectively to the GABAA α1 subunit

Improves sleep-onset latency and sleep quality

Caution in liver impairment

Onset: 30 minutes

Duration: approx. 4 hours

Shortest duration of all the “Z” drugs; can be used for nighttime wakeningif more than 4 hours of potential sleep remain

Rebound insomnia more likely with higher doses


Cost: approx. $3.70 per capsule (for generic)

Lexicomp zaleplon monograph. Schroeck JL et al. PL Detail-Document. 2019 Beers Criteria® Update.

Non-BzRAs: Eszopiclone (Lunesta®) Mechanism of action: Precise mechanism unknown; thought to result from

interaction with GABA-receptor complexes close to benzodiazepinereceptors Active metabolite contributes to sleep induction and maintenance effects

1mg dose improves sleep-onset latency; 2mg dose improves sleep-onsetlatency and sleep maintenance Typical adult dosing: 1mg PO immediately before bedtime, may be increased

to 2mg or 3mg

In elderly or debilitated patients, or concurrent use with strong CYP3A4inhibitors: maximum dose is 2mg

Onset: 30 minutes



Cost: approx. $12 per tablet (for generic; regardless of strength)

Lexicomp eszopiclone monograph. Schroeck JL et al. Eszopiclone Prescribing information. PL Detail-Document. 2019 Beers Criteria® Update.


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Melatonin Receptor Agonist: Ramelteon(Rozerem®) Mechanism of action: Selective agonist of melatonin receptors MT1 and MT2

in the SCN of the hypothalamus

MT1 induces sleepiness, MT2 influences regulation of circadian rhythms; is moreselective for MT1 vs. MT2 and has a higher affinity for MT1 than melatonin

Longer half-life than melatonin

Improves sleep-onset latency

Onset: 30 minutes


Some cautions with liver impairment (not recommended in severeimpairment)

Minimal ADEs; no withdrawal effects or rebound insomnia vs. placebo

Cost: approx. $15.50 per tablet (for brand, not available generically)

Lexicomp ramelteon monograph. Schroeck JL, et al. PL Detail-Document.

Orexin Antagonist: Suvorexant(Belsomra®) Mechanism of action: Blocks wake-promoting neuropeptides orexin A

and B, which is thought to inhibit activation of the arousal system andsuppress wake drive

Improves sleep induction and maintenance

Onset: 30 minutes


Requires minimum of 7 hours of planned sleep

Minimal ADEs; no rebound or withdrawal effects noted whendiscontinued

Cost: approx. $14 per tablet (for brand, not available generically;regardless of strength)

Lexicomp suvorexant monograph. Schroeck JL, et al. PL Detail-Document.


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Antidepressants

Typically used when patient has comorbid depression, or when otheroptions have failed

Sedating d/t antihistamine, anticholinergic, serotonin, and/oradrenergic antagonism activities

Lack data from randomized trials re: use in primary insomnia (exceptdoxepin)

Schroeck JL, et al.

Antidepressants: Trazodone (Desyrel®) Off-label use for insomnia

Mechanism: Serotonin reuptake inhibitor/antagonist; 5HT2a receptorantagonist; also blocks histamine (H1) and alpha1-adrenergic receptors

Has low anticholinergic activity vs. doxepin

Improvement in total sleep time, sleep efficiency, sleep continuity,number of awakenings; prolongs slow-wave sleep (including stages 3 and4); prolongs REM latency without affecting the proportion of REM sleep

In Alzheimer’s patients: Improved total sleep time and nighttime percentageof sleep vs. placebo

More data on its efficacy for secondary insomnia (i.e. d/t depression) vs.primary insomnia

Onset: 30-60 minutes

Duration: Unclear; half-life prolonged in elderly

Dose can be titrated q3-4 days (d/t relatively short half-life)

Schroeck JL, et al. PL Detail-Document. Lexicomp trazodone monograph.


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Antidepressants: Mirtazapine (Remeron®) Off-label use for insomnia

Mechanism: Central presynaptic alpha2-adrenergic antagonist effects increase therelease of norepinephrine and serotonin; potent antagonist of 5-HT2 and 5-HT3serotonin receptors and H1 histamine receptors; moderate alpha1-adrenergic andmuscarinic antagonist; also enhances noradrenergic neurotransmission whichincreases the synthesis of melatonin Has low anticholinergic activity vs. doxepin

Lower doses cause more sedation, can also increase appetite

Improves sleep-onset latency, sleep maintenance, and total sleep time (reducesnighttime awakenings)

Onset: Not available Steady state achieved after approx. 5 days of treatment

In one study: Improvements as early as 2 weeks after initiation

Increased risk of RLS

2019 Beers Criteria® Update: Use with caution in elderly, may exacerbate or causeSIADH or hyponatremia (monitor sodium levels when initiating or changing doses)

Schroeck JL, et al. PL Detail-Document. Lexicomp mirtazapine monograph. 2019 Beers Criteria® Update.

Tricyclic Antidepressants: Doxepin (Silenor®)

Silenor® (3-6mg dose) has FDA-approved indication for primary insomnia

Also available as Sinequan® (10mg and higher): FDA-approved indication fordepression, off-label use for insomnia and chronic urticaria

Mechanism: At low doses (3-6mg): Histamine antagonist (specifically H1);high selectivity for histamine receptors, and little to no effect onserotonin and adrenergic receptors

Anticholinergic side effects (at higher doses)

Improves sleep maintenance; increases total sleep time by approx. 30minutes

Onset of action: 30 minutes

Duration of effect: Unclear

2019 Beers Criteria® Update: Avoid doses higher than 6mg/day in theelderly; safety profile of doses <6mg/day comparable to placebo

Schroeck JL, et al. PL Detail-Document. Lexicomp doxepin monograph. 2019 Beers Criteria® Update.


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Tricyclic Antidepressants: Amitriptyline(Elavil®) Off-label for insomnia

Mechanism: Inhibits reuptake of serotonin and/or norepinephrine in CNS

Onset: unclear

Duration: unclear

Limited studies re: efficacy for insomnia, especially in elderly population

No longer recommended for insomnia d/t availability of newer agents andmeds with fewer ADEs

Anticholinergic adverse effects, can cause orthostatic hypotension

Increased half-life and reduced clearance in elderly (increasing risk of ADEs)


Bottom line… Not recommended for insomnia

Schroeck JL, et al. 2019 Beers Criteria® Update. LexiComp amitriptyline monograph.

Other Prescription Drugs: Antipsychotics E.g. haloperidol (Haldol®), quetiapine (Seroquel®), risperidone

(Risperdal®), olanzapine (Zyprexa®), ziprasidone (Geodon®)

Some typical (1st generation) antipsychotics are highly sedating (e.g.chlorpromazine, clozapine, thioridazine) – but haloperidol is about as sedatingas most atypical (2nd generation) antipsychotics

Olanzapine and quetiapine are the most sedating of the atypicals (and moresedating than haloperidol)

Mechanism: Sedating effects appear related to affinity for histamine H1and serotonin type 2A receptors in CNS (varies among the meds)

Often used in patients with insomnia –AND- behaviors, major depressivedisorder, or an organic brain syndrome

Very limited data re: use in insomnia alone


General consensus: Don’t use for insomnia/sleep effects alone, asbenefits don’t outweigh the risksSchroeck JL, et al. Lexi-Drugs Comparison of Antipsychotic Adverse Effects [table]. Mystakidou K, et al. 2019 Beers Criteria® Update.


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Other Prescription Drugs: Gabapentin(Neurontin®)

May be helpful for patients with insomnia –AND- restless legs syndrome(RLS) (off-label use) or chronic neuropathic pain

Mechanism: Structural analog of GABA, but does not bind to GABAA orGABAB receptors or appear to influence synthesis or uptake of GABA;interacts with presynaptic alpha2-delta1 subunit on voltage-gated calciumchannels, appears to modulate release of excitatory neurotransmitters

Drowsiness is common ADE

Renal dosing required

Not typically used for insomnia/sleep effects alone

Schroeck JL, et al. Lexicomp gabapentin monograph.

OTC Sleep Aids: Antihistamines Diphenhydramine (Benadryl®; also found in many “PM” products);

doxylamine

Mechanism: First-generation antihistamines (H1-receptor antagonists)

Can have anticholinergic ADEs: dry eyes/mouth, blurred vision, constipation,urinary retention, confusion/memory impairment, orthostatic hypotension,tachycardia

Can cause psychomotor impairment, dizziness, incoordination in elderly

Onset

Diphenhydramine: 30-60 minutes

Doxylamine: 30 minutes


Limited evidence on safety and efficacy when used for insomnia

Tolerance can develop with regular use

Schroeck JL, et al. PL Detail-Document. Kryger M, Kryger E. 2019 Beers Criteria® Update.


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OTC Herbal Supplements: Melatonin

Mechanism of action (endogenous): Hormone produced by the pinealgland, released at night; binds to MT1 and MT2 receptors in SCN, resultingin suppression of neuronal activity

Production is controlled by light -- inhibited by environmental light andstimulated by darkness. Duration of melatonin production varies throughoutthe year (shorter during the summer and longer during the winter).

Secretion starts at approx. 9pm; levels rise during evening hours, peak in themiddle of the night (2-3am), and remain low during the day

In elderly…

Peak melatonin levels tend to decrease with advanced age, d/t decreasedsecretion at night and altered hormone regulation (via renal/hepaticchanges, body composition changes) increasing risk for conditions relatedto circadian rhythms

Other possible causes of decreased endogenous melatonin levels:

Cancer, mood disorders, decreased renal function, medications

Schroeck JL, et al. Davis L. Natural Products Database melatonin monograph.

OTC Herbal Supplements: Melatonin, continued Melatonin supplements can mimic the function of endogenous melatonin

Evening administration: Advances circadian rhythm and induces sleep onset

Recommended dosing: Use lowest possible dose (maximum of 1-2mg inelderly; 3-5mg in non-elderly), given 1 hour before bedtime

Melatonin supplements increase endogenous melatonin in a dose-dependentmanner; 0.3mg dose produces supraphysiological levels in older adults; higherdoses can cause prolonged elevated melatonin levels and possiblydesensitization/loss of effectiveness, may regain effectiveness at lower doses

Avoid controlled-release forms in older adults

Conflicting results re: efficacy of melatonin supplementation in studies; isgenerally well tolerated; sedative effects can last for up to 7 hours, maycause residual daytime sedation

Schroeck JL, et al. Davis L. Kryger M, Kryger E. Natural Products Database melatonin monograph.


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AASM 2017 Guideline for Pharmacologic Treatment of Chronic Insomnia in Adults (Summary of Recommendations)

Drug (Trial Dose) Sleep Onset Insomnia Sleep Maintenance Insomnia

temazepam (15mg) X X

triazolam (0.25mg) X

zolpidem (10mg) X X

zaleplon (5mg, 10mg) X

eszopiclone (2mg, 3mg) X X

ramelteon (8mg) X

doxepin (3mg, 6mg) X

suvorexant (10mg, 15/20mg, 20mg) X

Sateia MJ, et al.

This table is an excerpt of recommendations, does not include here drugs that are “notrecommended for either”

Guidelines are for general adult population (not hospice-specific); also note dosesstudied

AASM used the GRADE approach (Grades of Recommendation, Assessment, Development,and Evaluation) to assess the quality of evidence (i.e. strength of evidence in publisheddata) -- all of their recommendations have a “weak” GRADE strength.

American Geriatrics Society (AGS) Beers Criteria®

“Intent of Criteria: …The criteria are intended for use in adults 65years and older in all ambulatory, acute, and institutionalized settingsof care, except for the hospice and palliative care settings.[emphasis added] …The intention of the AGS Beers Criteria® is toimprove medication selection; educate clinicians and patients; reduceadverse drug events; and serve as a tool for evaluating quality ofcare, cost, and patterns of drug use of older adults. … the goal of the2019 update continues to be improving the care of older adults byreducing their exposure to PIMs [Potentially InappropriateMedications] that have an unfavorable balance of benefits and harmscompared with alternative treatment options. …The AGS BeersCriteria® are not meant to be applied in a punitive manner.Prescribing decisions are not always clear-cut, and clinicians mustconsider multiple factors, ….”2019 Beers Criteria® Update.


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AGS Beers Criteria®: Drugs to Be Avoided (Summary)

Benzodiazepines (includes: estazolam, lorazepam, oxazepam,temazepam, triazolam, flurazepam, quazepam)

Elderly have increased sensitivity and decreased metabolism of long-actingagents; in general, all increase risk of cognitive impairment, delirium, falls,fractures, and motor vehicle crashes in older adults; may be appropriate forseizures, REM sleep behavior disorder, benzodiazepine or ethanolwithdrawal, severe GAD, periprocedural anesthesia

Non-BzRAs (“Z” drugs: zolpidem, zaleplon, eszopiclone)

ADEs similar to benzodiazepines in older adults (e.g. delirium, falls,fractures); increased ED visits/hospitalizations; motor vehicle crashes;minimal improvement in sleep latency and duration

2019 Beers Criteria® Update.

AGS Beers Criteria®: Drugs to Be Avoided (Summary),continued

Anticholinergics (diphenhydramine (PO), doxylamine)

Highly anticholinergic, clearance reduced with advanced age; use insituations such as acute treatment of severe allergic reaction may beappropriate

Antidepressants (doxepin >6mg/day; amitriptyline)

Highly anticholinergic, sedating, cause orthostatic hypotension; safetyprofile of low-dose doxepin (<6mg/day) is comparable to that of placebo

Antipsychotics, 1st and 2nd generation (haloperidol, quetiapine,risperidone, olanzapine, ziprasidone)

Avoid, except in schizophrenia or bipolar disorder, or for short-term use asantiemetic during chemotherapy; increased risk of CVA/stroke, greater rateof cognitive decline and mortality in dementia

2019 Beers Criteria® Update.


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Quiz Question #1 M.A., 68-year-old female hospice patient with breast cancer and hypothyroidism;

reports insomnia – specifically difficulty getting to sleep, states she “can’t turn hermind off” when she lays down at night; she is worried about the relationship betweenher two daughters who are estranged from each other and what will happen to thefamily once she is gone; patient’s pain is very well controlled; prognosis is likelyapprox. 5-6 months; husband is primary caregiver and is with her 24/7, excellentmonitoring; she has not yet tried anything for insomnia.

Medications: morphine ER 15mg po BID; morphine 20mg/mL 5-10mg po q2h PRNpain/sob; prochlorperazine 5-10mg po q6h PRN n/v; senna-S 1 tab po BID;levothyroxine 50mcg po qam

Which of the following would be the BEST option(s) to consider at this time?

A) Ramelteon (Rozerem®)

B) Lorazepam

C) Gabapentin

D) Non-pharmacologic measures such as meeting with social worker and/or chaplain, worry-journaling, meditation, etc.

E) B and D

Quiz Question #1 M.A., 68-year-old female hospice patient with breast cancer, and hypothyroidism;





B) Lorazepam

C) Gabapentin

D) **Non-pharmacologic measures such as meeting with social worker and/or chaplain,worry-journaling, meditation, etc.**

E) B and D


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Quiz Question #1 M.A., 68-year-old female hospice patient with breast cancer, and hypothyroidism;





B) Lorazepam

C) Gabapentin

D) **Non-pharmacologic measures such as meeting with social worker and/or chaplain,worry-journaling, meditation, etc.** --OR--

E) **B and D**

Quiz Question #2 J.K., 76-year-old male hospice patient with COPD and BPH; patient states that he

is having trouble sleeping at night, especially staying asleep; wife reports thatpatient seems sad and depressed lately; breathing and BPH symptoms are well-managed on current regimen and patient denies pain; patient does not havedementia; patient has not tried an antidepressant in the past; prognosis is approx.3 months.

Medications: albuterol/ipratropium neb 1 vial inh 4 times daily; albuterol neb0.083% 1 vial inh q4h PRN sob/wheezing; albuterol HFA inhaler 90mcg 2 puffs inhq4h PRN sob/wheezing, when away from home; prednisone 5mg po qam;morphine 20mg/mL 5mg po/sl q2h PRN pain/sob; lorazepam 0.5mg 1 tab po q4hPRN anxiety/sob; tamsulosin 0.4mg po once daily; senna-S 1 tab po BID PRNconstipation


A) Melatonin

B) Trazodone

C) Zolpidem (Ambien®)

D) Non-pharmacologic measures such as meeting with a social worker and/or chaplain

E) B and D


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Quiz Question #2 J.K., 76-year-old male hospice patient with COPD and BPH; patient states that he

is having trouble sleeping at night, especially staying asleep; wife reports thatpatient seems sad and depressed lately; breathing and BPH symptoms are well-managed on current regimen and patient denies pain; patient does not havedementia; patient has not tried an antidepressant in the past; prognosis is approx.3 months.

Medications: albuterol/ipratropium neb 1 vial inh 4 times daily; albuterol neb0.083% 1 vial inh q4h PRN sob/wheezing; albuterol HFA inhaler 90mcg 2 puffs inhq4h PRN sob/wheezing, when away from home; prednisone 5mg po qam;morphine 20mg/mL 5mg po/sl q2h PRN pain/sob; lorazepam 0.5mg 1 tab po q4hPRN anxiety/sob; tamsulosin 0.4mg po once daily; senna-S 1 tab po BID PRNconstipation


A) Melatonin

B) Trazodone

C) Zolpidem (Ambien®)

D) Non-pharmacologic measures such as meeting with a social worker and/or chaplain

E) **B and D**

Quiz Question #3

R.P., 84-year-old male hospice patient with Parkinson’s disease and HTN; hasrecently developed overnight agitation/hallucinations, and as a result, sleeps verylittle at night, per caregiver; prognosis is unclear, but likely 1-2 months.

Medications: carbidopa/levodopa 25/100mg 1 tab po TID; morphine 20mg/mL 5mgpo/sl q4h PRN pain/sob; lorazepam 0.5mg 1 tab po q4h PRN anxiety/restlessness;metoprolol succinate 25mg 1 tab po once daily; senna-S 2 tabs po BID

Which of the following would be the BEST option(s) to try at this time?

A) Haloperidol scheduled every evening and PRN

B) Risperidone every evening

C) Quetiapine every evening

D) Temazepam every evening

E) Non-pharmacologic measures such as relaxation techniques, meeting with chaplainand/or social worker, CBT-I, etc.

F) C and E


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Quiz Question #3

R.P., 84-year-old male hospice patient with Parkinson’s disease and HTN; hasrecently developed overnight agitation/hallucinations, and as a result, sleeps verylittle at night, per caregiver; prognosis is unclear, but likely 1-2 months.

Medications: carbidopa/levodopa 25/100mg 1 tab po TID; morphine 20mg/mL 5mgpo/sl q4h PRN pain/sob; lorazepam 0.5mg 1 tab po q4h PRN anxiety/restlessness;metoprolol succinate 25mg 1 tab po once daily; senna-S 2 tabs po BID

Which of the following would be the BEST option(s) to try at this time?

A) Haloperidol scheduled every evening and PRN

B) Risperidone every evening

C) **Quetiapine every evening**

D) Temazepam every evening

E) Non-pharmacologic measures such as relaxation techniques, meeting with chaplainand/or social worker, CBT-I, etc.

F) C and E

Key Points

Insomnia is often a result of another condition (e.g. pain, anxiety).Treat and/or resolve causes of insomnia first whenever possible,before starting an anti-insomnia medication.

Use non-pharmacologic measures whenever possible and appropriate

There is not a “one size fits all” anti-insomnia drug treatment; if thefirst option tried is ineffective, may need to adjust dose or switch to adifferent medication

Always use the lowest effective dose, monitor for adverse effects, andfrequently re-evaluate for effectiveness with any drug therapy


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30

Questions?

Any additional questions: [email protected]

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LLC, New York. 2017.

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References, continued Chung KF, et al. Sleep hygiene education as a treatment of insomnia: a systematic review and meta-

analysis. Fam Pract. 2018 Jul 23; 35(4): 365-375. [abstract]

Sateia MJ, Buysse DJ, Krystal AD, Neubauer DN, Heald JL. Clinical practice guideline for the pharmacologic treatment of chronic insomnia in adults: An American Academy of Sleep Medicine clinical practice guideline.Journal of Clinical Sleep Medicine. 2017; 13(2): 307-80.

PL Detail-Document, Comparison of Insomnia Treatments. Pharmacist’s Letter/Prescriber’s Letter. July 2014. Last modified January 2015.

2019 American Geriatrics Society Beers Criteria® Update Expert Panel. American Geriatrics Society 2019 Updated AGS Beers Criteria® for potentially inappropriate medication use in older adults. J Am Geriatr Soc 00:1-21, 2019. Available at: https://onlinelibrary.wiley.com/doi/epdf/10.1111/jgs.15767?referrer_access_token=nuwHd-eomXh0G4EfAX5qnIta6bR2k8jH0KrdpFOxC65t_FokpdxHvL7WaxkN527h7l3s9xxEMlD4211T518cxliTQ0jUZJvkCe39nbq3eDhQWopbDFzcvt3mr4h2_zLJKd88FJm52y49oOnFCvVuDA%3D%3D [last accessed 5/18/2019]

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