Sleep-Wake Disorders - Insomnia

Franco

Sleep Onset Insomnia definition

difficulty falling asleep

Sleep Maintenance Insomnia definition

difficulty staying asleep

• frequent awakening

• inability to fall back sleep

• early morning awakenings

Daytime Symptoms of Insomnia

excessive daytime sleepiness

fatigue, malaise, difficulty concentrating, memory impairement

Classification of Insomnia - Situational

not a disorder

• self-limiting

• jet lag/shift work

• stress

Classification of Insomnia - Short Term/Episodic

lasting 1-3 months

impacts 30-50% of the population (more common)

Classification of Insomnia - Chronic Insomnia Disorder

> 3 times per week for > 3 months

impacts 10% of the population (less common)

Insomnia Etiology

“3P Model”

Predisposing factors - risk of insomnia

Precipitating factors - make it worse

Perpetuating factors - continue

Insomnia Predisposing factors

Medical/psychiatric comorbitiies

genetics, female

personality factors - worrier

Insomnia Precipitating Factors

Situational Stress - work, finances, major life events, relationships

Environmental - noise, light, temperature extremes, time change

Perpetuating factors

Poor sleep hygiene

maladaptive coping strategies

Insomnia Common Medical Comorbidities

Allergies

Arthritis/Pain

Astham/COPD

BPH

Diabetes

GERD/Peptic Ulcer Disease

HF

IBS

Menopause

Pregnancy

all conditions must be treated concurrently to address insomnia

Insomnia Psychiatric Comorbities

Major Depressive Disorder

• > 5x more likely to suffer from chronic insomnia

Anxiety disorders

Bipolar Disorder

Substance Disorder

all conditions must be treated concurrently to address insomnia

Sleep Parameters

+ goal in insomnia

Sleep onset latency (SOL): sleep to sleep transition

• goal: <30 mins

Total Sleep Time (TST): goal: >6 hrs

Wake time After Sleep Onset (WASO): Time spent awake after initial sleep onset until final awakening

• goal: <30 mins

Sleep Onset: TST divided by time spent in bed

• goal: >80-85%

Rating scales in Insomnia

+name, rater, interpretation

Pittsburgh Sleep Quality Index (PSQI)

• rater: Self and clinician

• interpretation:

  • Good: ≤ 5

  • Poor: > 5

Epworth Sleepiness Scale (ESS)

• rater: self

• interpretation:

  • Average: 8-9

    Normal: < 10

    Mild: 11-12

    Moderate: 13-15

    Severe: 16-24

Insomnia Severity Index (ISI)

• rater: self

• interpretation:

  • Normal: 0-7

    Subthreshold: 8-14

    Moderate: 15-21

    Severe: 22-28

Insomnia Non-Pharm Treatment Options

Cognitive Behavioral Therapy for Insomnia (CBT-l)

• Sleep Hygiene

Digital CBT-l

Cognitive Behavioral Therapy for Insomnia (CBT-l) - Place in insomnia Therapy

+efficacy, options

FIRST LINE by most guidelines

comparable efficacy to pharmacological treatment

• sleep hygiene education (SHE) → not effective for sole treatment for chronic insomnia

• stimulus control → bedroom = sleep only

• sleep restriction → limits time in bed to sleeping

• cognitive therapy → change patient’s unrealistic expectation of sleep

• relaxation training → lower somatic/arousal states

Digital CBT-l - place in insomnia therapy

+def., efficacy

metered, interactive, tailored approach meant to stimulation face-to-face CBT-l

• Nox Health → 9-week prescription digital therapeutic (PDT) for chronic insomnia

may be just as effective as face-to-face CBT-l

Sleep Hygiene in Insomnia tips

YES

• wake up at same time

• evening walks

• comfortable bed

• cool and dark room

• bedtime routine

• relaxing bath

NO

• heavy food

• blue light

• alcohol, smoking

• caffeine

• hard training

• stress

When are Pharmacological treatment options recommended in insomnia

Only recommended for short term use (4-5 weeks), if CBT-l is unavailable or ineffective

List FDA approved Options for Insomnia

BZDz

BZD receptor agonists BZRAs (Z-drugs)

Duel Orexin Receptor Antagonists (DORAs)

Low-Dose Doxepin

Ramelteon

BZD use in insomnia

+moa, effect on sleep, schedule, metabolism, warnings, concerns

moa: positive allosteric modulator of GABA-A receptors

Effect on sleep:

• decreases sleep latency

• increase stage N2 sleep

• Reduced delta sleep and REM sleep

• increases TST

Sched.IV controlled substances

• tolerance can develop rapidly, leading to dose escalation

• abrupt discontinuation after continual use for 3-4 weeks can lead to rebound insomnia and withdrawal symptoms

Warnings

• complex sleep-related behaviors while asleep

• worsening of depression, suicidal ideation

• risk of respiratory depression when combined with alcohol, opioids, other CNS depressants

Metabolism

• most BZDs are CYP3A4 substrates → caution with inhibitors

Concerns

• often prescribed long-term despite being recommended for short term use

• BEERs recommends agist in elderly insomnia

No coconmitant depression, no elderly

BZDs approved for Insomnia

+duration, special characteristics

Q-FETT

Quazepam - long duration

• risk of next day hangover

Flurazepam - longest duration

• risk of next day hangover

• dose accumulation in females

Estazolam

• considerable DDIs (3A4)

Temezepam - short duration

• no active metabolites

• safer in elderly/hepatic impairment

Triazolam - shortest duration

• risk of rebound insomnia

• do not take >7-10 days

• DDIs (3A4)

FDA approved BZD Receptor Agonists

+list, moa, efficacy, duration, clinical pearl-general, special considerations (for each), safety

moa: selectively bind GABA-A receptors contain alpha 1 subunits

similar efficacy to BZDs

clinical pearsl

• less risk of withdrawal, tolerance, and rebound insomnia

Zaleplon

• shortest duration

• indicated for sleep-onset insomnia

• may be used for middle of the night awakening

Zolpidem

• regular and CR version

  • may accumulate in females: requires lower starting dose

• low dose SL → middle of the night awakening

Eszopiclone

• longest duration

• unpleasant metallic taste (transient)

BZRA ADEs and DDIs/Food-Drug Interactions

ADEs

• dependence - schedule IV

• Complex sleep behaviors: sleepwalking, eating, driving

  • if they occur → d/c drug!!

Food-Drug

• high fat meals = delayed absorption (up to 2 hours)

• 3A4 substrates: caution with 3A4 substrates

BZDs vs BZRAs

+selectivity, properties, impact on sleep, misuse potential, risks

BZD

• non-elective

• anxiolytic

• muscle relaxant

• anti seizure

• suppress REM, decrease slow wave sleep

• misuse potential

• higher risk of respiratory depression

BZRAs

• alpha-1 selectivity

• NOT anxiolytic

• NOT muscle relaxant

• NOT anti seizure

• NO significant impact on REM or slow wave sleep

• less misuse potential

• higher risk for complex sleep disorders

Duel Orexin Receptor Antagonists (DORAs)Duel Orexin Receptor Antagonists (DORAs)

+moa, indications, effect on sleep, efficacy

antagonists at the orexin receptors (OX1 and OX2)

approved for sleep onset and sleep maintenance insomnia

effects on sleep:

• increase REM sleep

• increase stage N2 sleep

• no change in stage N3 sleep

efficacy for use up to 6 months (lemborexant) to one year (daridorexant and suvorexant)

Duel Orexin Receptor Antagonists (DORAs)

+schedule, metabolism warnings, ADEs, clinical pearls

Sched. IV controlled substance though dependence risk and withdrawal are significantly lower than that of BZDs

Warnings

• narcolepsy-like symptoms

• daytime somnolence and next-day driving impairment

  • ensure least 7-8 hours of sleep

  • suicidal thoughts/behaviors (very small risk)

Metabolism

• CYP3A substrates

ADEs

• headache, abnormal dreams, somnolence

Clinical Pearls

• take on an empty stomach

  • absorption delayed by 1-3 hours with high-fat meal

List Duel Orexin Receptor Antagonists (DORAs)

+onset??, duration, special considerations

Suvorexant

• onset: 30 mins

• duration: longer half life

• special considerations:

  • higher AUC in women, obese patients

  • recommend NOT to drive with 20 mg

Lemborexant

• onset: 15-10 mins

• duration: longest half life

• special considerations: greater risk of next-day somnolence

Dardorexant

• onset: 30-40 mins

• duration: shortest half life

• special considerations: improvement in daytime symptoms with 50 mg

Doxepin

+indication, moa, ADEs

indication: insomnia (dose??)

moa:

• low doses: H1 antagonist

• high doses often used in practice

ADEs:

• Next-day somnolence

  • more common if taken with a meal

  • take on an empty stomach at least 3 hours apart form food

• Anticholinergic side effects → mostly at higher

• dangerous in overdose

Ramelteon

+moa, efficacy, clinical pearls, DDIs

moa: melatonin receptor agonist at MT1 and MT2

• regulates circadian rhythm and sleep onset

• approved for sleep onset insomnia

efficacy: considered safe, but only moderate efficacy at best

clinical pearls

• no misuse potential

ADEs:

• mild headache, dizziness, somnolence possible

• rare: angioedema, elevated prolactin, decreased testosterone

DDIs

• high-fat meals can delay absorption

• contraindicated with fluvoxamine

List Off-label Options for Insomnia

Trazodone

Mirtazepine

Second-gen antipsychotics → quetiapine, olanzapine, clozapine

Trazodone

+use, moa, Metabolism, ADEs, clinical pearls

arguable the most used agent in practice

use: insomnia

moa: 5HT2a alpah1/H1 antagonist: profound sedative effect

Metabolism:

• metabolizes into meta-chlorophenylpiperazine (mCPP) in ~ 1 hour

ADEs: mild

• rare- priapism (painful erection)

clinical pearls

• false positives for ecstasy

Hydroxyzine

+use, moa, clinical pearls

use: insomnia

moa: antihistamine with relatively low anticholinergic

clinical pearls:

• often used in co-occuring anxiety

Mirtazepine

+use, moa, clinical pearls

use: insomnia

moa: lower doses thought to be more sedating

clinical pearls:

• increased appetite

Second generation antipsychotics used in insomnia

+use, clinical pearls

Quetiapine, Olanzapine, Clozapine

• sedating properties

use with patients with comorbities (bipolar, schizophrenia, etc)

clinical pearls

• increased appetite

List OTC Options for Insomnia

Antihistamines - Diphenhydramine, Doxylamine

Melatonin

Valerian Root

Diphenhydramine, Doxylamine

+place in insomnia therapy, ades

place in therapy: not recommended

ADEs:

• anticholinergic side effects

• excessive daytime hangover

• tolerance develops within 7-10 days of regular use

Melatonin

+use, ades

use: well-tolerated; may cause vivid or abnormal dreams

Valerian Root

+use/place in therapy, moa, ades, clinical pearls

not recommended in insomnia (widely used in Europe)

moa: activity at the BZD receptor

ades:

• withdrawal may occur

clinical pearls

• very smelly

Agents preferred in insomnia sleep onset

TTERZ

•Triazolam, Temazepam

•Eszopiclone, Zaleplon, Zolpidem

•Ramelteon

Agents Sleep maintenance insomnia:

TEDS

•Temazepam,

•Eszopiclone, Zolpidem

•Doxepin

•Suvorexant

AHRQ Systematic Review?

BEERs criteria for insomnia

+drugs

most sleep aids are on the BEERs criteria

• BZDs and BZRAs: fall, fractures, cognitive impairment, delirium

  • BZRAs → better safety (still risks)

IF BZDs is used → LOT = recommended

Exceptions to BEERs criteria for insomnia

+drugs

Melatonin/Remelteon

Doxepin (<6mg) → only TCA exception

Mirtazepine → may helping comorbid anorexia, depression

• use with caution on BEERs list

Trazodone