a psychiatrist's guide to sleep disorder screening - the lung

Treatment of Insomnia for

Clinicians

Larry Pawluk, M.D., FRCPC

Diplomate, American Board of Sleep Medicine

Clinical Professor of Psychiatry,

Sleep Medicine Program, University of Alberta

What is Insomnia?

A complaint of:

• Difficulty falling asleep

• Difficulty staying asleep

• Poor quality sleep

Associated with:

• Distress

• Impaired function

Insomnia

And finally there was the sleepless night

When I decided to explore and fight

The foul, the inadmissible abyss,

Devoting all my twisted life to this

One task.

- Vladimir Nabokov (from Pale Fire)

Insomnia: Daytime Complaints

Fatigue, sluggishness

Sleepiness

Somatic complaints (aches & pains)

Stress about poor sleep

Mood disturbances

Poor concentration

Impaired performance

Insomnia: Consequences

Decreased quality of life

Increased healthcare costs

Increased absenteeism

Decreased productivity

Increased risk for developing psychiatric disorders

Increased accident risk

Chesson A Jr. et al. SLEEP 2000;23.

Sateia MJ et al. SLEEP 2000;23.

Insomnia: Prevalence

Insomnia is the most

common sleep complaint

in the industrialized

world

Complaints in 30% to

40%

Complaint with distress

or impairment: 8% to

19%

Sateia MJ et al. SLEEP 2000;23.

Major Risk Factors

Previous history of insomnia

Increasing age

Female gender

Psychiatric symptoms and disorders

Medical symptoms and disorders

Management of Insomnia

Insomnia

History

– Initiation vs. Maintenance vs. Early Morning

Awakening

– Description Speed of onset and precipitant

Temporal relationship to other symptoms

Course and duration

Exacerbating/alleviating factors

Insomnia

History

– Typical Night Pre-bed routine and bedtime

Sleep onset

Number of awakenings and duration

Final awakening

Variation in schedule on weekends/vacations

Daytime Naps

– Daytime Consequences

– Sleep Log/Diary

– Interview with bed partner

Insomnia

Common Causes

– Most often there is more than one cause.

– Insomnia related to a psychiatric disorder

makes up > 75% of primary or secondary

diagnoses in insomniacs presenting to sleep

centres (APA/NIMH DSM IV Field Trial).

Insomnia

Common Causes

– Poor sleep hygiene

– Alcohol, nicotine, caffeine, substances

– Medications

– Psychiatric disorders

– Medical disorders

– Psychophysiological (Conditioned) insomnia

– Restless Legs Syndrome and Periodic Limb

Movements

– Delayed Sleep Phase Syndrome

Prevalence of Insomnia in

Psychiatric Disorders (Weyerer and Dilling, 1991)

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Insomnia

Common Causes

– Clues suggestive of a psychiatric diagnosis Other psychiatric symptoms began in proximity to

insomnia.

Early morning awakening.

Non-restorative sleep.

Daytime fatigue/anergia.

Feelings of hopelessness, helplessness; anhedonia.

Agitation, worrying.

Overwhelmed by or excessively focused on insomnia.

Insomnia

Common Causes

– Medical disorders

» Neurological

Seizures, headache, Parkinsons, dementia, tumors, movement disorders.

» Endocrinopathies

Diabetes, hyperthyroidism, Addisons, Cushings.

» Respiratory

Obstructive Sleep Apnea, COPD, asthma, CF.

» Pain

Arthritis, various other.

» GI

GERD, PUD, inflammatory bowel disease.

» Renal, Cardiac, IDs, Dermatological

Insomnia

Common Causes

– Psychophysiological (Conditioned) insomnia

» Largest category of “non-psychiatric” chronic insomnia.

» May have obsessional or somatoform traits.

» Features:

Initiating factor= stressor in light sleeper.

Insomnia develops “life of its own” after stressor diminishes.

Excessive focus on poor sleep results in maladaptive associations promoting further wakefulness eg. clockwatching, ruminating, catastrophizing.

Occasionally sleeps better away from home.

Insomnia

Common Causes

– Restless Legs Syndrome and Periodic Limb

Movements

» Cardinal symptoms

Unusual sensations exclusively in lower legs typically at

bedtime often preventing sleep initiation.

Accompanied by strong urge to move legs which

alleviates the uncomfortable sensation.

Once asleep, bed partner may notice lower leg

jerking/kicking which may or may not be associated with

brief cortical arousals.

Insomnia

Common Causes

– Delayed Sleep Phase Syndrome

» Shift of entire sleep period in a phase delayed direction.

» Sleep initiation insomnia with difficulty awakening in the

morning – at times with morning daytime sleepiness.

» Usually adolescents and young adults.

» Disorder “disappears” when allowed to follow their preferred

sleep schedule.

» DDx includes mood disorders, substance abuse, poor sleep

hygiene.

Clinical Presentation

Predisposing, Precipitating and Perpetuating Factors

Assessment: Sleep/wake Diary

Assessment: Polysomnography

Indications

– Suspect other sleep disorder

– Poor treatment response

– Atypical clinical presentation

Not routinely indicated for the evaluation of insomnia

Practice parameters for the evaluation of chronic insomnia. SLEEP 2000;23.

Treatment of Insomnia

Nonpharmacologic Therapy: Sleep Hygiene and Cognitive Behavioral

Therapy (CBTI)

Cognitive Behavioral Therapy

Reset or reinforce biological rhythm with light

therapy and/or melatonin.

Circadian rhythm

entrainment

Reduce arousal & decrease anxiety Relaxation training

Address maladaptive thoughts and beliefs that

interfere with sleep.

Cognitive therapy

Restrict time in bed to improve sleep depth &

consolidation

Sleep restriction

Strengthen bed & bedroom as sleep stimulus Stimulus control

Promote habits that help sleep; provide rationale

for instructions.

Sleep hygiene

AIM TECHNIQUE

Behavioral Treatment: Sleep Hygiene

Regularize sleep / wake schedule

Avoid stimulants and stimulating behavior

Establish relaxing bedtime routine

Provide conducive sleep environment

Limit daytime naps

Reduce or eliminate alcohol, caffeine and

nicotine

Obtain regular exercise

Avoid clock watching

Behavioral Treatment:

Stimulus Control

Use bed for sleep (and sex)

Go to bed only when sleepy

Get out of bed when unable to sleep

Wake up at a consistent time (including weekends)

Do not take daytime naps

Behavioral Treatment: Sleep Restriction (Consolidation)

Determine average time asleep

Set time in bed = time asleep

Consistent wake-up time

No daytime naps

If time asleep > 90% of time in bed then increase time in bed (15-30 minutes)

If time asleep < 80% of time in bed then decrease time in bed (15-30 minutes)

Spielman AJ et al. SLEEP 1987;10.

Nonpharmacologic Treatment Efficacy

90

0

10

20

30

40

50

60

70

80

Stimulus

Control

Sleep

Restriction Relaxation Sleep

Hygiene Multi-component

Sle

ep L

aten

cy (

Min

ute

s)

Pre-treatment

Post-treatment

Adapted from Morin CM et al. Am J Psychiatry 1994;151.

Nonpharmacologic Therapy Efficacy

Sleep Efficiency

50

60

70

80

90

CBT Relaxation Placebo

Per

cen

t

Adapted from Edinger JD et al. JAMA, 2001;285.

Sleep Quality

2

2.5

3

3.5

4

CBT Relaxation Placebo

Rat

ing

Nonpharmacologic Treatment:

“The Minimum”

Review sleep hygiene

Limit time in bed

Establish regular wake-up time

Go to bed only when sleepy

Get out of bed if unable to sleep

Pharmacotherapy: Indications

Acute Stress

Shift Work

Jet Lag

Predictable Stress

Chronic Insomnia

Pharmacotherapy

Benzodiazepines

Newer GABA receptor agonists

Antidepressants

Antihistamines

Melatonin

Others

Benzodiazepines

temazepam (Restoril)

triazolam (Halcion)

clonazepam (Rivotril)

lorazepam (Ativan)

diazepam (Valium)

flurazepam (Dalmane)

Pharmacotherapy:

Benzodiazepine/GABA Receptor

Agonists

Non-benzodiazepines

zopiclone (Imovane)

zolpidem SL (Sublinox)

zaleplon (Starnoc)

Drug Onset of

Action

Elimination

Half-Life (h)

Typical Adult

Dose

Triazolam 10-20 min 1.5-5 0.125-0.25 mg

Temazepam 45-60 min 8-20 15-30 mg

Zaleplon 10-20 min 1.0 5-20 mg

Zopiclone 20-30 min 5 3.75-7.5 mg

Zolpidem SL 15-20 min 2.6 10 mg

Hypnotic Pharmacokinetics

Pharmacotherapy: Benzodiazepines

Actions

Hypnotic

Anxiolytic

Myorelaxant

Anticonvulsant

Side effects

Sedation

Anterograde amnesia

Ataxia, falls

Respiratory depression

Tolerance, dependence,

abuse


Agonists: Effects on Sleep

Sleep continuity

– Sleep latency

– Awakenings

– Sleep Duration

Slow Wave Sleep (BZs only)

REM (BZs only)

Duration and number of sleep spindles

Periodic limb movements and associated arousals

Benzodiazepines: Rebound

Insomnia

Is related to dose and half-life

Can be prevented by tapering dose

Cannot easily be distinguished from return of

original symptoms

Does not predict future pill-taking behavior

Varies among drugs

May not be seen with some agents


Agonists: Clinical Approach

Establish correct diagnosis

Evaluate carefully for apnea, respiratory impairment, organic

mental disorders, substance abuse history

Choose drug with desired pharmacokinetic profile

Use lowest effective dose

Monitor side effects (e.g. fall risk, sedation)

Aim for short-term, intermittent use

Consider long-term use in carefully selected patients

Sublinox® (zolpidem tartrate ODT):

Product Profile Product

Fast disintegrating, sublingual zolpidem tablet

Characteristics

Fast sublingual disintegration (≤ 2 minutes)

For patients with difficulty swallowing or those who don’t like to swallow pills or don’t have access to water

Ideal product profile for “on demand” treatment

Next day residual effects comparable to oral formulation

Product Monograph, Sublinox, Zolpidem tartrate orally disintegrating tablets. Montreal, Canada: MEDA Valeant Pharma Canada Inc.; 2011.

Mechanism of Action • Subunit modulation of the GABAA receptor chloride channel macromolecular complex is

hypothesized to be responsible for sedative, anticonvulsant, anxioytic, and myorelexant drug

properties.

• The major modulatory site of the GABAA receptor complex is located on its alpha () subunit

and is referred to as the benzodiazepine (BZ) or omega () receptor.

• Zolpidem has a chemical structure unrelated to benzodiazepines, barbiturates, or other drugs

with known hypnotic properties

• It interacts with the GABA-BZ receptor complex and shares some of the pharmacological

properties of the benzodiazepines.

• In contrast to the benzodiazepines, zolpidem in vitro binds the (ω1) receptor preferentially with

a high affinity ratio of the alpha1/alpha5 subunits.

• Selective binding of zolpidem on the (ω1) receptor may explain:

- the relative absence of myorelaxant and anticonvulsant effects in animal studies

- the preservation of deep sleep (stages 3 and 4) in human studies of zolpidem at

hypnotic doses (vs. benzodiazepines)


Incidence of Treatment-Emergent Adverse Experiences in Placebo-

Controlled Clinical Trials with zolpidem tartrate lasting up to 35 nights (Percentage of patients reporting)

Body System/

Adverse Event*

Zolpidem tartrate (≤ 10 mg)

(N=152)

Placebo

(N=161)

Central and Peripheral Nervous System

Drowsiness 8 5

Dizziness 5 1

Lethargy 3 1

Drugged feeling 3 -

Lightheadedness 2 1

Depression 2 1

Abnormal dreams 1 -

Amnesia 1 -

Sleep disorder 1 -

Gastrointestinal System

Diarrhea 3 2

Abdominal pain 2 2

Constipation 2 1

Respiratory System

Sinusitis 4 2

Pharyngitis 3 1

Skin and Appendages

Rash 2 1

*Reactions

reported by at

least 1% of

patients treated

with oral

zolpidem and at a

greater frequency

than placebo.

Only dizziness

and drugged

feeling were

reported with

statistically

significant

differences


Sublingual zolpidem in early onset of sleep

compared to oral zolpidem: polysomnographic study

in patients with primary insomnia

Staner L, et al. Curr Med Res Opin. 2010;26(6):1423-1431.

Study Design

Randomized, double-blind, two-period, cross-over multi-centre study

Polysomnographic study in patients with DSM-IV primary insomnia

Powered to test for superiority of sublingual oral zolpidem compared to oral zolpidem on latency to persistent sleep

Powered for “at least as good as” total sleep time and duration of wake after sleep onset

Staner L et al. Curr Med Res Opin. 2010;26(6):1423-1431.

Results – Sleep Initiation

Baseline Sublingual

zolpidem

Oral

zolpidem

Treatment

differences

Latency to persistent

sleep (min)

84.54±40.35 19.76±15.55 30.06±23.48 -

10.28(p=0.0

01)

Sleep onset latency

(min)

72.30±39.32 17.66±13.37 26.31±22.72 -8.63

(p<0.01)

Latency to stage 1 (min) 61.07±34.64 13.94±12.67 21.35±20.30 -7.43

(p<0.01)

Staner L, et al. Curr Med Res Opin. 2010;26(6):1423-1431.

Results – Sleep Continuity

and Architecture

Baseline Sublingual

zolpidem

Oral zolpidem Treatment

differences

SEI (%) 67.47±6.95 89.9±6.09 83.33±6.98 1.56 (p<0.05)

TTA (min) 153.94±46.43 45.80±29.23 53.41±33.57 -7.52 (p<0.05)

ST1 (min) 22.08±8.81 23.06±8.50 23.15±8.18 -0.06 (p=NS)

ST2 (min) 182.56±46.04 253.09±35.98 242.38±34.09 10.54 (p<0.05)

SWS (min) 51.65±25.19 71.91±32.69 73.60±29.96 -1.51 (p=NS)

REM (min) 70.44±19.64 86.74±24.72 88.31±20.64 -1.73 (p=NS)

RSL (min) 81.81±40.77 95.34±40.70 87.98±40.78 7.38 (p=NS)

• Sleep efficiency index and time spent in stage 2 were

significantly higher with sublingual zolpidem

• Patients receiving oral zolpidem demonstrated significantly

higher total time awake

Staner L et al. Curr Med Res Opin. 2010;26(6):1423-1431.

Sublinox® Contraindications Known hypersensitivity to zolpidem tartarte or to any of the

inactive ingredients in the formulation

Patients with significant obstructive sleep apnea syndrome

and acute and/or severe impairment of respiratory function.

Sublinox should not be given to patients with myasthenia

gravis and in patients with severe hepatic impairment.

Patients with a personal or family history of sleepwalking

Elderly (longer half life)

Not to be taken with alcohol


COMPLEX SLEEP-RELATED BEHAVIOURS: Warning

Complex sleep-related behaviours such as “sleep-driving” (i.e., driving

while not fully awake after ingestion of a sedative-hypnotic, with amnesia

for the event) have been reported in patients who have taken Sublinox.

Other potentially dangerous behaviours have been reported in patients who

got out of bed after taking a sedative-hypnotic and were not fully awake,

including preparing and eating food, making phone calls, leaving the house,

etc. As with “sleep-driving”, patients usually do not remember these events.

Although complex sleep-related behaviours may occur with Sublinox alone

at therapeutic doses, the use of alcohol and other CNS-depressants with

Sublinox appears to increase the risk of such behaviours, as does the use of

Sublinox at doses exceeding the maximum recommended dose.


The Right Dose of Sublinox®

Sublinox® recommended dose is 10 mg immediately before bedtime for adults

Sublinox® effect may be slowed by ingestion with food

Dose adjustment needed when used with other CNS depressants

The potential for drug interactions must always be considered.

Sublinox® course of treatment should not exceed 4 wks


Administration Instructions

• Should be taken right before bed time.

• Should not be taken with or immediately after a meal.

• Should not be taken when drinking alcohol, or with other CNS

depressants.

• Should be placed under the tongue, where it will disintegrate.

• Should not be chewed or swallowed and should not be taken with

water.

• Maximum recommended dose of 10mg should not be exceeded.

1. Product Monograph, Sublinox, Zolpidem tartrate orally disintegrating tablets. Montreal, Canada: MEDA Valeant Pharma Canada Inc.; 2011.

Antidepressants: Rationale

No antidepressant is FDA/HPB-approved for

treatment of insomnia

Some antidepressants have sedative, sleep-

promoting effects

Some insomnia patients have symptoms of

depression or anxiety

Low risk of abuse, but psychological dependence

occurs

Antidepressants: Sleep Effects

Sleep Continuity REM Sleep SWS Comments

Tricyclic

apnea, PLMS

SSRI

SNRI

Variable effects on

insomnia; may

PLMS; eye

movements in NREM

to

to

to to

to to

Trazodone Carry-over sedation

Mirtazapine

to

Sedation is inversely

related to dose

to

Pharmacotherapy: Antihistamines

Mechanism of action

– H1 receptor antagonism

– Variable antagonism of cholinergic,

serotonergic, adrenergic receptors

Adverse effects

– Sedation, grogginess

– Dry mouth

– Psychomotor impairment

– Delirium

Antihistamines: Sleep Efficacy

Diphenhydramine 50mg Placebo

Ord

inal

Rat

ing

Sca

le

0

0.5

1

1.5

2

2.5

3

3.5

Sleep

Latency

Number of

Awakenings

Sleep

Duration

Sleep

Quality

p<.01

Adapted from Rickels K et al. J Clin Pharmacol 1983;23.

p<.01 p<.001 p<.001

Pharmacotherapy: Melatonin

Naturally occurring hormone secreted during darkness at night

Broad range of physiological effects

Inconclusive findings concerning sleep promotion in insomnia

May be most useful in shifting circadian phase e.g. delayed sleep phase syndrome

Other Pharmacologic Agents

Tryptophan

Valerian

HRT

Pharmacologic Treatment: Approach

Select appropriate medication

Use lowest effective dose

Use at bedtime

Duration of therapy

– Use as needed for 2 to 4 weeks

– Reduce dose as tolerated

– Intermittent use suggested

– Reassess and adjust approach

Combine with behavioral strategies

Insomnia Case 1

40 year old female teacher

Unable to sleep for 5 years with worsening

over 3 months

Appears anxious

Worries she will lose job due to lack of

sleep

Insomnia Case 1

Evaluation

– 1. Description

» Initiation insomnia for 5 yrs; abrupt worsening X 3

months with EMW

» Typical noc:

» BT 10 pm, sleep onset 3 hrs (toss and turn, check

clock, ruminates, ++ focussing on need to sleep),

EMW ~ 5 am

» Sleep diary confirms

Insomnia Case 1

Evaluation

– 2. Common Causes

» Sleep hygiene incl. EtOH caffeine, substances: marks late

» Meds: occas. Antihistamine to sleep

» Medical: nil reported

» Psychiatric: sx of depression and anxiety, a few neuroveg. features, no suicidal ideation

» Psychophysiol: 5 yr hx of ++focus on sleep, check clock, ruminating

» RLS: no Circadian: no

Insomnia Case 1

Diagnoses:

– Major Depression with anxiety component

– Sleep hygiene factor: works til bedtime

– Psychophysiological insomnia component

Insomnia Case 1

Treatment

– Treat mood/anxiety disorder first:

» Antidepressant with anxiolytic properties

» Supportive therapy

» Review sleep hygiene principles eg. wind down

before bed

Insomnia Case 1

Treatment (cont.)

– After 2 months EMW and most

depressive/anxiety symptoms improve but sleep

initiation problem continues:

– Address conditioned component:

» Behavioral strategies: hide clock, stimulus control,

sleep consolidation

» Cognitive restructuring: address maladaptive

assumptions

Insomnia Case 1

Treatment (cont.)

– If required:

» Use short acting hypnotic for agreed upon period to

“help break cycle”

» If subsequent use required, use intermittently

Insomnia Case 1

40 year old female teacher

Unable to sleep for 5 years with worsening

over 3 months

Appears anxious

Worries she will lose job due to lack of

sleep

a psychiatrist's guide to sleep disorder screening - the lung

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