Insomnia from A to ZZzzsInsomnia from A to ZZzzsInsomnia from A to ZZzzsInsomnia from A to ZZzzs

October 2, 2013October 2, 2013

Tina Waters, MDTina Waters, MD

ObjectivesObjectivesObjectivesObjectives

• Summarize the basic principals of sleep and Summarize the basic principals of sleep and describe normal sleep patterns versus insomniadescribe normal sleep patterns versus insomnia

• Review the clinical and diagnostic evaluation of Review the clinical and diagnostic evaluation of insomnia as well as negative health and social insomnia as well as negative health and social consequences of sleep lossconsequences of sleep loss

• Achieve a basic understanding of the Achieve a basic understanding of the neurophysiology underlying sleep/wake cycles and neurophysiology underlying sleep/wake cycles and the benzodiazepine receptor site the benzodiazepine receptor site

• Differentiate among sedative hypnotics with Differentiate among sedative hypnotics with respect to their relative risks, benefits, and respect to their relative risks, benefits, and indications indications

Sleep architecture

Source: National Sleep Foundation (2008)

Two Process Model of SleepTwo Process Model of SleepTwo Process Model of SleepTwo Process Model of Sleep

Process SProcess S: Homeostatic sleep drive or sleep : Homeostatic sleep drive or sleep pressure - sleep occurs naturally in response to pressure - sleep occurs naturally in response to how long we are awake; longer awake, the how long we are awake; longer awake, the stronger sleep drive stronger sleep drive

Process CProcess C:: Circadian process - this process Circadian process - this process controls the timing of sleep and wakefulness controls the timing of sleep and wakefulness during the day-night cycle. Timing is regulated by during the day-night cycle. Timing is regulated by the circadian biological clock that is located in the circadian biological clock that is located in the brain in the SCN (suprachiasmatic nucleus)the brain in the SCN (suprachiasmatic nucleus)

Kilduff TS, Kushida CA. Sleep Disorders Medicine: Basic Science, Technical Considerations, and Clinical Aspects. 1999; based on Edgar DM, et al. J Neurosci. 1993.

Normal Sleep

Sleep inertia/ pressure builds over the course of the day

Helps us go to sleep at night

Circadian factors keep us awake- drive for wakefulness:

Afternoon low-normal

“second wind” then down again

NappingNAP

Less pressure to sleep at night;

More difficult to fall asleep at night

How Much Sleep Do You Really Need?How Much Sleep Do You Really Need?How Much Sleep Do You Really Need?How Much Sleep Do You Really Need?

This table identifies the "rule-of-thumb" amounts This table identifies the "rule-of-thumb" amounts most sleep experts have agreed upon; however most sleep experts have agreed upon; however there is no “magic number”there is no “magic number”

• 75% of adult Americans experience 75% of adult Americans experience sleep disorder symptoms at least a sleep disorder symptoms at least a few nights per weekfew nights per week

• Sleep loss impacts on all facets of life Sleep loss impacts on all facets of life and virtually all organ systemsand virtually all organ systems- Untreated apnea doubles the risk of Untreated apnea doubles the risk of

recurrent atrial fibrillationrecurrent atrial fibrillation- Sleep disorders cause academic and Sleep disorders cause academic and

behavior problems in kidsbehavior problems in kids- Sleep loss increases the risk of obesity Sleep loss increases the risk of obesity

and diabetesand diabetes- Drowsy driving is responsible for over $12 Drowsy driving is responsible for over $12

billion in reduced productivity/property billion in reduced productivity/property lossloss

Sleep Disorder Symptoms on the RiseSleep Disorder Symptoms on the RiseSleep Disorder Symptoms on the RiseSleep Disorder Symptoms on the Rise

Adults with sleep disorder symptoms > 3 nights per week

2004 2005 2006 2007 2008

Average adults sleep 6.9 hr (weekdays), 7.5 hr (weekends)Average adults sleep 6.9 hr (weekdays), 7.5 hr (weekends)68% sleep less than 8 hr on weeknights68% sleep less than 8 hr on weeknights39% sleep less than 7 hr on weeknights39% sleep less than 7 hr on weeknights

National Sleep Foundation 2008 Sleep In America Poll.

Habitual Sleep Duration < 6 hours is Habitual Sleep Duration < 6 hours is associated with a variety of adverse associated with a variety of adverse

consequences:consequences:

Habitual Sleep Duration < 6 hours is Habitual Sleep Duration < 6 hours is associated with a variety of adverse associated with a variety of adverse

consequences:consequences:

• risk of diabetes and heart problemsrisk of diabetes and heart problems

• inflammatory markersinflammatory markers

• risk for psychiatric conditions including risk for psychiatric conditions including depression and substance abuse depression and substance abuse

• health care utilizationhealth care utilization

• risk of motor vehicle accidentsrisk of motor vehicle accidents

• ability to pay attention, react to signals or ability to pay attention, react to signals or remember new informationremember new information

• leptin and ghrelin levels leptin and ghrelin levels greater likelihood greater likelihood of obesity due to increased appetite caused by of obesity due to increased appetite caused by sleep deprivation sleep deprivation

Banks S; Dinges DF. J Clin Sleep Med 2007;3:519-528.

More Sleep ≠ Better Health?More Sleep ≠ Better Health?More Sleep ≠ Better Health?More Sleep ≠ Better Health?

• Long sleep durations (> 9 hours) have Long sleep durations (> 9 hours) have been found to be associated with been found to be associated with increased morbidity (illness, accidents) increased morbidity (illness, accidents) and mortality. and mortality.

• Some research has found "U-shaped" Some research has found "U-shaped" curve where both sleeping too little and curve where both sleeping too little and sleeping too much may put you at risk. sleeping too much may put you at risk.

Insomnia definedInsomnia definedInsomnia definedInsomnia defined• Repeated difficulty with:Repeated difficulty with:

- Sleep initiationSleep initiation- Sleep durationSleep duration- Sleep maintenanceSleep maintenance- Sleep quality – nonrestorative sleepSleep quality – nonrestorative sleep

• ……despite an adequate time and opportunity for despite an adequate time and opportunity for sleepsleep

• ……and results in some form of daytime and results in some form of daytime impairmentimpairment

• Insomnia is not sleep deprivationInsomnia is not sleep deprivation

American Academy of Sleep Medicine. International classification of sleep disorders, 2nd ed.: Diagnostic and coding manual. Westchester, Illinois: American Academy of Sleep Medicine, 2005.

Daytime impairmentDaytime impairmentDaytime impairmentDaytime impairment

Must complain of at least one of these below: Must complain of at least one of these below:

Fatigue or malaise Tension, HAs or GI symptoms

Mood disturbance or irritability Proneness for errors or accidents at work or while driving

Memory, attention or concentration impairment

Motivation, energy or initiative reduction

Daytime sleepiness Concerns or worries about sleep

Social or vocational dysfunction or poor school performance

Insomnia’s EvolutionInsomnia’s EvolutionInsomnia’s EvolutionInsomnia’s Evolution

NIH-1983NIH-1983 NIH-1995NIH-1995

Insomnia as a symptom, Insomnia as a symptom, not a disordernot a disorder

Insomnia as a disorderInsomnia as a disorder

Insomnia as SECONDARYInsomnia as SECONDARYto a primary disorderto a primary disorder

Insomnia as CO-MORBID Insomnia as CO-MORBID with other disorderswith other disorders

Important to treat primary Important to treat primary disorder; insomnia may disorder; insomnia may receive attention, may notreceive attention, may not

Important to treat medical and Important to treat medical and psychiatric disorders as well as psychiatric disorders as well as co-morbid insomniaco-morbid insomnia

J Clin Sleep Med. 2005 Oct 15;1(4):412-21. NIH State of the Science Conference statement on Manifestations and Management of Chronic Insomnia in Adults statement.

Epidemiology of Insomnia Epidemiology of Insomnia Epidemiology of Insomnia Epidemiology of Insomnia

• General population: 10-15%General population: 10-15%• Elderly: 10-20% - Older adults, particularly women, Elderly: 10-20% - Older adults, particularly women,

and those residing in nursing facilities are much and those residing in nursing facilities are much more likely to use hypnoticsmore likely to use hypnotics

• Comorbid insomnia accounts for Comorbid insomnia accounts for >>80% of cases80% of cases- Impacts quality of life and worsens clinical Impacts quality of life and worsens clinical

outcomesoutcomes- Predisposes patients to recurrencePredisposes patients to recurrence- May continue despite treatment of the primary May continue despite treatment of the primary

conditioncondition

Mellinger et al. 1986; Ohayon, 2002

Prevalence Estimates by DefinitionPrevalence Estimates by DefinitionPrevalence Estimates by DefinitionPrevalence Estimates by Definition

4.4

8

9

10

16

30

11.7

18

15

28

21

48

0 10 20 30 40 50 60

Insomnia Diagnosis

Sleep Dissatisfaction

Insomnia Sxs +Daytime Effects

Insomnia w/ SeverityCriteria

Insomnia Sxs +Frequency Criteria

Insomnia Sxs Only

%

High

Low

Ohayon (2002) Sleep Medicine Reviews

The Economic Burden of InsomniaThe Economic Burden of InsomniaThe Economic Burden of InsomniaThe Economic Burden of Insomnia

Health CareConsultations

Transportation forConsultations

PrescriptionMedications

Over-the-counterProducts

Alcohol Used AsA Sleep Aid

Absenteeism

ProductivityLosses

Daley M et al. Sleep, 2009; 32: 55-64.

76%

15%

5%3%

About 5.3 billion in US dollars

Populations at Risk for InsomniaPopulations at Risk for InsomniaPopulations at Risk for InsomniaPopulations at Risk for Insomnia

• Female sexFemale sex• Increasing ageIncreasing age• Comorbid medical illness (respiratory, Comorbid medical illness (respiratory,

chronic pain, neurological disorders)chronic pain, neurological disorders)• Comorbid psychiatric illness Comorbid psychiatric illness

(depression, depressive symptoms)(depression, depressive symptoms)• Lower socioeconomic statusLower socioeconomic status• Widowed, divorcedWidowed, divorced• Non-traditional work schedulesNon-traditional work schedules

Prevalence of insomnia by age groupPrevalence of insomnia by age groupPrevalence of insomnia by age groupPrevalence of insomnia by age group

%

Age

Large-scale community survey of non-institutionalized American adults, Large-scale community survey of non-institutionalized American adults,

aged 18 to 79 yearaged 18 to 79 yearssMellenger GD, et al. Arch Gen Psychiatry. 1985;42:225-232..Mellenger GD, et al. Arch Gen Psychiatry. 1985;42:225-232..

Comorbid InsomniaComorbid Insomnia Comorbid InsomniaComorbid Insomnia

• Cardiovascular diseasesCardiovascular diseases- Ischemic heart diseaseIschemic heart disease- Nocturnal anginaNocturnal angina

• Respiratory diseasesRespiratory diseases- Chronic obstructive pulmonary disease Chronic obstructive pulmonary disease - Bronchial asthmaBronchial asthma

• Gastrointestinal diseasesGastrointestinal diseases- Peptic ulcer diseasePeptic ulcer disease- Gastroesophageal refluxGastroesophageal reflux

• Neurological diseasesNeurological diseases- Parkinson’s/Alzheimer’sParkinson’s/Alzheimer’s

• Rheumatic disordersRheumatic disorders- FibromyalgiaFibromyalgia- OsteoarthritisOsteoarthritis

• Psychiatric disordersPsychiatric disorders• Dyspnea Dyspnea

• Endocrine syndromesEndocrine syndromes- DiabetesDiabetes- MenopauseMenopause- HyperthyroidismHyperthyroidism

• Pain Pain • Associated sleep disordersAssociated sleep disorders

- Sleep apneaSleep apnea- Restless legs syndromeRestless legs syndrome- Periodic limb movement disorderPeriodic limb movement disorder

• Miscellaneous conditionsMiscellaneous conditions- DermatologicDermatologic- Chronic fatigue syndromeChronic fatigue syndrome- HIV/AIDSHIV/AIDS- Lyme diseaseLyme disease- Systemic cancerSystemic cancer- PregnancyPregnancy- Medical treatment inducedMedical treatment induced

Increased prevalence of medical disorders in Increased prevalence of medical disorders in those with insomniathose with insomnia

Increased prevalence of medical disorders in Increased prevalence of medical disorders in those with insomniathose with insomnia

Taylor DJ., et al. Sleep. 2007;30(2):213-218.

p values are for Odds Ratios adjusted for depression, anxiety, and sleep disorder symptoms. From a community-based population of 772 men and women, aged 20 to 98 years old.

Heart Disease

Cancer HTN Neuro Resp Urinary Diabetes Chronic Pain

GI Any medical problem

%

N=137

N=401

p<.05

p<.05

p<.01p<.01

p<.001

p<.001

p<.001

p<.001

Insomnia prevalence increases with medical comorbidityInsomnia prevalence increases with medical comorbidityInsomnia prevalence increases with medical comorbidityInsomnia prevalence increases with medical comorbidity

Foley D, et al. J Psychosom Res. 2004;56:497-502.

Self-reported questionnaire data from 1506 community-dwelling subjects aged 55 to 84 Self-reported questionnaire data from 1506 community-dwelling subjects aged 55 to 84 yearsyears

80

Number of Medical ConditionsNumber of Medical Conditions

0

10

20

30

40

50

60

70

Per

cen

t o

f R

esp

on

den

ts

Per

cen

t o

f R

esp

on

den

ts

Rep

ort

ing

an

y In

som

nia

Rep

ort

ing

an

y In

som

nia

0 1 2 or 3 4

ICSD2 Subtypes of InsomniaICSD2 Subtypes of InsomniaICSD2 Subtypes of InsomniaICSD2 Subtypes of Insomnia• Adjustment Insomnia (Acute Insomnia)Adjustment Insomnia (Acute Insomnia)• Psychophysiological InsomniaPsychophysiological Insomnia• Paradoxical InsomniaParadoxical Insomnia• Idiopathic InsomniaIdiopathic Insomnia• Insomnia due to Mental DisorderInsomnia due to Mental Disorder• Inadequate Sleep HygieneInadequate Sleep Hygiene• Behavioral Insomnia of ChildhoodBehavioral Insomnia of Childhood• Insomnia due to Drug or SubstanceInsomnia due to Drug or Substance• Insomnia due to Medical ConditionInsomnia due to Medical Condition• Insomnia not due to Substance or known Insomnia not due to Substance or known

Physiological Condition, unspecified Physiological Condition, unspecified • Physiological Insomnia, unspecifiedPhysiological Insomnia, unspecified

American Academy of Sleep Medicine. International classification of sleep disorders, 2nd ed.:

Diagnostic and coding manual. Westchester, Illinois: American Academy of Sleep Medicine, 2005

Adjustment InsomniaAdjustment InsomniaAdjustment InsomniaAdjustment Insomnia

• Associated with identifiable stressorAssociated with identifiable stressor- Psychological, psychosocial, interpersonal, Psychological, psychosocial, interpersonal,

environmental, or physicalenvironmental, or physical• Short duration: few days to weeksShort duration: few days to weeks• Must last < 3 monthsMust last < 3 months• Insomnia resolves when stressor resolves Insomnia resolves when stressor resolves

or when adapted to the stressoror when adapted to the stressor• Features may includeFeatures may include::

- Prolonged sleep latencyProlonged sleep latency- Increased number or duration of awakenings Increased number or duration of awakenings

from sleepfrom sleep- Short sleep durationShort sleep duration- Poor qualityPoor quality

Adjustment InsomniaAdjustment InsomniaAdjustment InsomniaAdjustment Insomnia• Estimated 1 year prevalence: 15-20% among Estimated 1 year prevalence: 15-20% among

adults (adults (especially women, older adults)especially women, older adults)

• Predisposing factors: h/o insomnia and Predisposing factors: h/o insomnia and adjustment insomniaadjustment insomnia

• Can have recurrent episodes to either the same Can have recurrent episodes to either the same or different stressoror different stressor

• Contributes to development of a sequence of Contributes to development of a sequence of maladaptive sleep behaviors and associations maladaptive sleep behaviors and associations which may lead to more persistent insomniawhich may lead to more persistent insomnia

Psychophysiological InsomniaPsychophysiological InsomniaPsychophysiological InsomniaPsychophysiological Insomnia

• Essential feature: heightened arousal Essential feature: heightened arousal and learned sleep-preventing and learned sleep-preventing associations that result in complaint of associations that result in complaint of insomnia & associated decreased insomnia & associated decreased functioning during wakefunctioning during wake

Psychophysiological Insomnia: Psychophysiological Insomnia: Diagnostic CriteriaDiagnostic Criteria

Psychophysiological Insomnia: Psychophysiological Insomnia: Diagnostic CriteriaDiagnostic Criteria

• Symptoms meet insomnia criteriaSymptoms meet insomnia criteria• Present for > 1 monthPresent for > 1 month• One or more of the following:One or more of the following:

- Excess focus on and heightened anxiety about sleepExcess focus on and heightened anxiety about sleep- Difficulty falling asleep in bed at desired time or during Difficulty falling asleep in bed at desired time or during

planned naps, but not during other monotonous activitiesplanned naps, but not during other monotonous activities- Ability to sleep better away from homeAbility to sleep better away from home- Mental arousal in bed: intrusive thoughts or perceived Mental arousal in bed: intrusive thoughts or perceived

inability to volitionally stop mind racinginability to volitionally stop mind racing- Heightened somatic tension in bed - perceived inability to Heightened somatic tension in bed - perceived inability to

relax the body to allow sleeprelax the body to allow sleep

Psychophysiological InsomniaPsychophysiological InsomniaPsychophysiological InsomniaPsychophysiological Insomnia

• Individuals have physiological arousal and Individuals have physiological arousal and learned sleep preventing associationslearned sleep preventing associations

• Physiological arousal may be associated with Physiological arousal may be associated with emotional reactions that do not meet criteria for emotional reactions that do not meet criteria for separate disordersseparate disorders

• Mental arousal in the form of “mind racing” is Mental arousal in the form of “mind racing” is characteristiccharacteristic

• Associations can be learned in response to Associations can be learned in response to internal thoughts or external stimuliinternal thoughts or external stimuli- Over-concern with inability to sleepOver-concern with inability to sleep

The vicious cycle…The vicious cycle…The vicious cycle…The vicious cycle…

Increased drive to sleepIncreased drive to sleep

Increased agitationReduced ability to fall asleep

• Demographics:Demographics:- 1-2% of general population1-2% of general population- 12-15% of patients seen at sleep centers12-15% of patients seen at sleep centers- Women > menWomen > men

• Predisposing factors:Predisposing factors:- H/o light sleepers or episodic poor sleepersH/o light sleepers or episodic poor sleepers- Stress, environmental factors, life changeStress, environmental factors, life change- Anxious over-concern about health, well-being or Anxious over-concern about health, well-being or

daytime functioningdaytime functioning

• Familial patterns are unknownFamilial patterns are unknown

• Onset:Onset:- Insidious onsetInsidious onset

• Insomnia present in early life or young adulthoodInsomnia present in early life or young adulthood

- Acute onsetAcute onset::• Adjustment insomnia failed to resolveAdjustment insomnia failed to resolve

• May persist for decades if untreatedMay persist for decades if untreated• Complications:Complications:

- Higher risk for first episode or recurrence of major Higher risk for first episode or recurrence of major depression depression

- Excessive use of prescription or OTC sleep aidsExcessive use of prescription or OTC sleep aids

• Further directionsFurther directions- Individuals may have innate vulnerability for insomnia Individuals may have innate vulnerability for insomnia

– altered sleep-inducing or arousal system– altered sleep-inducing or arousal system

The AASM guidelines do NOT The AASM guidelines do NOT recommend use of PSG for routine recommend use of PSG for routine evaluation of insomnia unless there is evaluation of insomnia unless there is a suspected additional sleep disorder a suspected additional sleep disorder or patient has failed previous or patient has failed previous behavioral and/or pharmacological behavioral and/or pharmacological treatment of insomnia. treatment of insomnia.

Neurotransmitters in WakeNeurotransmitters in WakeNeurotransmitters in WakeNeurotransmitters in Wake

Sullivan, Medical Clinics of North America, May 2010

Neurotransmitter (Activating/Arousal Promoting)

Location

Acetylcholine - Basal forebrain- Pedunculopontine tegmentum (PPT)/laterodorsal tegmentum (LDT)

Dopamine - Ventral periaqueductal gray matter- Substantia nigra

Glutamate - Ascending reticular activating system- Thalamocortical system

Histamine - Tuberomammillary nucleus (TMN)/posterior hypothalamus

Hypocretin/Orexin - Lateral hypothalamus

Norepinephrine - Locus coeruleus (LC)

Serotonin - Raphe nuclei, thalamus

The Wake “Switch” The Wake “Switch” The Wake “Switch” The Wake “Switch”

Sullivan, Medical Clinics of North America, May 2010

Neurotransmitters in SleepNeurotransmitters in SleepNeurotransmitters in SleepNeurotransmitters in Sleep

Neurotransmitter (Sleep Promoting)

Location

Adenosine - Basal forebrain

Melatonin - Pineal gland

GABA (located in 30% of all brain synapses)

- Ventrolateral preoptic nucleus (VLPO)

Galanin - Ventrolateral preoptic nucleus (VLPO)

Sullivan, Medical Clinics of North America, May 2010

The Sleep “Switch” The Sleep “Switch” The Sleep “Switch” The Sleep “Switch”

Sullivan, Medical Clinics of North America, May 2010

Management of InsomniaManagement of InsomniaManagement of InsomniaManagement of Insomnia

• Treat any underlying cause(s)/comorbid conditionsTreat any underlying cause(s)/comorbid conditions• Promote good sleep habits (improve sleep hygiene)Promote good sleep habits (improve sleep hygiene)• Most individuals with insomnia rely on passive Most individuals with insomnia rely on passive

strategies: “do nothing, read, try to relax’strategies: “do nothing, read, try to relax’• The first line of treatment often involves alcohol, OTC The first line of treatment often involves alcohol, OTC

drugs, dietary/natural productsdrugs, dietary/natural products• When professional help is sought by a physician, When professional help is sought by a physician,

treatment is usually limited to a sleep medicationtreatment is usually limited to a sleep medication

Epidemiology of hypnotic useEpidemiology of hypnotic useEpidemiology of hypnotic useEpidemiology of hypnotic use

• General adult population: 4% (3-10%)General adult population: 4% (3-10%)• Elderly: 10-20%Elderly: 10-20%• Older adults, particularly women, and Older adults, particularly women, and

those residing in nursing facilities are those residing in nursing facilities are much more likely to use hypnoticsmuch more likely to use hypnotics

(Mellinger et al. 1986; Ohayon, 2002)

Commonly Used Classes of Commonly Used Classes of Insomnia MedicationsInsomnia Medications

Commonly Used Classes of Commonly Used Classes of Insomnia MedicationsInsomnia Medications

• Benzodiazepines (BZ)Benzodiazepines (BZ)• Benzodiazepine Receptor Agonists (BzRAs)Benzodiazepine Receptor Agonists (BzRAs)• AntidepressantsAntidepressants• AntipsychoticsAntipsychotics• Melatonin Receptor AgonistsMelatonin Receptor Agonists• AntihistaminesAntihistamines• AnticonvulsantsAnticonvulsants• ““Natural” supplements/OTC AgentsNatural” supplements/OTC Agents

Relative Frequency of Insomnia AgentsRelative Frequency of Insomnia AgentsRelative Frequency of Insomnia AgentsRelative Frequency of Insomnia Agents

FDA-Indicated Sedative HypnoticsFDA-Indicated Sedative HypnoticsFDA-Indicated Sedative HypnoticsFDA-Indicated Sedative Hypnotics

• Benzodiazepines (BZs)Benzodiazepines (BZs)- Estazolam (ProSom)Estazolam (ProSom)- Flurazepam (Dalmane)Flurazepam (Dalmane)- Quazepam (Doral)Quazepam (Doral)- Temazepam (Restoril)Temazepam (Restoril)- Triazolam (Halcion)Triazolam (Halcion)

• Melatonin Receptor Melatonin Receptor Agonist: Rozerem Agonist: Rozerem (Ramelteon)(Ramelteon)

• Tricyclic Tricyclic Antidepressant: Antidepressant: Doxepin (Silenor)Doxepin (Silenor)

• Benzodiazepine Benzodiazepine Receptor Agonists Receptor Agonists (BzRAs)(BzRAs)- Eszopiclone (Lunesta) Eszopiclone (Lunesta)

- Zaleplon (Sonata)Zaleplon (Sonata)

- Zolpidem (Ambien)Zolpidem (Ambien)

- Zolpidem Extended Zolpidem Extended Release (Ambien CR)Release (Ambien CR)

- Zolpidem Sublingual Zolpidem Sublingual (Intermezzo) (Intermezzo)

FDA-Indicated Sedative HypnoticsFDA-Indicated Sedative HypnoticsFDA-Indicated Sedative HypnoticsFDA-Indicated Sedative Hypnotics

a = parent compound; b = active metabolite; SMI = sleep maintenance insomnia; SOI = sleep onset insomnia

Medication

Usual adult therapeutic dose (mg)

Time to onset (min) Terminal elimination half-life (hr)

Active metabolites

Indication

Benzodiazepines Estazolam (ProSom) Flurazepam (Dalmane) Quazepam (Doral) Temazepam (Restoril) Triazolam (Halcion)

0.5 – 2.015 – 30 7.5 – 30 7.5 – 300.125 – 0.25

15 – 3030 – 60 20 – 45 45 – 6015 – 30

8- 242- 5a

47 – 120b

15 - 40a

39 – 120b

8 – 201.5 – 5

NoYes Yes NoNo

SMISMI SMI SMISOI

Benzodiazepine Receptor Agonists Eszopiclone (Lunesta) Zaleplon (Sonata) Zolpidem (Ambien) Zolpidem CR (Ambien CR)

1 – 3 5 – 10 5 – 106.25 – 12.5

60153090

6.01.01.5 – 4.51.6 – 4.0

NoNoNoNo

SMISOI, SMISOISOI, SMI

Melatonin Receptor Agonist Ramelteon (Rozerem)

8

30 – 90

1 – 2.6a

2 – 5b

Yes

SOI

Tricyclic Antidepressant Doxepin (Silenor)

3-6

210

15.3a 31.0b

Yes

SMI

Medication

Dose (mg) Onset (min) Half-life (hr) Active metabolite

Indication

Benzodiazepines:

Estazolam Flurazepam Quazepam Temazepam Triazolam

 0.5 – 2.015 – 30

 7.5 – 30

 7.5 – 30

0.125 – 0.25 

 15 – 3030 – 60

 20 – 45

 45 – 6015 – 30

 

 8- 242- 5a

47 – 120b

15 - 40a

39 – 120b

8 – 201.5 – 5

 

 NoYes

 Yes

 NoNo 

 SMISMI

 SMI

 SMISOI

Benzodiazepine Receptor Agonists (BzRAs):

Eszopiclone Zaleplon Zolpidem Zolpidem ER Zolpidem SL

 

1 – 3 5 – 10 5 – 10

6.25 – 12.51.75 – 3.5

 

6015309035

 

6.01.0

1.5 – 4.51.6 – 4.0 1.4 – 3.6

 

NoNoNoNoNo

 

SMISOI, SMI

SOISOI, SMI

SMI

Melatonin Receptor Agonist

Ramelteon  8

 30 – 90

 1 – 2.6a

2 – 5b

 Yes

 SOI

Tricyclic Antidepressant

Doxepin  

3-6 

210 

15.3a 31.0b

 Yes

 SMI

QuestionQuestionQuestionQuestion

Which of the following medications have been Which of the following medications have been recommended by the NIH to treat insomnia? recommended by the NIH to treat insomnia?

•1: Benzodiazepines (BZ)1: Benzodiazepines (BZ)•2: Benzodiazepine Receptor Agonists (BzRAs)2: Benzodiazepine Receptor Agonists (BzRAs)•3: Antidepressants 3: Antidepressants

AnswerAnswerAnswerAnswer

• The 2005 NIH State-of-the-Science The 2005 NIH State-of-the-Science report on the management of chronic report on the management of chronic insomnia concluded: insomnia concluded: benzodiazepine benzodiazepine receptor agonistsreceptor agonists are the only are the only medications with an established medications with an established scientific basis (clearly defined risk scientific basis (clearly defined risk benefit by dose) for treating insomnia.benefit by dose) for treating insomnia.

http://consensus.nih.gov/2005/insomniastatement.htm

GABAGABAAA Receptor Complex Receptor ComplexGABAGABAAA Receptor Complex Receptor Complex

Berry, Fundamentals of Sleep Medicine, 2012, Ch 25

GABAGABAAA Receptor Alpha Receptor Alpha

SubunitsSubunitsGABAGABAAA Receptor Alpha Receptor Alpha

SubunitsSubunits

ACTIONACTION PROPORTION OF PROPORTION OF GABA RECEPTORSGABA RECEPTORS LOCATIONLOCATION

αα11Sedative, amnestic, Sedative, amnestic,

anticonvulsantanticonvulsant 60%60% All brain regionsAll brain regionscortex, hippocampuscortex, hippocampus

αα22 Anxiolytic, myorelaxantAnxiolytic, myorelaxant 15–20%15–20%Cortex, hippocampus, Cortex, hippocampus, amygdala, forebrain, amygdala, forebrain,

hypothalamushypothalamus

αα33 Anxiolytic, myorelaxantAnxiolytic, myorelaxant 10–15%10–15% Cerebral cortex, thalamus Cerebral cortex, thalamus (reticular nucleus)(reticular nucleus)

αα44, α, α66 Insensitive to BZInsensitive to BZ Dentate gyrusDentate gyrus

αα55

High affinity for BZHigh affinity for BZLow zolpidem affinity Low zolpidem affinity

BZ toleranceBZ tolerance

Cerebral cortex, Cerebral cortex, hippocampushippocampus

Nutt and Stahl, Journal of Psychopharmacology, Nov 2010

Receptor AffinitiesReceptor AffinitiesReceptor AffinitiesReceptor Affinities

ALPHA 1ALPHA 1 ALPHA 2ALPHA 2 ALPHA 3ALPHA 3 ALPHA 5ALPHA 5

ZaleplonZaleplon 17×17× 2×2× 2×2× 1×1×

ZolpidemZolpidem 21×21× 1×1× 1×1× NegligibleNegligible

EszopicloneEszopiclone 8×8× 5×5× 1×1× 8×8×

1× = the lowest affinity of a given drug for any receptor.

• Benzodiazepines (BZ) have a high affinity for all the Benzodiazepines (BZ) have a high affinity for all the subtypes.subtypes.

• On the other hand, the Benzodiazepine Receptor Agonists On the other hand, the Benzodiazepine Receptor Agonists (BzRAs) demonstrate selectivity: (BzRAs) demonstrate selectivity:

Nutt and Stahl, Journal of Psychopharmacology, Nov 2010

BZ & BzRAs: Effects on SleepBZ & BzRAs: Effects on SleepBZ & BzRAs: Effects on SleepBZ & BzRAs: Effects on Sleep

• Improved sleep continuityImproved sleep continuity- Decreased sleep latencyDecreased sleep latency- Increased total sleep timeIncreased total sleep time- Decreased wake after sleep onsetDecreased wake after sleep onset

• PSG changesPSG changes- Decreased NREM 3 (less with BzRAs)Decreased NREM 3 (less with BzRAs)- Reduced amplitude of slow wavesReduced amplitude of slow waves- Increased sleep spindles (BZ)Increased sleep spindles (BZ)

• Decrease in REM sleep (less with BzRAs)Decrease in REM sleep (less with BzRAs)• Decreased periodic limb movements (BzRAs)Decreased periodic limb movements (BzRAs)

BZ & BzRAs: Side EffectsBZ & BzRAs: Side EffectsBZ & BzRAs: Side EffectsBZ & BzRAs: Side Effects

• Residual daytime sedationResidual daytime sedation• Dose-related anterograde amnesiaDose-related anterograde amnesia• Discontinuation phenomenon: Discontinuation phenomenon:

- Rebound insomnia (worsening symptoms -Rebound insomnia (worsening symptoms -less with BzRAs) less with BzRAs)

- Withdrawal (new symptoms)Withdrawal (new symptoms)- Insomnia recurrenceInsomnia recurrence

• Falls/hip fractures in the elderly (long-acting BZ)Falls/hip fractures in the elderly (long-acting BZ)• Respiratory suppression (minor effect, more Respiratory suppression (minor effect, more

with long-acting BZ)with long-acting BZ)

BzRAs: WarningsBzRAs: WarningsBzRAs: WarningsBzRAs: Warnings

• Risk factors for complex sleep-related Risk factors for complex sleep-related behaviors while using BzRAs include: behaviors while using BzRAs include: - Higher doses (2-3 times the indicated Higher doses (2-3 times the indicated

clinical dose)clinical dose)- Prior history of parasomniasPrior history of parasomnias- Prior history of brain injuryPrior history of brain injury- Concurrent use with alcohol Concurrent use with alcohol

BzRAs: General ConsiderationsBzRAs: General ConsiderationsBzRAs: General ConsiderationsBzRAs: General Considerations

• Use lowest dose for shortest time possibleUse lowest dose for shortest time possible• Take on an empty stomach Take on an empty stomach • Not recommended in pregnant or nursing women Not recommended in pregnant or nursing women • Not recommended in advanced liver disease Not recommended in advanced liver disease • Rapid reduction in dose or withdrawal can cause Rapid reduction in dose or withdrawal can cause

withdrawal symptoms including rebound withdrawal symptoms including rebound insomnia insomnia

• Use long-acting BZ with caution in patients with Use long-acting BZ with caution in patients with OSA or lung disease (COPD) OSA or lung disease (COPD)

• Potential for abuse or dependence thought to be Potential for abuse or dependence thought to be low for BzRAs low for BzRAs

Berry, Fundamentals of Sleep Medicine, 2012, Ch 25

Tolerance? Tolerance? Tolerance? Tolerance?

• Eszopiclone (Lunesta) showed continued Eszopiclone (Lunesta) showed continued effect on sleep latency over 12-monthseffect on sleep latency over 12-months

• Led to discontinuation of duration limits Led to discontinuation of duration limits on BzRAs (prior had been 35 days)on BzRAs (prior had been 35 days)

Roth, et al., Sleep Medicine, Nov 2005

On January 10, 2013, the FDA informed On January 10, 2013, the FDA informed the manufacturers of zolpidem (Ambien) the manufacturers of zolpidem (Ambien) that the recommended dose be lowered that the recommended dose be lowered for women from for women from 10 to 5 mg10 to 5 mg for immediate- for immediate-release products and from release products and from 12.5 to 6.25 12.5 to 6.25 mg mg for extended-release products. for extended-release products.

AntidepressantsAntidepressantsAntidepressantsAntidepressants

• Hypnotic properties most strongly related to Hypnotic properties most strongly related to antagonism of serotonin 5-HTantagonism of serotonin 5-HT22, histamine H, histamine H11, ,

and α1 adrenergic receptorsand α1 adrenergic receptors

• Commonly used medications include trazodone, Commonly used medications include trazodone, mirtazapine, amitriptyline, and doxepinmirtazapine, amitriptyline, and doxepin

• Doses used for insomnia are much lower than Doses used for insomnia are much lower than those used for depressionthose used for depression

• Doxepin was approved in 2010 for maintenance Doxepin was approved in 2010 for maintenance insomnia (3 and 6 mg), because it has histamine insomnia (3 and 6 mg), because it has histamine selective properties at low dosesselective properties at low doses

AntidepressantsAntidepressantsAntidepressantsAntidepressants

• Few studies—strongest evidence for efficacy Few studies—strongest evidence for efficacy is for tricyclics (doxepin, amitriptyline, is for tricyclics (doxepin, amitriptyline, trimipramine)trimipramine)

• Specific adverse effects need to be Specific adverse effects need to be considered:considered:- TricyclicsTricyclics: anticholinergic side effects: anticholinergic side effects- TrazodoneTrazodone: hypotension, rare priapism: hypotension, rare priapism- MirtazapineMirtazapine: weight gain: weight gain- SSRIsSSRIs: insomnia, exacerbate RLS: insomnia, exacerbate RLS

AntipsychoticsAntipsychoticsAntipsychoticsAntipsychotics

• Atypical antipsychotics such as quetiapine and Atypical antipsychotics such as quetiapine and olanzapine have indications for psychotic olanzapine have indications for psychotic disorders and maniadisorders and mania

• Antagonize dopamine, histamine (HAntagonize dopamine, histamine (H11), serotonin ), serotonin

(5HT(5HT2A2A), muscarinic, cholinergic, and α1 receptors ), muscarinic, cholinergic, and α1 receptors

• Similar to antidepressants, used at lower doses Similar to antidepressants, used at lower doses for treating insomnia: quetiapine 25-200 mg, for treating insomnia: quetiapine 25-200 mg, olanzapine 2.5-20 mgolanzapine 2.5-20 mg

• Olanzapine has longer half-life than quetiapine: Olanzapine has longer half-life than quetiapine: 21-54 hours versus 6-7 hours, respectively21-54 hours versus 6-7 hours, respectively

AntipsychoticsAntipsychoticsAntipsychoticsAntipsychotics

• Studies in patient populations other than Studies in patient populations other than primary insomnia:primary insomnia:

- Decreased sleep latency Decreased sleep latency

- Olanzapine may increase deeper NREM sleepOlanzapine may increase deeper NREM sleep

- Quetiapine may reduce REM sleepQuetiapine may reduce REM sleep

• Significant potential risks:Significant potential risks:

- AkathesiaAkathesia

- Weight gainWeight gain

- Orthostatic hypotensionOrthostatic hypotension

- Contribution to metabolic syndromeContribution to metabolic syndrome

Melatonin Receptor AgonistMelatonin Receptor AgonistMelatonin Receptor AgonistMelatonin Receptor Agonist

• Ramelteon became first melatonin receptor Ramelteon became first melatonin receptor agonist approved for treating insomnia agonist approved for treating insomnia (2005) (2005)

• 17x more potent at melatonin type I 17x more potent at melatonin type I (decreased waking signal) than type II (decreased waking signal) than type II (circadian rhythms) receptors(circadian rhythms) receptors

• Primary benefit on sleep latency Primary benefit on sleep latency • Non-scheduled medication — lacks potential Non-scheduled medication — lacks potential

for abuse or dependencefor abuse or dependence• Adverse effects: nausea, headache, fatigueAdverse effects: nausea, headache, fatigue

AntihistaminesAntihistaminesAntihistaminesAntihistamines

• Diphenhydramine, doxylamine, and Diphenhydramine, doxylamine, and hydroxyzine are the most commonly hydroxyzine are the most commonly used for insomniaused for insomnia

• Tolerance to daytime sedation and Tolerance to daytime sedation and similar decrease in effectiveness as a similar decrease in effectiveness as a hypnotic can develop in 4 dayshypnotic can develop in 4 days11

• Anticholinergic activity needs to be Anticholinergic activity needs to be considered, especially in the elderly considered, especially in the elderly

1Roth et al, J. Clin. Psychopharm., Oct 2002

AnticonvulsantsAnticonvulsantsAnticonvulsantsAnticonvulsants

• Pregabalin and gabapentin bind to voltage-Pregabalin and gabapentin bind to voltage-gated calcium channels diminish release gated calcium channels diminish release of glutamate and norepinephrineof glutamate and norepinephrine

• FDA indications: partial seizures, pain, FDA indications: partial seizures, pain, fibromyalgiafibromyalgia

• Gabapentin used at doses of 100-900 mg for Gabapentin used at doses of 100-900 mg for insomniainsomnia

• Common adverse effects include sedation, Common adverse effects include sedation, dizziness, ataxiadizziness, ataxia

Krystal, Principles and Practice of Sleep Medicine, 5th ed., Chapter 82

MelatoninMelatoninMelatoninMelatonin

• Produced by pineal gland; "turned on" by Produced by pineal gland; "turned on" by the SCN at night by darknessthe SCN at night by darkness

• Melatonin on it’s own will not induce sleep, Melatonin on it’s own will not induce sleep, it is more like a “darkness” signaler it is more like a “darkness” signaler

• If taken in the evening or when it's dark, If taken in the evening or when it's dark, melatonin can speed up sleep preparation, melatonin can speed up sleep preparation, and it can tell the body clock to shift its and it can tell the body clock to shift its sleep cycle to an earlier timesleep cycle to an earlier time

• For some people, melatonin seems to help For some people, melatonin seems to help improve sleep. Of the few studies involving improve sleep. Of the few studies involving people with insomnia, results are people with insomnia, results are inconclusiveinconclusive

MelatoninMelatoninMelatoninMelatonin• Dosage is very important. Dosage is very important. • Most drug stores and health stores carry tablet Most drug stores and health stores carry tablet

sizes 3-10mg. sizes 3-10mg. • New evidence shows that adult males only need New evidence shows that adult males only need

150 micrograms, and the average female needs 150 micrograms, and the average female needs only 100 micrograms, so 20 - 50 times more than only 100 micrograms, so 20 - 50 times more than what is needed.what is needed.

• Large studies are needed to demonstrate if Large studies are needed to demonstrate if melatonin is effective and safe for some forms of melatonin is effective and safe for some forms of insomnia, particularly for long-term useinsomnia, particularly for long-term use. .

Hypnotic SelectionHypnotic SelectionHypnotic SelectionHypnotic Selection

Hypnotic indicatedHypnotic indicated

Consider cost, Consider cost, prior treatment prior treatment failures, side failures, side effects, co-effects, co-morbidities, morbidities, interactionsinteractions

Short to Short to intermediate BZRA intermediate BZRA

or Ramelteonor RamelteonSOI: Zaleplon, SOI: Zaleplon,

RamelteonRamelteonSOI, SMI: SOI, SMI: zolpidem, zolpidem,

eszopiclone, eszopiclone, temazepamtemazepam

ImprovedImproved

Duration Duration too long, too long,

AM AM grogginessgrogginess

Duration Duration not long not long enoughenough

IneffectiveIneffective

Intolerable Intolerable side effectsside effects

ContinueContinue

Use shorter Use shorter active active BZRABZRA

Use longer Use longer acting acting BZRABZRA

Increase Increase dose or dose or switchswitch

SwitchSwitch

Improved?Improved?

ContinueContinue

BZRA + BZRA + sedating sedating

antidepressantantidepressant

Sedating Sedating antidepressantantidepressant

or

Y

N

Adapted from Berry, Fundamentals of Sleep Medicine, 2012, Ch 25

Sedative Hypnotics: General Sedative Hypnotics: General ConsiderationsConsiderations

Sedative Hypnotics: General Sedative Hypnotics: General ConsiderationsConsiderations

• Ensure patients dedicated an adequate amount of Ensure patients dedicated an adequate amount of time to sleep time to sleep

• Consider pharmacokinetic and pharmacodynamic Consider pharmacokinetic and pharmacodynamic properties, cost, side effects, and duration of useproperties, cost, side effects, and duration of use

• Do not combine with alcohol!Do not combine with alcohol!• Use caution with other sedativesUse caution with other sedatives• Consider patient preference for treatment Consider patient preference for treatment

modality modality • Evaluate contributions to insomnia from other Evaluate contributions to insomnia from other

medications and medical conditionsmedications and medical conditions• Consider drug interactions when choosing an Consider drug interactions when choosing an

agentagent

Selecting a Sedative HypnoticSelecting a Sedative HypnoticSelecting a Sedative HypnoticSelecting a Sedative Hypnotic

• If patient has a history of alcohol or recreational If patient has a history of alcohol or recreational drug dependence: consider non-controlled drug dependence: consider non-controlled medications:medications:- Ramelteon, doxepin, antidepressants, Ramelteon, doxepin, antidepressants,

antipsychotics, or anticonvulsantsantipsychotics, or anticonvulsants- Antipsychotics should be reserved for cases Antipsychotics should be reserved for cases

with primary psychiatric disorders. with primary psychiatric disorders. • If patient has co-morbid pain, seizures, RLS, If patient has co-morbid pain, seizures, RLS,

PLMD, or fibromyalgiaPLMD, or fibromyalgia- Gabapentin or pregabalin Gabapentin or pregabalin

• Consider CBT-I (cognitive behavioral therapy for Consider CBT-I (cognitive behavioral therapy for insomnia) for chronic insomnia insomnia) for chronic insomnia

When to discontinue hypnotics…When to discontinue hypnotics…When to discontinue hypnotics…When to discontinue hypnotics…

• ……desire to stopdesire to stop• ……is no longer effectiveis no longer effective• ……is contraindicatedis contraindicated

- Alcohol abuse/dependenceAlcohol abuse/dependence- PregnancyPregnancy

• ……escalating dosage and demonstrating escalating dosage and demonstrating signs of tolerance and/or abusesigns of tolerance and/or abuse

• ……adverse effects such as cognitive adverse effects such as cognitive impairment or psychomotor performance impairment or psychomotor performance issuesissues

• ……has been using the medication longer has been using the medication longer than recommended?than recommended?

““Am I an addict?”Am I an addict?”““Am I an addict?”Am I an addict?”

• Tolerance – Reduction of pharmacological effect Tolerance – Reduction of pharmacological effect after repeated administration of drugafter repeated administration of drug

• Dependence – Neuroadaptation phenomenon Dependence – Neuroadaptation phenomenon resulting from chronic administration, resulting from chronic administration, characterized by withdrawal syndromecharacterized by withdrawal syndrome

• Abuse – Loss of control over drug taking, Abuse – Loss of control over drug taking, preoccupation with drug, continued use despite preoccupation with drug, continued use despite adverse consequences, use for “high”adverse consequences, use for “high”

Brady et al., Current Psychiatric Treatment II, 1997

Withdrawal SymptomsWithdrawal SymptomsWithdrawal SymptomsWithdrawal Symptoms

• Rebound InsomniaRebound Insomnia• AnxietyAnxiety• RestlessnessRestlessness• Increased perceptual acuityIncreased perceptual acuity• Impaired concentrationImpaired concentration• Tend to be more severe with higher Tend to be more severe with higher

dosages and with shorter half livesdosages and with shorter half lives

Rebound InsomniaRebound InsomniaRebound InsomniaRebound Insomnia

• Worsening of sleep upon discontinuation of Worsening of sleep upon discontinuation of medicationmedication

• Level of sleep disturbance can be more severe Level of sleep disturbance can be more severe than before starting medicationthan before starting medication

• This transient symptom is misinterpreted as a This transient symptom is misinterpreted as a chronic problem, therefore prompts patients to chronic problem, therefore prompts patients to resume or increase medication useresume or increase medication use

• Need to provide education on rebound insomnia Need to provide education on rebound insomnia phenomenon as well as implementing tapering phenomenon as well as implementing tapering plan to minimize withdrawalplan to minimize withdrawal

Cycle of Hypnotic Dependent InsomniaCycle of Hypnotic Dependent InsomniaCycle of Hypnotic Dependent InsomniaCycle of Hypnotic Dependent Insomnia

Dependence

Resume use of Medication

Withdrawal: Rebound Insomnia

Attempt to Stop Medication

Tolerance

Increase Sleep Medication

Tolerance: Decreased effectiveness

Sleep Medication

Insomnia

Strategies for discontinuing Strategies for discontinuing hypnotic medicationshypnotic medications

Strategies for discontinuing Strategies for discontinuing hypnotic medicationshypnotic medications

• Abrupt discontinuationAbrupt discontinuation• Tapering from short-acting hypnoticsTapering from short-acting hypnotics• Substitute and taper long-acting hypnoticSubstitute and taper long-acting hypnotic• Use of other drug to facilitate Use of other drug to facilitate • CBTi as an adjunctCBTi as an adjunct

Spielman Model: Three P’sSpielman Model: Three P’sSpielman Model: Three P’sSpielman Model: Three P’s

Cognitive-Behavioral Treatment Cognitive-Behavioral Treatment of Insomniaof Insomnia

Cognitive-Behavioral Treatment Cognitive-Behavioral Treatment of Insomniaof Insomnia

• Multi-component treatment Multi-component treatment • Sleep hygiene educationSleep hygiene education

• Stimulus controlStimulus control

• Sleep restrictionSleep restriction

• Relaxation therapyRelaxation therapy

• Cognitive restructuringCognitive restructuring

• Most behavioral sleep medicine Most behavioral sleep medicine clinicians use a multi-modal approach - clinicians use a multi-modal approach - combining the techniques abovecombining the techniques above

Psychophysiological Insomnia

Circadian DisruptionImproper Sleep

Scheduling

Cognitive FactorsDysfunctional Beliefs

Homeostatic DysregulationExcessive TIB

Napping

Inhibitory FactorsPoor sleep hygieneConditioned arousal

Pre-bed & In-bed habits

Edinger & Means, 2005

Sleep Hygiene

Stimulus Control

Sleep Restriction

Relaxation