Ruth Benca, MD PhD Wisconsin Sleep Insomnia and Primary Care.

Ruth Benca, MD PhDWisconsin Sleep

Insomnia and Primary Care

Diagnosis requires one or more of the following: difficulty initiating sleep difficulty maintaining sleep waking up too early, or sleep that is chronically nonrestorative or poor in

quality Sleep difficulty occurs despite adequate

opportunity and circumstances for sleep. Insomnia is not sleep deprivation, but the

two may coexist.

Insomnia defined

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

At least one daytime impairment related to the nighttime sleep difficulty must be present: Fatigue/malaise Attention, concentration, or memory impairment Social/vocational dysfunction or poor school

performance Mood disturbance/irritability Daytime sleepiness Motivation/energy/initiative reduction Proneness for errors/accident at work or while

driving Tension headaches, and/or GI symptoms in

response to sleep loss Concerns or worries about sleep

Insomnia must be associated with daytime impairment

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

Comorbid insomniaImpacts quality of life and worsens clinical

outcomes1,2

Predisposes patients to recurrence3

May continue despite treatment of the primary condition4

“Comorbid insomnia”more appropriate than “secondary insomnia,” because limited understanding of mechanistic pathways in chronic insomnia precludes drawing firm conclusions about the nature of these associations or direction of causality. Considering insomnia to be “secondary” may also result in undertreatment.5

1 Roth T, Ancoli-Israel S. Sleep. 1999;22:S354-S358.2 Katz DA, McHorney CA. J Fam Pract. 2002;51:229-235.3 Chang PP, et al. Am J Epidemiol. 1997;146:105-114.4 Ohayon MM, Roth T. Psychiatr Res. 2003;37:9-15.5 National Institutes of Health State of the Science Conference Statement on Manifestations and Management of Chronic Insomnia in Adults, June 13-15, 2005. National Institutes of Health. Sleep. 2005 Sep 1;28(9):1049-1057.

Epidemiology of insomnia General population: 10-15%Clinical Practice: > 50%The prevalence and treatment of

primary insomnia have been the most studied (less than 20% of cases)1,2

Comorbid insomnia accounts for >80% of cases

1 Simon GE,Vonkorff M. Am J Psychiatry. 1997;154:1417-1423.2 Hajak G. Sleep. 2000; 23:S54-S63.

At-risk populations for insomnia Female sex Increasing age Comorbid medical illness (especially

respiratory, chronic pain, neurological disorders)

Comorbid psychiatric illness (especially depression, depressive symptoms)

Lower socioeconomic status Race (African American > White) Widowed, divorced Non-traditional work schedules

Why insomnia is a disorder, not just a symptom

• Relative consistency of insomnia symptoms and consequences across comorbid disorders

• Course of insomnia does not consistently covary with the comorbid disorder

• Insomnia responds to different types of treatment than the comorbid disorder

• Insomnia responds to the same types of treatment across different comorbid disorders

• Insomnia poses common risk for development of and poor outcome in different disorders

Harvey, Clin Psychol RevClin Psychol Rev, 2001;, 2001; Lichstein et al., Lichstein et al., Treating Sleep Disorders, Treating Sleep Disorders, 20042004

Increased prevalence of medical disorders in those 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 Diseas

e

Cancer HTN Neuro-logic

Breath-ing

UrinaryDiabetes

Chronic Pain

GI Any medica

l proble

m

%

N=137

N=401

p<.05

p<.05

p<.01p<.01

p<.001

p<.001

p<.001

p<.001

Pre

vale

nce,

%

Survey Of Adults (N=2101) Living In Tucson, Arizona,

Assessed Via Self-administered Questionnaires

** ******

****

Increased prevalence of insomnia in those with medical disorders

Klink ME et al. Arch Intern Med. 1992;152:1634-1637.

*P ≤ .001, **P ≤ .005 vs. no health problemASVD, arteriosclerotic vascular disease; OAD, obstructive airway disease.

Insomnia prevalence increases with greater 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 years

80

Number of Medical Conditions

0

10

20

30

40

50

60

70

Perc

en

t of

Resp

on

den

ts

Rep

ort

ing

an

y I

nsom

nia

0 1 2 or 3 4

Psychiatric disorder is the most common condition comorbid with insomnia

Adjustment disorder (2%)

Anxiety disorder (24%)

Bipolar disorder (2%)

Depressive disorder (8%)

Psychiatric Disorders (36%)

Other DSM-IV Distribution of Insomnia(64%)

No DSM-IV diagnosis (24%)Other sleep disorders (5%)Insomnia due to a general medical condition (7%)Substance-induced insomnia (2%)Insomnia related to another mental disorder (10%)Primary insomnia (16%)

Ohayon MM. Sleep Med Rev. 2002;6:97-111.

N=20,536. European meta-analysis

Relative risk for psychiatric disorders associated with insomnia

1Breslau N, et al. Sleep disturbance and psychiatric disorders: a longitudinal epidemiological study of young adults. Biol Psychiatry. 1996;39:411-418.2Ford DE, Kamerow DB. Epidemiologic study of sleep disturbances and psychiatric disorders. An opportunity for prevention? JAMA. 1989;262(11):1479-1484.

1Breslau, 1996.

N=10072Ford and Kamerow,

1989.N=811

1

1

1

2

2

1,2

1,2

1,2

1,2

Timing of insomnia related to onset of psychiatric illness

Ohayon MM , Roth T. J Psychosom Res. 2003;37:9-15.

N=14,915

* Number of men included at each time point. Chang P et al. Am J Epidemiol. 1997;146:105-114.

Insomnia is a risk factor for later-life depression

Insomnia*Yes 137 135 133 127 117 106 99 27 9No 887 877 859 838 799 740 616 382 216

Cu

mu

lati

ve I

ncid

en

ce (

%)

YesNo

Total Cases137 23887 76

Insomnia

P=.0005

Follow-up Time (Years)

0

5

10

15

20

25

30

35

40

0 5 10 15 20 25 30 35 40

Objective sleep abnormalities are seen in psychiatric patients

Comparison of sleep EEG in groups of patients with psychiatric disorders or insomnia to age-matched normal controls.

TST SE SL SWS REM L

Mood

Alcoholism

Anxiety Disorders

Schizophrenia

Insomnia

Benca RM et al. Arch Gen Psych. 1992;49:651-668

Bidirectional relationship between psychiatric disorders and insomnia

ACTH, adrenocorticotropic hormoneTST, total sleep timeSOL, sleep onset latencySWS, slow wave sleep

Sleep and menopause

Peri- and postmenopausal women have more sleep complaints1

41% of early perimenopausal women report sleep difficulties2

Frequent awakenings suggest insomnia is secondary to vasomotor symptoms3 However, waking episodes may occur in

absence of hot flashes4

1Young T, et al. Sleep. 2003;26:667-672.2Gold E, et al. Am J Epidemiol. 2000;152:463-473.3Woodward S, Freedman RR. Sleep.1994;17:497-501.4Polo-Kantola P, et al. Obstet Gynecol. 1999;94:219-224.

1Young T, et al. Sleep. 2003;26:667-672.2Gold E, et al. Am J Epidemiol. 2000;152:463-473.3Woodward S, Freedman RR. Sleep.1994;17:497-501.4Polo-Kantola P, et al. Obstet Gynecol. 1999;94:219-224.

Age Group, y

50

40

30

20

10

0

Perc

en

t

10-19 20-29 30-39 40-49 50-59 60-69 70+

“Trouble With Sleeping” Assessed in a comprehensive survey of 1645 individuals in Alachua County, Florida

Complaints of sleep problems with age

Karacan I et al. Soc Sci Med. 1976;10:239-244.Karacan I et al. Soc Sci Med. 1976;10:239-244.

Prevalence of insomnia by age group

%

Age Group, years

Large-scale community survey of non-institutionalized American adults, aged 18 to 79 years

Mellenger GD, et al. Arch Gen Psychiatry. 1985;42:225-232.Mellenger GD, et al. Arch Gen Psychiatry. 1985;42:225-232.

Patients with pain report poor sleep

287 subjects reporting to pain clinic Mean age, 46.7 years; half with back pain

89% reported at least 1 problem with sleep

Significant correlations between sleep andPhysical disabilityPsychosocial disabilityDepressionPain

McCracken LM, Iverson GL. Pain Res Manag. 2002;7:75-79.McCracken LM, Iverson GL. Pain Res Manag. 2002;7:75-79.

Insomnia comorbid with pain

N=18,980; p<.001. Based on survey data.*Pain categories included limb pain, backaches, joint pain, GI pain, and headaches.

Ohayon MM. J Psychiatr Res. 2005 Mar;39(2):151-159.

Control Any pain*

%

Bidirectional relationship between pain and insomnia

DIS, difficulty initiating sleepDMS, difficulty maintaining sleep

Sleep and cancer• 30% to 75% of newly diagnosed or recently

treated cancer patients complain of insomnia (double that of the general population)

• Sleep complaints in cancer patients consist of• difficulty falling asleep• difficulty staying asleep• frequent and prolonged nighttime awakenings

• Complaints occur before, during and after treatment

Fiorentino L, Ancoli-Israel, S. Sleep dysfunction in patients with cancer. Curr Treat Opt Neurol. 2007;9:337–346.

Risk factors for insomnia in cancer patients

Risk Factor Examples

Disease factorsTumors that increase steroid production, symptoms of tumor invasion (pain, dyspnea, fatigue, nausea, pruritis)

Treatment factorsFrequent monitoring, corticosteroid treatment, hormonal fluctuations, fatigue

Medications

Narcotics, chemotherapy, neuroleptics, sympathomimetics, sedative/hypnotics, steroids, caffeine/nicotine, antidepressants, diet supplements

Environmental factors

Disturbing light and noise, temperature extremes

Psychosocial disturbances

Depression, anxiety, delirium, stress

Physical disorders Headaches, seizures, snoring/sleep apnea

O'Donnell JF. Clin Cornerstone. 2004;6(Suppl 1D):S6-S14. 

Bidirectional relationship between insomnia and cancer

SDB, sleep-disordered breathingFiorentino L, Ancoli-Israel, S. Sleep dysfunction in patients with cancer. Curr Treat Opt Neurol. 2007;9:337–346.

Insomnia and OSA or CSAStudies have shown that 39% to 55% of

patients with OSA have comorbid insomnia. Associated factors include: female genderpsychiatric diagnoseschronic pain

OSA patients with comorbid insomnia haveMore severe sleep apneaIncreased depression, anxiety and stress

Krell SB, Kapur VK. Sleep Breathing. 2005;9:104-10. Smith S, et al. Sleep Med. 2004;5:449-456.

AHI, apnea hypopnea index. CSA, central sleep apnea. DI, desaturation index. OSA, obstructive sleep apnea.

restless leg symptomslower AHI, lower DI

Insomnia and OSA or CSA< 1% of 1,000 patients with OSA surveyed

had been diagnosed with insomniaMood problems were not formally addressed

In a small study of patients with CSA (n=14):36% had sleep onset insomnia79% had maintenance insomnia

This rate was significantly higher than in patients with OSA (P =.016)

Morganthaler TI,et al. Sleep. 2006;29:1203-1209. Smith S, et al. Sleep Med. 2004;5:449-456.

Insomnia and COPD>50% of patients with COPD have insomnia

25% complain of excessive daytime sleepinessMedications for COPD contribute to insomnia

Inhaled or PO; anticholinergics, corticosteroids, beta-2-agonists, theophylline; bupropion used for smoking cessation

Sleep deprivation may attenuate ventilatory response to hypercapnia in patients with COPD, leading to further desaturation and sleep disruption

George CFP. Sleep. 2000;23:S31-S35. White DP, et al. Am Rev Respir Dis. 1983;128:984-986.

Insomnia and COPDInsomnia linked with comorbidities of COPD

Eg, depression, smoking, orthopnea, and nocturnal hypoxemia

Suggests multiple factors in pathogenesis of insomnia in COPD

Insomnia can impair pulmonary functionSpirometric decline is observed after one

night of sleep deprivationDespite importance of treating the

underlying COPD, this may not lead to improvement of insomnia in clinical practice

Cormick W, et al. Thorax. 1986;41:846-854. Kutty K. Curr Opin Pulm Med. 2004;10:104-112. Maggia S, et al. J Am Geriatric Soc. 1998;46:161-168. Phillips BA, et al. Chest. 1987;91:29-32. Wetter DW, et al. Prev Med. 1994;23:328-334.

Insomnia may be a predictor of hypertension

N=9237 male Japanese workers assessed for difficulty initiating and/or maintaining sleep and followed up for 4 years or until the development of HTN (initiation of anti-HTN therapy or a SBP of ≥140 mmHg or a DBP of ≥140 mmHg). Results adjusted for BMI, tobacco and alcohol use and job stress.

Suka M, et al. J Occup Health. 2003;45:344-350.

HTN

In

cid

en

ce

(%)

n=4602

n=192 n=41

57

n=286

95% CI: 1.42-2.70

95% CI: 1.45-2.45

Short sleep duration and hypertension: NHANES I and the Sleep Heart Health Study

Gangwisch et al. Hypertension. 2006;47:833-839. Gottlieb DJ, et al. Sleep. 2006;29(8):1009-1014.

≤5h

6h

7-8h

≥9h

≤6h

6-7h

7-8h

8-9h

≥9h

(1.0; referent)

(1.0; referent)

Hazard Ratios. N=4180. Subjects 32-59y. Sleep duration and increased risk of HTN, adjusted for multiple confounders including physical activity, alcohol/salt consumption, smoking, age, overweight/obesity, and diabetes.

Odds Ratios. N=5910. Subjects 40-100y. Sleep duration and increased risk of HTN adjusted for age, sex, race, apnea-hypopnea index and BMI.

Relationships between sleep disorders* and obesity

*Insomnia or sleep deprivation.1Bjorvatn B, et al. J Sleep Res. 2007;16(1):66-76.2Flint J, et al. J Pediatr. 2007;150(4):364-369.3Chaput JP, et al. Obesity (Silver Spring). 2007;15(1):253-261.4Gottlieb et al. Arch Intern Med. 2005;165:863-868.

Factors associated with reduced sleep time* may contribute to obesity

Management of insomniaTreat any underlying cause(s)/comorbid

conditions

Promote good sleep habits (improve sleep hygiene)

Consider cognitive behavior therapy

Consider medications to improve sleep

Kupfer DJ and Reynolds CF III. N Engl J Med. 1997;336:341-346.

Practicing good sleep hygieneAvoid:

“watching the clock”use of stimulants, eg, caffeine, nicotine, particularly near

bedtime1,3

heavy meals or drinking alcohol within 3 hours of bed1

exposure to bright light during the night 1,3

Enhance sleep environment: dark, quiet, cool temperature1,3

Increase exposure to bright light during the day 2

Practice relaxing routine 1-3

Reduce time in bed; regular sleep/wake cycle 1-3

Time regular exercise for the morning and/or afternoon 1,3

1 NHLBI Working Group on Insomnia. 1998. NIH Publication. 98-4088. 2 Kupfer DJ, Reynolds CF. N Engl J Med. 1997;336:341-346.3 Lippmann S et al. South Med J. 2001;94:866-873.

Behavioral techniquesTechnique Aim

Stimulus control therapy

Imprint bed and bedroom as sleep stimulus

Sleep restrictionRestrict actual time spent in bed to enhance sleep depth & consolidation

Cognitive therapy

Address dysfunctional beliefs and attitudes about sleep

Relaxation training

Decrease arousal and anxiety

Circadian rhythm entrainment

Reinforce or reset biological rhythm using light and/or chronotherapy

Cognitive behavior therapy

Combination of behavioral and cognitive approaches listed above

Drugs indicated for insomnia

* Modified formulation. †No short-term use limitation.

Generic BrandT1/2

(Hours)Dose (mg) Drug Class

Flurazepam Dalmane 48-120 15-30 BZD

Temazepam Restoril 8-20 15-30 BZD

Triazolam Halcion 2-6 0.125-0.25 BZD

Estazolam Prosom 8-24 1-2 BZD

Quazepam Doral 48-120 7.5-15 BZD

Zolpidem Ambien 1.5-2.4 5-10 non-BZD

Zaleplon Sonata 1 5-20 non-BZD

Eszopiclone† Lunesta 5-7 1-3 non-BZD

Zolpidem Ex Rel†

Ambien CR

1.5-2.4* 6.25-12.5 non-BZD

Ramelteon† Rozerem 1.5-5 8 MT agonist

Antidepressants for Insomnia: Indications

Patients with psychoactive substance use disorder history

Patients with insomnia related to depression, anxiety

Treatment failures with BzRASuspected sleep apneaFibromyalgiaPrimary insomnia (second-line agents)Not FDA-approved for use as

hypnotics

Antidepressant drug effects on sleep

Sleep continui

ty

Slow wave sleep

REM sleep

Other

Tricyclic To To To

PLMs Apnea

SSRI To To To Eye movements in

NREM PLM apnea

Trazodone, Nefazodone

To To Trazodone more sedating

Bupropion To No increase in PLM

Mirtazapine Low doses

sedating

When to refer an insomnia patient to Sleep Clinic:

Medical and psychiatric comorbidities have been assessed and are adequately treated

Patient has been instructed in sleep hygiene

Patient has failed trials of behavioral and/or pharmacological therapy

Other common sleep disorders treated by sleep specialists:Sleep apnea*Restless legs/periodic limb movement

disorderParasomniasCircadian rhythm disordersNarcolepsy*

*Typically require sleep laboratory testing as well as clinical evaluation for diagnosis

High density-EEG / TMS studies in health and disease pioneered by Giulio Tononi, MD, PhD

High density EEG (256 electrodes) recorded across entire night, TMS in wakefulness and sleep

Why high-density EEG in sleep?

• Can now be done routinely; noninvasive and relatively inexpensive

• What could be done with standard PSG has largely been done (NIH roadmap discourages it)

• Sleep apnea PSG likely to migrate to home-monitoring

• Spatial resolution is comparable to PET; temporal resolution is ideal

• Sleep is a window on spontaneous brain function, unconfounded by attention, motivation, etc.

• Broad patient population: sleep disorders, psychiatric disorders, neurological disorders (and connection to long-term epilepsy monitoring)

Spontaneous brain rhythms during sleep reflect brain functioning unconfounded by attention and motivation

slow wave activity spindle activity

Fz

Cz

P4

Sleep Slow Wave Activity is Homeostatically Regulated Throughout the Cortex

Slow waves originate more frequently in orbitofrontal and centroparietal regionsand propagate in an antero-posterior direction

P<

.05

100

80

60

40

20

Schizophrenics

Controls Depressed

Schizophrenics vs. Controls Schizophrenics vs. Depressed

Depressed vs. Controls

EE

G s

pin

dle

activ

ity (

13-

15 H

z)

Diagnosis: Sleep spindle activity is reduced in schizophrenia

Ferrarelli et al., Am. J. Psychiatry, 2007

Treatment: Sleep slow oscillations can be triggered by TMS

Massimini et al., submitted

• Sleep Clinic and 16 Bed Sleep Laboratory- UWMF clinic- Sleep Laboratory joint venture with Meriter

• Open with 12 beds, 5 nights/week

• Clinic operates 5 days/week

• Staff model - approx 30 FTE

• Sleep Equipment of Wisconsin - UWHC/Meriter joint venture

Psychiatry R. Benca, MD, PhDM. Rumble, PhD

PulmonaryM. Klink, MDS. Cattapan, MDJ. McMahon, MDG. DoPico, MDMihaela Teodorescu, MD

GeriatricsS. Barczi, MDMihai Teodorescu, MD

PediatricsC. Green, MD

NeurologyJ. Jones, MD

Interdisciplinary Clinical Expertise

Clinical Practice Model: Clinic

• Referral-based practice.

• Improve access.

• Standardized assessments of all patients using validated questionnaires, comprehensive evaluations, outcomes measures. All information on electronic database.

• Development of behavioral sleep medicine program.

• Outreach to primary care.

Clinical Practice Model: Laboratory

• Encourage referring providers to request studies with management.

• Laboratory studies read the next morning. Timely communication with referring physicians; reports sent and/or available electronically within 24 hours of completion.

• Sleep Equipment of Wisconsin on-site to provide immediate availability of treatment.

Educational program Directed by Steven Barczi, MD ACGME-accredited fellowship

Currently only 1 position; application for up to 3 slots per year pending

Plan to coordinate medical school and residency training in sleepLectures in medical school and residency

curriculaClinical electives

Translational research opportunity• Brand new program• Standardized assessment and outcomes

measures• State-of-the-art neurophysiological

recording techniques

Every patient a potential research subject