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
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