Download Comorbid insomnia

Insomnia and Primary Care
Ruth Benca, MD PhD
Wisconsin Sleep
Insomnia defined

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.
American Academy of Sleep Medicine. International classification of sleep disorders, 2nd ed.: Diagnostic and coding manual.
Westchester, Illinois: American Academy of Sleep Medicine, 2005.
Insomnia must be associated with
daytime impairment

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
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 insomnia
 Impacts 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.
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.
3 Chang
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
2 Hajak
GE,Vonkorff M. Am J Psychiatry. 1997;154:1417-1423.
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 Rev, 2001; Lichstein et al., Treating Sleep Disorders, 2004
Increased prevalence of medical
disorders in those with insomnia
N=401
N=137
%
p<.001
p<.001
p<.001
p<.001
p<.01
p<.05
p<.01
p<.05
Heart Cancer
Disease
HTN Neuro- Breath- Urinary Diabetes Chronic
logic
ing
Pain
GI
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.
Taylor DJ., et al. Sleep. 2007;30(2):213-218.
Any
medical
problem
Increased prevalence of insomnia in
those with medical disorders
Survey Of Adults (N=2101) Living In Tucson, Arizona,
Prevalence, %
Assessed Via Self-administered Questionnaires
*
*
**
*
*P ≤ .001, **P ≤ .005 vs. no health problem
ASVD, arteriosclerotic vascular disease; OAD, obstructive airway disease.
Klink ME et al. Arch Intern Med. 1992;152:1634-1637.
*
Insomnia prevalence increases
with greater medical comorbidity
Percent of Respondents
Reporting any Insomnia
80
70
60
50
40
30
20
10
0
0
1
2 or 3
4
Number of Medical Conditions
Self-reported questionnaire data from 1506 community-dwelling subjects aged 55 to 84 years
Foley D, et al. J Psychosom Res. 2004;56:497-502.
Psychiatric disorder is the most common
condition comorbid with insomnia
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%)
Adjustment disorder (2%)
Psychiatric Disorders (36%)
Anxiety disorder (24%)
Bipolar disorder (2%)
Depressive disorder (8%)
N=20,536.
European meta-analysis
Ohayon MM. Sleep Med Rev. 2002;6:97-111.
Relative risk for psychiatric disorders
associated with insomnia
1,2
1,2
1,2
1,2
2
1
1Breslau, 1996.
N=1007
2Ford
and
Kamerow, 1989.
N=811
1
2
1
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.
Timing of insomnia related to onset
of psychiatric illness
N=14,915
Ohayon MM , Roth T. J Psychosom Res. 2003;37:9-15.
Insomnia is a risk factor for
later-life depression
Cumulative Incidence (%)
40
Insomnia
Yes
No
35
30
25
Total
137
887
Cases
23
76
P=.0005
20
15
10
5
0
0
Insomnia*
Yes
No
5
10
15
20
25
30
35
40
99
616
27
382
9
216
Follow-up Time (Years)
137
887
135
877
133
859
127
838
* Number of men included at each time point.
Chang P et al. Am J Epidemiol. 1997;146:105-114.
117
799
106
740
Objective sleep abnormalities are
seen in psychiatric patients
TST
SE
SL
SWS
REM L
Mood
Alcoholism
Anxiety
Disorders
Schizophrenia
Insomnia
Comparison of sleep EEG in groups of patients with psychiatric disorders or
insomnia to age-matched normal controls.
Benca RM et al. Arch Gen Psych. 1992;49:651-668
Bidirectional relationship between psychiatric
disorders and insomnia
PSYCHIATRIC ISSUES
Anxiety
Depression
Insomnogenic drugs
Substance abuse
Altered ACTH and cortisol
Concerns or worries about sleep
ACTH, adrenocorticotropic hormone
TST, total sleep time
SOL, sleep onset latency
SWS, slow wave sleep
INSOMNIA
Decreased TST
Increased SOL
Impaired sleep efficiency
Decreased SWS
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.
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.
2Gold E, et
Complaints of sleep problems with age
50
40
30
20
10
0
10-19
20-29
30-39
40-49 50-59
Age Group, y
60-69
“Trouble With Sleeping” Assessed in a comprehensive
survey of 1645 individuals in Alachua County, Florida
Karacan I et al. Soc Sci Med. 1976;10:239-244.
70+
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.
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 and
 Physical disability
 Psychosocial disability
 Depression
 Pain
McCracken LM, Iverson GL. Pain Res Manag. 2002;7:75-79.
Insomnia comorbid with pain
Control
Any 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.
Bidirectional relationship between
pain and insomnia
PAIN
DIS, difficulty initiating sleep
DMS, difficulty maintaining sleep
INSOMNIA
Poor sleep quality
Nonrestorative sleep
DIS
DMS
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 factors
Tumors that increase steroid production, symptoms of tumor
invasion (pain, dyspnea, fatigue, nausea, pruritis)
Treatment factors
Frequent 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
CANCER-RELATED ISSUES
Pain
Psychiatric comorbidities
Fatigue
Opioids (daytime sedation, SDB)
Insomnogenic drugs
Napping
Preexisting sleep disorders
INSOMNIA
SDB, sleep-disordered breathing
Fiorentino L, Ancoli-Israel, S. Sleep dysfunction in patients with cancer. Curr Treat Opt Neurol. 2007;9:337–346.
Insomnia and OSA or CSA
 Studies have shown that 39% to 55% of patients with OSA
have comorbid insomnia. Associated factors include:
 female gender
 psychiatric diagnoses
 restless leg symptoms
 chronic pain
 lower AHI, lower DI
 OSA patients with comorbid insomnia have
 More severe sleep apnea
 Increased depression, anxiety and stress
AHI, apnea hypopnea index. CSA, central sleep apnea. DI, desaturation index. OSA, obstructive sleep apnea.
Krell SB, KapurVK. Sleep Breathing. 2005;9:104-10.
Smith S, et al. Sleep Med. 2004;5:449-456.
Insomnia and OSA or CSA
 < 1% of 1,000 patients with OSA surveyed had been
diagnosed with insomnia
 Mood problems were not formally addressed
 In a small study of patients with CSA (n=14):
 36% had sleep onset insomnia
 79% had maintenance insomnia
 This rate was significantly higher than in patients with OSA (P =.016)
MorganthalerTI,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 sleepiness
 Medications 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 COPD
 Insomnia 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 function
 Spirometric decline is observed after one night of sleep
deprivation
 Despite 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
HTN Incidence (%)
95% CI:
1.42-2.70
n=192
95% CI:
1.45-2.45
n=286
n=4602
n=4157
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.
Short sleep duration and hypertension:
NHANES I and the Sleep Heart Health Study
≤6h
≤5h
6-7h
6h
7-8h
7-8h
(1.0; referent)
8-9h
≥9h
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.
Gangwisch et al. Hypertension. 2006;47:833-839.
(1.0; referent)
≥9h
Odds Ratios. N=5910. Subjects 40-
100y. Sleep duration and increased risk of
HTN adjusted for age, sex, race, apneahypopnea index and BMI.
Gottlieb DJ, et al. Sleep. 2006;29(8):1009-1014.
Relationships between sleep
disorders* and obesity
Increased
BMI1
Increased
insulin
resistance2
Reduced
leptins3
Diabetes4
Impaired
glucose
tolerance4
Obesity
Increased TC,
HDL and
triglycerides1
Factors associated with reduced sleep time* may contribute to obesity
*Insomnia or sleep deprivation.
1
Bjorvatn B, et al. J Sleep Res. 2007;16(1):66-76.
2
Flint J, et al. J Pediatr. 2007;150(4):364-369.
3
Chaput JP, et al. Obesity (Silver Spring). 2007;15(1):253-261.
4
Gottlieb et al. Arch Intern Med. 2005;165:863-868.
Management of insomnia
 Treat 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 hygiene
 Avoid:
 “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.
DJ, Reynolds CF. N Engl J Med. 1997;336:341-346.
3 Lippmann S et al. South Med J. 2001;94:866-873.
2 Kupfer
Behavioral techniques
Technique
Aim
Stimulus control
therapy
Imprint bed and bedroom as sleep stimulus
Sleep restriction
Restrict 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
Generic
Brand
T1/2 (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
Ambien CR
1.5-2.4*
6.25-12.5
non-BZD
Rozerem
1.5-5
8
MT agonist
Zolpidem Ex Rel†
Ramelteon†
* Modified formulation. †No short-term use limitation.
Antidepressants for Insomnia:
Indications
 Patients with psychoactive substance use disorder history
 Patients with insomnia related to depression, anxiety
 Treatment failures with BzRA
 Suspected sleep apnea
 Fibromyalgia
 Primary insomnia (second-line agents)
 Not FDA-approved for use as hypnotics
Antidepressant drug effects
on sleep
Tricyclic
Sleep
continuity
Slow wave
sleep
REM sleep
Other
 To 
 To 
 To  

 PLMs
 Apnea
 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
SSRI
Improve
comorbid
conditions
Treat
insomnia
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 disorder
 Parasomnias
 Circadian rhythm disorders
 Narcolepsy*
*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)
V
Spontaneous brain rhythms during sleep reflect brain functioning
unconfounded by attention and motivation
ra
60
40
20
0
-20
-40
-60
spindle activity (
20
10
0
-10
-20
25
20
slow wave activity
15
upper threshold
absolute
spindle amplitude
spindle
activity
slow-wave activity (V2)
10000
Fz
Cz
P4
8000
6000
Fz
4000
Cz
P4
2000
0
0
2
4
6
8
Sleep Slow Wave Activity ishoursHomeostatically
Regulated Throughout the Cortex
Slow waves originate more frequently in
orbitofrontal and centroparietal regions
and propagate in an antero-posterior direction
Diagnosis: Sleep spindle activity is reduced in schizophrenia
Schizophrenics
Schizophrenics vs. Depressed
100
80
60
40
20
EEG spindle activity (13-15 Hz)
P<.05
Schizophrenics vs. Controls
Controls
Ferrarelli et al., Am. J. Psychiatry, 2007
Depressed vs. Controls
Depressed
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
Interdisciplinary Clinical Expertise
 Psychiatry
R. Benca, MD, PhD
M. Rumble, PhD
 Pulmonary
M. Klink, MD
S. Cattapan, MD
J. McMahon, MD
G. DoPico, MD
Mihaela Teodorescu, MD
 Geriatrics
S. Barczi, MD
Mihai Teodorescu, MD
 Pediatrics
C. Green, MD

Neurology
J. Jones, MD
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
sleep
 Lectures in medical school and residency curricula
 Clinical 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