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Behavioral versus Pharmacological
Therapy for Adult Insomnia
Gary K. Zammit, Ph.D.
Clinilabs
Columbia University College of Physicians and Surgeons
Conflict Statement
I am deeply conflicted. I have been so for many years. It is an affliction that I
blame on my parents, the Catholic church, and several institutions of higher
learning. Most of my conflicts were personal, until a few years ago when I had to
start revealing my conflicts to the public whenever I gave a lecture. Apparently,
this is a rule that only applies to me, since I’ve never seen anyone else reveal all
of their potential conflicts. Having been exposed to clinical training and
psychoanalytic psychotherapy for many years in my youth, my interpretation of
conflict may be more expansive than others, who seem to think that conflicts only
relate to one’s finances. I know better; conflicts certainly run deeper than that
and often are seated in the unconscious mind. I would be happy to speak with
you about all of my conflicts, preferably over a martini. However, if you primarily
are interested in learning about my financial conflicts, I can say with brevity and
unabashed honesty that I have none. I believe that I should be compensated for
an honest day’s work, I seek to obtain such compensation whenever possible,
and I encourage anyone who cares to listen to do the same. I see no conflict
there, and I will be happy to debate anyone on this topic so long as they do not
have other conflicts like I do because I find that those debates require lengthy
discussion for which I simply am not equipped and no longer have the time.
Conflicts of Interest
 Grants/Research Support: Abbott, Actelion, Ancile, Apnex, Arena, Aventis,
Cephalon Inc., CHDI, Elan, Epix, Evotec, Forest, Galderma, Glaxo Smith
Kline, H. Lundbeck A/S, King, Merck and Co., Johnson & Johnson,
National Institute of Health (NIH), Neurim, Neurocrine Biosciences,
Neurogen, Organon, Orphan Medical, Pfizer, Respironics, Sanofi-Aventis,
Sanofi-Synthelabo, Schering-Plough, Sepracor, Shire, Somaxon, Takeda
Pharmaceuticals North America, Targacept, Thymon, Transcept, UCB
Pharma, Predix, Vanda, Wyeth-Ayerst Research
 Consultant: Actelion, Alexza, Arena, Aventis, Biovail, Boehringer-Ingelheim,
Cephalon, Elan, Eli Lilly, Evotec, Forest, Glaxo Smith Kline, Jazz, King
Pharmaceuticals, Ligand, McNeil, Merck, Neurocrine Biosciences,
Organon, Pfizer, Renovis, Sanofi-Aventis, Select Comfort, Sepracor, Shire,
Somnus, Takeda Pharmaceuticals, Vela, Wyeth
 Honoraria: Neurocrine Biosciences, King Pharmaceuticals, McNeil, SanofiAventis, Sanofi-Synthelabo, Sepracor, Takeda Pharmaceuticals, Vela
Pharmaceuticals, Wyeth-Ayerst Research
 Ownership, Directorship: Clinilabs, Inc., Clinilabs IPA, Inc., Clinilabs
Physician Services, PC.
 Industry Stocks Held: None outside of mutual funds
Presentation and Learning Objectives
 The objectives of this presentation are to:
• Define primary and co-morbid insomnia
• Identify drug treatments for insomnia, and present data regarding
their efficacy and safety
• Identify behavioral treatments for insomnia, and present data
regarding their efficacy and safety
• Address the merits of behavioral and drug treatments of
insomnia, comparing and contrasting the utility of both in clinical
practice
• Attendees will gain an understanding of behavioral and drug
treatments for insomnia, and their possible use in clinical
practice.
The Definition of Insomnia
One or More of the Following Symptoms Must be Present
Difficulty Initiating
Sleep
Difficulty Maintaining
Sleep
Non-restorative1 or
Poor Quality Sleep2
Associated with Clinically Significant1 or Marked2 Distress or Impairment
At Least 1 Month in Duration1,2 (3x/Week2)
Preoccupation with Sleeplessness and Excessive Concern over its Consequences2
1
2
APA. Diagnostic and Statistical Manual of Mental Disorders - 4th Edition, Text Revision. 2000.
WHO. International Statistical Classification of Diseases and Related Health Problems, 10 th Revision, 2006
Prevalence of Insomnia
The American Insomnia Survey
 Methods: Epidemiological survey of managed health care plan
subscribers (n = 10,094), assessed for insomnia with the Brief
Insomnia Questionnaire, a clinically validated scale generating
diagnoses according to DSM-IV-TR; International, ICD-10, and
RDC criteria
 Results: Insomnia prevalence estimates varied widely, from 22.1%
for DSM-IV-TR to 3.9% for ICD-10 criteria
• Although ICD insomnia was associated with significantly worse
perceived health than DSM or RDC/ICSD insomnia, DSM-only cases
also had significant decrements in perceived health.
 Conclusions: Insomnia is highly prevalent and associated with
substantial decrements in perceived health.
Roth, T., Coulouvrat, C., Hajak, G., et. al., 2011, Biological Psychiatry, 69, 592 – 602.
Landmark Report on Insomnia
State-of-the-Science
 Estimates 10% of adults with insomnia associated with impairment
 National Institutes of Health State-of-the-Science Conference on
the Manifestations and Management of Chronic Insomnia in Adults
(2005) 1
• Underscores need for appropriate diagnosis and treatment of
insomnia
• Emphasizes need for further education and research on
insomnia as a condition2
 Chronic insomnia is a major public health problem affecting millions
of individuals, along with their families and communities
1. NIH State-of-the-Science Conference Statement on Manifestations and Management of Chronic Insomnia in Adults. J Clin
Sleep Med. 2005; 412 - 421
2. Colten HR et al. Institute of Medicine of the National Academies. Washington, DC. National Academies Press. 2006.
Sleep Maintenance Insomnia Most Common
 US results (n=2,061):
27.1% insomnia prevalence
• from an international
telephone survey (N=5,132)
 Of US patients with
sleep disturbances:*
• 42% have sleep problems
[nearly] every night
Difficulty
falling asleep
~50%
Sleep maintenance
problems†
~70%
Poor
sleep quality
~40%
• Mean number of symptoms is 1.9
• 24% report all 3 symptoms
*n=570
†Interrupted sleep and early morning awakening.
Leger D et al. Curr Med Res Opin. 2005;21:1785-1792.
Symptoms of individuals who
reported sleep disturbances
during last 12 months
Sleep Maintenance Insomnia:
A Clinically Relevant Distinction
 METHODS:
 Cross-sectional telephone study was performed in the non-institutionalized
general population of France, the United Kingdom, Germany, Italy and
Spain.
• Representative sample of 22,740 non-institutionalized individuals age ≥15
• DRS defined as a complaint of difficulty in resuming or inability to resume sleep occurring at least three
nights per week and lasting for at least one month.
 RESULTS:
 A total of 16.1% [95% CI: 15.6-16.6] of the sample had DRS
• Prevalence higher in women and increased with age, mean duration 40 months
• DRS individuals slept on average 30 min less than other subjects with insomnia symptoms and 60 min less
than the rest of the sample
• Psychiatric conditions more common. Daytime impairment was observed in 52.2% of DRS individuals
compared to 32.8% in individuals with classical insomnia symptoms (p < 0.0001).
 CONCLUSIONS:
• DRS affect a large segment of the population
• DRS is a good indicator of an ongoing sleep or mental disorder
• DRS has a stronger impact on daytime functioning than classical insomnia symptoms (OR: 4.7).
Ohayon, M. 2009. Journal of Psychiatry Research, 43, 934 – 940.
Symptoms of Insomnia are Persistent:
Chronicity Documented by Empirical Research
 Insomnia is a chronic condition1
 Insomnia is a chronic condition in the elderly2
 Epidemiological study included 870 subjects with insomnia
• 69% continued to have insomnia at 12-month follow-up3
 64-month longitudinal data in 28 patients well-characterized with
insomnia4
• Initial 100%
• 40 months 70.4%
• 64 months 88.2%
 Seven-year follow-up study of young adults with insomnia indicates that
insomnia persists in 8% - 10%, with recurrent, brief episodes of
insomnia in 13% - 19%5,6
1.Katz, McHorney, Arch. Internal Medicine, 1998; 2. Ganguli, M, Reynolds, CF, Gilby, JE. J. Am. Geritric Society, 1996; 3. Morphy, Dunn, Lewis, et. al.,
Sleep, 2007; 4. Mendelson, WB. Sleep, 1995; 5. Angst, J, Vollrath, M, Koch, R, et. al. Eur. Arch. Psychiatr. Clin. Neurosci., 1989; 6. Vollrath, M, Wicki,
W., Angst, J. Eur. Arch. Psychiatr. Clin. Neurosci, 1989
INSOMNIA DURING 2-YEAR FOLLOW-UP
Katz and McHorney, Arch Intern Med, 1998
80
70
60
50
40
30
20
10
0
Follow-up status
No insomnia
n = 801
No insomnia
Mild insomnia
n = 557
Baseline status
Mild insomnia
Severe insomnia
n = 264
Severe insomnia
NIH State-of-the-Science Conference Statement
Recognizes Chronic Insomnia:
The NIH report indicates that…
“the panel is concerned about the mismatch
between the potential lifelong nature of this
illness and the longest clinical trials, which have
lasted 1 year or less…”
An Important Paradigm Shift: Recognition of chronic insomnia may influence
research and clinical practice, with implications for long-term treatment
NIH. National Institutes of Health State of the Science Conference statement on Manifestations and Management of
Chronic Insomnia in Adults, June 13-15, 2005, Sleep, 2005 Sep 1;28(9):1049-57.
NIH State-of-the-Science Conference
and Co-Morbid Insomnia
 As much as 85% of all insomnia may be comorbid with other conditions
 “Co-morbid insomnia” is an appropriate term
• Mechanistic and causal pathways not known
• The term secondary insomnia may promote
undertreatment
NIH. National Institutes of Health State of the Science Conference statement on Manifestations and Management of
Chronic Insomnia in Adults, June 13-15, 2005, Sleep, 2005 Sep 1;28(9):1049-57.
Insomnia: Often Comorbid
 Cardiovascular diseases
• Ischemic heart disease
• Nocturnal angina
 Respiratory diseases
• Chronic obstructive pulmonary disease
• Bronchial asthma
 Gastrointestinal diseases
• Peptic ulcer disease
• Gastroesophageal reflux
 Neurological diseases
• Parkinson’s/Alzheimer’s
 Rheumatic disorders
• Fibromyalgia
• Osteoarthritis
 Psychiatric disorders
 Dyspnea (from any cause)
Thase ME. Gen Hosp Psychiatry. 2005;27:100-112.
 Endocrine syndromes
• Diabetes
• Menopause
• Hyperthyroidism
 Pain (from any cause)
 Associated sleep disorders
• Sleep apnea
• Restless legs syndrome
• Periodic limb movement disorder
 Miscellaneous conditions
• Dermatologic
• Chronic fatigue syndrome
• HIV/AIDS
• Lyme disease
• Systemic cancer
• Pregnancy
• Medical treatment induced
QUALITY OF LIFE IN INSOMNIA
METHODS
362 men and women,18 - 75 years of age, were prospectively studied
261 (72%) met criteria for the insomnia group
101 (28%) met criteria for the control group
INSOMNIA GROUP
 Insomnia at least 3 times per
week for at least 1 month
 Typical sleep latency greater than
or equal to 30 minutes
 3 or more awakenings per night,
with difficulty returning to sleep
 Total sleep time less than 6.5
hours per night
 No history of serious medical,
psychiatric, or sleep disorder
Zammit GK et al. Sleep. 1999;22(suppl):S379-S385.
CONTROL GROUP
 No history of insomnia
 Regular periods of nighttime sleep
 No history of serious medical,
psychiatric, or sleep disorder
Burden of Insomnia on Quality of Life
Insomnia Impacts Quality of Life
95
SF-36 Scale Score
P<.0001
75
N=362
55
Control
Insomnia
35
Body Pain
General
Health
Mental
Health
Role
Emotional
Role
Physical
Social
Functioning
Vitality
Physical
Functioning
Significant differences were observed between insomnia and control subjects on all scales of the
SF-36, all significant at the P<.0001 level
Zammit GK et al. Sleep. 1999;22(suppl):S379-S385.
Health and Insomnia
 Short sleep duration is associated with myriad health
risks
•
•
•
•
•
Obesity
Diabetes
Hypertension
Hypercholesterolemia
Depression
 Insomnia is associated with risk of psychiatric illness
• Depression
• Anxiety
Gangwisch, J., et. al., 2005, Sleep, 28, 1289 – 1296; Gangwisch, J. et. al., 2007, Seep, 30, 1667 – 1673; Gangwisch, J.
E., et. al., 2006, Hypertension, 47, 833 – 839; Gangwisch, J. E., 2010, Sleep, 33, 956 – 961; Gangwisch, J. E., 2010,
33, 97 – 106; Breslau, N., et. al., 1996, Arch. Gen. Psychiatry.; Buysse, D., et. al., 2008, Sleep.
The Debate: Treatment Considerations
 Insomnia is a common condition
• Treatment should be widely available
 Sleep maintenance insomnia is the most common form
of insomnia
• Treatment should enable patients to stay asleep or fall asleep
easily after an awakening
 Insomnia is a chronic condition
• Should have sustained efficacy or available for long-term use
 Insomnia often is co-morbid
• Treatment should be able to be used in context of other illness
 Insomnia is associated with impairment and health risk
• Treatment should be safe and reduce impairment and improve
health outcomes
Treatments for Insomnia
 Pharmacologic treatments
• Hypnotics
 Behavioral treatments
• Sleep hygiene
• Stimulus control therapy
• Sleep restriction therapy
• Cognitive-behavioral therapy
• Relaxation therapy
• Paradoxical intent
Hypnotics are Widely Available
 Primary care physicians increasingly aware of sleep
disorders, including insomnia
 Primary care physicians and “physician extenders”
(e.g., physician assistants) can prescribe hypnotics
 Common treatment indicated for insomnia is now
generic (zolpidem)
• Affordability
 Greater than 56 million prescriptions for insomnia were
issued in 2008 indicating wide availability of hypnotics1
1IMS
Health, 2009, reference in USA Today 03/01/2009
Eszopiclone Efficacy and Safety
 Randomized, double-blind, placebo-controlled,
multicenter, outpatient study in adults with chronic
primary insomnia
 Entry criteria
• Primary insomnia, self-reported average sleep duration  6.5
hrs/night and sleep onset latency > 30 min
 Treatments and duration
• Six month double-blind Tx period: Esz 3 mg vs placebo nightly
• Six-month open-label extension period: Esz 3 mg nightly
 Method
• Subjects required to use  3 doses per week (7-day period), or 15
doses per month (30-day period), to continue in study
Krystal et al. Sleep. 2003:26;793-799
Self-Reported Sleep Onset Latency (SOL)
70
ESZ Observed
ESZ Completers
ESZ LOCF
Median minutes
60
Placebo Observed
Placebo Completers
Placebo LOCF

50
40
30
**
20
**
**
**
**
**
**
1
2
3
4
5
6
10
0
0
Month
**P < 0.01; P-values represent within-group pairwise comparisons at each point for all groups.
Krystal et al. Sleep. 2003:26;793-799
Median minutes
Self-Reported Wake Time After Sleep Onset (sWASO)
60
ESZ Observed
Placebo Observed
50
ESZ Completers
ESZ LOCF
Placebo Completers
Placebo LOCF
40
30
20
*
10
*
*
*
*
*
*
2
3
4
5
6
0
0
1
Month
*P < 0.05; +P = 0.07 for Observed; P-values represent within group pairwise comparisons at each point for all groups.
Krystal et al. Sleep. 2003:26;793-799
Low-Dose Doxepin Reduces WASO
 Objective: To evaluate the efficacy and safety of doxepin 1 mg
and 3 mg in elderly subjects with chronic primary insomnia
 Methods:
• Randomized, double-blind, parallel-group, placebo-controlled trial
• Subjects meeting DSM-IV-TR criteria for primary insomnia were
•
•
•
•
randomized to 12 weeks of nightly treatment with doxepin (DXP) 1 mg
(n = 77) or 3 mg (n = 82), or placebo (PBO; n = 81)
Efficacy was assessed using polysomnography (PSG), patient reports,
and clinician ratings
Objective efficacy data were reported for Nights (N) 1, 29, and 85
Self-report efficacy data during Weeks 1, 4, and 12, Clinical Global
Impression (CGI) scale, and Patient Global Impression (PGI) were
obtained
Safety assessments were conducted throughout the study.
Krystal, A., et. al., 2010, Sleep, 33 (11), 1553 - 1561
Low-Dose Doxepin Reduces WASO
*P< 0.05,** p< 0.0001
130
120
110
100
*
*
90
80
**
**
70
Baseline
Placebo
Night 1
Doxepin 1 mg
Night 85
Doxepin 3 mg
Efficacy of Non-Nightly Zolpidem over 8
Weeks: Self Reported Total Sleep Time
420
*
*
*
*
Weeks 1-2
Weeks 3-4
Weeks 5-6
Weeks 7-8
minutes
400
380
360
340
320
300
Placebo pill n=71
Zolpidem 10 mg pill n=63
Walsh et al., Sleep, 2000
Placebo no pill n=71
Zolpidem no pill n=63
* p < .001 for zolpidem-pill vs. placebo-pill
Use of Hypnotics in Co-Morbid Insomnia
 Depression
• Improvements in SL, WASO, and TST after treatment with
eszopiclone and fluoxetine1
 Generalized anxiety disorder
• Total sleep time improved after treatment with zolpidem and
escitalopram2
 Chronic pain
• Eszopiclone significantly improved all patient-reported sleep
measures (WASO, SL, and TST), sleep quality, depth of sleep,
and daytime function (P < .05 vs placebo); 48% of eszopiclonetreated patients had no clinically meaningful insomnia as
assessed by ISI score (versus 30% of placebo-treated patients
(P = .03)3
A., et. al., 2007, J. Clinical Sleep Medicine,3, 48 – 55; 2Fava, M., et. al., 2009, J. Clinical
Psychopharmacol., 29, 222 – 230; 3Roth, T., et. al., 2007, Primary Care Companion J. Clinical Psychiatry, 11,
292 - 301
1Krystal,
Most Common AEs in 5-Week Placebo-Controlled Study
of Ramelteon in Adults with Insomnia
Placebo
n = 131
Ramelteon 8 mg
N = 139
Ramelteon 16 mg
n = 135
Any
48.1%
51.1%
54.8%
Headache NOS
18.3%
19.4%
17.8%
Somnolence
1.5%
7.9%
7.4%
Fatigue
2.3%
9.4%
4.4%
Nausea
2.3%
4.3%
4.4%
Nasopharyngitis
3.1%
2.9%
3.7%
Diarrhea NOS
1.5%
1.4%
3.7%
URI NOS
3.1%
4.3%
0.7%
Dizziness
3.8%
3.6%
1.5%
Nasal Congestion
0.8%
1.4%
3.0%
AE
* All reported AEs ≥ 3%
Zammit et al. 2007. Journal of Clinical Sleep Medicine, 3, 495 - 504
Low Frequency of Reported Adverse Reactions to
Sedative Hypnotics in Hospital Setting
•Data derived from 3,000 cases per year of adverse drug reactions
•Presented to Drug Outcomes Management Committee for review
•AEs entered into database over 3 year period
Drug Class
Total Doses
Dispensed
Reported Adverse
Events
Frequency (%)
Chloral Hydrate
2,768
0
0
Pentobarbital
546
0
0
Temazepam
79,016
3
0.004
Triazolam
9,656
2
0.02
Mendelson, W., et. al. (1996). Sleep, 19, 702 – 706;
Low Rate of AEs Reported in Outpatient
Clinical Practice
 Uncontrolled surveillance study
• Office-based physicians
• Examined 16,944 patients with insomnia who were given zolpidem
during a four-week period
 Total of 268 AEs (1/113, 2/53, >2/16)
• Overall rate of 0.006%
 There were 118 discontinuations due to AEs
• Nausea (36)
• Dizziness (35)
• Malaise (23)
• Nightmares (20)
• Agitation (19)
• Headache (18)
Hajak, G. & Bandelow, B. (1998). Int. Clin. Psychopharmacol., 13, 157 - 167
Residual Effects of Hypnotics
 Residual effects refer to continued sedation or impairment in
memory and psychomotor functioning following morning awakening
 Assessed using self-report measures and objective test data
• Digit symbol substitution test
• Symbol copying test
• Immediate and delayed recall tests
• Driving performance
 Residual effects of BZRAs may be related to dose, half-life, and
time of dose
 Recently-approved therapeutics not associated with significant
residual effects
Blin, et. al., 2006. J. Clin. Psychopharmacol., 26, 284 – 289; Vermeeren, A., 2004, CNS Drugs, 18, 297 - 328
Potential Residual Memory Effects of
Benzodiazepine Hypnotics
16
14
12
10
Placebo
Flurazepam
Lorazepam
Triazolam
8
6
4
2
0
Mean Items Immediate
Recall
Mean Digits Immediate
Recall
Mean Items Morning
Recall
Roth, et. al., (1980). Psychopharmacology, 70, 231 - 237
Mean Digits Morning
Recall
Next-Day Psychomotor Functioning
70
Morning DSST Scores^
Score (median)
Improvement
60
50
40
30
20
10
0
Baseline Placebo
^Mean of 3 time points (days 1, 15, & 29)
Baseline ESZ 3 mg
Mean +/- 1 SD for age group 35-44 norm – Wechsler adult intelligent scale
Zammit et al. Curr. Med. Res. Op., 2004, 20, 1979 - 1991
Driving Studies




Standardized highway driving tests
100 km (61 miles) over highway circuit at constant speed
Primary outcome: standard deviation from lateral position (SDLP)
11 studies using this methodology have provided data
• Zaleplon 10 mg, 20 mg: No significant effects > 2hours postadministration
• Temazepam 10 mg, 20 mg, 30 mg: Low incidence of driving
impairment
• Zolpidem 10 mg: Moderate to severe impairing effects 5 – 7
hours post-administration
• Flurazepam 30 mg: Severe impairment, greater than equivalent
BAC of 1.0 g/L
• Triazolam 0.5 mg: Marked residual effects, dose-dependent; with
effects in first hour after rising following 0.25 mg and 0.125 mg
Vermeeren, A., 2004, CNS Drugs, 18, 297 - 328
Benzodiazepine Use and Risk of Falls1
and Fractures2 in Older Women
Relative Risk
2
n=8,127
Short-acting
Long-acting
1
0
Frequent falls
1Ensrud
Non-spine fracture
Outcome
Hip fracture
KE et al. J Am Geriatr Soc 2002;50:1629–37; 2Ensrud KE et al. Arch Intern Med 2003;163:949–57.
Postural Instability and Hypnotic Use
SOT Score Change from Baseline
Sensory Organization Test Composite Score
0
-5
P =0.837
-10
-15
-20
-25
-30
P <0.001
-35
Placebo
Zammit, G. K. 2008. BMC Geriatrics.
Ramelteon
Zolpidem
Abuse and Dependence Liability
 Hypnotic abuse and dependence are a concern
of practitioners and patients
 Evidence of hypnotic abuse or dependence
among people with insomnia is minimal
 Most indicators of abuse or dependence not
evident in people with insomnia who use
hypnotics
• Withdrawal
• Non-therapeutic use
• Tolerance
• Dose escalation
Discontinuation Effects of Hypnotics
 Rebound insomnia is most frequently reported
discontinuation effect
• Typically 1 – 2 nights
• May occur following even short-term use1
• Does not increase in severity with longer durations of
use
• More likely to occur with high doses
 Rebound insomnia must be differentiated from
recrudescence or withdrawal2
1. Roehrs, T., et. al., 1992, Psychopharmacology, 107, 480 – 484; 2. Walsh, J., et. al., Principles and Practice of
Sleep Medicine, 4th Edition
Limited Evidence of Withdrawal Effects
with Commonly-Prescribed Hypnotics
Period 1
Period 2
Period 3
Period 4
TST
Baseline
319.5
320.3
321.2
323.5
1st Night Off
307.0
315.4
334.6
337.5
76.1
75.7
75.9
72.3
*90.1
89.4
76.2
75.5
Baseline
2.35
2.34
2.38
2.41
1st Night Off
2.62
2.25
2.24
2.09
SL
Baseline
1st Night Off
NAW
Walsh, J., et. al., 2000, Sleep, 23, 1087 - 1096
*P < 0.04
Relative Abuse Liability of 19 Hypnotics
Pentobarbital
Methaqualone
Diazepam
Flunitrazepam
Lorazepam
GHB
Temazepam
Zaleplon
Eszopiclone
Triazolam
Zopiclone
Flurazepam
Zolpidem
Estazolam
Oxazepam
Diphenhydramine
Quazepam
Trazodone
Ramelteon
Likelihood of Abuse
Toxicity
0
20
40
60
Score
Griffiths R, Johnson M. 2005, J Clin Psychiatry, 66 (suppl 9): 31 - 41
80
100
Sedative-Hypnotic Drug Products Class
Safety Labeling





December 2006, FDA requested that the whole
class of hypnotic drugs revise product labeling
to include warnings about the following potential
adverse events:
Anaphylaxis (severe allergic reaction)
Angioedema (severe facial swelling)
Complex sleep-related behaviors
Letters to health care providers.
Patient Medication Guides to inform consumers
Treatment Considerations
Variable
Pharmacotherapy
Widely Available
Yes
WASO or sWASO
Yes
Sustained Efficacy or
Available for Long Term Use
Yes
Use in Co-Morbid Insomnia
Yes
Reduce Impairment or Health
Risk
No
Safe
Concerns
Behavioral
Therapy
Behavioral Treatment for Insomnia is
Not Widely Available
 Availability of behavioral treatment is severely
limited
• Lack of trained clinicians
• Poor geographic distribution of knowledgeable
providers
• Inaccessibility to treatments and clinicians
 Behavioral treatment paid at lower rates than
physician visits for medical care
 Multiple visits required for treatment that meets
current standard of care
Ritterband, L. M., et. al., 2009, Archives of General Psychiatry, 66, 692 - 698
Meta-Analysis of the Efficacy of
Behavioral Treatments for Insomnia
 Objective: Meta-analysis of behavioral treatments for insomnia
 Methods: A systematic review was conducted on 37 treatment
studies (N = 2246 subjects/patients) published between 1998 and
2004 inclusively
 Criteria for inclusion of a study were as follows
• Main sleep diagnosis was insomnia (primary or comorbid)
• At least 1 treatment condition was psychological or behavioral in content
• The study design was a randomized controlled trial, a nonrandomized
group design, a clinical case series or a single subject experimental
design with a minimum of 10 subjects
• The study included at least 1 of the following as dependent variables:
sleep onset latency, number and/or duration of awakenings, total sleep
time, sleep efficiency, or sleep quality
Morin, C., et. al., Sleep, 2006, 29, 1398 1414
Meta-Analysis of the Efficacy of
Behavioral Treatments for Insomnia
 Seventeen studies examined CBT in primary insomnia,
five of which were randomized, controlled clinical trials
 Overall, studies showed that CBT had greater
improvement on sleep diary and PSG variables than
control conditions
 Twenty-six studies provided follow-up data, indicating
the durability of behavioral treatment over short,
intermediate, and long (>12 months) periods
 Benefits observed when specialists or non-specialists
(e.g., primary care physicians, nurse practitioners)
administered treatment
Morin, C., et. al., Sleep, 2006, 29, 1398 1414
Behavioral Therapy Reduces WASO
 Objective To test the efficacy of a hybrid cognitive behavioral therapy
(CBT) compared with both a first-generation behavioral treatment and a
placebo therapy for treating primary sleep-maintenance insomnia.
 Design: Randomized, double-blind, placebo-controlled clinical trial
 Patients Seventy-five adults (n=35 women; mean age, 55.3 years) with
chronic primary sleep-maintenance insomnia (mean duration of symptoms,
13.6 years)
 Interventions Patients were randomly assigned to receive outpatient CBT
(sleep education, stimulus control, and time-in-bed restrictions; n=25),
progressive muscle relaxation training (RT; n=25), or a quasidesensitization (placebo) treatment (n=25) for six weeks, with follow-up
conducted at 6 months.
 Main Outcome Measures: Polysomnography and sleep log measures of
total sleep time, middle and terminal wake time after sleep onset (WASO),
and sleep efficiency
Edinger, J., et. al., 2006, JAMA, 285, 1856 - 1864
Behavioral Therapy Reduces WASO
Measure
Baseline
Mean
CBT
RT
Placebo
P Value
TST Log
336.8m
360.0m
362.0m
361.0m
0.99
TST PSG
352.1m
372.4m
337.9m
334.0m
0.02
CBT>P
WASO Log
56.2m
28.1m
44.4m
47.1m
0.004
CBT<RT&P
WASO PSG
50.8m
30.1m
50.6m
66.4m
0.02
CBT<P
WAST Log
47.7m
21.1m
36.2m
47.0m
0.02
CBT<P
WAST PSG
14.1m
4.2m
10.2m
12.4m
0.02
CBT<P
SE Log
72.0%
84.3%
78.1%
76.2%
0.002
CBT>RT&P
SE PSG
77.8%
85.5%
78.1%
75.7%
0.002
CBT>RT&P
Edinger, J., et. al., 2006, JAMA, 285, 1856 - 1864
Post-Hoc Test
Behavioral Therapy & Co-Morbid Insomnia
 Chronic pain:
• SOL, WASO, SE improved following CBT versus control1
o
o
SOL reduced from 55 minutes to 28 minutes
SE increased from 72% to 85%
 Medical Illness
• In a study of 51 older adults, WASO and SE improved following
CBT or RT versus control2
• In a study of 49 older adults with insomnia associated with
medical and psychiatric conditions,3 a combined intervention of
stimulus control, relaxation, and education reduced WASO 25
min and increased SE 11% at post treatment
o
Fifty-seven percent (57%) of treated patients achieved clinically significant
improvements on SE relative to 19% of control patients
S.R., et. al., 2000, Journal of Consulting and Clinical Psychology, 68, 407 – 416; 2Rybarczyk, B., et.
al., 2002, Psychological Aging, 17, 288 – 298; 3Lichstein, K.L., et. al., 2000, Psychol Aging, 15, 232 - 240
1Currie,
Brief Behavioral Treatment for Insomnia
 Objective: To assess the efficacy of individualized behavioral
treatment for insomnia, delivered in two sessions and two
telephone calls
 Primary outcome: Categorical status at four weeks following the
initiation of treatment
 Sample: Seventy-nine elderly adults, 54 female, recruited from the
community and one primary care clinic
 Method: Participants were randomly assigned to receive BBTI or IC
(information control) over a four-week period.
• All treatments were administered by a nurse clinician
Buysse, D., et. al., Archives of Internal Medicine, 2011, e-pub January 24, 2011
Brief Behavioral Treatment for Insomnia
Outcome After Four Weeks of Treatment
70
60
(P<.001)
60
50
50
40
40
30
30
20
20
10
10
0
Remission
Response
BBTI (n = 39)
Partial
Remission
IC (n = 40)
NonResponse
0
No Longer Meet DSM-IV Criteria
BBTI (n = 39)
Buysse, D., et. al., Archives of Internal Medicine, 2011, e-pub January 24, 2011
IC (n = 39)
Internet Expansion of Access to Care
 OBJECTIVE: Evaluate structured behavioral Internet intervention for adults with
insomnia.
 DESIGN, SETTING, AND PARTICIPANTS
• Forty-five adults randomly assigned to an Internet intervention (n = 22) or waitlist control group (n = 23).
 INTERVENTION: The Internet intervention based on well-established face-to-face
cognitive behavioral therapy incorporating the primary components of sleep
restriction, stimulus control, sleep hygiene, cognitive restructuring, and relapse
prevention
 MAIN OUTCOME MEASURES: The Insomnia Severity Index and daily sleep diary
data were used to determine changes in insomnia severity and the main sleep
variables, including wake after sleep onset and sleep efficiency
 RESULTS
• Insomnia Severity Index significantly improved from 15.73 for the Internet group
but did not change for the control group (P < .001)
• The Internet group maintained gains at the 6-month follow-up
• Internet participants achieved significant decreases in wake after sleep onset
(55%) and increases in sleep efficiency (16%) compared with the nonsignificant
control group changes of wake after sleep onset 8% and sleep efficiency 3%
Ritterband, L.M., et. al. 2009. Arch. Gen. Psychiatry, 66, 692
Comparison of CBT, Zopiclone, and Placebo
 Objective: To examine short- and long-term clinical efficacy of CBT,
zopiclone 7.5 mg, and placebo in older adults experiencing chronic primary
insomnia.
 Design: Randomized double-blinded, placebo controlled trial of 46 adults
(mean age, 60.8 y; 22 women) with chronic primary insomnia
 Intervention: CBT (sleep hygiene, sleep restriction, stimulus control,
cognitive therapy, and relaxation; n=18), sleep medication (7.5-mg
zopiclone each night; n=16), or placebo (n=12)
• All treatment duration was 6 weeks
• Follow-up at 6 months.
 Main Outcome Measures: Ambulatory PSG and sleep diaries
 Results:
• CBT resulted in improved short- and long-term outcomes compared with
zopiclone on 3 out of 4 outcome measures.
• At 6 weeks, CBT improved sleep efficiency from 81.4% at pretreatment to 90.1%
at 6-month follow-up compared with a decrease from 82.3% to 81.9% in the
zopiclone group
• At 6 months patients receiving CBT had better sleep efficiency using
polysomnography than those taking zopiclone
Silversten, B. et. al. 2006. JAMA, 295, 2851
Combined use of B and P
 Objectives To evaluate the added value of medication over CBT alone for acute
treatment of insomnia and the effects of maintenance therapies
 Design: Randomized controlled trial involving 2-stage therapy for 160 adults with
persistent insomnia
 Interventions CBTalone or CBT plus 10mg/d zolpidem for an initial 6-week therapy,
followed by extended 6-month therapy.
• CBT received monthly maintenance CBT for 6 months or received no additional treatment
• Combined continued with CBT plus intermittent use of zolpidem or CBT only
 Main Outcome Measures SoL, TST, SE derived from diaries; treatment response
and remission rates derived from the Insomnia Severity Index
 Results CBT used singly or in combination with zolpidem produced significant
improvements in SoL, SE during initial therapy (all P.001)
 Larger increase of sleep time was obtained with the combined approach (P=.04)
 Combined therapy produced a higher remission rate compared with CBT alone
during the 6-month extended therapy phase and the 6-month follow-up period (56%
vs 43%, P=.05)
 Best long-term outcome seen in combined therapy initially, followed by CBT alone,
as evidenced by higher remission rates at the 6-month follow-up compared with
patients who continued to take zolpidem during extended therapy (68% vs 42%,
p<.04)
Zolpidem 10 Mg PRN Alone and with
Stimulus Control Therapy
Overview
 Prospective, observational study in 550 primary care settings in
Germany
Sample
 2,690 patients with chronic insomnia (mean age 59 years)
 Female 66%
 Average duration of insomnia = 5.2 years
 Prior use of patients who received prior pharmacotherapy = 49.7%
Method
 Zolpidem 10 mg HS alone prescribed for “as needed” use, up to a
maximum of 5 tablets per week for three weeks
 After three weeks of treatment, use of standard stimulus control
therapy was optional on non-drug nights. Hajak, Bandelow, Zulley, et. al., Annals of
Clinical Psychiatry, 14, 2002
Average Zolpidem Use During
Treatment Periods
4
3.7
3.7
Tabs
Number of Tablets
3.5
3
2.62.6
Tabs
2.5
2
1.5
1
0.5
0
Zolpidem 10 mg PRN
After 3 Weeks (Opt. SC)
P < 0.00001
Hajak, Bandelow, Zulley, et. al., Annals of Clinical Psychiatry, 14, 2002
Treatment Considerations
Pharmacotherapy
Behavioral
Therapy
Widely Available
Yes
Not Yet
WASO or sWASO
Yes
Yes
Sustained Efficacy or
Available for Long Term Use
Yes
Yes
Use in Co-Morbid Insomnia
Yes
Yes
Reduce Impairment or Health
Risk
No
No
+
-
Variable
Safety Concerns
Relative Merits and Considerations
 Drug treatments are widely available, efficacious, and
impact key sleep outcomes (WASO), but safety
concerns persist
 Behavioral treatments are not as widely available but
are efficacious, impact key sleep outcomes, and are
associated with fewer concerns than drug treatments
 Neither drug or behavioral treatments have been shown
to improve daytime functioning or health outcomes
 Practice guidelines emphasize the value of clinician
judgment in treatment planning
“B vs. P” State of the Science
 Studies are needed to evaluate the effectiveness
insomnia treatments in improving measures of clinical
significance, such as daytime function, quality of life,
health outcomes
 Further research is needed to comparing the
effectiveness of single versus combined drug, device,
psychological, or behavioral therapies for insomnia.
 Further research is to identify patient groups where
combination or single therapy is most appropriate.
 Studies are needed that compare treatments for
insomnia with regard to their short and long-term
effectiveness, risks/benefits, costs, and patient
satisfaction.