Behavioral versus Pharmacological Therapy for Adult Insomnia

Gary K. Zammit, Ph.D.Clinilabs

Columbia University College of Physicians and Surgeons

Conflict StatementI 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, Sanofi-Aventis, 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

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 APA. Diagnostic and Statistical Manual of Mental Disorders - 4th Edition, Text Revision. 2000.2 WHO. International Statistical Classification of Diseases and Related Health Problems, 10 th Revision, 2006

One or More of the Following Symptoms Must be Present

Prevalence of InsomniaThe 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 InsomniaState-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.

Difficulty falling asleep

~50%

Sleep maintenance problems†

~70%

Poor sleep quality

~40%

*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 Most Common

US results (n=2,061):27.1% insomnia prevalence • from an international

telephone survey (N=5,132)

Of US patients withsleep disturbances:*

• 42% have sleep problems[nearly] every night

• Mean number of symptoms is 1.9

• 24% report all 3 symptoms

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-UPKatz and McHorney, Arch Intern Med, 1998

0

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70

80

No insomnian = 801

Mild insomnian = 557

Severe insomnian = 264

Baseline statusNo insomnia Mild insomnia Severe insomniaFollow-up status

% o

f su b

j ec t

s

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 co-morbid 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)

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

Thase ME. Gen Hosp Psychiatry. 2005;27:100-112.

QUALITY OF LIFE IN INSOMNIAMETHODS

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

CONTROL GROUP No history of insomnia Regular periods of nighttime sleep No history of serious medical,

psychiatric, or sleep disorder

362 men and women,18 - 75 years of age, were prospectively studied 261 (72%) met criteria for the insomnia group101 (28%) met criteria for the control group

Zammit GK et al. Sleep. 1999;22(suppl):S379-S385.

Burden of Insomnia on Quality of Life

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.

95

75

55

35

P<.0001

N=362

Control

Insomnia

Body Pain General Health

Mental Health

Role Emotional

Role Physical

Social Functioning

Vitality Physical Functioning

SF

-36

Sca

le S

core

Insomnia Impacts Quality of Life

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)

**P < 0.01; P-values represent within-group pairwise comparisons at each point for all groups.

**************

ESZ LOCF Placebo LOCF

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ESZ Observed Placebo ObservedESZ Completers Placebo Completers

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Month

Krystal et al. Sleep. 2003:26;793-799

Self-Reported Wake Time After Sleep Onset (sWASO)

*P < 0.05; +P = 0.07 for Observed; P-values represent within group pairwise comparisons at each point for all groups.

Month

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60

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ESZ Observed Placebo Observed

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ESZ LOCF Placebo LOCFESZ Completers Placebo Completers

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

70

80

90

100

110

120

130

Baseline Night 1 Night 85

Placebo Doxepin 1 mg Doxepin 3 mg

**

** **

*P< 0.05,** p< 0.0001

p < .001 for zolpidem-pill vs. placebo-pill

Efficacy of Non-Nightly Zolpidem over 8 Weeks: Self Reported Total Sleep Time

300

320

340

360

380

400

420

Weeks 1-2 Weeks 3-4 Weeks 5-6 Weeks 7-8

Placebo pill n=71 Placebo no pill n=71

Zolpidem 10 mg pill n=63 Zolpidem no pill n=63

min

utes

* * * *

*Walsh et al., Sleep, 2000

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 eszopiclone-treated patients had no clinically meaningful insomnia as assessed by ISI score (versus 30% of placebo-treated patients (P = .03)3

1Krystal, 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

Most Common AEs in 5-Week Placebo-Controlled Study of Ramelteon in Adults with Insomnia

AE 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%

* 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

Drug ClassTotal 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

•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

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

0

2

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14

16

Mean Items ImmediateRecall

Mean Digits ImmediateRecall

Mean Items MorningRecall

Mean Digits MorningRecall

Placebo

Flurazepam

Lorazepam

Triazolam

Roth, et. al., (1980). Psychopharmacology, 70, 231 - 237

Next-Day Psychomotor FunctioningS

co

re (

med

ian

)

Zammit et al. Curr. Med. Res. Op., 2004, 20, 1979 - 1991

Mean +/- 1 SD for age group 35-44 norm – Wechsler adult intelligent scale

Morning DSST Scores^

^Mean of 3 time points (days 1, 15, & 29)

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Placebo ESZ 3 mgBaselineBaseline

Imp

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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 post-administration

• 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

0

1

2

Frequent falls Non-spine fracture Hip fracture

Outcome

Short-acting

Long-acting

n=8,127

1Ensrud KE et al. J Am Geriatr Soc 2002;50:1629–37; 2Ensrud KE et al. Arch Intern Med 2003;163:949–57.

Rel

ativ

e R

isk

Postural Instability and Hypnotic UseSensory Organization Test Composite Score

SO

T S

core

Cha

nge

from

Bas

elin

e

Zammit, G. K. 2008. BMC Geriatrics.

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

SL

Baseline 76.1 75.7 75.9 72.3

1st Night Off *90.1 89.4 76.2 75.5

NAW

Baseline 2.35 2.34 2.38 2.41

1st Night Off 2.62 2.25 2.24 2.09

Walsh, J., et. al., 2000, Sleep, 23, 1087 - 1096 *P < 0.04

Relative Abuse Liability of 19 HypnoticsPentobarbital

MethaqualoneDiazepam

FlunitrazepamLorazepam

GHBTemazepam

ZaleplonEszopiclone

TriazolamZopiclone

FlurazepamZolpidem

EstazolamOxazepam

DiphenhydramineQuazepamTrazodoneRamelteon

0 20 40 60 80 100

Likelihood of Abuse

Toxicity

Score

Griffiths R, Johnson M. 2005, J Clin Psychiatry, 66 (suppl 9): 31 - 41

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 PharmacotherapyBehavioral Therapy

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 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 quasi-desensitization (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

Edinger, J., et. al., 2006, JAMA, 285, 1856 - 1864

MeasureBaseline

MeanCBT RT Placebo P Value Post-Hoc Test

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

Behavioral Therapy & Co-Morbid Insomnia Chronic pain:

• SOL, WASO, SE improved following CBT versus control1o SOL reduced from 55 minutes to 28 minuteso 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

1Currie, 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

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 InsomniaOutcome After Four Weeks of Treatment

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Remission Response PartialRemission

Non-Response

BBTI (n = 39) IC (n = 40)

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No Longer Meet DSM-IV Criteria

BBTI (n = 39) IC (n = 39)

(P<.001)

Buysse, D., et. al., Archives of Internal Medicine, 2011, e-pub January 24, 2011

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 wait-list

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

GermanySample 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

3.7

2.6

0

0.5

1

1.5

2

2.5

3

3.5

4

Zolpidem 10 mg PRN After 3 Weeks (Opt. SC)

Hajak, Bandelow, Zulley, et. al., Annals of Clinical Psychiatry, 14, 2002

P < 0.00001

3.7 Tabs

2.6 Tabs

Num

ber

of T

able

ts

Treatment Considerations

Variable PharmacotherapyBehavioral 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

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.