1. Insomnia from A to ZZzzs
October 2, 2013
Tina Waters, MD

2. Objectives
Summarize the basic principals of sleep and describe normal sleep patterns versus insomnia
Review the clinical and diagnostic evaluation of insomnia as well as negative health and social consequences of sleep loss
Achieve a basic understanding of the neurophysiology underlying sleep/wake cycles and the benzodiazepine receptor site
Differentiate among sedative hypnotics with respect to their relative risks, benefits, and indications

3. rapid eye movement (REM) sleep and
4/19/2017
What happens when we sleep? “Although it’s common to think of sleep as a time of ‘shutting down,’ sleep is actually an active physiological process. While metabolism generally slows down during sleep, all major organs and regulatory systems continue to function.” Sleep can be categorized into two distinct types:
rapid eye movement (REM) sleep and
non-rapid eye movement (NREM) sleep.
We typically alternate REM and NREM sleep throughout the night in a cycle that repeats itself every 90 minutes. This is called our sleep architecture because when measured by an electroencephalogram (EEG), which uses electrodes on the scalp to monitor the electrical activity of the brain, the brain wave pattern recorded on a computer typically resembles a city skyline (see the States and Stages of Sleep graphic).
Source: National Sleep Foundation (2008)
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4. Two Process Model of Sleep
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Two Process Model of Sleep
Process S: Homeostatic sleep drive or sleep pressure - sleep occurs naturally in response to how long we are awake; longer awake, the stronger sleep drive
Process C: Circadian process - this process controls the timing of sleep and wakefulness during the day-night cycle. Timing is regulated by the circadian biological clock that is located in the brain in the SCN (suprachiasmatic nucleus)
SCN influenced by light so that we naturally tend to get sleepy at night when it is dark and are active during the day when it is light.
In addition to timing the sleep-wake cycle, the circadian clock regulates day-night cycles of most body functions, ensuring that the appropriate levels occur at night when you are sleeping. For example, important hormones are secreted, blood pressure is lowered and kidney functions change.
Borbély & Achermann, Principles and Practice of Sleep Medicine, 4th ed., Chapter 33.
Process C (for Circadian)
The body’s clock is needed for daily predictive physiological preparation for day phases.
The body’s clock has temporal inertia.
Process S (for Sleep)
The body’s stopwatch for wakefulness for keeping track of what already happened
Starts when sleep stops, resets with getting sleep.
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7. How Much Sleep Do You Really Need?
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How Much Sleep Do You Really Need?
This table identifies the "rule-of-thumb" amounts most sleep experts have agreed upon; however there is no “magic number”
Are you productive, healthy and happy on seven hours of sleep? Or does it take you nine hours of quality ZZZs to get you into high gear? Do you have health issues such as being overweight? Are you at risk for any disease? Are you experiencing sleep problems? Do you depend on caffeine to get you through the day? Do you feel sleepy when driving? These are questions that must be asked before you can find the number that works for you.
Nevertheless, it's important to pay attention to your own individual needs by assessing how you feel on different amounts of sleep.
Not only do different age groups differ, sleep needs are also individual. It is most important to pay attention to individual needs by assessing how the individual feel on different amounts of sleep.
Sleep need depends upon genetic and physiological factors and also varies by age, sex, and previous sleep amounts
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8. 75% of adult Americans experience sleep disorder symptoms at least a few nights per week
Sleep loss impacts on all facets of life and virtually all organ systems
Untreated apnea doubles the risk of
recurrent atrial fibrillation
Sleep disorders cause academic and
behavior problems in kids
Sleep loss increases the risk of obesity and diabetes
Drowsy driving is responsible for over $12 billion in reduced productivity/property loss

9. Sleep Disorder Symptoms on the Rise
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Sleep Disorder Symptoms on the Rise
Adults with sleep disorder symptoms > 3 nights per week
Sleep is a vital and necessary function, and sleep needs (like thirst and hunger) must be met
Acute and chronic sleep loss substantially impair physical, cognitive and emotional functioning
The need for sleep is genetically determined and cannot be modified
Most adults need about 8 hr of sleep to function optimally
Average adults sleep 6.9 hr (weekdays), 7.5 hr (weekends)
68% sleep less than 8 hr on weeknights
39% sleep less than 7 hr on weeknights
National Sleep Foundation 2008 Sleep In America Poll.
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10. 4/19/2017
Habitual Sleep Duration < 6 hours is associated with a variety of adverse consequences:
risk of diabetes and heart problems
inflammatory markers
risk for psychiatric conditions including depression and substance abuse
health care utilization
risk of motor vehicle accidents
ability to pay attention, react to signals or remember new information
leptin and ghrelin levels  greater likelihood of obesity due to increased appetite caused by sleep deprivation
Banks S; Dinges DF. J Clin Sleep Med 2007;3:
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11. More Sleep ≠ Better Health?
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More Sleep ≠ Better Health?
Long sleep durations (> 9 hours) have been found to be associated with increased morbidity (illness, accidents) and mortality.
Some research has found "U-shaped" curve where both sleeping too little and sleeping too much may put you at risk.
This research found that variables such as low socioeconomic status and depression were significantly associated with long sleep.
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12. Insomnia defined Repeated difficulty with:
Sleep initiation
Sleep duration
Sleep maintenance
Sleep quality – nonrestorative sleep
…despite an adequate time and opportunity for sleep
…and results in some form of daytime impairment
Insomnia is not sleep deprivation
American Academy of Sleep Medicine. International classification of sleep disorders, 2nd ed.:
Diagnostic and coding manual. Westchester, Illinois: American Academy of Sleep Medicine, 2005.

13. Daytime impairment Must complain of at least one of these below:
Fatigue or malaise
Tension, HAs or GI symptoms
Mood disturbance or irritability
Proneness for errors or accidents at work or while driving
Memory, attention or concentration impairment
Motivation, energy or initiative reduction
Daytime sleepiness
Concerns or worries about sleep
Social or vocational dysfunction or poor school performance

14. Insomnia’s Evolution NIH-1983 NIH-1995 Insomnia as a disorder
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Insomnia’s Evolution
NIH NIH-1995
Insomnia as a disorder
Insomnia as a symptom,
not a disorder
Insomnia as CO-MORBID
with other disorders
Insomnia as SECONDARY
to a primary disorder
Important to treat primary
disorder; insomnia may
receive attention, may not
Important to treat medical and psychiatric disorders as well as co-morbid insomnia
J Clin Sleep Med Oct 15;1(4): NIH State of the Science Conference statement on
Manifestations and Management of Chronic Insomnia in Adults statement.
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15. Epidemiology of Insomnia
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Epidemiology of Insomnia
General population: 10-15%
Elderly: 10-20% - Older adults, particularly women, and those residing in nursing facilities are much more likely to use hypnotics
Comorbid insomnia accounts for >80% of cases
Impacts quality of life and worsens clinical outcomes
Predisposes patients to recurrence
May continue despite treatment of the primary condition
Mellinger et al. 1986; Ohayon, 2002
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16. Prevalence Estimates by Definition
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Prevalence Estimates by Definition
Ohayon (2002) Sleep Medicine Reviews
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17. The Economic Burden of Insomnia
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The Economic Burden of Insomnia 3% 5%
15%
76%
About 5.3 billion in US dollars
Daley M et al. Sleep, 2009; 32:
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18. Populations at Risk for Insomnia
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Populations at Risk for Insomnia
Female sex
Increasing age
Comorbid medical illness (respiratory, chronic pain, neurological disorders)
Comorbid psychiatric illness (depression, depressive symptoms)
Lower socioeconomic status
Widowed, divorced
Non-traditional work schedules
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19. Prevalence of insomnia by age group
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Prevalence of insomnia by age group %
PERHAPS FORMAT THIS ONE AND THE PREVIOUS SLIDE SIMILARLY
Age
Large-scale community survey of non-institutionalized American adults,
aged 18 to 79 years
Mellenger GD, et al. Arch Gen Psychiatry. 1985;42:
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20. Comorbid Insomnia Cardiovascular diseases Respiratory diseases
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Comorbid Insomnia
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
Endocrine syndromes
Diabetes
Menopause
Hyperthyroidism
Pain
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
Insomnia may occur with many different, sometimes overlapping conditions, including cardiovascular diseases, respiratory diseases, gastrointestinal diseases, neurological diseases, rheumatic disorders, psychiatric disorders, endocrine syndromes, associated sleep disorders, and such miscellaneous conditions as chronic fatigue syndrome, human immunodeficiency virus/acquired immunodeficiency syndrome, Lyme disease, and cancer. Insomnia may also be induced by pregnancy and as a side effect from various pharmacologic treatments.
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21. Increased prevalence of medical disorders in those with insomnia
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Increased prevalence of medical disorders in those with insomnia
Heart Disease
Cancer
HTN
Neuro
Resp
Urinary
Diabetes
Chronic Pain GI
Any medical problem %
N=137
N=401
p<.05
p<.01
p<.001
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 ;30(2):
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22. Insomnia prevalence increases with medical comorbidity
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Insomnia prevalence increases with medical comorbidity 80
Number of Medical Conditions 10 20 30 40 50 60 70
Percent of Respondents Reporting any Insomnia 1
2 or 3 4
Sleep Problems and Multiple Medical Conditions
The objective of the study undertaken by Foley and colleagues was to assess the association between sleep problems and chronic disease in older adults.
A majority of the participants (83%) reported 1 or more of 11 medical conditions and nearly 1 in 4 elderly respondents (age 65–84 years) had major comorbidity (ie, ³4 conditions). As shown on the slide, there was a correlation between reports of insomnia and the number of medical conditions reported. Depression, heart disease, bodily pain, and memory problems were associated with more prevalent symptoms of insomnia (not shown).
The authors concluded that the sleep complaints common in older adults are often secondary to their comorbidities and not to the aging process itself. Furthermore, the authors suggest that these types of studies may be useful in promoting sleep awareness among health professionals and among older adults, especially those with heart disease, depression, chronic bodily pain, or major comorbidity.
Foley D, et al. J Psychosomatic Res. 2004;56:
Self-reported questionnaire data from 1506 community-dwelling subjects aged 55 to 84 years
Foley D, et al. J Psychosom Res. 2004;56:
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23. ICSD2 Subtypes of Insomnia
Adjustment Insomnia (Acute Insomnia)
Psychophysiological Insomnia
Paradoxical Insomnia
Idiopathic Insomnia
Insomnia due to Mental Disorder
Inadequate Sleep Hygiene
Behavioral Insomnia of Childhood
Insomnia due to Drug or Substance
Insomnia due to Medical Condition
Insomnia not due to Substance or known Physiological Condition, unspecified
Physiological Insomnia, unspecified
American Academy of Sleep Medicine. International classification of sleep disorders, 2nd ed.:
Diagnostic and coding manual. Westchester, Illinois: American Academy of Sleep Medicine, 2005

24. Adjustment Insomnia Associated with identifiable stressor
Psychological, psychosocial, interpersonal, environmental, or physical
Short duration: few days to weeks
Must last < 3 months
Insomnia resolves when stressor resolves or when adapted to the stressor
Features may include:
Prolonged sleep latency
Increased number or duration of awakenings from sleep
Short sleep duration
Poor quality
AKA: Acute insomnia, transient insomnia, short-term insomnia, stress-related insomnia, adjustment disorder

25. Adjustment Insomnia
Estimated 1 year prevalence: 15-20% among adults (especially women, older adults)
Predisposing factors: h/o insomnia and adjustment insomnia
Can have recurrent episodes to either the same or different stressor
Contributes to development of a sequence of maladaptive sleep behaviors and associations which may lead to more persistent insomnia
The exact prevalence of adjustment insomnia is unknown, however epidemiologic studies indicate that the one-year prevalence of adjustment insomnia among adults is likely to be in the range of 15-25%.
It can occur in indiciduals of any age, although establishing a relationship between a particular stress and slep disturbance may be difficult in infants. Adjustment insomnia is more common in women than men, and in older adults than younger adults and children.

26. Psychophysiological Insomnia
Essential feature: heightened arousal and learned sleep-preventing associations that result in complaint of insomnia & associated decreased functioning during wake
AKA Learned insomnia, conditioned insomnia, functionally autonomous insomnia, chronic insomnia, primary insomnia, chronic somatized tension, internal arousal without psychopathology

27. Psychophysiological Insomnia: Diagnostic Criteria
Symptoms meet insomnia criteria
Present for > 1 month
One or more of the following:
Excess focus on and heightened anxiety about sleep
Difficulty falling asleep in bed at desired time or during planned naps, but not during other monotonous activities
Ability to sleep better away from home
Mental arousal in bed: intrusive thoughts or perceived inability to volitionally stop mind racing
Heightened somatic tension in bed - perceived inability to relax the body to allow sleep
The patient has evidence of conditioned sleep difficulty and or heightened arousal in bed as indicated by 1 or more of the following:
…Not better explained by another sleep disorder, medical or neurological disorder, mental disorder, medication use, or substance use disorder

28. Psychophysiological Insomnia
Individuals have physiological arousal and learned sleep preventing associations
Physiological arousal may be associated with emotional reactions that do not meet criteria for separate disorders
Mental arousal in the form of “mind racing” is characteristic
Associations can be learned in response to internal thoughts or external stimuli
Over-concern with inability to sleep
The arousal can reflect a cognitive hypervigilance.
Learned associations are marked by overconcern with the inability to sleep

29. The vicious cycle… Increased drive to sleep Increased agitation
Reduced ability to fall asleep
A cycle develops in which the more one strives to sleep, the more agitated one becomes, and the less able one is to fall asleep.
Conditioned environmental cues causing insomnia develop from the continued association of sleeplessness with situations and behaviors that are related to sleep.
The usual sleep environment exerts a weakened stimulus control over the sleep response.
Patients with this conditioned arousal may report that they sleep better away from home and from their usual routines.
Sleep preventing associations may be learned during a bout of insomnia caused by other precipitating factors such as depression, pain , disturbed sleep environment or shift work.
Psychophysiological insomnia then persists long after the precipitating factors have been removed or are no longer relevant.
Ultimately people have diminished feeling of well-being during the day, which may lead to deteriorated mood, motivation, attention, vigilance, energy, and concentration; increased fatigue and malaise.

30. Predisposing factors:
Demographics:
1-2% of general population
12-15% of patients seen at sleep centers
Women > men
Predisposing factors:
H/o light sleepers or episodic poor sleepers
Stress, environmental factors, life change
Anxious over-concern about health, well-being or daytime functioning
Familial patterns are unknown
However, since heightened arousal and conditioned associations that disrupt or prevent sleep are common complications of many types of insomnia, psychophysiological insomnia may be considered as a secondary diagnosis in a significantly higher percentage of patients.
Individuals with insomnia characteristically demonstrate effortful preoccupation with both the consequences of and the potential solutions for their sleep problems

31. May persist for decades if untreated Complications:
Onset:
Insidious onset
Insomnia present in early life or young adulthood
Acute onset:
Adjustment insomnia failed to resolve
May persist for decades if untreated
Complications:
Higher risk for first episode or recurrence of major depression
Excessive use of prescription or OTC sleep aids
Further directions
Individuals may have innate vulnerability for insomnia – altered sleep-inducing or arousal system
May gradually worsen as a vicious cycle of fitful sleep, daytime irritability, and poor concentration may develop.
A sense of repeated failure to resolve sleep problems often leads to intermittent periods of resigned helplessness and help-seeking behavior.
PSG: increased sleep latency or increased wake time after sleep onset and reduced sleep efficiency; usually > 30 minutes, but 1-2 hour periods are not uncommon.
Altered sleep architecture with increase in stage 1 sleep and decrease SWS.
Patients with a pronounced conditioned sleep difficulty at home may show a reverse first night effect in the sleep lab.
Patients often underestimate their actual sleep time shown by PSG, but they do not show the gross underestimates of sleep time shown by those with paradoxical insomnia
MSLT testing: normal daytime alertness or even hyperalertness; although a minority show evidence of sleepiness;
Nocturnal monitoring with actigraphy procudes overestimates of sleep time and underestimates wake time, because they can lay motionless in bed

32. The AASM guidelines do NOT recommend use of PSG for routine evaluation of insomnia unless there is a suspected additional sleep disorder or patient has failed previous behavioral and/or pharmacological treatment of insomnia.

33. Neurotransmitters in Wake
Neurotransmitter (Activating/Arousal Promoting)
Location
Acetylcholine
- Basal forebrain
- Pedunculopontine tegmentum (PPT)/laterodorsal tegmentum (LDT)
Dopamine
- Ventral periaqueductal gray matter
- Substantia nigra
Glutamate
- Ascending reticular activating system
- Thalamocortical system
Histamine
- Tuberomammillary nucleus (TMN)/posterior hypothalamus
Hypocretin/Orexin
- Lateral hypothalamus
Norepinephrine
- Locus coeruleus (LC)
Serotonin
- Raphe nuclei, thalamus
Sullivan, Medical Clinics of North America, May 2010

34. The Wake “Switch”
Sullivan, Medical Clinics of North America, May 2010

35. Neurotransmitters in Sleep
Neurotransmitter (Sleep Promoting)
Location
Adenosine
- Basal forebrain
Melatonin
- Pineal gland
GABA (located in 30% of all brain synapses)
- Ventrolateral preoptic nucleus (VLPO)
Galanin
Sullivan, Medical Clinics of North America, May 2010

36. The Sleep “Switch”
Sullivan, Medical Clinics of North America, May 2010

37. Management of Insomnia
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Management of Insomnia
Treat any underlying cause(s)/comorbid conditions
Promote good sleep habits (improve sleep hygiene)
Most individuals with insomnia rely on passive strategies: “do nothing, read, try to relax’
The first line of treatment often involves alcohol, OTC drugs, dietary/natural products
When professional help is sought by a physician, treatment is usually limited to a sleep medication
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38. Epidemiology of hypnotic use
General adult population: 4% (3-10%)
Elderly: 10-20%
Older adults, particularly women, and those residing in nursing facilities are much more likely to use hypnotics
(Mellinger et al. 1986; Ohayon, 2002)

39. Commonly Used Classes of Insomnia Medications
Benzodiazepines (BZ)
Benzodiazepine Receptor Agonists (BzRAs)
Antidepressants
Antipsychotics
Melatonin Receptor Agonists
Antihistamines
Anticonvulsants
“Natural” supplements/OTC Agents

40. Relative Frequency of Insomnia Agents

41. FDA-Indicated Sedative Hypnotics
Benzodiazepines (BZs)
Estazolam (ProSom)
Flurazepam (Dalmane)
Quazepam (Doral)
Temazepam (Restoril)
Triazolam (Halcion)
Melatonin Receptor Agonist: Rozerem (Ramelteon)
Tricyclic Antidepressant: Doxepin (Silenor)
Benzodiazepine Receptor Agonists (BzRAs)
Eszopiclone (Lunesta)
Zaleplon (Sonata)
Zolpidem (Ambien)
Zolpidem Extended Release (Ambien CR)
Zolpidem Sublingual (Intermezzo)
In 2002, only 4/16 of the most commonly used drugs for insomnia had an FDA indication.

42. FDA-Indicated Sedative Hypnotics
Medication
Dose (mg)
Onset (min)
Half-life (hr)
Active metabolite
Indication
Benzodiazepines:
Estazolam Flurazepam
Quazepam
Temazepam Triazolam
0.5 – 2.0
15 – 30
7.5 – 30
0.125 – 0.25
30 – 60
20 – 45
45 – 60
8- 24
2- 5a
47 – 120b a
39 – 120b
8 – 20
1.5 – 5 No
Yes
SMI
SOI
Benzodiazepine Receptor Agonists (BzRAs): Eszopiclone
Zaleplon
Zolpidem Zolpidem ER Zolpidem SL
1 – 3
5 – 10
6.25 – 12.5
1.75 – 3.5 60 15 30 90 35
6.0
1.0
1.5 – 4.5
1.6 – 4.0
1.4 – 3.6
SOI, SMI
Melatonin Receptor Agonist
Ramelteon 8
30 – 90
1 – 2.6a
2 – 5b
Tricyclic Antidepressant
Doxepin
3-6
210
15.3a 31.0b
Medication
Usual adult therapeutic dose (mg)
Time to onset (min)
Terminal elimination half-life (hr)
Active metabolites
Indication
Benzodiazepines
Estazolam (ProSom) Flurazepam (Dalmane)
Quazepam (Doral)
Temazepam (Restoril) Triazolam (Halcion)
0.5 – 2.0
15 – 30
7.5 – 30
0.125 – 0.25
30 – 60
20 – 45
45 – 60
8- 24
2- 5a
47 – 120b a
39 – 120b
8 – 20
1.5 – 5 No
Yes
SMI
SOI
Benzodiazepine Receptor Agonists Eszopiclone (Lunesta)
Zaleplon (Sonata)
Zolpidem (Ambien) Zolpidem CR (Ambien CR)
1 – 3
5 – 10
6.25 – 12.5 60 15 30 90
6.0
1.0
1.5 – 4.5
1.6 – 4.0
SOI, SMI
Melatonin Receptor Agonist
Ramelteon (Rozerem) 8
30 – 90
1 – 2.6a
2 – 5b
Tricyclic Antidepressant
Doxepin (Silenor)
3-6
210
15.3a 31.0b
Notice Ativan, Klonopin, and Xanax, though frequently used as hypnotics, do not have FDA indications for insomnia.
Benzodiazepines (“Traditional” Benzodiazepine Receptor Agonists or BzRAs)
Estazolam (ProSom)
Flurazepam (Dalmane)
Quazepam (Doral)
Temazepam (Restoril)
Triazolam (Halcion)
Non-Traditional or Non-Benzodiazepine BzRAs
Eszopiclone (Lunesta)
Zaleplon (Sonata)
Zolpidem (Ambien)
Zolpidem CR (Ambien CR)
Melatonin Receptor Agonist: Rozerem (Ramelteon)
Tricyclic Antidepressant: Doxepin (Silenor)
a = parent compound; b = active metabolite; SMI = sleep maintenance insomnia; SOI = sleep onset insomnia

43. Question
Which of the following medications have been recommended by the NIH to treat insomnia?
1: Benzodiazepines (BZ)
2: Benzodiazepine Receptor Agonists (BzRAs)
3: Antidepressants

44. Answer
The 2005 NIH State-of-the-Science report on the management of chronic insomnia concluded: benzodiazepine receptor agonists are the only medications with an established scientific basis (clearly defined risk benefit by dose) for treating insomnia.

45. GABAA Receptor Complex
Two particular combinations of isoforms that are often noted are the Type-I (alpha 1, beta 2, gamma 2) and Type-II (alpha 3, beta 2, gamma 2) configurations. The former, the most common type representing roughly 40% of GABAA receptors, is found in most areas of the brain and localized in interneurons of the hippocampus and cortex. Type II is half as common.
Berry, Fundamentals of Sleep Medicine, 2012, Ch 25

46. GABAA Receptor Alpha Subunits
ACTION
PROPORTION OF GABA RECEPTORS
LOCATION α1
Sedative, amnestic, anticonvulsant
60%
All brain regions cortex, hippocampus α2
Anxiolytic, myorelaxant
15–20%
Cortex, hippocampus, amygdala, forebrain, hypothalamus α3
10–15%
Cerebral cortex, thalamus (reticular nucleus)
α4, α6
Insensitive to BZ
Dentate gyrus α5
High affinity for BZ Low zolpidem affinity BZ tolerance
Cerebral cortex, hippocampus
Alpha 3 subunits are present in reticular nucleus of thalamus—area responsible for thalamic-cortical oscillations (sleep spindles)
In mice, thalamocortical relay neurons but
Nutt and Stahl, Journal of Psychopharmacology, Nov 2010

47. Receptor Affinities 17× 2× 1× 21× Negligible 8× 5×
Benzodiazepines (BZ) have a high affinity for all the subtypes.
On the other hand, the Benzodiazepine Receptor Agonists (BzRAs) demonstrate selectivity:
ALPHA 1
ALPHA 2
ALPHA 3
ALPHA 5
Zaleplon
17× 2× 1×
Zolpidem
21×
Negligible
Eszopiclone 8× 5×
1× = the lowest affinity of a given drug for any receptor.
Nutt and Stahl, Journal of Psychopharmacology, Nov 2010

48. BZ & BzRAs: Effects on Sleep
Improved sleep continuity
Decreased sleep latency
Increased total sleep time
Decreased wake after sleep onset
PSG changes
Decreased NREM 3 (less with BzRAs)
Reduced amplitude of slow waves
Increased sleep spindles (BZ)
Decrease in REM sleep (less with BzRAs)
Decreased periodic limb movements (BzRAs)
Decrease in REM is mild, less with alpha 1-selective drugs

49. BZ & BzRAs: Side Effects
Residual daytime sedation
Dose-related anterograde amnesia
Discontinuation phenomenon:
Rebound insomnia (worsening symptoms -less with BzRAs)
Withdrawal (new symptoms)
Insomnia recurrence
Falls/hip fractures in the elderly (long-acting BZ)
Respiratory suppression (minor effect, more with long-acting BZ)
Decrease in REM is mild, less with alpha 1-selective drugs. Bitter aftertaste with Lunesta.

50. BzRAs: Warnings
Risk factors for complex sleep-related behaviors while using BzRAs include:
Higher doses (2-3 times the indicated clinical dose)
Prior history of parasomnias
Prior history of brain injury
Concurrent use with alcohol

51. BzRAs: General Considerations
Use lowest dose for shortest time possible
Take on an empty stomach
Not recommended in pregnant or nursing women
Not recommended in advanced liver disease
Rapid reduction in dose or withdrawal can cause withdrawal symptoms including rebound insomnia
Use long-acting BZ with caution in patients with OSA or lung disease (COPD)
Potential for abuse or dependence thought to be low for BzRAs
Berry, Fundamentals of Sleep Medicine, 2012, Ch 25

52. Tolerance?
Eszopiclone (Lunesta) showed continued effect on sleep latency over 12-months
Led to discontinuation of duration limits on BzRAs (prior had been 35 days)
Roth, et al., Sleep Medicine, Nov 2005

53. On January 10, 2013, the FDA informed the manufacturers of zolpidem (Ambien) that the recommended dose be lowered for women from 10 to 5 mg for immediate-release products and from 12.5 to 6.25 mg for extended-release products.
Women metabolized lower; found on driving simulation that they were more vulnerable to morning-after daytime sedation. FDA recommending that lower dose be discussed with men as well though.

54. Antidepressants
Hypnotic properties most strongly related to antagonism of serotonin 5-HT2, histamine H1, and α1 adrenergic receptors
Commonly used medications include trazodone, mirtazapine, amitriptyline, and doxepin
Doses used for insomnia are much lower than those used for depression
Doxepin was approved in 2010 for maintenance insomnia (3 and 6 mg), because it has histamine selective properties at low doses
In 2002, 3 of the top 5 medications prescribed for insomnia were antidepressants.

55. Antidepressants
Few studies—strongest evidence for efficacy is for tricyclics (doxepin, amitriptyline, trimipramine)
Specific adverse effects need to be considered:
Tricyclics: anticholinergic side effects
Trazodone: hypotension, rare priapism
Mirtazapine: weight gain
SSRIs: insomnia, exacerbate RLS
In 2002, 3 of the top 5 medications prescribed for insomnia were antidepressants.

56. Antipsychotics
Atypical antipsychotics such as quetiapine and olanzapine have indications for psychotic disorders and mania
Antagonize dopamine, histamine (H1), serotonin (5HT2A), muscarinic, cholinergic, and α1 receptors
Similar to antidepressants, used at lower doses for treating insomnia: quetiapine mg, olanzapine mg
Olanzapine has longer half-life than quetiapine: hours versus 6-7 hours, respectively
In 2002, 3 of the top 5 medications prescribed for insomnia were antidepressants.
Quetiapine = Seroquel
Olanzapine = Zyprexa

57. Antipsychotics
Studies in patient populations other than primary insomnia:
Decreased sleep latency
Olanzapine may increase deeper NREM sleep
Quetiapine may reduce REM sleep
Significant potential risks:
Akathesia
Weight gain
Orthostatic hypotension
Contribution to metabolic syndrome
In 2002, 3 of the top 5 medications prescribed for insomnia were antidepressants.

58. Melatonin Receptor Agonist
Ramelteon became first melatonin receptor agonist approved for treating insomnia (2005)
17x more potent at melatonin type I (decreased waking signal) than type II (circadian rhythms) receptors
Primary benefit on sleep latency
Non-scheduled medication — lacks potential for abuse or dependence
Adverse effects: nausea, headache, fatigue
Ramelteon = Rozerem

59. Antihistamines
Diphenhydramine, doxylamine, and hydroxyzine are the most commonly used for insomnia
Tolerance to daytime sedation and similar decrease in effectiveness as a hypnotic can develop in 4 days1
Anticholinergic activity needs to be considered, especially in the elderly
Diphenhydramine = Benadryl
Doxylamine = Nyquil
Hydroxyzine = Vistaril
1Roth et al, J. Clin. Psychopharm., Oct 2002

60. Anticonvulsants
Pregabalin and gabapentin bind to voltage-gated calcium channels diminish release of glutamate and norepinephrine
FDA indications: partial seizures, pain, fibromyalgia
Gabapentin used at doses of mg for insomnia
Common adverse effects include sedation, dizziness, ataxia
Krystal, Principles and Practice of Sleep Medicine, 5th ed., Chapter 82

61. 4/19/2017
Melatonin
Produced by pineal gland; "turned on" by the SCN at night by darkness
Melatonin on it’s own will not induce sleep, it is more like a “darkness” signaler
If taken in the evening or when it's dark, melatonin can speed up sleep preparation, and it can tell the body clock to shift its sleep cycle to an earlier time
For some people, melatonin seems to help improve sleep. Of the few studies involving people with insomnia, results are inconclusive
Because melatonin is a hormone that is part of the human sleep-wake cycle, many people think that by taking more of it as a pill, it will help them to fall asleep faster or stay asleep longer.
Mistake #3: Melatonin is a natural supplement, so it can't do any harm.
The wrong amounts of melatonin or melatonin at the wrong time of day can cause serious health risks. Daytime melatonin has been shown to cause depression. This makes sense, especially when you consider that melatonin causes us to pull back, withdraw, become disoriented and irritable - the classic hibernation response. It's best to avoid using melatonin that could be in our system during the day
Evidence that melatonin can reset the body clock is more well established, although it is not clear whether exposure to light may be more effective. Overall, research indicates improved sleep when melatonin is taken at the appropriate time for jet lag and shift work.
Insomnia

62. Melatonin Dosage is very important.
Most drug stores and health stores carry tablet sizes 3-10mg.
New evidence shows that adult males only need 150 micrograms, and the average female needs only 100 micrograms, so times more than what is needed.
Large studies are needed to demonstrate if melatonin is effective and safe for some forms of insomnia, particularly for long-term use.
It may be true that melatonin is effective and safe for some types of insomnia and for children but not for other types of sleep problems. How much to take, when to take it and its effectiveness, if any, for particular disorders is only beginning to be understood.
Melatonin is effective as a signal augmenter (reinforcing external cues), or as a tool to help shift sleep and circadian rhythms.
Long term use of melatonin indicates a more serious underlying sleep disorder that should be investigated by a sleep professional.

63. Hypnotic Selection Hypnotic indicated Improved Continue
Consider cost, prior treatment failures, side effects, co-morbidities, interactions
Use shorter active BZRA
Continue
Duration too long, AM grogginess Y
Improved? N
Duration not long enough
Use longer acting BZRA
BZRA + sedating antidepressant or
Short to intermediate BZRA or Ramelteon
SOI: Zaleplon, Ramelteon
SOI, SMI: zolpidem, eszopiclone, temazepam
Ineffective
Increase dose or switch
Sedating antidepressant
Intolerable side effects
Switch
Adapted from Berry, Fundamentals of Sleep Medicine, 2012, Ch 25

64. Sedative Hypnotics: General Considerations
Ensure patients dedicated an adequate amount of time to sleep
Consider pharmacokinetic and pharmacodynamic properties, cost, side effects, and duration of use
Do not combine with alcohol!
Use caution with other sedatives
Consider patient preference for treatment modality
Evaluate contributions to insomnia from other medications and medical conditions
Consider drug interactions when choosing an agent
Specific side effects such as a bitter aftertaste with eszopiclone.

65. Selecting a Sedative Hypnotic
If patient has a history of alcohol or recreational drug dependence: consider non-controlled medications:
Ramelteon, doxepin, antidepressants, antipsychotics, or anticonvulsants
Antipsychotics should be reserved for cases with primary psychiatric disorders.
If patient has co-morbid pain, seizures, RLS, PLMD, or fibromyalgia
Gabapentin or pregabalin
Consider CBT-I (cognitive behavioral therapy for insomnia) for chronic insomnia
Consider drug interactions: Sertraline/zolpidem; fluoxetine/zolpidem
Fluvoxamine/ramelteon; doxepin/ramelteon

66. When to discontinue hypnotics…
…desire to stop
…is no longer effective
…is contraindicated
Alcohol abuse/dependence
Pregnancy
…escalating dosage and demonstrating signs of tolerance and/or abuse
…adverse effects such as cognitive impairment or psychomotor performance issues
…has been using the medication longer than recommended?

67. 4/19/2017
“Am I an addict?”
Tolerance – Reduction of pharmacological effect after repeated administration of drug
Dependence – Neuroadaptation phenomenon resulting from chronic administration, characterized by withdrawal syndrome
Abuse – Loss of control over drug taking, preoccupation with drug, continued use despite adverse consequences, use for “high”
Majority of patients at Sleep Center have developed tolerance, much more rare to see pt’s abusing hypnotics, more commonly psychological dependence than physical dependence
Brady et al., Current Psychiatric Treatment II, 1997
Insomnia

68. Withdrawal Symptoms Rebound Insomnia Anxiety Restlessness
Increased perceptual acuity
Impaired concentration
Tend to be more severe with higher dosages and with shorter half lives

69. Rebound Insomnia Worsening of sleep upon discontinuation of medication
4/19/2017
Rebound Insomnia
Worsening of sleep upon discontinuation of medication
Level of sleep disturbance can be more severe than before starting medication
This transient symptom is misinterpreted as a chronic problem, therefore prompts patients to resume or increase medication use
Need to provide education on rebound insomnia phenomenon as well as implementing tapering plan to minimize withdrawal
Heightens the patients anxiety and reinforces belief that they cannot sleep without medication
Insomnia

70. Cycle of Hypnotic Dependent Insomnia
Fear of not sleeping maintains the pill taking behavior
Caught in a vicious cycle, medication lost its sleep promoting effect but attempt to stop abruptly causes withdrawal sx and rebound insomnia which heightens anticipatory anxiety and reinforces belief that cannot sleep without medication
Conditioning principles – taking medication alleviates aversive state (sleeplessness) so drug taking behavior is negatively reinforced
People with insomnia on medications tend to have impaired recollection of wakefulness, upon withdrawal of drug patients become acutely aware of their sleep disturbance
Dependence upon sleep aids often tends to be more psychological than physical

71. Strategies for discontinuing hypnotic medications
Abrupt discontinuation
Tapering from short-acting hypnotics
Substitute and taper long-acting hypnotic
Use of other drug to facilitate
CBTi as an adjunct

72. Spielman Model: Three P’s

73. Cognitive-Behavioral Treatment of Insomnia
Multi-component treatment
Sleep hygiene education
Stimulus control
Sleep restriction
Relaxation therapy
Cognitive restructuring
Most behavioral sleep medicine clinicians use a multi-modal approach - combining the techniques above
(Morin, Colecchi, Stone, Sood, & Brink, 1999)
CBT + meds show slightly greater short term sleep improvements than CBT alone
However, CBT alone showed better maintenance of sleep improvements at end of 2 year follow up than combo
70-80% of patients with primary insomnia benefit from CBT interventions
Insomnia in primary care (Espie et al., 2007; Edinger & Sampson, 2003; Germain et al., 2006).
Insomnia associated with medical (pain, cancer) and psychiatric (depression, substance abuse) conditions (Currie et al., 2004; Lichstein et al., 2000; Manber et al., 2008; Savard et al., 2005; Taylor et al., 2007)
Insomnia in older adults (Lichstein et al., 2001; McCrae et al., 2007; Pallesen et al., 2003)
Chronic hypnotic use (Morgan et al., 2003; Morin et al., 2004; Soeffing et al., 2008)
Recent review by Smith, Huang, and Manber concluded that CBT-I is effective treatment for those with chronic insomnia who suffer from a wide range of comorbid psychiatric and medical conditions
Very effective for psychophysiological insomnia as well as comorbid insomnia
Benefits outlast pharmacologic agents
Clinical and polysomnographic evidence to prove it’s efficacy
CBT-I is usually delivered by a therapist in 4-8, minute individual sessions
Most people who seek treatment are given prescription sleep medication
Relative inaccessibility of CBT-I? – not enough trained clinicians, lack of accessibility due to mobility, transportation and financial restrictions
CRITICAL NEED TO MAKE CBT-I MORE ACCESSIBLE TO GENERAL PUBLIC

74. Dysfunctional Beliefs
4/19/2017
Cognitive Factors
Dysfunctional Beliefs
Sleep Hygiene
Stimulus Control
Inhibitory Factors
Poor sleep hygiene
Conditioned arousal
Pre-bed & In-bed habits
Circadian Disruption
Improper Sleep
Scheduling
Homeostatic Dysregulation
Excessive TIB
Napping
Cognitive factors: misattributions about causes of insomnia, misconceptions about sleep needs, propensity towards catastrophizing about consequences of poor sleep, dysfunctional beliefs about sleep promoting practices
These cognitions, in turn, support and sustain sleep-disruptive habits and conditioned emotional responses that either interfere with normal sleep drive or timing mechanisms or serve as environmental/behavioral inhibitors of sleep.
Psychophysiological
Insomnia
Relaxation
Sleep Restriction
Edinger & Means, 2005
Insomnia