A. Normal Sleep [1]

1. Studies suggest normal sleep time is 9-9.5 hours per 24 hour cycle
2. Supriachiasmatic Nucleus in Hypothalamus
   1. Primary controller of circadian sleep-wakefulness cycle
   2. Sensitive to light and dark
   3. Sensitive to hormone melatonin, which is made by pineal gland
   4. Wakefulness promoted by influencing activity of brainstem reticular formation
   5. Suprachiasmatic nucleus has major influences on other circadian hormones (see below)
3. Reticular Formation
   1. Helps regulate sleep-inducing neurons
   2. With reduced sensory input (darkness), non-rapid eye movement (REM) sleep promoted
   3. Also helps induce cortical slow-wave activity
4. Other Influences
   1. Forebrain structures, particularly in preoptic area, help induce non-REM sleep
   2. Gamma-aminobutyric acid (GABA)-neurons in the cortex contribute to slow wave activity
   3. REM sleep is generated by cholinergic neurons in the pons
   4. Onset of REM sleep is accompanied by cessation of brainstem noradrenergic and serotonergic neurons
5. Effect of Aging on Sleep
   1. As people age, they require less sleep
   2. In addition, they sleep less soundly
   3. These are normal changes and should not be confused with illness
6. People usually begin with Non-REM sleep
   1. Staged by electroencephalographic (EEG) changes
   2. Stages 1-2 are mild-moderate slowing on EEG
   3. Stages 3-4 are slow wave sleep and are hardest to arouse from
   4. About 80% of all sleep is spent in non-REM phase
7. REM Sleep is reached in ~30-90 minutes in normal persons
   1. Dreams
   2. Rapid Eye Movements (REM)
   3. Paralysis
   4. Lots of autonomic activity
   5. Repeat cycles every ~90 minutes or 5-6 times per night
8. Hypocretin (Orexin) Neurotransmitters [13]
   1. Hypocretins (orexins) 1 and 2 are neuropeptides expressed in lateral hypothalamus
   2. Sequence similarity to gut-protein secretin (hypothalamic secretin-like peptides)
   3. Hypocretin producing neurons project widely to olfactory bulb, cerebral cortex, thalamus, hypothalamus, brainstem, locus ceruleus, bueromamillary nucleus, raphe nucleus
   4. At least two receptors for hypocretins
   5. Narcolepsy/cataplexy patients have extremely low levels of cerebrospinal fluid hypocretin
9. Other Hormones with Circadian Fluctuation
   1. Growth hormone
   2. Prolactin
   3. Maltonin
   4. Cortisol
   5. Thyroid-stimulating hromone (TSH)
   6. Oxytocin
   7. Placental hormones: HCG, progesterone, estriol, dihydroepiandrosterone (DHEA)

B. Causes of Insomnia [2,4]

1. Epidemiology
   1. Overall 5% or higher prevalence of insomnia in general population
   2. Higher rates in women, particularly with those with poorer education
   3. May lead to excessive daytime sleepiness and other complications
   4. Classified as either Primary or Secondary Insomnia
2. Primary Insomnia
   1. Idiopathic - arising in infancy or childhood with persistent, unremitting course
   2. Psychophysiologic - due to maladaptive conditioned response
   3. Paradoxical - sleep state misperception: patient's and polysomnographic results differ
3. Secondary
   1. Adjustment - associated with active psychosocial stressors
   2. Inadequate Sleep Hygiene - lifestyle habits that impair sleep
   3. Psychiatric Disorder - often anxiety or depression
   4. Medical condition - restless leg syndrome (below), chronic pain, hot flashes, dyspnea
   5. Medication or Drug of Abused (below)
   6. Restless leg syndrome (RLS; below)
4. Medications Associated with Insomnia
   1. Sympathomimetics: amphetamines, decongestants, cocaine
   2. Methylxanthines: caffeine, theophylline
   3. Alcohol - initial drowsiness with by premature awakening
   4. ß-Adrenergic Blockers
   5. Glucocorticoids
   6. Certain serotonin reuptake inhibitors (SSRI and SNRIs): fluoxetine (Prozac®), sertraline (Zoloft®), venlafaxine (Effexor®), others
5. Varicose Veins
   1. Even minor varicosities are also associated with poor sleep
   2. Relief with surgery is sometimes observed
6. Pain
7. Psychiatric Disorders
   1. Depression
   2. Anxiety
   3. Mania
8. Sleep Apnea (see below)
9. Pregnancy [1]
   1. Several hormonal rhythms are altered during pregnancy
   2. Cortisol levels increase during pregnancy with altered circadian behavior
   3. Estrogen and progesterone both affect many stages of sleep
   4. Estrogen reduces REM sleep
   5. Progesterone increases non-REM sleep (perhaps through GABA receptor agonism)
   6. All stages of pregnancy have decreased stage 3 and 4 non-REM sleep
   7. Trimester specific sleep anomalies have bene documented
   8. Sleep disordered breathing also occurs in pregnancy (increased small airway closure)
   9. Pregnancy associated sleep disorder is well recognized
10. Fatal Familial Insomnia
11. Multiple etiologies may be present concurrently

C. Treatment of Insomnia [2,4,5]

1. Evaluation [5]
   1. Obtain details from patient and from bedpartner
   2. Family history, habitual light sleeper, sensitivity to noise, shift work
   3. Nocturnal symptoms or events including nightmares, others
   4. Attempt to rule out underlying causes, particularly depression
   5. Timing of exercise, sexual activity, any other influences on sleep
   6. Use of caffeine, alcohol, drugs (all types)
   7. Sleep log (diary) for 7 consecutive days may be helpful
   8. Sleep questionnaire may also be useful
   9. Caution with use of sedative-hypnotics in elderly persons with insomnia [29,30]
2. Sleep Hygiene
   1. Restrict nighttime stimulants and fluids
   2. Establish a bedtime routine which relaxes patient
   3. Avoid stimulating activity (including exercise) very late in the day
   4. Leave bed if unable to fall asleep in 20-30 minutes
   5. Pursue quiet, relaxing activity
   6. Eat small amount of food with high tryptophan content, such as milk products
   7. Sleep Restriction - patient told to stay awake until rather late (for example, 2-3 AM)
   8. Cognitive behavioral therapy superior to zopiclone (non-benzodiazepine GABA agonist) in chronic primary insomnia in older adults [29]
3. Hypnotic Medications [4,5,16]
   1. Benzodiazapines: short term use only (intermittent use ONLY recommended)
   2. Chronic Agents: trazadone, tricyclic antidepressant (for example amitriptyline, imipramine)
   3. Short term: chloral hydrate, antihistamines (diphenhydramine) intermittantly only
   4. Benzodiazepine receptor agonists: zolpidem (Ambien®), zaleplon (Sonata®), S-zopiclone (Lunesta®), indiplon (not yet approved)
   5. Melatonin Agonists: may play a normal role in circadian rhythms (see below)
   6. Older persons: Adverse effects of sedatives outway improvements in sleep quality [30]
   7. Pregnancy: if agent must be used, zolpidem or diphenhydramine (Benadryl® and others)
4. Zolpidem (Ambien®) [7]
   1. Non-benzodiazapine hypnotic agent which binds benzodiazepine receptors
   2. Rapid onset of action, relatively short duration, does not affect REM sleep
   3. Half-life 3 hours, mainly for induction of sleep onset
   4. Dose is 5-10mg po qhs (Schedule 4 Controlled Substance)
   5. Drug interactions minimal and no impairment of mental functions on day after use
   6. At least in short term studies, as effective as benzodiazepines [7]
   7. May be used in pregnancy-associated sleep disorder [1]
   8. Highly recommended in most patients over benzodiazepines
   9. Not lableled for long term use, but has been used safely over long term
5. Zaleplon (Sonata®) [8,16]
   1. Pyrazolopyridimine hypnotic for short term treatment of insomnia
   2. Binds to benzodiazepine receptors (Schedule 4 Controlled Substance)
   3. Rapid onset of action (amy be slightly faster than zolpidem)
   4. Shorter half life (~1 hour) than zolpidem, with increased frequency of early awakening
   5. Usual dose is 10mg po qhs (reduce dose by 50% for elderly or hepatic impairment)
   6. Dose may be increased to 20mg qhs, but increased risk of transient visual halucinations
   7. Metabolized in part by CYP3A4 so caution with drugs that inhibit this enzyme
6. S-Zopiclone (eszopiclone, Lunesta®) [23]
   1. Nonbenzoziazepine pyrrolopyrazine hypnotic with long (6 hour) half-life
   2. Approved for acute and long term insomnia
   3. Initial dose 2mg qhs, maximum dose 3mg qhs; reduce dose in elderly
   4. Headache, unpleasant taste, dry mouth, dizziness side effects
   5. Metabolized by CYP3A4 and CYP2E1 so caution with drugs that inhibit these enzymes
   6. Labelled for chronic use and probably maintains sleep longer than other agents
7. Ramelteon (Rozerem®) [4,9]
   1. Melatonin receptor agonist approved for sleep onset insomnia
   2. Does not increase sleep duration
   3. Dose 8mg po qhs
   4. Causes drowsiness, dizziness, increased prolactin levels
   5. Short duration of action (half-life 2-5 hours)
   6. Metabolized by CYP1A2; caution with fluvoxamine, ciprofloxacin, hepatic failure, pregnancy
   7. More predictable efficacy than melatonin
   8. Not a controlled substance but relatively weak activity
8. Melatonin (N-acetyl-5-methoxytryptamine) [10,11]
   1. Hormone synthesized from tryptophan exclusively in the pineal gland
   2. In normal persons, the hormone is secreted at night (peaking at 2-4 AM)
   3. Older persons and blind persons have decreased and/or abnormal melatonin secretion
   4. Melatonin 5mg taken at bedtime x 3 weeks relieved nocturnal insomnia in blind persons
   5. Melatonin resets the circadian rhythm in blind persons [12]
   6. Some data to support use in jet lag treatment AFTER arrival in new time zone
   7. Mild hypnotic effects 1-2mg given at bedtime reduced time to fall asleep by 10 minutes
   8. No suppression of REM sleep
   9. Agent is sold in health food stores and is not FDA approved to date
   10. If purchased, brands which use "good manufacturing practices" (GMP) should be sought
   11. A number of uncharacterized contaminants have been found in most preparations [17]
9. Trazadone (Desyrel®) [6]
   1. Atypical Agent - triazolopyridine (unrelated to all other classes)
   2. Mainly for sleep disorders with good activity for insomnia
   3. Weak activity on serotonin transport, 5-HT2A receptors
   4. Activity at 5HT1A receptors may increase anxiolytic activity
   5. Mild anti-depressant effects, weaker than other agents
   6. May be added to SSRIs and other agents if insomnia is a problem
   7. Agent may be useful in patients with manic response to SSRIs (as second agent)
   8. Cerebral alpha1-adrenergic and H1-histaminergic blockade contribute to priapism and sedative side effects
   9. Dose is 50-200mg po qhs for sleep problems (up to 400mg po qhs maximum)
10. Benzodiazepines [4,7]
    1. Only selected agents are useful for sleep disorders
    2. Acceptable only very short term use (3-4 weeks duration, 3-4 times per week) [7]
    3. May be used in low doses over longer terms for chronic, severe insomnia only
    4. Increases stages 1 and 2 and supresses stages 3 and 4 (Deep) and REM sleep
    5. In general, these agents should be replaced by zolpidem or zaleplon (see above)
    6. Triazolam (Halcion®) - 0.25mg po qhs, may have increased rebound confusion, t1/2 <6 hr
    7. Temazepam (Restoril®) - 7.5mg-30mg po qhs (lower range in geriatrics), t1/2 <25 hr
    8. Estazolam (ProSom®) - 0.5mg-2mg po qhs (lower range in geriatrics), t1/2 <24 hr
    9. Oxazepam (Serax®) - 10-30mg po qhs, half life <6 hours, slow onset
    10. Avoid quazepam (Doral®) and clorazepate (Tranxene®) due to active metabolites
    11. Avoid diazepam (Valium®) and clonazepam (Klonopin®) due to long half lives (24-72 hrs)
    12. Alprazolam (Xanax®) is not recommended due to high abuse potential
    13. Most trials of benzodiazepines have limited duration of use and little followup [7]
11. Cognitive-Behavioral Therapy [4]
    1. Beneficial with good maintenance of improved sleep hygiene
    2. Aids in reduction in use of pharmacologic agents
    3. Stimulus Control Therapy
    4. Sleep Restriction Therapy
    5. Relaxation - muscle relaxation, biofeedback
    6. Cognitive - alter faulty beliefs and attitudes about sleep
    7. Sleep hygiene (as above)
12. Stimuls Control Therapy
    1. Go to bed only when sleepy
    2. Use bedroom only for sleeping and sex
    3. Go to another when unable to sleep in 15-20 minutes; read or other quiet activity
    4. Regular wake-time regardless of sleep duration
    5. Avoid daytime napping
13. Sleep Restriction Therapy
    1. Reduce time in bed to estimated total sleep time (minimum 5 hours)
    2. Increase time in bed by 15 minutes every week when estimated sleep efficiency ~90%
    3. Sleep efficiency is ratio of time asleep to time in bed

D. Restless Leg Syndrome (RLS) [3,31]

1. Symptoms
   1. As soon as lie down, patients get uncomfortable feeling in legs
   2. Often described as "creepy-crawly feelings" in legs
   3. Urge to move legs, often with discomfort or pain
   4. Myoclonic jerks once they fall asleep
2. Occurs in 1-5% of population
3. Causes [3]
   1. Medications are most comon: anti-depressants
   2. Uremia
   3. Hypocalcemia
   4. Hypokalemia
   5. Idiopathic
   6. Often familial
4. Treatment [3,31]
   1. Ropinirole (Requip®) and pramipexole (Mirapex®), D2/3 selective agonists, approved for RLS
   2. Ropinirole starting dose is 0.25mg po qpm and may be increased to maximum 4mg
   3. Pramipexole, a non-ergot D2/3 agonist, also effective
   4. Pramipexole starting dose 0.12mg qd 2-3 hours before bedtime; increase dose to q4-7 days by 0.125mg to maximum dose 0.5mg qd
   5. Pergolide (Permax®), an ergot dopamine agonist (0.05-0.65mg/d, self adjusted) also effective but concern for long-term ergot effects [12]
   6. Sinamet® (Carbidopa/Levodopa) was often used but now replaced with dopamine agonists
   7. Quinine 300mg po qhs is no longer recommended first or second line
   8. Valproic acid may also show efficacy
   9. Treatment during pregnancy with agents other than zolpidem is not recommended [1]

E. Excessive Sleepiness [13]

1. Sleep Deprivation
2. Shift-Work Sleep Disorder
3. Drugs
   1. ß-Blockers
   2. Opiates
   3. Benzodiazepines
   4. Barbiturates
   5. Alcohol
4. Medical Problems
   1. Hypothyroidism
   2. Decreased Cardiac Output
   3. Anemia
   4. Renal Failure
   5. Inflammatory Disease - fatigue is often a prominant symptom
5. Sleep Apnea Syndrome
6. Narcolepsy and Cataplexy (see below)
7. Idiopathic hypersomnia
8. Hypersomnia associated with depression
9. Restless Leg / Sleep Related Myoclonus

F. Narcolepsy [13,14]

1. Prevalence ~0.05% in Caucasians; ~140,000 in USA
2. Excessive daytime sleepiness and sudden, uncontrollable periods of sleep
   1. Lifelong disorder of fragmentary, nighttime sleep
   2. Fall asleep in permissive situation - excessive sleepiness
   3. Patients abnormally enter REM sleep at sleep onset
   4. Associated with cataplexy in 60-75% of patients
3. Cataplexy
   1. Narcolepsy with cataplexy occurs in ~0.02% worldwide
   2. Emotional events trigger sudden loss of muscle strength / tone
   3. Anger, laughter, surprise, excitement trigger most events
   4. Stress, fear, or physical effort rarely induce cataplexy
   5. May be restricted to specific muscles, but usual result is collapse
4. Bimodal peak ages of onset: 15 (major peak) and 36 (minor peak) years
5. Etiology
   1. Most cases are sporadic; <5% run in families
   2. In ~90% of white patients, linkage with HLA DQB1*0602
   3. Hypocretin type 2 receptor (HCRTR2) gene located between DQB1*0602 and DQA1*0102
   4. HCRTR2 is in linkage disequilibrium with these Class II MHC genes
   5. Most cases due to defect in HCRTR2 gene [15]
   6. Mutation in HCRTR2 gene (found in HLA complex) causes disease
   7. Hypocretin-1 levels are low (<110pg/mL) or undetectable in most patients with disease
   8. Most familial cases do not involve hypocretin axis [22]
6. Treatment
   1. Hyperactive REM state responds to amphetamines
   2. Methylphenidate (Ritalin®) often used
   3. Effects of methylphenidate (5-15mg/d initially, 60mg max) last 2-3 hours
   4. Pemoline (Cylert®) 37.5mg initially, up to 112.5mg/d, is longer acting, less strong
   5. Modafinil (see below)
   6. Gamma-Hydroxybutyrate (GHB, see below)
   7. SSRIs and mixed reuptake inhibitors (SNRIs) effective for cataplexy
   8. Venlafaxine (75-300mg/d) is usually first line, with fluoxetine (20-60mg/d), citalopram (20-40mg/d), atomoxetine (40-100mg/d) also effective for cataplexy [13]
7. Modafinil (Provigil®, Alertec®) [19,24,25]
   1. Another stimulant with good efficacy and tolerability, approved initially for narcolepsy
   2. Approved for excessive sleepiness due to obstructive sleep apnea or shift work disorder
   3. Likely acts on hypothalamus in areas maintaining normal wakefulness and sleep
   4. Inhibits sleep-promoting neurons of ventrolateral preoptic nucleus
   5. Blocks norepinephrine reuptake
   6. Dose is 200mg initially, can be increased to 300mg or 400mg maximum
   7. Available in 100mg and 200mg tablets
   8. Well tolerated up to 12 weeks with no cardiovascular side effects
   9. Mild headache, neasea, nervousness have occurred
   10. Schedule IV controlled substance (low abuse potential)
8. GHB (sodium oxybate, Xyrem®) [13,18,26,28]
   1. Rapidly acting hypnotic acts through GHB and GABA-B receptors
   2. Approved for narcolepsy patients with or without cataplexy [28]
   3. Can be used in patients also taking stimulants
   4. GHB intoxication (direct or through 1,4 butanediol ingestion) can cause intoxication
   5. GHB intoxication: bradycardia, hypothermia, delirium, myoclonus, seizures, transient coma, amnesia and has been implicated in "date rape" [21,26]

G. Sleep Apnea [14]

1. Sleep disordered breathing - general term for abnormal sleep with oxygen desaturation
2. Subsets of Sleep Disordered Breathing
   1. Apnea = repetitive prolonged (>10 seconds) cessation of airflow associated with an arousal from sleep
   2. Hypopnea is >50% reduction in air flow with either an oxygen desaturation >3% or an arousal from sleep (defined electroencephalographically)
   3. Apnea-hypopnea index (episodes per hour of sleep) >4 makes SA likely
3. Types of Apnea
   1. Central: no airflow or respiratory effort (CNS lesions, trauma, hypothalamic abnormality)
   2. Obstructive: no airflow despite respiratory effort
   3. Mixed: combination of above
4. Obstructive Sleep Apnea
   1. Usual obstruction of hypopharynx at base of tongue WITH
   2. Hypotonia of neck strap muscles
5. Sleep Apnea Syndrome
   1. Repeated episodes of apnea or hypopnea (index >4 episodes per hour) during sleep AND
   2. Daytime sleepiness OR
   3. Altered cardiopulmonary function
6. Occurs during non-REM (rapid eye movement) sleep
7. Associated with increased risk cardiac and vascular disease, heart failure
8. Diagnosis with sleep study (measures oxygen desaturations during sleep)
9. Treatment includes CPAP, BiPAP, surgical intervention

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