INSOMNIA

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INSOMNIA Sleep Disorders

• W. Klugh Kennedy, PharmD, BCPP, FASHP, FCCP
• Professor of Pharmacy Practice and Psychiatry
• Mercer University (Savannah Campus)
• Memorial University Medical Center
• 2015

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OBJECTIVES

• Describe the types of insomnia and associated
  symptoms
• Recognize social situations, medications and
  medical conditions that may lead to insomnia
• Define treatment plans for insomnia
• Be able to select an appropriate pharmacologic
  agent for different types of insomnia
• Understand and define treatment plans for other
  sleep disorders such as Circadian Rhythm
  Disorders and Narcolepsy

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BACKGROUND

• We spend about one-third of our lives asleep.
• Sleep-Wake Cycle
• Usually lasts 25 hours, so there is some internal
  resetting required.
• The reticular activating system maintains
  wakefulness and when activity here declines,
  sleep occurs.

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CIRCADIAN RHYTHM
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SLEEP CYCLE
Non-Rapid Eye Movement (NREM) -- 75 Non-Rapid Eye Movement (NREM) -- 75
Stage 1 Drowsiness
Stage 2 Light sleep, mild muscle relaxation Heart rate slows, body temperature decreases
Stage 3 4 Deepest sleep (delta-sleep)
Rapid Eye Movement (REM) -- 25 Rapid Eye Movement (REM) -- 25
REM Sleep Slow-wave state of sleep Brain becomes electrically and metabolically activated Increase in cerebral blood-flow Generalized muscle atonia, vivid dreams, fluctuations in respiratory and cardiac rate
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How much sleep do we need?
AGE Amount
Infants 16 hours per day
Babies and Toddlers (6 months to 3 years) 10-14 hours per day
Children 9-12 hours per day (decreases an hour every 3 years from 6 to 12)
Teenagers 9 hours per night
Adults 7-8 hours per night
Older Adults 7-8 hours per day
Pregnant Women Usually require 3 hours more sleep than usual
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SLEEP WAKE DISORDERS

• DSM-5 Categorizations
• Insomnia Disorder
• Hypersomnolence Disorder
• Narcolepsy
• Breathing-Related Disorders
• Obstructive Sleep Apnea Hypopnea
• Central Sleep Apnea
• Sleep-Related Hypoventilation
• Circadian Rhythm Disorders
• Parasomnias
• Non-REM Sleep Arousal Disorders
• Nightmare Disorder
• REM Sleep Behavior Disorder

• Restless-Legs Syndrome
• Substance/Medication-Induced Sleep Disorder
• Other Specified Insomnia Disorders
• Unspecified Insomnia Disorders
• Other Specified Hypersomnolence Disorders
• Unspecified Hypersomnolence Disorders
• Other Specified Sleep-Wake Disorders

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How do we measure sleep?

• Subjective Questioning
• But not too subjective
• Objective Studies
• Polysomnography (PSG)
• Multiple Sleep Latency Test (MSLT)
• Maintenance of Wakefulness Test (MWT)

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INSOMNIA
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INSOMNIA

• Difficulty falling asleep, maintaining sleep,
  arising, or not feeling rested despite a
  sufficient opportunity to sleep.

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Prevalence

• In the United States, people report
• gt50 experienced insomnia during their lifetime
• 40 get less than 7 hrs of sleep every night
• 15 report some type of daytime impairment
• Elderly up to 80
• Chronic insomnia make up 6-15 of cases

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INSOMNIA

• Cost
• 35 billion per year
• Diagnosis
• Physicians detect insomnia in only about 50 of
  those experiencing it
• Primary Providers often rate their knowledge
  regarding as insomnia as fair or poor

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Complications from Insomnia
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Associated Factors

• Gender
• Age
• Situational Stressors
• Environmental
• Poor Sleep Hygiene
• Psychiatric Conditions
• General Medical Conditions
• Substances and Medications
• Unemployment
• Lower Socioeconomic Status

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Insomnia Classification

• Transient
• Lasts a few days, usually associated with
  stressful situation
• Examples jet lag, a stressful event, change in
  work schedule
• Short-Term
• Lasts up to 4 weeks and is usually associated
  with acute or situational stress
• Examples death of loved one, medical illness,
  surgery recovery
• Long-Term
• Lasts more than 4 weeks
• Examples caffeine misuse, chronic stress,
  secondary to underlying condition

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Causes of Insomnia

• Medical Illnesses
• Cancer
• Chronic Pain
• Restless Leg Syndrome (RLS)
• Sleep Apnea
• Incontinence
• Allergies
• Menopause/Hot Flashes
• Asthma and Chronic Obstructive Pulmonary Disease
  (COPD)
• Dementia
• Fibromyalgia
• Irritable Bowel Syndrome (IBS)
• Arthritis
• Seizure Disorders

• Mental Illnesses
• Depression
• Generalized Anxiety Disorder
• Panic Disorder
• PTSD
• Substance Abuse
• Somatoform Disorders
• Adjustment Disorders
• Personality Disorders
• Inadequate Sleep Hygiene
• Daytime napping
• Inconsistent sleep schedule
• Eating, exercise, caffeine and/or nicotine
• Etc.

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Causes of Insomnia

• Medication Induced Insomnia
• Decongestants
• Appetite Suppressants
• Stimulants
• Steroids
• Antidepressants
• Beta-agonists
• Beta-blockers
• Diuretics
• Dopamine agonists/replacement
• Hypoglycemics
• Thyroid Hormones
• CNS Depressant Withdrawal

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TREATMENT OF INSOMNIA
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Pharmacotherapy of Insomnia

• Part of an overall plan to deal with the causes
  and used for well-defined time
• Should only be considered adjunctive therapy for
  short-term and chronic insomnia
• Used SHORT-TERM for managing symptoms
• NOT a permanent solution!

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BENZODIAZEPINES
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Benzodiazepines (BZDs)

• Class IV Substances
• Used when
• Immediate response needed
• Non-pharmacologic measures do not work
• Short-term use
• FDA-Approved for Insomnia Half-Life Onset of
  Action
• Triazolam (Halcion) SHORT 15 30 minutes
• Estazolam (ProSom) INTERMEDIATE 30 minutes
• Temezepam (Restoril) INTERMEDIATE 45 minutes
• Quazepam (Doral) LONG 30 minutes
• Flurazepam (Dalmane) VERY LONG 30 minutes
• Effect Increase sleep time and reduce time to
  onset of sleep

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BZDs

• Use LOWEST effective dose
• Avoid residual daytime sedation
• Use for a SHORT DURATION (only 2-4 weeks) and
  intermittently
• Not indicated for chronic use, may develop
  tolerance
• AVOID in substance abuse and respiratory
  impairment
• Monitor for escalating doses or early refill
  requests
• Anterograde amnesia
• Can worsen depression
• Use caution in elderly (Beers List pretty much
  all hypnotics)
• Pregnancy Category X
• Withdrawal Anxiety, depression, nightmares,
  rebound insomnia
• TAPER DOSE prior to discontinuing to avoid

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NON-BZDs

• Pharmacologic Options

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Non-BZDs
Class Drugs
NBRAs (Z-Drugs) Zolpidem (Ambien) Zaleplon (Sonata) Eszopiclone (Lunesta)
Melatonin Agonist Ramelteon (Rozerem)
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Zolpidem (Ambien)
Drug (Trade) What you need to know
Zolpidem Ambien Ambien CR Intermezzo Usual dose 5-10mg PO 30 min before HS Duration IR 5 hours (fall asleep) CR Released over longer period of time (stay asleep) Onset 10-20 minutes Lacks anticonvulsant action, muscle-relaxant properties, and respiratory depressant effects Lower risk of tolerance and withdrawal Avoid in obstructive sleep apnea Must be hepatically adjusted (half dose) Controlled release formulation available (Ambien CR) as well as SL tablets and Oral Spray (Edluar and Zolpimist) and the SL Intermezzo which may be taken during nighttime awakenings Women clear zolpidem slower than men Adverse Effects may include HA, dizziness, daytime somnolence, GI complaints Psychotic symptoms, sensory distortions, parasomnias, amnesia...
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Zaleplon (Sonata)
Drug (Trade) What you need to know
Zaleplon Sonata Usual dose 5-20mg PO before HS Duration lt4 hours Onset 10-20 min FDA Approved for Short-Term Treatment of Insomnia to improve sleep onset May cause fewer problems in AM due to 1 hour half-life No apparent rebound insomnia, withdrawal symptoms, daytime anxiety, sedation, or impairment Can be given late and preserves all sleep stages Low risk of dependence Food can delay onset and dose should be reduced in elderly, liver disease, concomitant cimetidine use Side Effects dizziness, headache, somnolence, nausea
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Eszopiclone (Lunesta)
Drug (Trade) What you need to know
Eszopiclone (Lunesta) Usual Dose 2-3mg adults, 1-2mg elderly Duration 8 hours, longer in elderly Onset 30 min 3mg for sleep maintenance 1mg for elderly having trouble falling asleep Morning effects possible if taken late Can be used for chronic insomnia Food causes delayed onset Less tolerance risk Metallic aftertaste (34) HA, dizziness, unpleasant dreams
What the?
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Ramelteon (Rozerem)
Drug (Trade) What you need to know
Ramelteon (Rozerem) Melatonin Agonist Usual Dose 8mg Duration 8 hours Onset 20 minutes? Not a controlled substance! No dependence/tolerance May use long-term Do not take with high-fat meal Avoid in liver dysfunction AE HA, fatigue, dizziness, nausea, increased prolactin levels
Your dreams miss you!
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OTHER agents
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Other Agents
Class Drugs
Sedating Antidepressants Mirtazapine (Remeron) 15mg Trazodone (Desyrel) 50 150mg Doxepin (Silenor) 10 - 50mg
Antihistamines Diphenhydramine (Benadryl) 25 50mg Doxylamine (Unisom) 25 50mg Hydroxyzine (Atarax, Vistaril) 25 50mg
Atypical Antipsychotics Quetiapine (Seroquel) 50 - 100mg Olanzapine (Zyprexa) 5 10mg
Antihypertensive Prazosin 1- 6mg/day
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Mirtazapine (Remeron)
Drug (Trade) What you need to know
Mirtazapine (Remeron) Class Antidepressant DOSING 15mg adult 15mg elderly Renal/Hepatic dose adjustments required HALF-LIFE 20-40 hours NOT FDA-Approved for Insomnia Increases risks of RLS and periodic limb movements May be useful for insomnia in depression Available in 15mg tablets May cause increased appetite and weight gain along with constipation and asthenia Lower doses tend to be more sedating
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Trazodone (Desyrel)
Drug (Trade) What you need to know
Trazodone (Desyrel) Class Antidepressant DOSING 50-150mg adult 25-50mg elderly ONSET 1 hour HALF-LIFE 5-9 hours NOT FDA-Approved for Insomnia Often used with SSRIs if patient is experiencing insomnia related to their use Limited efficacy data for insomnia Little anticholinergic activity Long-term use is acceptable Adverse Effects priapism (lt0.1), orthostatic hypotension nausea, xerostomia, blurry vision
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Antihistamines
Medications What you need to know
Diphenhydramine Benadryl OTC Doxylamine Unisom OTC Hydroxyzine Atarax Rx Vistaril Rx Adverse Effects Dizziness, headache, blurry vision, hypotension, photosensitivity, constipation, dry mouth, increased liver enzymes Often a hangover effect is experienced Avoid in patients with urinary retention problems and closed angle glaucoma Inappropriate for use in elderly (Beers Criteria) Not effective for chronic insomnia because tolerance develops after 1-2 weeks of continued use consider off night after 3 days use Counsel patients not to use Tylenol PM for sleep.
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ALTERNATIVE/HERBAL TREATMENT
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Alternative/Herbal Treatment
Class Drug
Herbal/Alternative Valerian Melatonin Kava-Kava (illegal in the USA)
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Valerian
Therapy What it Does What you need to know
Valerian Root (valeriana officinalis) sedative, anxiolytic, antidepressant, anticonvulsant, hypotensive and antispasmodic effects One of the most common OTCs used for sleep Evidence Grade C (conflicting) Causes CNS depression and muscle relaxation Safe for short-term use, long-term safety not determined Does not work until 2-3 weeks after initiation Usually well-tolerated, may have GI distress, morning sedation, headache Avoid in patients with hepatic disease and in pregnancy Do not take with EtOH, benzos, other hypnotics Interacts with drugs metabolized by CYP3A4
Valerian Flower
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Melatonin
Therapy About What you need to know
Melatonin (N-acetyl-5-methoxytryptamine) Hormone produced from tryptophan which is secreted by pineal gland. Exogenous OTC Melatonin is synthetically produced to mimic the natural hormone. DOSE 5mg PO 3-4 hours prior to HS May be useful in treating abnormalities of the circadian clock (i.e. shift work, jet lag, blind) Adverse Effects sedation, headache, depression, tachycardia, pruritus Avoid in pregnancy
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OTHER SLEEP DISORDERS

• Sleep Apnea
• Circadian Rhythm Disorder
• Narcolepsy

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Sleep apnea
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SLEEP APNEA

• Neurological condition that results in periods of
  breathing cessation about 10-25 times per hour
• Brain will respond and patient awakens usually
  with no memory of the episode
• Types
• Obstructive Sleep Apnea (OSA)
• Most common
• Usually due to physical blocking (obesity,
  tonsils, tongue, thyroid)
• Central Sleep Apnea (CSA)
• 10 of all apneas
• Due to delay of brain signal for breathing
• Idiopathic
• Requires O2 as treatment
• Diagnosis Polysomnography (PSG)

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Treatment Obstructive Sleep Apnea

• Weight Loss
• Smoking Cessation
• Positional changes
• CPAP (face-mask)
• Oral Appliances
• Avoid CNS depressants
• Modafanil and Armodafanil
• (Provigil and Nuvigil) to improve daytime
  sleepiness
• Methylphenidate or stimulants classically used
• Surgical

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Modafanil (Provigil) Armodafanil (Nuvigil)
Drug (Trade) What you need to know
Modafanil and Armodafanil (Provigil and Nuvigil) CNS Activating exact MOA unknown DOSING Modafanil 200mg qAM Armodafanil 150-250mg qAM Hepatic adjustment required Schedule IV Less abuse potential than stimulants May reduce effectiveness of oral birth control Onset 2 hours AE Headache (34), insomnia, anxiety, SJS (rare)
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Circadian rhythm disorders
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CIRCADIAN RHYTHM DISORDERS

• Examples Shift Work and Jet Lag
• Non-Pharmacologic Interventions
• Adjusting sleep schedule prior to event
• Avoid naps, EtOH, stimulants
• Pharmacologic Interventions
• Melatonin
• Zolpidem for 3 nights

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Narcolepsy
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NARCOLEPSY

• Chronic, incurable disorder characterized by
  irrepressible sleep attacks and cataplexy
• Patient moves directly into REM sleep without
  NREM period
• Symptoms
• Excessive Daytime Sleepiness
• Cataplexy
• Loss of muscle tone in face or limb muscles
  induced by emotions or laughter
• May be subtle (limp) or dramatic (drops to the
  floor)
• Hallucinations
• Hypnagogic
• Hypnopompic
• Sleep paralysis
• Genetic link

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NARCOLEPSY Treatment

• Schedule naps, approximately one to two lasting
  20 min/day
• No EtOH, caffeine, nicotine
• For EDS
• 1st line Wake Promoting Agents
• Modafinil (Provigil) and R-enantiomer
  armodafinil (Nuvigil)
• 2nd line Stimulants
• Methlyphenidate (Ritalin) and Amphetamines
• SSRIs/SNRIs (last line)

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NARCOLEPSY Treatment

• For Cataplexy
• Sodium Oxybate (Xyrem)
• Scheduled Substance C-III (medical use) and C-I
  (illicit use)
• FDA approved for cataplexy in patients with
  narcolepsy
• Changes sleep architecture by decreasing
  night-time awakenings and increasing REM sleep
• Prescribers MUST be enrolled in Xyrem Success
  Program
• Must enroll in post-marketing surveillance
  program
• First Rx can only be written for a ONE MONTH
  supply and following Rxs for only THREE month
  supply at a time
• Dosing
• Initial 4.5/day in two divided doses (one at HS
  and second in 2.5 to 4 hours)
• Maximum May increase up to 9mg/day
• Taken on empty stomach

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SLEEP HYGIENECounseling
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SLEEP HYGIENE STRATEGIES

• Maintain regular hours of going to bed and
  arising
• Do not eat heavy meals 2-3 hours before bedtime
  but do not go to bed hungry try a light snack.
• Avoid napping during the daytime.
• Only use the bed for sleep, sexual activity or
  pillow fights Dont watch TV in bed.
• Exercise daily but NOT within 2 hours of sleep
• Minimize cigarette smoking and caffeine intake
  none after noon!

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SLEEP HYGIENE STRATEGIES

• Avoid clock-watching try facing clock AWAY
• Release worrisome thoughts before bedtime
• Do not stay in bed if unable to sleep get up
  for 30 minutes and then try again
• Make the bedroom as comfortable and dark as
  possible (black out curtains, blinds, etc.)
• Avoid alcohol as a sleep aid
• IF YOU SNORE frequently, see your doctor!

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Conclusion

• The physiologic process of sleep is essential to
  normal restorative functioning in humans
• Untreated sleep deprivation increases risk for
  multiple medical disorders and makes underlying
  medical problems difficult to treat -- it may
  also increase mortality
• When non-pharmacologic options do not offer
  optimal benefit, drug therapy may be utilized
• Benzodiazepines, Non-Benzodiazepine Hypnotics,
  Sedating Antidepressants, Antihistamines or
  Alternative Therapies may be viable options for
  sleep aid
• Other sleep disorders include sleep apnea,
  circadian rhythm disorders and narcolepsy and all
  require different approaches to treatment
• Pharmacotherapy should be used for the shortest
  periods possible to alleviate symptoms -- they
  are NOT a cure -- always consider there may be
  more to the problem than just the inability to
  sleep

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References

• Diagnostic and Statistical Manual of Mental
  Disorders DSM-5. Washington, D.C. American
  Psychiatric Association, 2013. Print.
• Erman MK. Therapeutic options in the treatment of
  insomnia. J Clin Psychiatry. 200566
  (suppl9)18-23.
• Lande RG, Gragnani C. Nonpharmacologic approaches
  to the management of insomnia. J Am Osteopath
  Assoc. 2010110(12)695-701.
• Stahl, Stephen M. Stahl's Essential
  Psychopharmacology Prescriber's Guide. 5th ed.
  New York Cambridge, 2014. Print.