Download INSOMNIA

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
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
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.
CIRCADIAN RHYTHM
SLEEP CYCLE
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%
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
NREM
REM
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
SLEEP & WAKE DISORDERS
DSM-5 Categorizations
 Insomnia Disorder
 Hypersomnolence Disorder
 Narcolepsy
 Breathing-Related Disorders
 Restless-Legs Syndrome
 Substance/Medication-Induced
Sleep Disorder
 Other Specified Insomnia
Disorders
• Obstructive Sleep Apnea Hypopnea
• Central Sleep Apnea
 Unspecified Insomnia Disorders
• Sleep-Related Hypoventilation
 Other Specified
 Circadian Rhythm Disorders
Hypersomnolence Disorders
 Parasomnias
 Unspecified Hypersomnolence
• Non-REM Sleep Arousal Disorders
Disorders
• Nightmare Disorder
 Other Specified Sleep-Wake
• REM Sleep Behavior Disorder
Disorders
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)
INSOMNIA
INSOMNIA
“Difficulty falling asleep, maintaining sleep,
arising, or not feeling rested despite a sufficient
opportunity to sleep.”
Prevalence
• In the United States, people report:
• >50% 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
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
Complications from Insomnia
Associated Factors
• Gender
• Age
• Situational Stressors
• Environmental
• Poor Sleep Hygiene
• Psychiatric Conditions
• General Medical Conditions
• Substances and Medications
• Unemployment
• Lower Socioeconomic Status
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
Causes of Insomnia
Medical Illnesses
• Cancer
• Chronic Pain
• Restless Leg Syndrome (RLS)
• Sleep Apnea
• Incontinence
• Allergies
• Menopause/Hot Flashes
Mental Illnesses
•
•
•
•
•
•
•
•
Depression
Generalized Anxiety Disorder
Panic Disorder
PTSD
Substance Abuse
Somatoform Disorders
Adjustment Disorders
Personality Disorders
• Asthma and Chronic Obstructive
•
•
•
•
•
Pulmonary Disease (COPD)
Dementia
Fibromyalgia
Irritable Bowel Syndrome (IBS)
Arthritis
Seizure Disorders
Inadequate Sleep Hygiene
• Daytime napping
• Inconsistent sleep schedule
• Eating, exercise, caffeine and/or
nicotine
• Etc.
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
TREATMENT OF INSOMNIA
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 shortterm and chronic insomnia
• Used SHORT-TERM for
managing symptoms
• NOT a permanent solution!
BENZODIAZEPINES
Benzodiazepines (BZDs)
• Class IV Substances
• Used when:
• Immediate response needed
• Non-pharmacologic measures do not work
• Short-term use
• FDA-Approved for Insomnia:
• Triazolam (Halcion®)
• Estazolam (ProSom®)
• Temezepam (Restoril®)
• Quazepam (Doral®)
• Flurazepam (Dalmane®)
Half-Life
Onset of Action
SHORT
INTERMEDIATE
INTERMEDIATE
LONG
VERY LONG
15 – 30 minutes
30 minutes
45 minutes
30 minutes
30 minutes
• Effect: Increase sleep time and reduce time to onset of sleep
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
NON-BZDS
Pharmacologic Options
Non-BZDs
Class
Drugs
NBRAs (“Z”-Drugs)
• Zolpidem (Ambien®)
• Zaleplon (Sonata®)
• Eszopiclone (Lunesta®)
Melatonin Agonist
• Ramelteon (Rozerem®)
Zolpidem (Ambien®)
Drug (Trade)
What you need to know:
Zolpidem
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...
Ambien®
Ambien CR®
Intermezzo®
Zaleplon (Sonata®)
Drug (Trade)
What you need to know:
Zaleplon
Sonata®
Usual dose: 5-20mg PO before HS
Duration: <4 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
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
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!
OTHER AGENTS
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
Mirtazapine (Remeron®)
Drug (Trade)
What you need to know:
Mirtazapine
(Remeron®)
Class:
DOSING:
Antidepressant
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
Trazodone (Desyrel®)
Drug (Trade)
What you need to know:
Trazodone
(Desyrel®)
Class:
DOSING:
Antidepressant
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 (<0.1%), orthostatic hypotension
nausea, xerostomia, blurry vision
Antihistamines
Medications
What you need to know:
Diphenhydramine
Benadryl® OTC
• 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.
Doxylamine
Unisom® OTC
Hydroxyzine
Atarax® Rx
Vistaril® Rx
ALTERNATIVE/HERBAL
TREATMENT
Alternative/Herbal Treatment
Class
Drug
Herbal/Alternative
• Valerian
• Melatonin
• Kava-Kava* (illegal in the USA)
Valerian
Therapy
What it Does:
What you need to know:
Valerian
Root
sedative, anxiolytic,
antidepressant,
anticonvulsant,
hypotensive and
antispasmodic effects
•
•
•
•
(valeriana
officinalis)
•
•
•
•
•
Valerian Flower
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
Melatonin
Therapy
About
What you need to know:
Melatonin
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
(N-acetyl-5methoxytryptamine)
• 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
OTHER SLEEP DISORDERS
• Sleep Apnea
• Circadian Rhythm Disorder
• Narcolepsy
SLEEP APNEA
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)
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
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)
CIRCADIAN RHYTHM
DISORDERS
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
NARCOLEPSY
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
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)
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
SLEEP HYGIENE
COUNSELING
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 –
Don’t watch TV in bed.
Exercise daily but NOT within 2 hours of sleep
Minimize cigarette smoking and caffeine intake – none after
noon!
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!
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
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. 2005;66 (suppl9);18-23.
• Lande RG, Gragnani C. Nonpharmacologic approaches to the
management of insomnia. J Am Osteopath Assoc.
2010;110(12):695-701.
• Stahl, Stephen M. Stahl's Essential Psychopharmacology:
Prescriber's Guide. 5th ed. New York: Cambridge, 2014. Print.