Download INSOMNIA VS. SLEEP APNEA LEARNING OBJECTIVES List key

LEARNING OBJECTIVES
List key differences between insomnia and
obstructive sleep apnea
Identify at least two appropriate pharmacologic
treatment options for insomnia
Assess how current FDA warnings have affected
options for the treatment of insomnia
INSOMNIA VS. SLEEP APNEA
Morganne Smyth, Pharm.D.
Pharmacy Practice Resident
St. Luke’s Medical Center, Boise, ID
ISHP 2013 Spring Meeting
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INTRODUCTION – OBSTRUCTIVE SLEEP APNEA
Obstructive Sleep Apnea (OSA)
SLEEP APNEA
Affects up to 4% of middle-aged adults
Common complaints
At least ten-second intervals of absence of breathing
Multiple seconds to minutes (up to 30 times/hr)
Snorting/choking/gasping sound may occur when
breathe again
Loud snoring
Disrupted sleep
Daytime sleepiness
Up to 80% of patients with OSA are undiagnosed
50% of patients who present with a stroke have sleep
apnea
35% of patients with high blood pressure have sleep
apnea
Victor LD, Am Fam Physician, 1999, Nov 15;60(8):2279-86.
National Stroke Foundation, 2005, www.stroke.org
“Apnea” is Greek for “without breath”
Breathing ‘pauses’ during sleep
Usually not associated with breathing problems
during the day
3
Difficult to diagnose
Symptoms usually recognized by spouse (loud snoring)
Polysomnogram (sleep study) for diagnosis
4
U.S. Food and Drug Administration, Consumer Updates, 2013.
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OBSTRUCTIVE SLEEP APNEA
Normal airway
SLEEP APNEA QUESTIONNAIRE
Abnormal airway
during sleep
Obstruction
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Victor LD, Am Fam Physician, 1999, Nov 15;60(8):2279-86.
Victor LD, Am Fam Physician, 1999, Nov 15;60(8):2279-86.
SLEEP APNEA RISK FACTORS
CONSEQUENCES OF SLEEP APNEA
Age
40-60 years highest risk
Ethnicity
Increased risk of the following:
African American, Pacific Islander, and Hispanic groups
at higher risk
Chest pain
Cardiac arrhythmias (irregular heartbeat)
Heart attack
Stroke
Family history
Obesity
Physical characteristics
Motor vehicle accidents
Work-related accidents
Depression
Large neck (>17” in men; >16” in women)
Facial/Shull characteristics (narrow upper jaw, receding
chin, overbite, large tongue, soft palate changes)
Heart conditions
Smoking and alcohol use
Other medical conditions
Diabetes, GERD
Victor LD, Am Fam Physician, 1999, Nov 15;60(8):2279-86.
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U.S. Food and Drug Administration, Consumer Updates, 2013.
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TREATING SLEEP APNEA
CPAP THERAPY
First line Behavioral measures
Lose weight
Decrease alcohol intake
Decrease/stop taking medications that make you
drowsy
Second line CPAP
Other options
Connects to machine
kept at the bedside
Mild air pressure used
to keep airway open
Decreases sleep
disruptions from
decreased oxygen intake
Decreases snoring
Leads to decreased
daytime sleepiness
CPAP (continuous positive airway pressure) machine
Dental appliances/devices
Surgery
There are currently NO medication therapies
available to treat obstructive sleep apnea
Mask over nose/mouth
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10
National Heart, Lung, and Blood Institute [Internet], Department of Health and Human Services, 2012, www.nhlbi.nih.gov
U.S. Food and Drug Administration, Consumer Updates, 2013, www.fda.gov
DENTAL APPLIANCES/DEVICES
DENTAL APPLIANCES/DEVICES
Used for OSA in patients unable to tolerate or
have not have improvement with CPAP therapy
Mandibular advancement device (MAD)
Tongue retaining device (TRD)
Disadvantages
Mandibular
advancement device
Most widely used
Forces lower jaw forward and down
Splint that hold the tongue in place
Not as effective as CPAP
Pain, dry lips, tooth discomfort
May cause long term changes in dental structure
11
Tongue retaining
device
12
University of Maryland Medical Center, obstructive sleep apnea - dental devices, 2009, www.umn.edu
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INTRODUCTION - INSOMNIA
CLASSIFICATION OF SLEEP DISORDERS
One of the most common medical complaints
Primary Sleep Disorders
35% of the population reports insomnia within the
last year
Dyssomnias – abnormality in amount, quality, or timing of sleep
Primary insomnia
Primary hypersomnia
Narcolepsy
Breathing-related sleep disorder
Circadian rhythm sleep disorder
Jet lag
Shift work
Increasing prevalence with increasing age
More common in:
Females
Unemployed
Divorced, widowed, separated
Lower socioeconomic status
Parasomnias – abnormal behavioral or psychological events
associated with sleep
Nightmare/Sleep terror disorder
Sleepwalking
Only 30% of patients with insomnia report the
problem to their physician
UpToDate, Overview of Insomnia, 2013, www.uptodate.com
INSOMNIA DIAGNOSIS
Transient (2-3 days) or short term (up to 3 weeks)
Jet lag
Shift work changes
Acute illness
Major life events
One or more of the following:
Difficulty initiating sleep
Difficulty maintaining sleep
Waking up too early or nonrestorative/poor sleep
quality
Problems with sleep despite adequate
opportunity for sleep
Must also have daytime impairment from
sleep difficulty
Chronic insomnia (greater than 1 month)
Medical disorder
Psychiatric disorder
Medication-related cause
Different from sleep deprivation
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Wells BG, Pharmacotherapy Handbook, 2009, pg. 814.
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Wells BG, Pharmacotherapy Handbook, 2009, pg. 814.
DURATION
Sleep disorders related to another mental disorder
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Schutte-Rodin S, J Clin Sleep Med, 2008 Oct 15;4(5):487-504.
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DAYTIME IMPAIRMENT
One of the following to qualify for daytime
impairment
Average Amount of Required Sleep
Fatigue or lethargy
Problems with attention, concentration, or memory
Poor school/work performance
Irritability
Low motivation or energy
Increased errors/accidents at work or while driving
Headaches
GI symptoms
Concerns or worries about sleep loss
Hours of Sleep
HOW MUCH SLEEP IS ENOUGH?
18
16
14
12
10
8
6
4
2
0
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Schutte-Rodin S, J Clin Sleep Med, 2008 Oct 15;4(5):487-504.
U.S. Food and Drug Administration, Consumer Updates, 2013, www.fda.gov
INSOMNIA OR NOT?
HOW IS OSA DIFFERENT THAN INSOMNIA?
Some people require only a few hours of sleep
with no residual daytime sleepiness
As people age, they require less sleep
NOT considered insomnia due to absence of daytime
symptoms
Does not appear to be associated with adverse health
outcomes
Called “short sleep requirement” or “short sleepers”
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Obstructive sleep apnea is caused by a physical
obstruction of the airway
Awakening due to decreased oxygen intake
Given the opportunity to sleep (without the
obstruction), individuals are able to sleep
Similar to “sleep deprivation” problem
Many medications used to treat insomnia need to be avoided
in patients with obstructive sleep apnea
Avoid central nervous system depressants (i.e.
benzodiazepines)
Spending less time sleeping due to busy lifestyle
NOT considered insomnia if sleep comes easily when
given the opportunity
Known as “sleep deprivation”
Schutte-Rodin S, J Clin Sleep Med, 2008 Oct 15;4(5):487-504.
Would sleep if had adequate opportunity
CANNOT be treated with medication
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UpToDate, Overview of Insomnia, 2013, www.uptodate.com
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CONSEQUENCES OF INADEQUATE SLEEP
MEDICATION-RELATED CAUSES
Decreased quality of life
Beta blockers
Asthma medications
Antidepressants
Decongestants
Stimulants
Steroids
Tired, sleepiness, confusion, anxiety, depression
Less likely to receive job promotions, more sick time
Comorbidities
May have increased risk of high blood pressure, heart
attacks, and other heart conditions
Strongly associated with development of psychiatric
disorders
Depression, anxiety, drug abuse
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UpToDate, Overview of Insomnia, 2013, www.uptodate.com
Albuterol, theophylline
Fluoxetine, nortriptyline
Pseudoephedrine
ADHD medications
Prednisone, methylprednisolone
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MENOPAUSE AND INSOMNIA
Prevalence of Chronic Insomnia in other
Medical Conditions
More sleep complaints during perimenopausal
period
Insomnia common complaint in women with early
menopause
May be secondary to vasomotor symptoms (hot
flashes, night sweats) during menopause
Insomnia
No Insomnia
Sleep quality has shown to be better after
menopause
More deep sleep and longer sleep times
More self-reported dissatisfaction with sleep (even
though getting ‘better’ sleep)
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Taylor DJ, Sleep, 2007 Feb;30(2):213-8.
*List not inclusive
of all medicationrelated causes
Chawla J, Insomnia, 2013, emedicine.medscape.com
INSOMNIA AND OTHER MEDICAL CONDITIONS
80
70
60
50
40
30
20
10
0
Metoprolol
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Young T, Sleep, 2003, Sep;26(6):667-72.
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MANAGEMENT
Identifying cause of insomnia (if identifiable)
BEHAVIORAL THERAPY
Sleep hygiene
Stimulus control
Relaxation
Sleep restriction
Cognitive therapy
Cognitive behavioral therapy
Treat comorbid conditions
Education
Sleep hygiene
Stress management
Monitoring of mood symptoms
Eliminating unnecessary pharmacotherapy
Pharmacologic therapies
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UpToDate, Overview of Insomnia, 2013, www.uptodate.com
Schutte-Rodin S, J Clin Sleep Med, 2008 Oct 15;4(5):487-504.
Schutte-Rodin S, J Clin Sleep Med, 2008 Oct 15;4(5):487-504.
SLEEP HYGIENE
STIMULUS CONTROL
Sleep only as long as you need to feel rested
People who suffer from insomnia associated the
bed/bedroom with fear of not sleeping
Do not go to bed unless sleepy
Get out of bed
Maintain a regular sleep schedule
Do NOT force sleep
Avoid caffeine after lunch
Avoid alcohol near bedtime
Avoid smoking/nicotine intake
Decrease stimuli in bedroom
Take care of worries before bed
Exercise 20 mins. during the day
Only used the bed for sleep or sex
Do not spend > 20 mins in bed without falling
asleep
Alarm set to wake a same time everyday
Get up and do something relaxing
No naps allowed
4 – 5 hours prior to bedtime
Avoid daytime naps
UpToDate, Overview of Insomnia, 2013, www.uptodate.com
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UpToDate, Overview of Insomnia, 2013, www.uptodate.com
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RELAXATION THERAPY
Used each evening prior to sleep
Progressive muscle relaxation
SLEEP RESTRICTION THERAPY
Stay in bed longer to make up for lost sleep
Decrease time spent in bed to time actually
sleeping (not < 5 hours)
Sleep efficiency calculated
Head-to-toe progression of contraction followed by
relaxation
Relaxation response
Lie or sit comfortably
Close eyes and focus on deep breathing
Focus on one neutral image
Shift in circadian rhythm
No naps during the day
Time sleeping/time in bed (%)
↑ time by 15-30 mins when > 85%
Peaceful word or place
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UpToDate, Overview of Insomnia, 2013, www.uptodate.com
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UpToDate, Overview of Insomnia, 2013, www.uptodate.com
COGNITIVE BEHAVIORAL THERAPY
COGNITIVE THERAPY
Combines many strategies over several weeks
Patients awake at night
Concern of poor functioning next day
Worry exacerbates difficulty sleeping
Stimulus
Control
Education
Work with therapist
Deal with anxiety
Establish realistic expectations
Sleep
Hygiene
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UpToDate, Overview of Insomnia, 2013, www.uptodate.com
Sleep
Restriction
Cognitive
Therapy
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UpToDate, Overview of Insomnia, 2013, www.uptodate.com
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PHARMACOLOGICAL THERAPY
PHARMACOLOGICAL TREATMENT
Benzodiazepines
Non-benzodiazepine sedatives
Melatonin agonist
Antihistamines
Caution in the following patient groups
Pregnancy
Alcohol consumption
Renal/hepatic disease
Pulmonary disease/Sleep apnea
Nighttime decision-makers
Older adults
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UpToDate, Treatment of Insomnia, 2013, www.uptodate.com
Excessive sedation
Accumulation of drug
Worsen disease/hypoventilation
On-call, taking care of children
Increased risk of side effects
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UpToDate, Overview of Insomnia, 2013, www.uptodate.com
BENZODIAZEPINES
Fetal malformations in first trimester
BENZODIAZEPINES
Benzodiazepines have sedative, anxiolytic, muscle
relaxant, and anticonvulsant properties
Reduce time to onset of sleep
Increase total sleep time
All schedule IV controlled substances
Adverse Effects
Drowsiness, incoordination, decreased concentration, and
cognitive deficits
Daytime tolerance to these effects may occur
Anterograde amnesia
Abuse risk
Medications commonly used
Triazolam (Halcion®)
Lorazepam (Ativan®)
Estazolam (Prosom®) and temazepam (Restoril™)
Flurazepam (Dalmane®) and quazepam (Doral®)
Tolerance
Rebound insomnia
Quick-acting, but also short-acting
Short-intermediate acting
Intermediate-acting
Long-acting due to active metabolites
Wells BG, Pharmacotherapy Handbook, 2009, pg. 814.
Decrease risk by taking lowest dose and tapering
medication
Increased falls and hip fractures
35
May develop after 2 – 12 weeks of continuous use
Longer-acting flurazepam and quazepam increase
falls/fractures especially in the elderly
36
Wells BG, Pharmacotherapy Handbook, 2009, pg. 814.
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NON-BENZODIAZEPINES
NON-BENZODIAZEPINES
Zolpidem (Ambien™)
Minimal anxiolytic activity
No muscle relaxant properties
Not an anticonvulsant
Comparable efficacy to benzodiazepines
Zaleplon (Sonata®)
Rapid onset, half-life of 1 hour
Does NOT reduce nighttime awakenings or help
increase total sleep time
Eszopiclone (Lunesta™)
Rapid onset
Approved to help with sleep onset and maintenance
Drug
Indication
Half-life
Notes
Zolpidem
(Ambien)
Sleep onset
insomnia
~2.5 hrs
New warnings released in
January 2013
Zolpidem CR
(Ambien CR)
Sleep onset or
maintenance
insomnia
1.4 – 4.5
hrs
Controlled-release formula
Zolpidem
sublingual
(Intermezzo)
Sleep
maintenance
insomnia
1.4 – 6.7
hrs
To be given in the middle of
the night
Zaleplon
(Sonata)
Sleep onset
insomnia
1 hour
Not indicated for long-term
use
Eszopiclone
(Lunesta)
Sleep onset or
maintenance
insomnia
6 – 9 hrs
For sleep onset and
maintenance
37
UpToDate, Treatment of Insomnia, 2013, www.uptodate.com
Wells BG, Pharmacotherapy Handbook, 2009, pg. 814.
NON-BENZODIAZEPINES
COMPLEX SLEEP-RELATED BEHAVIORS
Adverse effects
38
Similar to benzodiazepines
Non-benzodiazepines
Sleep eating
Sleep driving
Phone calls while sleeping
Engaging in sexual behaviors
while not fully awake
Less severe
Dizziness
Headache
Somnolence
Daytime sedation
Complex-sleep related behaviors
Unpleasant taste (Eszopiclone)
Hallucinations (Zolpidem)
Less risk of abuse versus benzodiazepines
Higher doses of medications
have been attributed to these
complex sleep behaviors
39
Wells BG, Pharmacotherapy Handbook, 2009, pg. 814
UpToDate, Treatment of Insomnia, 2013, www.uptodate.com
40
U.S. Food and Drug Administration, Consumer Updates, 2013.
Hwang TJ, J Clin Psychiatry, 2010 Oct;71(10):1331-5
10
MELATONIN AGONIST
ANTIHISTAMINES
Ramelteon (Rozerem™)
Involved with circadian rhythm
Fewer and less severe side effects than
benzodiazepines and non-benzodiazepines
First-generation (sedating) antihistamines
Most common
Less daytime residual effects
No withdrawal or rebound insomnia
Not known to be habit-forming
Only sedative-hypnotic that is not a controlled
substance
Common side effects
Somnolence
Nausea
Fatigue
Headache
Less effective than other options
Anticholinergic side effects
Dry mouth
Blurred vision
Urinary retention
Constipation
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INSOMNIA TREATMENT
Recognize how the medication will affect you
New recommendations to consider lower doses in all
patients
Decrease dose especially in women due to slower
elimination of the drug from the body
Slower elimination has not been demonstrated in men,
but lower doses should be recommended in general
Decrease risk of tolerance
Try other non-medication therapies
UpToDate, Treatment of Insomnia, 2013, www.uptodate.com
January 2013 FDA Safety Communication
Blood levels of zolpidem in certain patients may be high
enough in the morning to impair activities requiring
alertness (i.e. driving)
Highest risk in extended-release product (Ambien CR®)
Decrease daytime sleepiness/side effects
Easier to taper off medication
Caution during next day when starting new
insomnia medications
42
Use for the shortest time necessary
Do not take medications for insomnia unless you
have a full 7-8 hours to dedicate to sleep
Lowest doses needed
Side effects usually more severe in elderly patients
ZOLPIDEM WARNING
General recommendations
UpToDate, Treatment of Insomnia, 2013, www.uptodate.com
Wells BG, Pharmacotherapy Handbook, 2009, pg. 814
UpToDate, Treatment of Insomnia, 2013, www.uptodate.com
Diphenhydramine (Benadryl®)
Doxylamine (Unisom®)
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U.S. Food and Drug Administration [Internet], Zolpidem Containing Products: Drug Safety Communication - FDA Requires
Lower Recommended Doses, 2013, www.fda.gov
11
NON-PHARMACOLOGIC OPTIONS IN THE
ELDERLY
INSOMNIA IN THE ELDERLY
Up to 60% of adults > 65 years of age suffer from
insomnia
Identify and manage exacerbating factors
Age-related changes in sleep patterns
Underlying illness
Medication side effects
Less sleep necessary
Risk of using traditional sleep aids is higher in
elderly patients
Pain
Shortness of breath (heart failure)
Chest pain
COPD
GI disease (acid reflux, ulcer)
Neurologic or mood disorders
Parkinson’s, dementia, anxiety, depression
5 - 33% of elderly patients receive a benzodiazepine
or other non-benzodiazepine sleep aids
46
45
Insomnia in the elderly. Pharmacist's Letter/Prescriber's Letter 2009;25(9):250919.
Insomnia in the elderly. Pharmacist's Letter/Prescriber's Letter 2009;25(9):250919.
NON-PHARMACOLOGIC OPTIONS IN THE
ELDERLY
PHARMACOLOGIC OPTIONS
Target sleep hygiene
Avoid nicotine, alcohol, and caffeine
Increase exercise and light exposure in the day
Limit napping
Reduce light and noise in the sleep environment
Some evidence that newer non-benzodiazepine
hypnotics are safer for the elderly
Keep temperature comfortable
Avoid meals and liquids close to bedtime
↓ sleep cycle changes, rebound insomnia, tolerance,
and hangover
Start with lower doses in older patients
May try ramelteon (Rozerem)
No dependence/abuse risk
Helps in sleep initiation, but not maintenance
47
Insomnia in the elderly. Pharmacist's Letter/Prescriber's Letter 2009;25(9):250919.
48
Insomnia in the elderly. Pharmacist's Letter/Prescriber's Letter 2009;25(9):250919.
12
PHARMACOLOGIC OPTIONS
SELF-TREATMENT IN THE ELDERLY
Other options
Trazodone, an antidepressant, may increase deep
sleep
Alcohol
Antihistamines (i.e. diphenhydramine)
Not well studied, early on appears to be beneficial
Non-habit forming
AE: Dry mouth, nausea, arrhythmias, orthostatic
hypotension
Causes early awakening
Anticholinergic effects, cognitive impairment, urinary
retention
Residual daytime sleepiness
Melatonin
Valerian
Kava
49
Insomnia in the elderly. Pharmacist's Letter/Prescriber's Letter 2009;25(9):250919.
Helps with difficulty falling asleep
May takes several night/weeks to see benefit
50
AVOID, may cause hepatotoxicity
Insomnia in the elderly. Pharmacist's Letter/Prescriber's Letter 2009;25(9):250919.
META-ANALYSIS – TREATMENT BENEFIT
META-ANALYSIS - ELDERLY INSOMNIA
24 Randomized Controlled Trials
2417 subjects with insomnia > 60 years of age
No other psychiatric/psychological disorders
Treated with benzodiazepines, zopiclone, zolpidem, zapelon,
diphenhydramine, and placebo
Results
Sleep time increased by ~25 min/night
Benzodiazepines increased sleep by ~34 min/night
Adverse effects
Cognitive events ~5 times as common
Daytime fatigue ~4 times more common
Adverse events similar between benzodiazepine and nonbenzodiazepines
51
Glass J, BMJ, 2005 Nov 19;331(7526):1169.
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Glass J, BMJ, 2005 Nov 19;331(7526):1169.
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META-ANALYSIS – ADVERSE EFFECTS
META-ANALYSIS
Limitations
Medications grouped together
Subjective measures
Excluded patients with other
psychiatric/psychological disorders
Did not assess dependence risk
Conclusions
Clinical benefits of sleep aids in the elderly may be
modest
Greater risk of adverse events occurring in the older
population
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53
Glass J, BMJ, 2005 Nov 19;331(7526):1169.
Glass J, BMJ, 2005 Nov 19;331(7526):1169.
SUMMARY
Difficultly initiating, maintaining, or poor
quality/nonrestorative sleep
Daytime impairment
Difficulty despite adequate time for sleep
Obstructive sleep apnea treatments
REFERENCES
Insomnia diagnosis
Lifestyle changes
CPAP therapy
No medication therapies available
Insomnia treatments
Behavioral therapies are first line
New zolpidem recommendations
Lower doses in women due to slower elimination
Risks of pharmacologic treatment in the elderly may
outweigh the benefit
55
Chawla J, Park Y, Passaro EA. Insomnia. Medscape Reference. c2013 WebMD LLC
[updated 18 Jan 2013, cited 15 Mar 2013]. Available from:
http://emedicine.medscape.com/article/1187829-overview
Glass J, Lanctôt KL, Herrmann N, Sproule BA, Busto UE. Sedative hypnotics in older
people with insomnia: metaanalysis of risks and benefits. BMJ. 2005 Nov
19;331(7526):1169.
Hwang TJ, Ni HC, Chen HC, Lin YT, Liao SC. Risk predictors for hypnosedativerelated complex sleep behaviors: a retrospective, cross-sectional pilot study. J Clin
Psychiatry. 2010 Oct;71(10):1331-5
Insomnia in the elderly. Pharmacist's Letter/Prescriber's Letter 2009;25(9):250919.
National Heart, Lung, and Blood Institute [Internet]. What is CPAP? Department of
Health and Human Services [updated 13 Dec 2011, cited 15 Mar 2013]. Available from:
http://www.nhlbi.nih.gov/health/health-topics/topics/cpap/
National Stroke Foundation [Internet]. Stroke Related Sleep Disorders. National
Stroke Foundation c2005 [cited 13 Mar 2013]. Available from:
http://www.stroke.org/site/DocServer/SLEEPQ.pdf?docID=862
Schutte-Rodin S, Broch L, Buysse D, Dorsey C, Sateia M. Clinical guideline for the
evaluation and management of chronic insomnia in adults. J Clin Sleep Med. 2008 Oct
15;4(5):487-504.
Taylor DJ, Mallory LJ, Lichstein KL, Durrence HH, Riedel BW, Bush AJ. Comorbidity
of chronic insomnia with medical problems. Sleep. 2007 Feb;30(2):213-8.
56
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REFERENCES (CONT.)
U.S. Food and Drug Administration [Internet]. Consumer Updates. U.S. Department of
Health and Human Services Available from:
www.fda.gov/consumer/features/sleepdrugs073107.html
U.S. Food and Drug Administration [Internet]. Zolpidem Containing Products: Drug
Safety Communication - FDA Requires Lower Recommended Doses. U.S. Department of
Health and Human Services [updated 1 Jan 2013, cited 14 Mar 2013]. Available from:
http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalPr
oducts/ucm334738.htm
University of Maryland Medical Center [Internet]. Obstructive sleep apnea - Dental
Devices. c2011 University of Maryland Medical Center [updated 23 Jun 2009, cited 15 Mar
2013]. Available from:
http://www.umm.edu/patiented/articles/what_dental_devices_used_treat_sleep_apnea_000
065_9.htm
UpToDate [database on the Internet]. Overview of insomnia. Waltham, MA: UpToDate,
Inc.; c2013. Available from: www.uptodate.com
Victor LD. Obstructive sleep apnea. Am Fam Physician. 1999 Nov 15;60(8):2279-86.
Wells BG, DiPiro JT, Schwinghammer TL, DiPiro CV. Sleep Disorders. In:
Pharmacotherapy Handbook. 7th ed. New York, NY: McGraw-Hill;2009:814.
Young T, Rabago D, Zgierska A, Austin D, Laurel F. Objective and subjective sleep quality
in premenopausal, perimenopausal, and postmenopausal women in the Wisconsin Sleep
Cohort Study. Sleep. 2003 Sep;26(6):667-72.
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QUESTIONS?
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