1

INSOMNIA VS. SLEEP APNEAMorganne Smyth, Pharm.D.

Pharmacy Practice Resident

St. Luke’s Medical Center, Boise, ID

ISHP 2013 Spring Meeting

LEARNINGOBJECTIVES

� 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

2

INTRODUCTION – OBSTRUCTIVE SLEEP APNEA

� Obstructive Sleep Apnea (OSA)

� Affects up to 4% of middle-aged adults

� Common complaints

� 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 3

Victor LD, Am Fam Physician, 1999, Nov 15;60(8):2279-86.

National Stroke Foundation, 2005, www.stroke.org

SLEEP APNEA

� “Apnea” is Greek for “without breath”

� Breathing ‘pauses’ during sleep

� 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

� Usually not associated with breathing problems

during the day

� Difficult to diagnose

� Symptoms usually recognized by spouse (loud snoring)

� Polysomnogram (sleep study) for diagnosis4

U.S. Food and Drug Administration, Consumer Updates, 2013.

2

OBSTRUCTIVE SLEEP APNEA

5

Normal airway Abnormal airway

during sleep

Obstruction

Victor LD, Am Fam Physician, 1999, Nov 15;60(8):2279-86.

SLEEP APNEA QUESTIONNAIRE

6

Victor LD, Am Fam Physician, 1999, Nov 15;60(8):2279-86.

SLEEP APNEA RISK FACTORS

� Age � 40-60 years highest risk

� Ethnicity� African American, Pacific Islander, and Hispanic groups at higher risk

� Family history

� Obesity

� Physical characteristics� Large neck (>17” in men; >16” in women)

� Facial/Shull characteristics (narrow upper jaw, receding chin, overbite, large tongue, soft palate changes)

� Smoking and alcohol use

� Other medical conditions� Diabetes, GERD 7

Victor LD, Am Fam Physician, 1999, Nov 15;60(8):2279-86.

CONSEQUENCES OF SLEEP APNEA

� Increased risk of the following:

� Heart conditions

� Chest pain

� Cardiac arrhythmias (irregular heartbeat)

� Heart attack

� Stroke

� Motor vehicle accidents

� Work-related accidents

� Depression

8

U.S. Food and Drug Administration, Consumer Updates, 2013.

3

TREATING SLEEP APNEA

� First line � Behavioral measures

� Lose weight

� Decrease alcohol intake

� Decrease/stop taking medications that make you

drowsy

� Second line � CPAP

� CPAP (continuous positive airway pressure) machine

� Other options

� Dental appliances/devices

� Surgery

� There are currently NO medication therapies available to treat obstructive sleep apnea

9

U.S. Food and Drug Administration, Consumer Updates, 2013, www.fda.gov

CPAP THERAPY

� Mask over nose/mouth

� 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

10

National Heart, Lung, and Blood Institute [Internet], Department of Health and Human Services, 2012, www.nhlbi.nih.gov

DENTAL APPLIANCES/DEVICES

� Used for OSA in patients unable to tolerate or have not have improvement with CPAP therapy

� Mandibular advancement device (MAD)

� Most widely used

� Forces lower jaw forward and down

� Tongue retaining device (TRD)

� Splint that hold the tongue in place

� Disadvantages

� Not as effective as CPAP

� Pain, dry lips, tooth discomfort

� May cause long term changes in dental structure11

University of Maryland Medical Center, obstructive sleep apnea - dental devices, 2009, www.umn.edu

DENTAL APPLIANCES/DEVICES

12

Mandibular

advancement device

Tongue retaining

device

4

INTRODUCTION - INSOMNIA

� One of the most common medical complaints

� 35% of the population reports insomnia within the

last year

� Increasing prevalence with increasing age

� More common in:

� Females

� Unemployed

� Divorced, widowed, separated

� Lower socioeconomic status

� Only 30% of patients with insomnia report the problem to their physician

13

UpToDate, Overview of Insomnia, 2013, www.uptodate.com

CLASSIFICATION OF SLEEP DISORDERS

Primary Sleep Disorders

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

Parasomnias – abnormal behavioral or psychological events

associated with sleep

Nightmare/Sleep terror disorder

Sleepwalking

Sleep disorders related to another mental disorder14

Wells BG, Pharmacotherapy Handbook, 2009, pg. 814.

DURATION

� Transient (2-3 days) or short term (up to 3 weeks)

� Jet lag

� Shift work changes

� Acute illness

� Major life events

� Chronic insomnia (greater than 1 month)

� Medical disorder

� Psychiatric disorder

� Medication-related cause

15

Wells BG, Pharmacotherapy Handbook, 2009, pg. 814.

INSOMNIA DIAGNOSIS

� 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

� Different from sleep deprivation

� Must also have daytime impairment from

sleep difficulty

16

Schutte-Rodin S, J Clin Sleep Med, 2008 Oct 15;4(5):487-504.

5

DAYTIME IMPAIRMENT

� One of the following to qualify for daytime impairment

� 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 loss17

Schutte-Rodin S, J Clin Sleep Med, 2008 Oct 15;4(5):487-504.

HOW MUCH SLEEP IS ENOUGH?

024681012141618

Ho

ur

s o

f S

lee

p

Average Amount of Required Sleep

18

U.S. Food and Drug Administration, Consumer Updates, 2013, www.fda.gov

INSOMNIA OR NOT?

� 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”

� Spending less time sleeping due to busy lifestyle

� NOT considered insomnia if sleep comes easily when

given the opportunity

� Known as “sleep deprivation” 19

Schutte-Rodin S, J Clin Sleep Med, 2008 Oct 15;4(5):487-504.

HOW IS OSA DIFFERENT THAN INSOMNIA?

� 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

� Would sleep if had adequate opportunity

� CANNOT be treated with medication

� Many medications used to treat insomnia need to be avoided

in patients with obstructive sleep apnea

� Avoid central nervous system depressants (i.e.

benzodiazepines)

20

UpToDate, Overview of Insomnia, 2013, www.uptodate.com

6

CONSEQUENCES OF INADEQUATE SLEEP

� Decreased quality of life

� 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

21

UpToDate, Overview of Insomnia, 2013, www.uptodate.com

MEDICATION-RELATED CAUSES

� Beta blockers � Metoprolol

� Asthma medications � Albuterol, theophylline

� Antidepressants � Fluoxetine, nortriptyline

� Decongestants � Pseudoephedrine

� Stimulants � ADHD medications

� Steroids� Prednisone, methylprednisolone

*List not inclusive

of all medication-

related causes

22

Chawla J, Insomnia, 2013, emedicine.medscape.com

INSOMNIA AND OTHERMEDICAL CONDITIONS

01020304050607080

Prevalence of Chronic Insomnia in other

Medical Conditions

Insomnia

No Insomnia

Taylor DJ, Sleep, 2007 Feb;30(2):213-8.

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MENOPAUSE AND INSOMNIA

� More sleep complaints during perimenopausalperiod

� Insomnia common complaint in women with early

menopause

� May be secondary to vasomotor symptoms (hot

flashes, night sweats) during menopause

� 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)

Young T, Sleep, 2003, Sep;26(6):667-72.

24

7

MANAGEMENT

� Identifying cause of insomnia (if identifiable)

� Treat comorbid conditions

� Education

� Sleep hygiene

� Stress management

� Monitoring of mood symptoms

� Eliminating unnecessary pharmacotherapy

� Pharmacologic therapies

25

Schutte-Rodin S, J Clin Sleep Med, 2008 Oct 15;4(5):487-504.

BEHAVIORAL THERAPY

� Sleep hygiene

� Stimulus control

� Relaxation

� Sleep restriction

� Cognitive therapy

� Cognitive behavioral therapy

26

Schutte-Rodin S, J Clin Sleep Med, 2008 Oct 15;4(5):487-504.

UpToDate, Overview of Insomnia, 2013, www.uptodate.com

SLEEPHYGIENE

� Sleep only as long as you need to feel rested� 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 � 4 – 5 hours prior to bedtime

� Avoid daytime naps 27

UpToDate, Overview of Insomnia, 2013, www.uptodate.com

STIMULUS CONTROL

� People who suffer from insomnia associated the bed/bedroom with fear of not sleeping

� Do not go to bed unless sleepy

� Only used the bed for sleep or sex

� Do not spend > 20 mins in bed without falling asleep

� Get up and do something relaxing

� Alarm set to wake a same time everyday

� No naps allowed

28

UpToDate, Overview of Insomnia, 2013, www.uptodate.com

8

RELAXATION THERAPY

� Used each evening prior to sleep

� Progressive muscle relaxation

� 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

� Peaceful word or place

29

UpToDate, Overview of Insomnia, 2013, www.uptodate.com

SLEEP RESTRICTION THERAPY

� Stay in bed longer to make up for lost sleep

� Shift in circadian rhythm

� Decrease time spent in bed to time actually sleeping (not < 5 hours)

� No naps during the day

� Sleep efficiency calculated

� Time sleeping/time in bed (%)

� ↑ time by 15-30 mins when > 85%

30

UpToDate, Overview of Insomnia, 2013, www.uptodate.com

COGNITIVE THERAPY

� Patients awake at night

� Concern of poor functioning next day

� Worry exacerbates difficulty sleeping

� Work with therapist

� Deal with anxiety

� Establish realistic expectations

31

UpToDate, Overview of Insomnia, 2013, www.uptodate.com

COGNITIVE BEHAVIORAL THERAPY

� Combines many strategies over several weeks

32

Stimulus Control

Sleep Restriction

Cognitive Therapy

Sleep Hygiene

Education

UpToDate, Overview of Insomnia, 2013, www.uptodate.com

9

PHARMACOLOGICAL THERAPY

� Benzodiazepines

� Non-benzodiazepine sedatives

� Melatonin agonist

� Antihistamines

33

UpToDate, Treatment of Insomnia, 2013, www.uptodate.com

PHARMACOLOGICAL TREATMENT

� Caution in the following patient groups

� Pregnancy

� Fetal malformations in first trimester

� Alcohol consumption

� Excessive sedation

� Renal/hepatic disease

� Accumulation of drug

� Pulmonary disease/Sleep apnea

� Worsen disease/hypoventilation

� Nighttime decision-makers

� On-call, taking care of children

� Older adults

� Increased risk of side effects34

UpToDate, Overview of Insomnia, 2013, www.uptodate.com

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

� Medications commonly used� Triazolam (Halcion®)

� Quick-acting, but also short-acting

� Lorazepam (Ativan®)

� Short-intermediate acting

� Estazolam (Prosom®) and temazepam (Restoril™)

� Intermediate-acting

� Flurazepam (Dalmane®) and quazepam (Doral®)

� Long-acting due to active metabolites 35

Wells BG, Pharmacotherapy Handbook, 2009, pg. 814.

BENZODIAZEPINES

� Adverse Effects� Drowsiness, incoordination, decreased concentration, and cognitive deficits

� Daytime tolerance to these effects may occur

� Anterograde amnesia

� Abuse risk

� Tolerance� May develop after 2 – 12 weeks of continuous use

� Rebound insomnia� Decrease risk by taking lowest dose and tapering medication

� Increased falls and hip fractures� Longer-acting flurazepam and quazepam increase falls/fractures especially in the elderly 36

Wells BG, Pharmacotherapy Handbook, 2009, pg. 814.

10

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 37

Wells BG, Pharmacotherapy Handbook, 2009, pg. 814.

NON-BENZODIAZEPINES

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

38

UpToDate, Treatment of Insomnia, 2013, www.uptodate.com

NON-BENZODIAZEPINES

� Adverse effects

� Similar to benzodiazepines

� Less severe

� Dizziness

� Headache

� Somnolence

� Daytime sedation

� Complex-sleep related behaviors

� Unpleasant taste (Eszopiclone)

� Hallucinations (Zolpidem)

� Less risk of abuse versus benzodiazepines

39

Wells BG, Pharmacotherapy Handbook, 2009, pg. 814

UpToDate, Treatment of Insomnia, 2013, www.uptodate.com

COMPLEX SLEEP-RELATED BEHAVIORS

� Non-benzodiazepines

� Sleep eating

� Sleep driving

� Phone calls while sleeping

� Engaging in sexual behaviors

while not fully awake

� Higher doses of medications

have been attributed to these

complex sleep behaviors

40

U.S. Food and Drug Administration, Consumer Updates, 2013.

Hwang TJ, J Clin Psychiatry, 2010 Oct;71(10):1331-5

11

MELATONIN AGONIST

� Ramelteon (Rozerem™)� Involved with circadian rhythm

� Fewer and less severe side effects than benzodiazepines and non-benzodiazepines� 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 41

UpToDate, Treatment of Insomnia, 2013, www.uptodate.com

ANTIHISTAMINES

� First-generation (sedating) antihistamines

� Most common

� Diphenhydramine (Benadryl®)

� Doxylamine (Unisom®)

� Less effective than other options

� Anticholinergic side effects

� Dry mouth

� Blurred vision

� Urinary retention

� Constipation

� Side effects usually more severe in elderly patients 42

UpToDate, Treatment of Insomnia, 2013, www.uptodate.com

Wells BG, Pharmacotherapy Handbook, 2009, pg. 814

INSOMNIA TREATMENT

� General recommendations

� Do not take medications for insomnia unless you

have a full 7-8 hours to dedicate to sleep

� Lowest doses needed

� Decrease daytime sleepiness/side effects

� Easier to taper off medication

� Use for the shortest time necessary

� Decrease risk of tolerance

� Try other non-medication therapies

� Caution during next day when starting new

insomnia medications

� Recognize how the medication will affect you43

UpToDate, Treatment of Insomnia, 2013, www.uptodate.com

ZOLPIDEMWARNING

� 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®)

� 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

44

U.S. Food and Drug Administration [Internet], Zolpidem Containing Products: Drug Safety Communication - FDA Requires

Lower Recommended Doses, 2013, www.fda.gov

12

INSOMNIA IN THE ELDERLY

� Up to 60% of adults > 65 years of age suffer from insomnia

� 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

� 5 - 33% of elderly patients receive a benzodiazepine

or other non-benzodiazepine sleep aids45

Insomnia in the elderly. Pharmacist's Letter/Prescriber's Letter 2009;25(9):250919.

NON-PHARMACOLOGICOPTIONS IN THE

ELDERLY

� Identify and manage exacerbating factors

� Pain

� Shortness of breath (heart failure)

� Chest pain

� COPD

� GI disease (acid reflux, ulcer)

� Neurologic or mood disorders

� Parkinson’s, dementia, anxiety, depression

46

Insomnia in the elderly. Pharmacist's Letter/Prescriber's Letter 2009;25(9):250919.

NON-PHARMACOLOGICOPTIONS IN THE

ELDERLY

� 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

� Keep temperature comfortable

� Avoid meals and liquids close to bedtime

47

Insomnia in the elderly. Pharmacist's Letter/Prescriber's Letter 2009;25(9):250919.

PHARMACOLOGICOPTIONS

� Some evidence that newer non-benzodiazepine hypnotics are safer for the elderly

� ↓ 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

48

Insomnia in the elderly. Pharmacist's Letter/Prescriber's Letter 2009;25(9):250919.

13

PHARMACOLOGICOPTIONS

� Other options

� Trazodone, an antidepressant, may increase deep

sleep

� Not well studied, early on appears to be beneficial

� Non-habit forming

� AE: Dry mouth, nausea, arrhythmias, orthostatic

hypotension

49

Insomnia in the elderly. Pharmacist's Letter/Prescriber's Letter 2009;25(9):250919.

SELF-TREATMENT IN THE ELDERLY

� Alcohol

� Causes early awakening

� Antihistamines (i.e. diphenhydramine)

� Anticholinergic effects, cognitive impairment, urinary

retention

� Residual daytime sleepiness

� Melatonin

� Helps with difficulty falling asleep

� Valerian

� May takes several night/weeks to see benefit

� Kava

� AVOID, may cause hepatotoxicity50

Insomnia in the elderly. Pharmacist's Letter/Prescriber's Letter 2009;25(9):250919.

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 non-benzodiazepines

51

Glass J, BMJ, 2005 Nov 19;331(7526):1169.

META-ANALYSIS – TREATMENT BENEFIT

52

Glass J, BMJ, 2005 Nov 19;331(7526):1169.

14

META-ANALYSIS – ADVERSE EFFECTS

53

Glass J, BMJ, 2005 Nov 19;331(7526):1169.

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

54

Glass J, BMJ, 2005 Nov 19;331(7526):1169.

SUMMARY

� Insomnia diagnosis� Difficultly initiating, maintaining, or poor quality/nonrestorative sleep

� Daytime impairment

� Difficulty despite adequate time for sleep

� Obstructive sleep apnea treatments� 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

REFERENCES

� 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 hypnosedative-related complex sleep behaviors: a retrospective, cross-sectional pilot study. J ClinPsychiatry. 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. Comorbidityof chronic insomnia with medical problems. Sleep. 2007 Feb;30(2):213-8.

56

15

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/SafetyAlertsforHumanMedicalProducts/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_000065_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.

57

QUESTIONS?

58