1. 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

2. 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

3. 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.

4. CIRCADIAN RHYTHM

5. SLEEP CYCLE Non-Rapid Eye Movement (NREM) -- 75% Stage 1 Drowsiness
Light sleep, mild muscle relaxation
Heart rate slows, body temperature decreases
Stage 3 & 4
Deepest sleep (delta-sleep)
Rapid Eye Movement (REM) %
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

6. 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

7. 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

8. How do we measure sleep? Subjective Questioning Objective Studies
But not too subjective
Objective Studies
Polysomnography (PSG)
Multiple Sleep Latency Test (MSLT)
Maintenance of Wakefulness Test (MWT)

9. INSOMNIA

10. INSOMNIA
“Difficulty falling asleep, maintaining sleep, arising, or not feeling rested despite a sufficient opportunity to sleep.”

11. 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

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

13. Complications from Insomnia

14. Associated Factors Gender Age Situational Stressors Environmental
Poor Sleep Hygiene
Psychiatric Conditions
General Medical Conditions
Substances and Medications
Unemployment
Lower Socioeconomic Status

15. 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

16. Causes of Insomnia Medical Illnesses Mental 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.

17. 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

18. TREATMENT OF INSOMNIA

19. 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!

20. BENZODIAZEPINES

21. 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
Benzo Pearls:
Estazolam – Concurrent administration of azole antifungals is contraindicated; no active metabolites
Flurazepam – Avoid in elderly, high potential for daytime drowsiness
Quazepam – Should be avoided in elderly – long half life and active metabolite
Temezepam – no CYP interactions; preferred in liver impairment
Triazolam – Concurrent administration with efavirenz, delavirdine, azole antifungals or protease inhibitors is contraindicated; tolerance develops sooner than with other benzos

22. 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

23. NON-BZDs
Pharmacologic Options

24. Non-BZDs Class Drugs NBRAs (“Z”-Drugs) Zolpidem (Ambien®)
Zaleplon (Sonata®)
Eszopiclone (Lunesta®)
Melatonin Agonist
Ramelteon (Rozerem®)
All FDA approved

25. Zolpidem (Ambien®) Drug (Trade) What you need to know: Zolpidem
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: 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...

26. Zaleplon (Sonata®) Drug (Trade) What you need to know: Zaleplon
Usual dose: 5-20mg PO before HS
Duration: <4 hours
Onset: 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

27. 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…?

28. Ramelteon (Rozerem®) Drug (Trade) What you need to know: Ramelteon
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!

29. OTHER agents

30. Other Agents Class Drugs Sedating Antidepressants
Mirtazapine (Remeron®) 15mg
Trazodone (Desyrel®) 50 – 150mg
Doxepin (Silenor®) mg
Antihistamines
Diphenhydramine (Benadryl®) 25 – 50mg
Doxylamine (Unisom®) 25 – 50mg
Hydroxyzine (Atarax®, Vistaril®) 25 – 50mg
Atypical Antipsychotics*
Quetiapine (Seroquel®) mg
Olanzapine (Zyprexa®) 5 – 10mg
Antihypertensive
Prazosin 1- 6mg/day

31. 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: 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

32. Trazodone (Desyrel®) Drug (Trade) What you need to know: Trazodone
Class: Antidepressant
DOSING: mg adult
25-50mg elderly
ONSET: hour
HALF-LIFE: 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

33. 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.
Benadryl – 25mg elderly, 25-50mg adult / min onset, hour half-life
Doxylamine dose – 25mg, onset min, 10 hour half-life

34. ALTERNATIVE/HERBAL TREATMENT

35. Alternative/Herbal Treatment
Class
Drug
Herbal/Alternative
Valerian
Melatonin
Kava-Kava* (illegal in the USA)
*Kava-Kava not recommended due to hepatotoxicity

36. Valerian Valerian Root Therapy What it Does: What you need to know:
(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

37. Melatonin Melatonin Therapy About What you need to know:
(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

38. Sleep Apnea Circadian Rhythm Disorder Narcolepsy
OTHER SLEEP DISORDERS
Sleep Apnea
Circadian Rhythm Disorder
Narcolepsy

39. Sleep apnea

40. SLEEP APNEA
Neurological condition that results in periods of breathing cessation about 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)

41. 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

42. 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 mg 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)

43. Circadian rhythm disorders

44. 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

45. Narcolepsy

46. 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

47. 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)

48. 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

49. SLEEP HYGIENE Counseling

50. 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!

51. 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!

53. 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

54. References
Diagnostic and Statistical Manual of Mental Disorders: DSM-5. Washington, D.C.: American Psychiatric Association, 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):
Stahl, Stephen M. Stahl's Essential Psychopharmacology: Prescriber's Guide. 5th ed. New York: Cambridge, Print.