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SaturdayGeneralSession

SleepQualityandItsImpactonOverallPatientHealthandChronicMedicalConditions

AlonAvidan,MD,MPHProfessorandViceChair,DepartmentofNeurologyDirector,UCLASleepDisordersCenterDavidGeffenSchoolofMedicineatUCLALosAngeles,CaliforniaEducationalObjectivesBytheendofthiseducationalactivity,participantsshouldbebetterableto:

1. Recognizetheassociationbetweenpoorsleepqualityonpatientqualityoflifeanditsimpactonchronicmedicalconditions.

2. Identifystrategiestoimprovecommunicationwithpatientstoassesssleepquality.

3. Evaluatecurrentpharmacologicoptionstoimprovepatientqualityofsleep.SpeakerDisclosureDr.Avidanhasdisclosedthatheisonthespeaker’sbureauforArborPharmaceuticalsandPernix.SupporterDisclosureThiseducationalactivityissupportedbyaneducationalgrantfromMerck&Company.IthasbeenplannedandproducedbyVemcoMedEdwithTexasAcademyofFamilyPhysiciansstrictlyasanaccreditedcontinuingmedicaleducationactivity.

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ACTIVITY DESCRIPTION

Target AudienceThis activity is designed to meet the needs of primary care providers, including primary care physicians, doctors of osteopathy, physician assistants, nurse practitioners, and allied healthcare professionals, who are involved in the care of adult patients that would benefit from improved sleep quality.

Learning ObjectivesThis activity is designed to improve the competence and skills of primary care providers to: • Recognize the association between poor sleep quality on patient quality of life and its

impact on chronic medical conditions• Identify strategies to improve communication with patients to assess sleep quality • Evaluate current pharmacologic options to improve patient quality of sleep

FACULTY AND DISCLOSURE

Alon Y. Avidan MD, MPHProfessor and Vice Chair UCLA, Department of NeurologyDirector, UCLA Sleep Disorders CenterDavid Geffen School of Medicine at UCLALos Angeles, CA

Dr. Alon Avidan, MD has relevant financial relationships with the following commercial interests:Speakers Bureau: Pernix, Silenor.

Dr. Avidan does plan to discuss the off-label uses of the following: Discussion will include off-label uses of various CNS-actingmedications for insomnia. Specifically he will cover the use of sedating antidepressants, such as trazodone,amitriptyline, mirtazapine, doxepin; the antipsychotic quetiapine. Antihistamine compounds such as doxylamine, and thoseavailable over-the-counter marketed as sleep aids as single compounds or as a combination therapy with analgesics(ibuprofen or acetaminophen). Dietary supplement sleep aids such as chamomile, passionflower, valerian, hops, kava ,Tart cherry juice and melatonin.

No (other) speakers, authors, planners or content reviewers have any relevant financial relationships to disclose.

Content review confirmed that the content was developed in a fair, balanced manner free from commercial bias. Disclosure of arelationship is not intended to suggest or condone commercial bias in any presentation, but it is made to provide participants with information that might be of potential importance to their evaluation of a presentation.

Difficulties Falling Asleep

(˃ 30 min)

Difficulties Maintaining

Sleep

Early Morning Awakenings

(> 30 minutes before desired wake time)

Next Day Consequences

• Fatigue

• Attention, concentration, or memory impairment

• Social/vocational dysfunction Mood disturbance/irritability

• Proneness for errors/accident at work or while driving

• Tension headaches, and/or GI symptoms in response to sleep loss

• Concerns or worries about sleep

Despite adequate

opportunity for sleep

ICSD III

What is Insomnia?

© Alon Y. Avidan MD, MPH

Clinically significant distress

≥3 nights/week, ≥3 months Not due to substance,

medical condition, inadequate sleep time.

±±

• 62% Family Physician/ Internist

• 8% Psychiatrist

• 4% OB/GYN

• 4% Sleep Specialist

• 22% Other

No one

70%

SecondaryReason for

Consultation

24%

Primary Reason for Consultation

6%

Where do Patients with InsomniaGo for Management?

Ancoli-Israel S, Roth T. Sleep. 1999;22:S347-S353. The Gallup Organization for the National Sleep Foundation, 1995. National Sleep Foundation. “Sleep in America” Poll. March 2005. Available at: https://sleepfoundation.org/sleep-polls-data/sleep-in-america-poll/2005-adult-sleep-habits-and-styles.

29%

70%

0%

20%

40%

60%

80%

Yes No

“Has your doctor ever asked you about sleep issues?”

Psychiatric 40%

Primary / psychophysiologic

20%

Periodic limb movement

10%

Circadian rhythm (DSPS /

shift ) 10%

Breathing related 5%

Substances 5%

Other 10%

Presentations of Insomnia by Underlying Causes

Ohayon MM. Sleep Med Rev. 2002;6:97-111.

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Impact of Insomnia

InsomniaMedical Illnesses

Reduced Quality of

Life

Higher Absenteeism

Increased Accident

Risk Higher Healthcare

Costs

Cognitive Impairment

Psychiatric Disorders

Benca RM. J Clin Psychiatry. 2001;62(suppl 10):33-38.

Contribution of Medical Conditions to Insomnia

CARDIACIschemia

Congestive heart failure

NEUROLOGICStrokeDegenerative conditionsDementiaPeripheral nerve damage Myoclonic jerksRestless leg syndromeHypnic jerkCentral sleep apneaChronic pain

PULMONARYCOPDAsthmaCentral alveolar hypoventilation Obstructive sleep apnea

GASTROINTESTINALGastroesophageal reflux

disease

ENDOCRINEHyperthyroidism

MenopauseMenstrual cycle

PregnancyHypogonadism

SUBSTANCESStimulantsOpioidsCaffeineAlcoholOr withdrawal from any of these

Medications - decongestants, corticosteroids, and bronchodilators

Bidirectionality of Insomnia & Psychiatric Conditions

Alterations in REM sleep As many as 40% of people

with depression have insomnia

DEPRESSION PTSD

Vivid and terrifying nightmares

ANXIETY

Generalized anxiety disorder, panic disorder, and anxiety disorders not otherwise specified

Predispose to insomnia

OTHER

Thought disorders and misperception of sleep state

PSYCH MEDS

Antidepressants may interfere with normal REM sleep patterns

Benzodiazepines or other hypnotic agents rebound insomnia

INSOMNIA

When did the insomnia begin?

When did the insomnia begin?

Was thereA specific Trigger?

Was thereA specific Trigger?

Frequency?Days/week?Frequency?Days/week?

Is it problems with:InitiationMaintenanceEarly AM awakening?

What have you tried so far?

What have you tried so far?

Why are you seeking help now?

Why are you seeking help now?

What is your expectation for management?

What is your expectation for management?

How has insomnia affected you?

How has insomnia affected you?

Insomnia Evaluation | History

Difficulties Maintaining

Sleep

Difficulties Maintaining

Sleep

Early morning

awakening

Insomnia According to Timing at Night

ASPSDepression

Drugs

RLSAnxietyDrugs

Primary Sleep Disorder:

OSA, NocturiaPoor sleep

environment

RLS, restless leg syndrome; OSA, obstructive sleep apnea; ASPS, advanced sleep phase syndrome

Difficulties Initiating

Sleep

Polysomnogram: Indications in the Evaluation of Insomnia

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AASMN Sleep Diary. Available at: http://yoursleep.aasmnet.org/pdf/sleepdiary.pdf.

A 17y/o girl presents with her mother for evaluation of nighttime insomnia and difficulties with daytime functioning. She goes to bed at 2 AM and struggles to make it to her 7AM classes. She sleep in until 2-4PM on the weekends. She is an honors student, does homework on the computer until 1AM, but is now struggling academically. The best treatment is

Patient Case 1

1. Zolpidem at bedtime2. Melatonin at bedtime3. Bright light in the AM, avoidance of light at night4. Insight oriented psychotherapy

Delayed Sleep Phase Disorder Treatment – Intervention

• Light exposure in the morning upon waking

• Incremental advancement of sleep schedule by 15 minutes every day

• Avoid light exposure in evening

• Timed low dose melatonin (low dose is 0.5mg) 9 to 11 hours before middle of sleep episode

• Exposure to light from media – Delays circadian rhythm

• Media activities are stimulating

Treatment – Prevention

• Later school day starting times

• Schools limit late-evening activities

• Schools to educate students about sleep and circadian rhythms

• Parents to set appropriate bedtime

• Avoid light exposure and stimulating activities

4

Nadolski N. Plast Surg Nurs. 2005;25:167-173. Roth T, Culpepper L. Clin Symp. 2008;58:3-32.

• Restore and improve sleep quality and duration

• Prevent progression from acute to chronic insomnia

• Reduce impact on comorbid condition

Kupfer DJ, Reynolds CF III. N Engl J Med. 1997;336:341-346.Consensus Conference. JAMA. 1984;251:2410-2414.

Stepwise Approach for Managing Insomnia

Discuss Sleep

Diagnosis

Education, Including

Good Sleep Practices

Nonpharmacologicand/or

Pharma-cologicTherapy

Goals of Treatment• Relieve an upsetting symptom• Improve next-day consequences• Improve outcome of co-morbidity

• Psychiatric• Medical

Refer toSleep

Specialist(If Treatment

Failure)

Non-pharmacologic Approaches Patient Education Sleep Hygiene Aerobic exercise Cognitive behavior therapy–insomnia

(CBT-I) and other types of therapy

Pharmacologic Approaches• FDA-approved medications• Off-label prescription medications• Over-the-counter medications• Dietary supplements (unregulated)

Current Approaches for Treatment

1. Spielman AJ et al. Psychiatr Clin North Am. 1987;10:541-553. 2. Walsh JK et al. NIH Publication No. 98-4088. 3. Morin CM. Principles and Practice of Sleep Medicine, 4th ed. 2005:726-737. 4. Ringdahl EN et al. J Am Board Fam Pract. 2004;17:212-219.

This technique… Targets these symptoms

Stimulus control

Relaxation Techniques

Cognitive

Sleep hygiene education

Associating bed with wakefulness

Excessive time spent in bed; fragmented sleepExcessive time spent in bed; fragmented sleep

High physiologic, cognitive, or emotional arousal

Misconceptions about sleep and insomnia

Behaviors that undermine good quality sleep

Sleep restriction ☞

☞

☞

☞

☞

Cognitive & Behavioral Therapy

Do’s:• Enhance sleep environment: dark, quiet, cool temperature• Increase exposure to bright light during the day• Practice relaxing routine• Reduce time in bed; regular sleep/wake cycle• Incorporate regular exercise in the morning and/or afternoon

Don’ts: • “Watch the clock”• Use stimulants

(e.g., caffeine, nicotine, particularly near bedtime)• Consume a heavy meal or drink alcohol within 3 hours of bed• Use bright lights during the night, avoid TV/computers, e-gadgets.

Sleep Hygiene 101

NHLBI Working Group on Insomnia. 1998. NIH Publication. 98‐4088.Kupfer DJ, Reynolds CF. N Engl J Med. 1997;336:341‐346.Lippmann S, et al. South Med J. 2001;94:866‐873.

• CBT-I is the treatment of choice for:‒ Most patients with insomnia

‒ Better short-term efficacy compared to hypnotics‒ Better durability of effectiveness following cessation of hypnotics Rx

Downside: Some patients may lack:‒ Access to CBT-I‒ Response to CBT-I‒ Capacity of utilizing CBT-I

• Short-term course of hypnotic medication + CBT-I: may enhance outcome

Cognitive & Behavioral Therapy

5

Sleep Hygiene CBTi

Avoid stimulants for several hours before bedtime.• Avoid alcohol around bedtime.• Exercise regularly but not too late.• Allow 1-hour period to unwind before bedtime.• Keep bedroom environment quiet, dark and cool.• Maintain a regular sleep schedule.

• Sleep Restriction• Stimulus Control• Relaxation Training• Cognitive Therapy• Sleep Hygiene Education

Standard Guideline Individualized Multi-Component Intervention

Helps Normal Sleepers Maintain Sleep Health Treatment for Insomnia Disorder

Preventative Curative

The Dental Hygienist The dentist

Minimal Impact on Insomnia Disorder Very Effective Insomnia Disorder Treatment

Inactive Condition in Insomnia Research Active Condition in Insomnia Research

CBTi vs. Sleep Hygiene

Alcohol1,2,3

Herbals3,4

Dietary supplements1,4

Homeopathic preparations4

Melatonin1,3,4

OTC sleep aids2

Sedating antidepressants1

Sedative-hypnotics1,5

Melatonin-receptor agonistHypocretin-receptor antagonist

What Do People Take to Try to Improve Their Sleep?

1. Neubauer DN. Clinical Cornerstone. 2003;5:16-27. 2. Ancoli-Israel S, Roth T. Sleep. 1999;22(suppl 2):S347-S353. 3. Wagner J, et al. Neuropsychiatry. 1998;32:680-691. 4. Larzelere MM, Wiseman P. Prim Care Clin Office Pract. 2002;29:339-360. 5. Mitler MM. Sleep. 2000;23(suppl 1):S39-S47.

Drug ClassesDrug Classes

Histamine-Receptor

Antagonist

Histamine-Receptor

Antagonist

Melatonin-Receptor Agonist

Melatonin-Receptor Agonist

ZolpidemEszopiclone

ZaleplonTriazolam

ZolpidemEszopiclone

ZaleplonTriazolam

DoxepinDoxepinSuvorexant Ramelteon

BZA-Receptor Agonists

Hypocretin-Receptor

Antagonist

Hypnotics: Mechanism of Action & LabelingClass1 Drugs1,2 Acts on:1 Controlled Substance

Schedule2

Non-benzodiazepines Zolpidem, eszopiclone, zaleplon GABA IV

BenzodiazepinesTemazepam, estazolam, flurazepam, quazepam, triazolam

GABA IV

Melatonin-receptor agonist

Ramelteon Melatonin Not scheduled

Orexin-receptor antagonist4 Suvorexant Orexin IV

Antihistamines Diphenhydramine5 Histamine Not scheduled

Antidepressants Tradozone, amitriptyline Serotonin/histamine Not scheduled

BarbituratesPhenobarbital, mephobarbital, amobarbital, secobarbital

Non-selective CNS depressants II, III, IV

Antipsychotics Quetiapine, risperidone, aripiprazole Dopamine, serotonin Not scheduled

Selective H1

receptor antagonist3 Doxepin Histamine H1 Not scheduled

1. Roth T, Culpepper L. Clinical Symposia. 2008;58:1-32; 2. Controlled Substances Act. http://www.deadiversion.usdoj.gov/21cfr/21usc/812.htm. Accessed June 12, 2017; 3. SILENOR® (doxepin) [package insert]. Morristown, NJ: Pernix Therapeutics; 2014; 4. Belsomra® (suvorexant) [package insert]. Whitehouse Station, NJ; Merck and Co. 2016; 5. Richardson GS, et al. J Clin Psychopharmacol. 2002;22:511-515.

A 57 y/o male executive presents with middle of the night insomnia, beginning at 1AM. 2-3 times a week. He needs to be awake at 7AM. He would like to start a medication to help him with sleep maintenance difficulties. Which would be the most appropriate choice for him?

Patient Case 2

1. Ramelteon, 8mg po QHS2. Melatonin, 3mg po QHS3. Zolpidem, 5mg po QHS4. Sublinguial Zolpidem, 3.5mg Sublingual PRN, middle of the night

insomnia.

Agent Initiates Sleep

Maintains Sleep

Sleep with limited

opportunity

Required Inactivity

(hr)

Dose (mg)

Eszopiclone √ 8+ 1,2,3

Zaleplon √ √ 4 5,10

Zolpidem √ 7-8 5,10

Extended-release √ 7-8 6.25, 12.5

Sublingual √ (4 hrs) 4 1.75, 3.5

Oral spray √ 4 5, 10

Sublingual √ 4 5, 10

Doxepin (Ultra-low dose) 7-8 3, 6

Ramelteon √ - 8

Suvorexant √ 7 5, 10, 15, 20

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Address underlying pathophysiology

Rapid sleep induction

Minimal adverse effect on

sleep physiology

Optimal duration of action

No formation of active metabolites

No memory deficits

No respiratorydepression

No interaction with

ethanol

No physicaldependence

No reboundinsomnia

No residualeffects

Ideal Hypnotic

Ideal Hypnotic

Rapid absorption

No tolerance

Characteristics of the Ideal Hypnotics

Adapted from Mendelson WB, et al. Sleep Med Rev. 2004;8:7-17. FDA. Available at: https://www.fda.gov/downloads/Drugs/DrugSafety/UCM335007.pdf.

BZRA Hypnotics: Possible Adverse Effects Mechanism of Action of Hypnotics

OREXIN

MELATONIN

HISTAMINE

Newer HypnoticsClass1 Drugs Specific Indication: Notes:

Non-benzodiazepines

“Z-Drugs” Zolpidem(R/ER) eszopiclone, zaleplon

All: Sleep initiation insomnia.Zolpidem ER & Eszopicolone: Sleep initiation and maintenance insomnia. Zolpidem Sublingual: Middle of the night insomnia

Complex Nocturnal BehaviorsAmnesiaDepression

Melatonin-receptor agonist

Ramelteon Sleep initiation insomnia Complex Nocturnal BehaviorsAmnesiaDepression

Orexin-receptor antagonist3

Suvorexant Sleep initiation/maintenance insomnia Complex Nocturnal BehaviorsAmnesiaDepressionUnique side effects: sleep paralysis, cataplexy.Contraindication: Narcolepsy

Selective H1

receptorantagonist2

Doxepin Middle of the night insomnia Complex Nocturnal BehaviorsAmnesiaDepression

1. Roth T, Culpepper L. Clinical Symposia. 2008;58:1-32; 2. SILENOR® (doxepin) [package insert]. Morristown, NJ: Pernix Therapeutics; 2014; 3. Belsomra® (suvorexant) [package insert]. Whitehouse Station, NJ; Merck and Co. 2016.

FDA-approved Hypnotics & T½

0 20 40 60 80 100 120

Zaleplon

Zolpidem

Rozerem

Trazolam

Eszopiclone

Temazepam

Estazolam

Quazepam

Flurazepam

HOURS

HALF-LIFE

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Stahl SM. Stahl’s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications, 3rd Edition. Cambridge University Press, 2008. p.835.

Moderately Long Half-Life Hypnotics Do Not Wear Off Until After Time to Awaken (Hangover)

Ultrashort Half-Life Hypnotics Wear Off Before Time to Awaken (Loss of Sleep Maintenance)

Stahl SM. Stahl’s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications, 3rd Edition. Cambridge University Press, 2008. p.840.

Half-Life ≈ 6 hours Optimized Duration of Action

Stahl SM. Stahl’s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications, 3rd Edition. Cambridge University Press, 2008. p.841.

Guideline Consensus Recommendations

Sateia MJ, Buysse DJ, Krystal AD, Neubauer DN, Heald JL. Clinical practice guideline for the pharmacologic treatment of chronic insomnia in adults: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med. 2017;13(2): 307–349.

USE: As a treatment for sleep onset and/or sleep maintenance insomnia1. Suvorexant2. Eszopiclone3. Zaleplon4. Zolpidem 5. Triazolam6. Temazepam7. Ramelteon8. Doxepin

DO NOT USE as a treatment for sleep onset or sleep maintenance insomnia:1. Trazodone2. Tiagabine 3. Diphenhydramine4. Melatonin5. Tryptophan6. Valerian

Data Compares: Versus no treatment, in adults. Level of Evidence: WEAK

Sateia MJ, et al. J Clin Sleep Med. 2017;13:307-49.

2017 AASM Treatment Recommendations

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Qaseem, A., et al. (2016). "Management of chronic insomnia disorder in adults: A clinical practice guideline from the American College of Physicians." Annals of Internal Medicine 165(2): 125-133 (Appendix 2).

CBTI vs. Medication for Insomnia

Adapted from Morin CM et al. JAMA 1999; 281.

The Sleepless Patient: Summary

• Assessment requires careful inventory of potential confounders• CBT-I is an important option• Numerous medications are available, BUT:

‒ Risk analysis: Evaluate cost-benefit‒ Rx has variable benefit profiles‒ Insomnia therapy needs to be individualized to meet patient’s

expectations and needs• Insomnia is highly prevalent and can impact the general well-being

of patients• Evaluation of sleep should be a routine part of acute care and well

visits

MedicationIndexSleepQualityandItsImpactonOverallPatientHealthandChronicMedicalConditions

GenericName TradeNameAmitriptyline NoneAmobarbital NoneAripiprazole Abilify,AristadaDiphenhydramine BenadrylDoxepin Silenor,ZonalonEstazolam NoneEszopiclone LunestaFlurazepam NoneMephobarbital NonePhenobarbital NoneQuazeopam DoralQuetiapine SeroquelRamelteon RozeremRisperidone RisperdalSecobarbital SeconalSodiumSuvorexant BelsomraTemazepam RestorilTiagabine GabitrilTrazodone NoneTriazolam HaliconZaleplon SonataZolpidem Ambien,Edluar,Intermezzo,Zolpimist

Thefollowingmedicationswerediscussedinthispresentation.Thetablebelowliststhegenericandtradename(s)ofthesemedications.

Notes