complex patients in insomnia: top 5 dos and don’ts when a ...2019/... · plos one....

Complex Patients in Insomnia:Top 5 Dos and Don’ts When a Patient Fails

First-Line Insomnia Therapy

David N. Neubauer, MDAssociate ProfessorDepartment of Psychiatry and Behavioral SciencesJohns Hopkins University School of MedicineBaltimore, Maryland

Faculty Disclosure• Dr. Neubauer: Consultant—Eisai Inc, Imbrium Therapeutics.

Disclosure• The faculty have been informed of their responsibility to disclose to the

audience if they will be discussing off-label or investigational use(s) of drugs, products, and/or devices (any use not approved by the US Food and Drug Administration).

• Applicable CME staff have no relationships to disclose relating to the subject matter of this activity.

• This activity has been independently reviewed for balance.

• Brand names are included in this presentation for participant clarification purposes only. No product promotion should be inferred.

Learning Objectives

• List 5 important aspects of a patient’s history to assess when evaluating someone with persistent insomnia complaints

• Discuss behaviors that may undermine good quality sleep and changes that help restore good sleep

• Describe how comorbid sleep disorders can contribute to insomnia symptoms

Key Insomnia Disorder Diagnostic Criteria

International Classification of Sleep Disorders. Third Edition. Darien, IL: American Academy of Sleep Medicine; 2014. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Arlington, VA: American Psychiatric Association Publishing; 2013.

Insomnia ComplaintDifficulty initiating sleep

Difficulty maintaining sleepEarly-morning awakening

Daytime Consequences or ImpairmentFatigue or malaise

Attention, concentration, or memoryPerformance

(social, family, occupational, academic)Mood disturbance/irritability

Daytime sleepinessBehavioral disturbances

(hyperactivity, impulsivity, aggression)Motivation, energy, or initiative

Concerns or dissatisfaction with sleep

AdequateOpportunity

Circumstances

Frequency At least 3 nights/week

Duration At least 3 months

Not better explained by Another sleep-wake disorder

Effects of a substance or medicationCoexisting mental disorders or medical conditions

What is first-line insomnia therapy?

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

Qaseem A, et al. Ann Intern Med. 2016;165(2):125-133.

Morgenthaler T, et al. Sleep. 2006;29(11):1415-1419.

Sateia MJ, et al. J Clin Sleep Med. 2017;13(2):307-349.

2019 American Geriatrics Society Beers Criteria® Update Expert Panel. J Am Geriatr Soc. 2019;67(4):674-694.

What is first-line insomnia therapy?

1. Cognitive-behavioral therapy for insomnia (CBT-I)

2. Pharmacotherapy – wisely applied

#1: Do incorporate cognitive and behavioral strategies into your practice

When a patient fails first-line insomnia therapy

Cognitive-Behavioral Therapy for Insomnia (CBT-I)• Evidence-based

– Traditional CBT-I• 6 to 8 individual or group sessions with certified therapist, typically

manualized• Multimodal intervention

– Sleep hygiene education– Cognitive strategies– Sleep restriction– Stimulus control– Relaxation– Paradoxical intention

• Durable improvements in sleep onset and maintenance• Limited availability of providers in many areas

van Straten A, et al. Sleep Med Rev. 2018;38:3-16.

Alternate Cognitive and Behavioral Approaches• Evidence-based

– Brief Behavioral Treatment of Insomnia (BBTI)• 4-session manualized treatment approach

–2 face-to-face–2 by telephone

• Non-psychologist health professional• Performed in general medical settings• Behavioral guidelines targeting homeostatic and circadian

drives• Improvement in sleep onset and maintenance

Gunn HE, et al. Sleep Med Clin. 2019;14(2):235-243.

Alternate Cognitive and Behavioral Approaches (cont’d)

• Available strategies– Online CBT-I– Telephone CBT-I– CBT-I apps– Self-help CBT-I books– Smartphone apps with education and guidelines– Monitoring apps with providing feedback and recommendations

Buenaver LF, et al. Sleep Med Clin. 2019;14(2):275-281. van Straten A, et al. Sleep Med Rev. 2009;13(1):61-71. Ritterband LM, et al. Arch Gen Psychiatry. 2009;66(7):692-698. Drerup ML, et al. Sleep Med Clin. 2019;14(2):283-290.

#2: Don’t fail to do a detailed insomnia history


Key Insomnia History Assessments• Primary insomnia complaint

– Nighttime symptoms– Daytime/evening symptoms

• Course of sleep disturbance• Sleep-wake schedule• Additional sleep-related symptoms• Medication and substance use

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Arlington, VA: American Psychiatric Association Publishing; 2013. Schutte-Rodin S, et al. J Clin Sleep Med. 2008;4(5):487-504. Morin CM, et al. Lancet. 2012;379(9821):1129-1141.

Insomnia History: Nighttime Symptoms• Sleep onset difficulty

– Timing– Experience

• Awakenings– Frequency and duration– Associated symptoms and experiences– Difficulty returning to sleep– Behaviors during the night

• Early morning awakening• Estimated sleep amount• Sleep quality


Insomnia History: Daytime/Evening Symptoms• Fatigue• Sleepiness, napping,

inadvertent sleep episodes• Reduced motivation, energy, or

initiative• Mood disturbance or irritability• Cognitive dysfunction

– Attention– Concentration– Memory

• Proneness for errors and accidents

• Quality of life• Functional and performance

impairment– Social– Occupational– Educational– Academia– Behavioral


Insomnia History: Course of Sleep Disturbance• Premorbid sleep pattern• Onset (abrupt or gradual?)• Associated circumstances

– Precipitating factors• Physical or mental conditions• Life circumstances (stressful events)

– Perpetuating factors• Frequency when affected by insomnia symptoms (days/week)• Duration (weeks, months, years)


Insomnia History: Course of Sleep Disturbance (cont’d)

• Pattern of insomnia symptoms– Acute– Episodic– Persistent

• Severity– Intensity– Impact on functioning


Insomnia History: Sleep-Wake Schedule• Opportunity and circumstances for adequate sleep• Bedtime and typical sleep latency• Time of final awakening and rise time• Schedule regularity and variations

– School– Work (including shift work) and days off– Vacation– Transmeridian travel


Insomnia History: Sleep-Wake Schedule (cont’d)

• Pre-sleep conditions– Usual evening routines– Mental state (eg, worry about sleep)– Bedroom environment

• Light• Noise• Temperature• Sleep surface (bed, sofa, floor, other?)

– Activities in bed (reading, television, electronic screens)– Bed partners (including pets)


Insomnia History: Sleep-Wake Schedule (cont’d)

• Daytime or evening napping• Typical daytime activities

– Exercise– Light exposure– Fatigue/sleepiness countermeasures


Insomnia History: Additional Sleep-Related Symptoms

• Breathing related– Snoring, gasping, or coughing– Witnessed cessation of breathing– Preferred sleeping position

• Body sensations and movements– Kicking or twitching– Restlessness (especially evening or nighttime)

• Urinary frequency• Gastrointestinal reflux• Pain


Insomnia History: Medication and Substance Use• Prescription and over-the-counter medications• Dietary supplement use (including melatonin)• Alcohol (including “self-medicating” for sleep)• Nicotine• Cannabis• Other substance use


Insomnia History: Additional Topics• Previous and current treatments

– Response– Adverse events

• Coexisting sleep-wake disorders• Mental health history• Medical history• Family history of sleep-related symptoms and disorders


#3: Do have patients maintain sleep diaries or sleep logs

Helpful for initial diagnosisImportant for differential diagnosis

Useful for monitoring treatment efficacyNew options: Online, apps, and trackers (wearables, nearables)


#4: Don’t fail to consider sleep-disordered breathing in patients complaining of insomnia

Obstructive sleep apneaCentral sleep apnea

Sleep-related hypoventilation


STOP-BANG OSA Screen

OSA = obstructive sleep apnea.Nagappa M, et al. PLoS One. 2015;10(12):e0143697.

S

T

O

P

Have you been told that you snore?

Are you tired during the day?

Do you know if you stop breathing or has anyone witnessed you stop breathing while you are asleep?

Do you have high blood pressure or on medication to control high blood pressure?

Y/N

Y/N

Y/N

Y/NAnswering Yes to ≥ 2 indicates risk for OSA

STOP-BANG OSA Screen (cont’d)

Nagappa M, et al. PLoS One. 2015;10(12):e0143697.

B

A

N

G

Is you body mass index greater than 28?

Are you 50 years old or older?

Are you a male with a neckcircumference > 17 inches, or a female with a neck circumference > 16 inches?

Are you a male?

Y/N

Y/N

Y/N

Y/NThe more Yes answers, the greater the OSA severity

#5: Don’t assume that more is better whenprescribing sedating medications


Patients I’ve SeenCase A• Zolpidem 10 mg bedtime• Zolpidem extended-release 12.5 mg bedtime• Zolpidem extended-release 6.25 mg bedtime• Clonazepam 0.5 mg BID and 1 mg bedtime• Quetiapine 50 mg bedtime• Gabapentin 300 mg in AM and 900 mg in AM• Lamotrigine 100 mg BID• Ziprasidone 40 mg in AM and 160 mg in PM• Trazodone 200 mg at bedtime

More Patients I’ve SeenCase B• Zolpidem 40 mg at bedtime• Temazepam 120 mg at bedtime

Case C• Quetiapine 2000 mg at bedtime• Flurazepam 60 mg at bedtime

Case D• Clonazepam 2 mg at bedtime• Diphenhydramine 500 mg at bedtime

Another Patient I’ve SeenCase E• Melatonin 5 mg• Concentrated cannabis oil 15 mg• Doxepin 10 mg• Eszopiclone 18 mg

2001 mgChiaro G, et al. J Clin Sleep Med. 2018;14(7):1257-1259.

#6: Do think carefully about prescribing trazodone


Trazodone: Highlights of Prescribing Information• Indications and Usage: “a selective serotonin reuptake inhibitor

indicated for the treatment of major depressive disorder (MDD)”• Dosage and Administration

– Maximum dose: 400 mg/day in divided doses– Should be taken shortly after a meal– When discontinued, gradual doses reduction is recommended

US Food and Drug Administration. Drugs@FDA: FDA Approved Drug Products. www.accessdata.fda.gov/scripts/cder/daf/.

Trazodone: Pharmacology• Pharmacodynamics

– 5-HT2A antagonist (Ki = 35.6 nM)– 5-HT2B antagonist (Ki = 78.4 nM)– 5-HT2C antagonist (Ki = 224 nM)– Serotonin reuptake inhibition (Ki = 367 nM)– α1A antagonist (Ki = 153 nM)– α2C antagonist (Ki = 155 nM)– 5-HT1A partial agonist (Ki = 118 nM)

• Pharmacokinetics– Peak plasma level (empty stomach) approximately 1 hour– Elimination half-life: Biphasic 10–12 hours– Active metabolite (CYP3A4): m-chlorophenylpiperazine (mCPP)

US Food and Drug Administration. Drugs@FDA: FDA Approved Drug Products. www.accessdata.fda.gov/scripts/cder/daf/.Bryant SG, et al. Clin Pharm. 1982;1(5):406-417.

Trazodone: Highlights of Prescribing InformationWarnings and Precautions

• Suicidal thoughts and behaviors• Serotonin syndrome• Cardiac arrhythmias: Increases the QT interval• Orthostatic hypotension and syncope• Increased risk of bleeding• Priapism (including clitoral priapism*)• Activation of mania or hypomania• Potential for cognitive and motor impairment• Angle-closure glaucoma• Hyponatremia

US Food and Drug Administration. Drugs@FDA: FDA Approved Drug Products. www.accessdata.fda.gov/scripts/cder/daf/.*Battaglia C, et al. J Sex Med. 2009;6(10):2896-900. Medina CA. Obstet Gynecol. 2002;100(5 Pt 2):1089-1091.

Trazodone: Potential Drug Interactions• Central nervous system depressants• Strong CYP3A4 inhibitors

– Consider trazodone dose reduction– Examples: itraconazole, ketoconazole, clarithromycin, and indinavir

• Strong CYP3A4 inducers– Consider trazodone dose increase– Examples: rifampin, carbamazepine, phenytoin, St. John’s wort

• QT interval prolongation: Avoid in combination with drugs known to prolong the QTc– Class 1A antiarrhythmics: quinidine, procainamide, disopyramide– Class 3 antiarrhythmics: amiodarone, sotalol– Antipsychotics: ziprasidone, chlorpromazine, thioridazine– Antibiotics: gatifloxacin


“mCPP has psychostimulant, anxiety-provoking and hallucinogenic effects.”

“Among patients with psychiatric disorders a greater degree of anxiety, euphoria, perceptual changes, and hostility were observed compared

with healthy control subjects…”

www.who.int/medicines/areas/quality_safety/5.3cExpertreview-mCPPprereview.pdf?ua=1. Accessed July 25, 2019.www.who.int/substance_abuse/right_committee/en/. Accessed July 25, 2019.

Bossong MG, et al. J Psychopharmacol. 2010;24(9):1395-1401.

High and clinically significant daytime m-CPP levels (about 100 ng/ml or a tenth of plasma trazodone levels) continue to be documented in normal humans taking a common trazodone dose for sleep, 150 mg once at

bedtime (Mercolini et al. 2008). This is comparable to levels attained when anxiety or panic attacks are provoked by i.v. m-CPP in studies with normal human volunteers (Van Veen et al. 2007).

Kast RE. World J Biol Psychiatry. 2009;10(4 Pt 2):682-685.

New use of low-dose trazodone was no safer with regard to a risk of a fall-related injury than new use of benzodiazepines.

Bronskill SE, et al. J Am Geriatr Soc. 2018;66(10):1963-1971.

#7: Do consider pharmacokinetics and pharmacodynamics when prescribing


Insomnia PharmacotherapyCurrent FDA-Approved Medications

• Benzodiazepine receptor agonists– Benzodiazepine hypnotics– Nonbenzodiazepine hypnotics

• Selective melatonin receptor agonist– Ramelteon

• Selective histamine receptor antagonist– Low-dose doxepin

• Dual orexin/hypocretin receptor antagonist– Suvorexant

Generic Name Brand Name Available Doses (mg) Elimination Half-life (hours)

Benzodiazepine Receptor AgonistsBenzodiazepines Immediate-Release

Estazolam ProSom™ 1, 2 10 to 24Flurazepam Dalmane® 15, 30 2.3 (active metabolite: 48–160)Quazepam Doral® 7.5, 15 39 (active metabolite 73)Temazepam Restoril™ 7.5, 15, 22.5, 30 3.5 to 18.4Triazolam Halcion® 0.125, 0.25 1.5 to 5.5

Nonbenzodiazepines Immediate-ReleaseEszopiclone Lunesta® 1, 2, 3 ~6 (~9 in elderly)Zaleplon Sonata® 5, 10 1Zolpidem Ambien® 5, 10 ~2.5

Nonbenzodiazepines Extended-ReleaseZolpidem ER Ambien CR® 6.25, 12.5 2.8 in males (longer in females)

Nonbenzodiazepines Alternate DeliveryZolpidem oral spray Zolpimist™ 5, 10 2.7–3.0Zolpidem sublingual Edluar® 5, 10 ~2.5Zolpidem sublingual Intermezzo® 1.75, 3.5 ~2.5

FDA-Approved Insomnia Medications

Neubauer DN. Continuum. 2013;19(1):50-66. US Food and Drug Administration. Drugs@FDA: FDA Approved Drug Products. www.accessdata.fda.gov/scripts/cder/daf/.

Generic Name Brand Name Available Doses (mg) Elimination Half-life (hr)

Selective Melatonin Receptor Agonist

Ramelteon Rozerem® 8 1–2.6

Selective Histamine H1 Receptor AntagonistDoxepin Silenor® 3, 6 15.3

Dual Orexin Receptor Antagonist

Suvorexant Belsomra® 5, 10, 15, 20 12

FDA-Approved Insomnia Medications (cont’d)


Medication Unspecified Insomnia Sleep Onset Sleep Maintenance Early Awakening

Estazolam √ √ √Flurazepam √ √ √Quazepam √ √ √Temazepam √Triazolam √Eszopiclone √ √Zaleplon √Zolpidem √Zolpidem ER √ √Zolpidem spray √Zolpidem sublingual √Zolpidem sublingual-MOTN √Ramelteon √Low-dose doxepin √Suvorexant √ √

MOTN = middle-of-the-night.US Food and Drug Administration. Drugs@FDA: FDA Approved Drug Products. www.accessdata.fda.gov/scripts/cder/daf/.

#8: Don’t try second-line treatments without considering the insomnia disorder

differential diagnosis


Insomnia Disorder Differential Diagnosis• Normal variant – short sleeper• Chronic volitional sleep restriction• Sleep-disruptive environmental

circumstances• Comorbid psychiatric disorders (eg,

mood and anxiety)• Substance/medication-induced

sleep disorder, insomnia type• Circadian rhythm sleep-wake

disorders, especially– Delayed sleep phase– Advanced sleep phase

• Breathing-related sleep disorders– OSA– Central sleep apnea– “Complex insomnia”

• Parasomnias– REM-related disorders

• Nightmares• REM sleep behavior disorder

– Non-REM arousal disorders• Sleep terrors• Confusional arousals

• RLSREM = rapid eye movement; RLS = restless legs syndrome.International Classification of Sleep Disorders. Third Edition. Darien, IL: American Academy of Sleep Medicine; 2014. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Arlington, VA: American Psychiatric Association Publishing; 2013.

Restless Legs Syndrome• Key characteristics

– Uncomfortable and unpleasant urge to move the legs• Starts or worsens during rest or inactivity• Relieved by movement• Worse or occurs only during the evening or nighttime

– At least 3×/week for at least 3 months– Significant distress or impairment– Not attributable to another mental disorder, medical condition, behavioral

condition, substance, or medication (akathisia!)• Common associated features

– Periodic leg movements in sleep – up to 90% of those diagnosed with RLS –significance depends on sleep study rate associated with arousals

– Insomnia– Daytime sleepiness

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Arlington, VA: American Psychiatric Association Publishing; 2013.

#9: Don’t give up

Insomnia is associated with impaired quality of life and a multitude of future health risks

Mental health disordersMedical disorders

Substance use disorders


Insomnia and Quality of Life• Insomnia and Impaired Quality of Life in the United States

– National Epidemiologic Survey on Alcohol and Related Conditions-III– QALYs using SF-6D– Sample: 34,712 adults– Insomnia 27.3% (previous 1 year)– QALYs loss associated with insomnia

• 5.6 million• Significantly larger than any of the other 18 medical conditions

assessed

QALYs = quality-adjusted life-years; SF-6D = Short-Form 6-dimensional health state classification.Olfson M, et al. J Clin Psychiatry. 2018;79(5).

“Insomnia is prevalent and associated with substantial population-level burden in self-assessed health”

DSM-5: Insomnia Complications• Interpersonal, social, occupational problems• Increased future risk

– Major depression– Hypertension– Myocardial infarction– Absenteeism– Reduced productivity– Reduced quality of life– Increased economic burden– Medication misuse– Alcohol use– Caffeine and stimulant use

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Arlington, VA: American Psychiatric Association Publishing; 2013.

Percent of Individuals With and Without Insomnia Having a Health Condition

Taylor DJ, et al. Sleep. 2007;30(2):213-218.

21.9

43.1

7.3

24.8

19.7

50.4

33.6

9.5

18.7

1.2

5.7

9.5

18.2

9.2

Heart disease High bloodpressure

Neurologicdisease

Breathingproblems

Urinaryproblems

Chronic pain GI problems

Insomnia No Insomnia

Percent of Individuals With and Without Health Conditions Having Insomnia

Taylor DJ, et al. Sleep. 2007;30(2):213-218.

44.141.4

44

66.7

59.6

41.5

48.6

55.4

22.8 24.6

19.3

24.321.4 23.3

17.720

Heart disease Cancer High bloodpressure

Neurologicdisease

Breathingproblems

Urinaryproblems

Chronic pain GI problems

With Condition Without Condition

Vgontzas AN, et al. Sleep. 2009;32(4):491-497.

Vgontzas AN, et al. Diabetes Care. 2009;32(11):1980-1985.

#10: Do offer reassurance and hope


Insomnia ManagementLast Words

• Personalize your care• Try to understand why patients

present with their sleep concerns at the current time

• Understand their symptoms in the context of their lives – not just as a diagnosis checklist

• Be sure to address their primary motivation for seeking treatment

• Empathize with their distress• Offer hope for the future

Learning Objective #1• List 5 important aspects of a patient’s history to assess when

evaluating someone with persistent insomnia complaints– Current life circumstances– Circadian rhythm tendencies– Sleep-disordered breathing risk factors– Comorbid mental health disorder

• Mood• Anxiety• Stress/trauma related• Substance use

Learning Objective #2• Discuss behaviors that may undermine good quality sleep and

changes that help restore good sleep– Sleep-wake timing– Sleep environment– Daytime activities– Evening routines– Meal timing– Substance use

Learning Objective #3• Describe how comorbid sleep disorders can contribute to

insomnia symptoms– Sleep-disordered breathing

• OSA• Central sleep apnea

– Circadian rhythm sleep-wake phase disorders• Advanced• Delayed

– RLS– Parasomnias

complex patients in insomnia: top 5 dos and don’ts when a ...2019/... · plos one....

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