Updates in Insomnia

Paul P. Doghramji, MD, FAAFP

Family Practice Physician

Collegeville Family Practice & Pottstown Medical Specialists, Inc.

Medical Director of Health Services, Ursinus College – Collegeville, PA

Attending Family Practice Physician, Pottstown Memorial Medical Center – Pottstown, PA

Learning Objectives

▪ Define insomnia as a disorder

▪ Recognize signs, symptoms, and risk factors that should

trigger screening of and more thorough questioning of

patients for insomnia

▪ Assess comorbidities and causes of insomnia to inform

treatment decisions based on guideline recommendations

▪ Discuss the safety, efficacy, and appropriate use of the

pharmacologic agents for insomnia

Insomnia: Definition and Types

▪ Patient report of difficulty:

▪ Initiating sleep

▪ Maintaining sleep

▪ Adequate opportunity and

circumstances for sleep

▪ Daytime impairment

Sateia MJ. Chest. 2014;146:1387-1394; Sateia MJ, et al. J Clin Sleep Med. 2017;13:307-349.

Desired

wake time

Bedtime

Sleep-onset

insomnia

Sleep-maintenance

insomnia

Pathophysiology of Insomnia

EEG = electroencephalogram; HPA = hypothalamic-pituitary axis

Bonnet MH, et al. Sleep Med Rev. 2010;14:9-15.

Hyperarousal

Increased brain & body metabolism

EEG arousal

HPA axis activationSympathetic nervous

system activation

Cognitive arousal

2%

19%

25%

21%

33%

Prevalence of Insomnia Symptoms* in the US

Never

Rarely

A few nights per month

A few nights per week

Every night or almostevery night

Epidemiology of Insomnia

HCP = healthcare provider

National Sleep Foundation. https://www.sleepfoundation.org/professionals/sleep-america-polls/2005-adult-sleep-habits-and-styles. Published 2005.

Accessed 2019; Bailes S, et al. Fam Pract. 2009;26:294-300; Ancoli-Israel S, et al. Sleep. 1999;22(suppl 2):S347-S353.

69%

26%

5%

Proportion of Patients with Insomnia†

Who Discuss Symptoms with HCP

Never discuss

Mention during discussionof a different problem

Specifically seekevaluation for insomnia

*Insomnia symptoms defined as trouble falling asleep, waking

frequently at night, waking too early and unable to fall back

asleep, or waking feeling unrefreshed

†Insomnia defined as having any history of difficulty sleeping

Impact of Insomnia

▪ Impaired daytime functioning

▪ Drowsy driving and fatal crashes

▪ Injuries and accidents

▪ Decreased quality of life

▪ Increased presenteeism and

absenteeism

▪ Risk factor for:

▪ Depression

▪ Diabetes

▪ Obesity

▪ Hypertension

▪ Stroke

▪ Coronary artery disease

▪ Suicide attempts

▪ Overall mortality

Liu Y, et al. MMWR. 2016;65:137-141; Winkelman JW. N Engl J Med. 2015;373:1437-1444; National Center for Statistics and Analysis.

https://crashstats.nhtsa.dot.gov/Api/Public/ViewPublication/812446. Published October 2017. Accessed 2019; Daley M, et al. Sleep. 2009;32:55-64.

3% 1%

5%0.30%

15%

76%

Distribution of Direct and Indirect Costs of Insomnia

Economic Burden of Insomnia

▪ Estimated annual cost in the US:

▪ Total (direct and indirect): $411 billion

▪ Equivalent to 2.28% of GDP

▪ Increasing nighttime sleep duration from

<6 hours to 6-7 hours could save $226

billion in lost productivity

GDP = gross domestic product; OTC = over-the-counter

Hafner M, et al. Why Sleep Matters: The Economic Costs of Insufficient Sleep. www.rand.org/pubs/research_briefs/RB9962.html. Published 2017.

Accessed 2019; Daley M, et al. Sleep. 2009;32:55-64.

Healthcare

consultations

Transportation for

consultations

Alcohol as sleep aid

Prescription and OTC

medications

Absenteeism

Presenteeism

Case Study: Su

▪ 42 yo Asian American female; CFO for a software company

▪ Wakes up around 3 AM every night; lies in bed going into and

out of sleep until final awakening

▪ Worries about not being able to function at work

▪ Symptoms started with stress about a major work deadline 6 months ago

▪ Falls asleep during meetings despite drinking coffee

▪ Wants something to help her sleep through the night

8

Case Study: Su (cont’d)

▪ Medical history: hypertension; no surgeries

▪ Nonsmoker; drinks 3-4 glasses of wine on weekends

▪ Medication: amlodipine

▪ Vital signs:

▪ BP 125/78; HR 83; RR 16

▪ Ht 5 ft 4 in; Wt 130 lb; BMI 22 kg/m2

▪ Physical exam: anxious affect; otherwise normal

▪ Testing within past year:

▪ Normal CMP, CBC, TFT

BMI = body mass index; BP = blood pressure; CBC = complete blood count; CMP = complete metabolic panel; HR = heart rate; Ht = height;

RR = respiratory rate; TFT = thyroid function test; Wt = weight.9

Risk Factors for Insomnia

▪ Older age

▪ Female

▪ Shift work

▪ Stressors (eg, unemployment, divorce)

▪ Lower socioeconomic status

▪ Comorbid conditions

Schutte-Rodin S, et al. J Clin Sleep Med. 2008;4:487-504; Matheson E, et al. Am Fam Physician. 2017;96:29-35.

What To Ask About When Taking a Thorough Insomnia History

▪ Trouble falling sleep (eg, time to fall

asleep)

▪ Awakenings (eg, number, duration)

▪ Quality of sleep (poor or unrefreshing)

▪ When symptoms first started

▪ Frequency and severity of symptoms

▪ Duration of sleep

▪ Contributing and perpetuating factors

Schutte-Rodin S, et al. J Clin Sleep Med. 2008;4:487-504; Riemann D, et al. J Sleep Res. 2017;26:675-700.

Include history from bed partners or caregivers whenever possible

▪ Activities before bed

▪ Bedroom environment

▪ Daytime symptoms and activities (fatigue,

naps, work, quality of life)

▪ Disturbance in mood or cognitive function

▪ Associated symptoms and behaviors

surrounding and during sleep

▪ Contributing comorbid conditions,

medications, and substances

▪ Prior treatments and responses

Common Comorbid Conditions in Insomnia

Organ System Conditions and Symptoms

Cardiovascular Congestive heart failure, angina, dyspnea

Endocrine Hypo- or hyperthyroidism, diabetes

Neurologic Seizure disorder, stroke, Parkinson’s disease, dementia, peripheral neuropathy, headache, multiple

sclerosis, traumatic brain injury

Psychiatric Mood disorder (depression, anxiety, bipolar), psychotic disorder (schizophrenia), dementia, ADD, PTSD,

panic disorder

Pulmonary Asthma, COPD

Gastrointestinal Peptic ulcer disease, IBS, reflux, cholelithiasis

Musculoskeletal Fibromyalgia, osteoarthritis, rheumatoid arthritis

Genitourinary BPH, nocturia, incontinence, interstitial cystitis

Reproductive Menopause, pregnancy

Sleep disorders Restless legs syndrome, periodic limb movement disorder, obstructive sleep apnea, parasomnias

Other Rhinitis, sinusitis, bruxism, alcohol and substance abuse

ADD = attention deficit disorder; BPH = benign prostatic hypertrophy; COPD = chronic obstructive pulmonary disease; IBS = irritable bowel syndrome;

PTSD = post-traumatic stress disorder.

Schutte-Rodin S, et al. J Clin Sleep Med. 2008;4:487-504; Riemann D, et al. J Sleep Res. 2017;26:675-700.

Increased Prevalence of Medical Disorders in People With Insomnia

GI = gastrointestinal

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

Heart

Disease

0

70

100

30

90

50

Pati

en

ts (

%)

Any

Medical

Problems

Hyper-

tension

GI

Problems

Breathing

ProblemsDiabetes

40

80

10

60

20

Chronic

Pain

Urinary

ProblemsNeuro-

logical

Disease

Cancer

No Insomnia (n = 401)

Insomnia (n = 137)

P <.05

P <.001

P <.05

P <.01

P <.001

P <.001

P <.001

P <.01

Contributing Medications and Substances in Insomnia

Category Medications or Substances

Stimulants Caffeine, amphetamines, methylphenidate, ephedrine, cocaine

Antidepressants SSRIs (eg, sertraline, citalopram), duloxetine, venlafaxine, MAOIs

Decongestants Pseudoephedrine, phenylephrine, phenylpropanolamine

Opioids Codeine, oxycodone, propoxyphene, hydrocodone, meperidine, morphine, heroin

Cardiovascular Diuretics

Pulmonary Albuterol, theophylline

Alcohol Alcohol

ACE = angiotensin converting enzyme; MAOI = monoamine oxidase inhibitor; SSRI = selective serotonin reuptake inhibitor

Schutte-Rodin S, et al. J Clin Sleep Med. 2008;4:487-504; Serdarevic M, et al. Sleep Health. 2017;3:368-372.

ACTION ITEM: Identify medications and substances that may cause insomnia and

discontinue use whenever possible

▪ Bedtime between 9 PM to 11 PM

▪ Falls asleep almost immediately

▪ Wakes up around 3 AM every night; lies in bed going into and out of sleep

until final awakening at 6 AM (desired wake-up time)

▪ Forgetful, fatigued, and slow to complete tasks at work

▪ Feels irritable, tense, and on edge, especially at bedtime

▪ Very anxious about not getting enough sleep

15

Case Study: Su (cont’d)

▪ Occasional snoring

▪ No breathing pauses during sleep per boyfriend

▪ Denies uncomfortable sensations in legs that are relieved with movement

▪ No limb movements during sleep per boyfriend

▪ Drinks 6 cups of coffee per day

▪ No caffeine intake after 4 PM

▪ No OTC sleep aids: “Those are for people who have trouble falling asleep”

▪ Symptoms gradually worsening over time

16

Case Study: Su (cont’d)

A. Dissatisfaction with sleep quantity or quality with one or more of the following:

1. Difficulty initiating sleep (children: w/o caregiver intervention)

2. Difficulty maintaining sleep (children: w/o caregiver intervention)

3. Early morning awakening w/ inability to return to sleep

B. Significant distress or impairment

C. ≥3 nights per week

D. ≥3 months

E. Adequate opportunity for sleep

F. Not better explained by or solely due to another sleep-wake disorder

G. Not attributable to medication or substance use

H. Not adequately explained by comorbid medical or mental disorders

Specifiers (not all listed): with other medical comorbidity; with other sleep disorder; with non-sleep

disorder mental comorbidity

How Su Meets the DSM-5 Diagnostic Criteria for Insomnia

Center for Behavioral Health Statistics and Quality. https://www.ncbi.nlm.nih.gov/books/NBK519704/table/ch3.t36/. Published 2016. Accessed 2019.

Items B-H must also

be fulfilled for a

diagnosis of insomnia

ACTION ITEM: Characterize the type of sleep difficulty when diagnosing insomnia to guide treatment decisions

Su’s Results on the Insomnia Severity Index (ISI)

Bastien CH, et al. Sleep Med. 2001;2:297-307.

Question Points

1 2 3 4 5

SEVERITY of insomnia symptoms?

Difficulty falling asleep None Mild Moderate Severe Very

Difficulty staying asleep None Mild Moderate Severe Very

Problem waking up too early None Mild Moderate Severe Very

SATISFIED with current sleep pattern? Very Much Somewhat A little Not at all

Symptoms INTERFERE with daily function? Not at all A little Somewhat Much Very much

NOTICEABLE impact on quality of life? Not at all Barely Somewhat Much Very much

WORRIED about your sleep problem? Not at all A little Somewhat Much Very much

No Insomnia Subthreshold Insomnia Moderate Insomnia Severe Insomnia

0-7 8-14 15-21 22-28

Su’s Sleep Diary

Date

Day of

week

Type

of

day No

on

1 P

M

2 3 4 5 6 P

M

7 8 9 10

11 P

M

Mid

nig

ht

1 A

M

2 3 4 5 6 A

M

7 8 9 10

11 A

M

6/2 Tuesday Work C C C A ↓ ↑ E C M C C

6/3 Wednesday Work C C C ↓ ↑ C M C

6/4 Thursday Work C C C C ↓ ↑ E C M C

6/5 Friday Work C C C A ↓ ↑ M C C

6/6 Saturday Off C C A ↓ ↑ M C

6/7 Sunday Off C C E ↓ ↑ M C C

6/8 Monday Work C C C C ↓ ↑ C M C

American Academy of Sleep Medicine. http://yoursleep.aasmnet.org/pdf/sleepdiary.pdf. Accessed 2019.

A = Alcohol; C = Caffeine; E = Exercise; M = Medication

↓ = Going to bed; ↑ = Out of bed

Shaded boxes = naps and nighttime sleep

Week 1

ACTION ITEM: Consider using a sleep diary to track sleep habits and aid in insomnia diagnosis and treatment

Diagnostic Testing To Consider in Insomnia

▪ Order testing only if a comorbid medical disorder or another sleep

disorder is suspected

▪ Diagnostic testing for suspected medical disorders

▪ Bloodwork: CMP, CBC, TFT, ferritin, vitamin B12, CRP

▪ Other testing: EEG, ECG, CT, MRI

▪ Diagnostic testing for other suspected sleep disorders:

▪ Polysomnography (eg, OSA, PLMD)

▪ Actigraphy (eg, circadian rhythm disorder)

CBC = complete blood count; CMP = complete metabolic panel; CRP = C-reactive protein; CT = computed tomography; ECG = electrocardiogram;

EEG = electroencephalogram; MRI = magnetic resonance imaging; OSA = obstructive sleep apnea; PLMD = periodic limb movement disorder

Riemann D, et al. J Sleep Res. 2017;26:675-700.

Differential Diagnosis of Insomnia

▪ Insomnia associated with other sleep disorders

▪ Movement disorders (eg, RLS or PLMD)

▪ Sleep-related breathing disorders (eg, OSA)

▪ Circadian rhythm sleep disorders (eg, delayed sleep disorder, shift work disorder)

▪ Shift work, jet lag, total blindness

▪ Very early or very late sleep/wake times

▪ Sleep-wake disturbance

▪ Daytime impairment

▪ Comorbid insomnia due to medical disorders, psychiatric disorders, medications or

substance use

OSA = obstructive sleep apnea; PLMD = periodic limb movement disorder; RLS = restless legs syndrome.

Schutte-Rodin S, et al. J Clin Sleep Med. 2008;4:487-504; Sateia MJ. Chest. 2014;146:1387-1394; Sack RL, et al. Sleep. 2007;30:1460-1483; Sack RL,

et al. Sleep. 2007;30:1484-1501.

▪ Recent blood work (CMP, CBC, TFT) was normal

▪ Hypertension is well-controlled

▪ No additional testing needed at this time

▪ Su receives a diagnosis of sleep maintenance insomnia

22

Case Study: Su (cont’d)

Sleep Hygiene: Necessary But Not Necessarily Sufficient

Doghramji K, Doghramji PP. Clinical Management of Insomnia. Professional Communications, Inc; 2015; Ancoli-Israel S, et al. Postgrad Med. 2004;116(6

Suppl Insomnia):166.

Patient should… Patient should avoid…

▪ Awaken at same time every morning

▪ Increase exposure to bright light during the day

▪ Establish daily activity routine

▪ Exercise regularly in morning and/or afternoon

▪ Set aside a “worry time”

▪ Establish comfortable sleep environment

▪ Do something relaxing before bed

▪ Consider a warm bath before bed

▪ Napping (unless shift worker)

▪ Alcohol

▪ Caffeine, nicotine, other stimulants

▪ Bright light during the night

▪ Exercise within 3 hours of bedtime

▪ Heavy meals or drinking within 3 hours of bedtime

▪ Noise

▪ Excessive heat/cold in bedroom

▪ Using bed for other than sleep or sex

▪ Watching the clock

▪ Trying to sleep

Treatment of Insomnia: Overview

Doghramji K, Doghramji PP. Clinical Management of Insomnia. Professional Communications, Inc; 2015; Ancoli-Israel S, et al. Postgrad Med. 2004;116(6

Suppl Insomnia):48-50.

Obtain details about

pattern of insomnia

Possible short sleeper;

supportive reassurance

Insomnia Disorder

Is insomnia contributing

to decreased daytime

functioning and quality

of life or worsening

of chief complaint?

Does insomnia

occur

in isolation?

Is insomnia

associated with

comorbid medical

or psychiatric

condition?

Is use of insomnia

medication unsafe

in this patient?

Treat with

behavioral therapy

Treat with behavioral

and/or pharmacologic

therapy

No further

treatment needed

Treat

comorbid condition

CONSIDER

also treating

insomnia

directly

If not

directly treated,

Is insomnia

persistent?

YES

YES

YESNO

YES

YES

NO

NO

NO

Treatment of Comorbid Conditions in Patients With Insomnia

▪ Depression or anxiety

▪ Behavioral therapy

▪ Pharmacologic therapy (eg, SSRI)

▪ Chronic pain (eg, osteoarthritis, fibromyalgia)

▪ Pain control

▪ Consider antidepressant

▪ Obstructive sleep apnea

▪ CPAP, lifestyle modifications

▪ RLS/PLMD

▪ Iron supplementation (RLS), Pramipexole, carbidopa/levodopa, rotigotine patch,

gabapentin, pregabalin

McCrae CS, et al. Sleep Med Rev. 2001;5:47-61; Khurshid KA. Innov Clin Neurosci. 2018;15:28–32; Ramar K, et al. Am Fam Physician. 2013;88:231-238.

ACTION ITEM: Treat comorbid conditions prior to or combined with direct treatment of insomnia

Cognitive Behavioral Therapy for Insomnia (CBT-I)

▪ First-line treatment for insomnia (with or without comorbid conditions)

▪ Addresses sleep-related beliefs and behaviors that may perpetuate insomnia

Winkelman JW. N Engl J Med. 2015;373:1437-1444.

Component Purpose Recommendations

Stimulus control ▪ Reduce arousal in sleep environment

▪ Associate bed with sleep

Go to bed when sleepy; use bed only for sleep or sexual

activity; get out of bed when awake or anxious

Sleep restriction ▪ Increase sleep drive

▪ Stabilize circadian rhythm

Reduce amount of time in bed (no less than 5-6 hours);

gradually increase time in bed as sleep symptoms improve

Sleep hygiene ▪ Minimize behaviors that disrupt sleep

drive or increase arousal

Avoid napping; limit caffeine and alcohol; increase exercise

(but not close to bedtime); keep bedroom dark and quiet

Cognitive therapy ▪ Restructure maladaptive beliefs about

consequences of insomnia

Challenge perception of catastrophic consequences of

insomnia; manage expectations about sleep

Relaxation therapy ▪ Reduce arousal (physical,

physiological) in sleep environment

Practice breathing exercises, meditation, progressive

muscle relaxation

Cognitive Behavioral Therapy for Insomnia (CBT-I)

▪ Administered by a trained provider to individuals or groups (6 to 8 sessions)

▪ Improves time to sleep onset

▪ Decreases time awake after sleep onset

▪ Provides benefit for 6 to 12 months after treatment is complete

▪ Sleep hygiene education alone is NOT effective for insomnia

▪ Face-to-face CBT-I not always available

▪ Alternatives to conventional CBT-I:

▪ Shorter treatment course

▪ Telephone review of questionnaires, sleep logs

▪ Internet-based CBT-I

Winkelman JW. N Engl J Med. 2015;373:1437-1444; Schutte-Rodin S, et al. J Clin Sleep Med. 2008;4:487-504.

ACTION ITEM: Refer patients for CBT-I as first-line treatment for insomnia

▪ You counsel on sleep hygiene and refer Su to a certified

CBT-I provider

▪ Returns to office in 2 months

▪ Night waking decreased from every night to 3 times per week

▪ Daytime anxiety improved

▪ Anxious at bedtime and after waking up at night

▪ Still “slow” and “dragging” at work

▪ Symptoms improved, but have plateaued over the last 2 weeks

28

Case Study: Su (cont’d)

Pharmacologic Treatment for Insomnia: FDA Indications and AASM Recommendations

on Approved Agents

Drug class Agent FDA Indication AASM

Recommendation

Schedule IV Dose Range

Benzodiazepine Triazolam Insomnia Onset √ 0.125 mg – 0.25 mg

Temazepam Insomnia Onset, maintenance √ 7.5 mg – 30 mg

Benzodiazepine

receptor agonist

Eszopiclone Onset, maintenance Onset, maintenance √ 1 mg – 3 mg

Zaleplon Onset Onset √ 5 mg – 10 mg

Zolpidem Onset Onset, maintenance √ 5 mg – 10 mg

Zolpidem ER Onset, maintenance Onset, maintenance √ 6.25 mg – 12.5 mg

Zolpidem SL MOTN awakening None √ 1.75 mg – 3.5 mg

Melatonin agonist Ramelteon Onset Onset 8 mg

Histamine receptor

antagonist

Doxepin Maintenance Maintenance 3 mg – 6 mg

Orexin receptor

antagonist

Suvorexant Onset, maintenance Maintenance √ 10 mg – 20 mg

FDA = Food and Drug Administration; ER = extended release; MOTN = middle-of-the-night; SL = sublingual

Sateia MJ, et al. J Clin Sleep Med. 2017;13:307-349; Matheson E, et al. Am Fam Physician. 2017;96:29-35; Doxepin [PI]. 2010; Eszopiclone [PI]. 2019;

Ramelteon [PI]. 2018; Suvorexant [PI]. 2018; Temazepam [PI]. 2019; Triazolam [PI]. 2016; Zaleplon [PI]. 2019; Zolpidem [PI]. 2019; Zolpidem ER [PI]. 2019;

Zolpidem SL [PI]. 2019.

Pharmacologic Treatment for Insomnia: Adverse Reactions

Drug Class Agent Black Box Warning Adverse Reactions†

Benzodiazepine* Triazolam Use w/ opioids:

respiratory depression,

coma, death

Drowsiness, headache, dizziness, daytime anxiety

Temazepam Drowsiness, headache, fatigue, nervousness, lethargy, dizziness

Benzodiazepine receptor

agonist*

Eszopiclone Complex sleep behaviors:

sleep walking, sleep

driving, or other activities

while not fully awake

Unpleasant taste, headache, somnolence, respiratory infection

Zaleplon Headache, dizziness, nausea, asthenia, somnolence, abdominal pain

Zolpidem Drowsiness, dizziness, lethargy, drugged feeling, diarrhea

Zolpidem ER Headache, somnolence, dizziness, hallucination, back pain, myalgia

Zolpidem SL Headache, nausea, fatigue

Melatonin agonist Ramelteon N/A Somnolence, dizziness, fatigue, nausea, worsening of insomnia

Histamine receptor

antagonist

Doxepin N/A Somnolence/sedation, nausea, upper respiratory tract infection

Orexin receptor

antagonist

Suvorexant N/A Somnolence, headache, dizziness, diarrhea, abnormal dreams

N/A = not applicable

Matheson E, et al. Am Fam Physician. 2017;96:29-35; Doxepin [PI]. 2010; Eszopiclone [PI]. 2019; Ramelteon [PI]. 2018; Suvorexant [PI]. 2018;

Temazepam [PI]. 2019; Triazolam [PI]. 2016; Zaleplon [PI]. 2019; Zolpidem [PI]. 2019; Zolpidem ER [PI]. 2019; Zolpidem SL [PI]. 2019.

*Avoid use in elderly and in patients with untreated sleep apnea or chronic nocturnal hypoxia†All hypnotics carry risk for complex sleep-related behaviors (eg, sleep driving)

Pharmacologic Treatment for Insomnia: Additional AASM Recommendations

▪ No specific guideline recommendations (inadequate evidence)

▪ Other BZDs approved for insomnia (onset, maintenance, and early awakening):

estazolam, flurazepam, quazepam

▪ Agents used off-label for insomnia: oxazepam, quetiapine, gabapentin, paroxetine

▪ AASM does NOT recommend for insomnia:

▪ OTC supplements: melatonin, L-tryptophan, valerian

▪ Diphenhydramine (although FDA approved for insomnia)

▪ Trazodone (off-label use)

▪ Tiagabine (off-label use)

BZD = benzodiazepine

Sateia MJ, et al. J Clin Sleep Med. 2017;13:307-349; Diphenhydramine [PI]. 2018.

Pharmacologic Treatment: Factors to Consider When Selecting an Agent for Insomnia

▪ Symptom pattern

▪ Response to prior therapies

▪ Comorbid conditions

▪ Potential medication interactions

▪ Adverse effect profile

▪ Patient preference

▪ Cost

▪ Risk for dependency

Sateia MJ, et al. J Clin Sleep Med. 2017;13:307-349; Schutte-Rodin S, et al. J Clin Sleep Med. 2008;4:487-504.

ACTION ITEM: Consider comorbidities and respect patient preferences when starting

prescription treatment

▪ Starts zolpidem ER 6.25 mg at bedtime

▪ Continues CBT-I practices

▪ Returns to office 4 weeks later

▪ Zolpidem ER makes her feel drowsy at bedtime

▪ Still waking up at night 3 times per week

33

Case Study: Su (cont’d)

Orexin (Hypocretin) Neuropeptides

▪ Different names by different discovering

groups

▪ Orexin-A and -B: promote feeding

(orexis)

▪ Hypocretin-1 and -2: similar to

incretins, produced in hypothalamus

▪ Physiological roles

▪ Sleep and wakefulness

▪ Feeding and appetite

▪ Reward pathways

▪ Narcolepsy: absence of orexin neurons

Tsujino N, et al. Front Behav Neurosci. 2013;7:28; Scammell TE, et al. Annu Rev Pharmacol Toxicol. 2011;51:243-266.

Orexin Receptor Antagonists

FDA = Food and Drug Administration; GIRK = G protein-regulated inward rectifier; MOA = mechanism of action; NMDA = N-methyl-D-aspartate receptor

Scammell TE, et al. Annu Rev Pharmacol Toxicol. 2011;51:243-266; Stahl SM. CNS Spectr. 2016;21:215-218; Suvorexant [PI]. 2018; Payesko J. Neurology Live.

www.neurologylive.com/clinical-focus/fda-accepts-nda-lemborexant-treatment-insomnia. Published 2019. Accessed 2019; Payesko J. Neurology Live.

www.neurologylive.com/clinical-focus/seltorexant-achieves-primary-secondary-endpoints-in-phase-2b-trial-in-insomnia. Published 2019. Accessed 2019;

Murphy P, et al. J Clin Sleep Med. 2017;13:1289-1299; ClinicalTrials.gov. Accessed 2019; De Boer P, et al. J Psychopharmacol. 2018;32:668-677; Muehlan C,

et al. Eur Neuropsychopharmacol. 2019;29:847-857.

Agent Mechanism of Action Status

Suvorexant Dual orexin receptor

antagonist

Approved

Lemborexant Dual orexin receptor

antagonist

Phase 3 (complete); under

FDA review

Daridorexant

(ACT-541468)

Dual orexin receptor

antagonist

Phase 3 (ongoing)

Seltorexant

(MIN-202)

Selective orexin-2 receptor

antagonist

Phase 2 (complete)

Suvorexant: Phase 3 Efficacy Data in Sleep Maintenance

▪ WASO: wake time after

sleep onset on

polysomnogram

▪ Co-primary endpoint for

40/30 mg

▪ Secondary/exploratory

endpoint for 20/15 mg

▪ Significantly improved

vs placebo (both doses)

▪ Significantly shortened

sleep latency in Trials 1 & 2

Herring WJ, et al. Biol Psychiatry. 2016;79:136-148; Shrivastava D, et al. J Community Hosp Intern Med Perspect. 2014;4:24983.

Wakefulness After Persistent Sleep Onset (WASO)

Trial 1 Trial 2

P <0.001 vs placebo P <0.001 vs placebo

Ad

juste

d M

ea

n C

ha

ng

e F

rom

Base

lin

e

(min

ute

s)

Ad

juste

d M

ea

n W

ith C

ha

ng

e F

rom

Ba

se

lin

e

(min

ute

s)

0

-20

-40

-60

-80

0

-20

-40

-60

-80

BaselineNight 1 Month 1 Month 3

BaselineNight 1 Month 1 Month 3

Suvorexant 40/30 mg (n = 383)

Suvorexant 20/15 (n = 254)

Placebo (n = 384)

Suvorexant 40/30 mg (n = 387)

Suvorexant 20/15 (n = 239)

Placebo (n = 383)

Suvorexant: Phase 3 Safety Data

▪ Dose-related increase in AEs (eg, suicidal ideation, complex sleep behaviors)

▪ FDA-approved doses differ from Trial 1 & 2

▪ Min dose 10 mg:

▪ No AEs ≥2% in crossover study

▪ Max dose 20 mg:

▪ Similar efficacy and better safety vs 40 mg

▪ Contraindicated in narcolepsy

▪ Abrupt discontinuation after 1 year

▪ No withdrawal or rebound insomnia symptoms

AE = adverse event; FDA = Food and Drug Administration; URI = upper respiratory infection

Suvorexant [PI]. 2018; Herring WJ, et al. Biol Psychiatry. 2016;79:136-148; Herring WJ, et al. Neurology. 2012;79:2265-2274; Michelson D, et al. Lancet

Neurol. 2014;13:461-471; Rhyne DN, et al. Ther Adv Drug Saf. 2015;6:189-195.

Suvorexant

20/15 mg

(n = 493)

Suvorexant

40/30 mg

(n = 770)

Placebo

(n = 767)

Somnolence 7% 11% 3%

Headache 7% 7% 6%

Dizziness 3% 2% 2%

Diarrhea 2% 1% 1%

Dry mouth 2% 2% 1%

URI 2% 1% 1%

Cough 2% 1% 1%

Abnormal dreams 2% 2% 1%

Pooled Incidence of AEs

(≥2% of Patients) in Trials 1 and 2

Lemborexant: Phase 3 Efficacy Data in Sleep Maintenance

▪ SUNRISE 1

▪ 5 mg, 10 mg vs zolpidem and placebo

▪ Shortened sleep latency (LPS) and

improved sleep maintenance (WASO;

P <0.01 for all)

▪ SUNRISE 2

▪ 5 mg, 10 mg vs placebo

▪ Shortened sleep latency (sSOL; 1º

endpoint)

▪ Improved sleep maintenance (sWASO;

2º endpoint)

LPS = latency to persistent sleep; sSOL = subjective sleep onset latency; sWASO = subjective wakefulness after sleep onset

Rosenberg R, et al. J Sleep Res. 2018;27(Suppl S1):e12751; Yardley J, et al. SUNRISE-2. Poster presented at: Advances in Sleep and Circadian Science;

February 1-4, 2019, Clearwater, FL; Payesko J. Neurology Live. www.neurologylive.com/clinical-focus/fda-accepts-nda-lemborexant-treatment-insomnia.

Published 2019. Accessed 2019.

sWASO in SUNRISE 2

*P <0.001; †P <0.01; §P <0.05

BL = baseline

Under FDA review for treatment of insomnia

Lemborexant: Phase 3 Safety Data

▪ 6-month safety data from SUNRISE 2

▪ Most (>96%) of AEs were mild to

moderate severity

▪ 1 treatment-related cataplexy event

(lemborexant 10 mg)

▪ No dose-related increase in suicidal

ideation or self-harm

URI = upper respiratory tract infection

Kärppä M, et al. Lemborexant Treatment for Insomnia: 6-Month Safety. Poster presented at: 33rd Annual Meeting of the Associated Professional Sleep

Societies; June 8-12, 2019; San Antonio, TX.

Lemborexant

5 mg

(n = 314)

Lemborexant

10 mg

(n = 314)

Placebo

(n = 319)

Somnolence 27% 41% 5%

Headache 28% 21% 21%

Influenza 15% 16% 15%

Arthralgia 14% 3% 9%

URI 13% 11% 10%

Fatigue 12% 11% 1%

Back pain 12% 9% 8%

Incidence of AEs (≥3% of Patients) in SUNRISE 2

Case Conclusion

▪ You discuss with Su switching to an orexin receptor antagonist

▪ She prefers to just stop zolpidem ER since it’s not helping

▪ Declines to try another agent

▪ “Things aren’t perfect, but I can function”

▪ Wants to continue CBT-I practices for now

▪ Willing to consider an orexin receptor antagonist if insomnia symptoms

don’t improve

40

Questions to Consider

▪ When should a patient with chronic insomnia return for follow-up?

▪ How long should prescription sleep aids be used?

▪ When should you switch to another prescription sleep aid?

▪ When should you refer the patient to a sleep medicine specialist?

Summary

▪ Identify medications and substances that may cause insomnia and

discontinue use whenever possible

▪ Characterize the type of sleep difficulty when diagnosing insomnia to

guide treatment decisions

▪ Consider using a sleep diary to track sleep habits and aid in insomnia

diagnosis and treatment

▪ Treat comorbid conditions prior to or combined with direct treatment

of insomnia

▪ Refer patients for CBT-I as first-line treatment for insomnia

▪ Consider comorbidities and respect patient preferences when starting

prescription treatment