The Pharmacoeconomic Burden of Insomnia

The Pharmacoeconomic Burden of Insomnia:

Current Treatment Challenges and an Update on Safe and Efficacious Options

Julie A. Dopheide, PharmD, BCPP, FASHP Douglas S. Burgoyne, PharmD, FAMCP Professor of Clinical Pharmacy, Adjunct Associate Professor Psychiatry and the Behavioral Sciences Department of Pharmacotherapy University of Southern California School University of Utah College of Pharmacy of Pharmacy and Keck School of Medicine Salt Lake City, Utah Los Angeles, California This activity is supported by an educational grant from Eisai. Educational Objectives

After completion of this activity, participants will be able to: • Characterize the pathophysiology, epidemiology, and disease burden of insomnia including the impact on quality of life in vulnerable patient groups • Identify appropriate pharmacotherapy for insomnia based on guideline recommendations, drug efficacy and safety profiles, and patient factors • Examine the economic burden of insomnia and impact of available treatment options, including effects on vulnerable patient groups Insomnia Overview Julie Dopheide, PharmD, BCPP, FASHP

Emily Morris, 16 years old

Emily Morris, 16 years old 2020 National Sleep Foundation Poll Shows High Levels of Daytime Sleepiness and Negative Health Impact #1 Cause of Daytime Sleepiness: Insomnia Health Impacts of Feeling Sleepy Feeling Sleepy How Many Days Per Week? 5-7 days

28% 28% 2-4 days

44% 0-1 days

0 20 40 60 1-2 days 2-4 days 5-7 days Feeling Unwell Headache Irritability

Sleep in America Poll 2020. National Sleep Foundation. Published March 2020. Accessed October 8, 2020. sleepfoundation.org/professionals/sleep-america-polls/2020- sleepiness-and-low-action. What Are the Different Types of Insomnia?

• Difficulty falling asleep (DFA) How Is It Categorized? • Difficulty maintaining sleep (DMS); frequent awakenings • Situational • Waking up too early in the morning (EMA) • Short-term: less than 3 months • • Poor quality or nonrestorative sleep 30%-50% of population • Chronic: insomnia at least 3 times per week for 3 months or more • 10% of population

Dopheide JA. Am J Manag Care. 2020;26(4):S76-S84; Sateia M, et al. Chest. 2014;146(5);1387-1394. Insomnia Impacts Everyone

1 of 3 adults get less sleep Shift workers have high rates than needed. of insomnia due to erratic schedules.

Women are twice as likely to experience insomnia; Up to Two-Thirds of Iraq/Afghanistan menopause increases risk. veterans experience chronic insomnia.

Hughes JM, et al. Clin Psychol Rev. 2018;59:118-125; Dopheide JA. Am J Managed Care. 2020;26. Sleep and sleep disorders. Centers for Disease Control and Prevention (CDC). Updated April 15, 2020. Accessed October 8, 2020. cdc.gov/sleep/index.html; https://www.cdc.gov/nchs/products/databriefs/db286.htm. Short-Sleepers (<6 Hours per Night) Are at Greater Risk for Disease and Early Death

• Increased risk of ischemic stroke • Increased risk of myocardial infarction • Increased obesity • Impaired glucose tolerance and increased risk of type 2 diabetes • Increased cancer risk: breast, prostate, endometrial, colorectal • 2-3x greater risk for depression, anxiety, alcohol use disorder

Dopheide JA. Am J Manag Care. 2020;26(4):S76-S84; Luyster FS, et al. Sleep. 2012;35(6):727-734. COVID-19 Increases Risk for Insomnia

• Home confinement disrupts routine • Worries contribute to inability to sleep • Increased screen time prevents release of melatonin and sleep-promoting neuropeptides • Reestablish routine/minimize news time • Intentional relaxation: yoga, exercise

Voulgaris A, et al. Sleep Med. 2020;73:170-176; Altena E, et al. J Sleep Res. 2020;29:e13052; COVID-19 and sleep. American Sleep Association. Accessed October 8, 2020. sleepassociation.org/about-sleep/covid-19-and-sleep/ Bidirectional Connection Between Medical/Psychiatric Conditions and Chronic Insomnia Chronic Insomnia Co-occurring Chronic Insomnia • Depression/anxiety: >5 times more likely to experience chronic insomnia • Hypertension, gastrointestinal disorders, cancer, pain syndromes: 2-3x more likely to experience chronic insomnia • Need to treat all conditions concurrently

Medical/Psychiatric Condition

Morin C, Benca R. Lancet. 2012;379(9821):1129-1141; Dopheide JA. Am J Manag Care. 2020;26(4):S73-S83. Neurochemistry of the Sleep-Wake Cycle

• Wakefulness and sleep: antagonistic states competing for control of brain activity • Wakefulness promoting: norepinephrine (NE), dopamine (DA), histamine, acetylcholine, hypocretin/orexin • Sleep promoting: γ-aminobutyric acid (GABA), opioids, enkephalins, endorphins, serotonin (5HT) • Environment, stress, genetics, medications, exercise, and medical/psychiatric illnesses all influence the sleep/wake cycle

Dopheide J, Stimmel G. Sleep disorders. In: Alldredge BK, et al, eds. Koda-Kimble & Young’s Applied Therapeutics, 10th ed. Lippincott Williams & Wilkins; 2013:1900-1920. Polysomnography (EEG/EOG/EMG) and Sleep Stage Significance (Sleep Architecture)

• Non-Rapid Eye Movement (NREM) - 75% of total sleep time • Stage 1 - relaxed wakefulness Hypnotics increase • Stage 2 - rest for brain and muscles time in NREM Stage 2 • Stage 3 - feeling of rejuvenation DORAs increase time in REM • Stage 4 - immune enhancement, growth hormone • Rapid Eye Movement (REM) - 25% of total sleep time • Higher cortical areas and neurotransmitters active while body resting,  cholinergic tone • Autonomic instability (pulse, BP), temperature drops BP, blood pressure; NREM, non-rapid eye movement sleep; REM, rapid eye movement sleep. Dopheide J, Stimmel G. Sleep disorders. In: Alldredge BK, et al, eds. Koda-Kimble & Young’s Applied Therapeutics, 10th ed. Lippincott Williams & Wilkins; 2013:1900-1920 Herring WJ, Roth T, Krystal AD et al. J Sleep Research 2019. Electroencephalogram (EEG); Electrooculogram (EOG), Electromyogram (EMG). The Clinician’s Role in Insomnia

✓ Recommend optimal assessment for patients with sleep complaints ✓ Educate providers and patients on appropriate nondrug and drug treatment ✓ Given a medication regimen, screen for causes of insomnia and drug interactions ✓ Counsel patients with hypnotic prescriptions on how to safely and effectively use their medication Patient Assessment

• Type of insomnia: DFA or DMS, EMA • Duration of insomnia? • Resulting daytime impairment? • Difficulty falling asleep? maintaining sleep? • What has the patient tried? • Consider drug and alcohol use • Engage patient to set goals of treatment • Determine if medical or neuropsychiatric comorbidities need to be addressed along with sleep hygiene, CBT-I, or medication CBT-I, cognitive behavioral therapy for insomnia. Dopheide J, Stimmel G. Sleep disorders. In: Alldredge BK, et al, eds. Koda-Kimble & Young’s Applied Therapeutics, 10th ed. Lippincott Williams & Wilkins; 2013:1900-1920; Buysse DJ. JAMA. 2013;309(7):706-716. Treatment of Insomnia Clinical Guidelines for Management of Insomnia

All Guidelines Recommend CBT-I First-Line for Chronic Insomnia

• American Academy of Sleep Medicine (AASM) (2017) • American College of Physicians (ACP) (2016) • Agency for Healthcare Research and Quality (AHRQ) (2017) • British Association for Psychopharmacology (2019)

Wilson S, et al. J Psychopharmacol. 2019;33(8):923-947; ACP recommends cognitive behavioral therapy as initial treatment for chronic insomnia. News release. ACP; May 3, 2016. Accessed October 8, 2020. acponline.org/acp-newsroom/acp-recommends-cognitive-behavioral-therapy-as-initial-treatment-for-chronic-insomnia; Management of insomnia disorder in adults: current state of the evidence. AHRQ. Published August 1, 2017. Accessed October 8, 2020. effectivehealthcare.ahrq.gov/products/insomnia/clinician; Sateia MJ, et al. J Clin Sleep Med. 2017;13(2):307-349. Cognitive Behavioral Therapy-Insomnia (CBT-I) Can take 3-6 weeks for significant improvement. 40%-45% of patients achieve remission. CBT approach Comments Sleep hygiene education (SHE) Teaches healthy lifestyles for sleep; not effective as sole treatment for chronic insomnia Stimulus control Restrict bedroom activities to sleep only, creating a positive association between the bed and sleep (no television or computer work in bed) Sleep restriction Limits time in bed to sleeping

Cognitive therapy Cognitive therapy (goal to change the patient’s unrealistic expectations of sleep)

Relaxation training Lowers somatic and cognitive arousal states (eg, progressive muscle relaxation guided imagery, meditation)

Morin CM, Benca R. Lancet. 2012;379(9821):1129-1141; Dopheide J. Am J Manag Care. 2020;26(4):S76-S84. Digital Cognitive Behavioral Therapy-Insomnia (dCBT-I) • Metered, interactive, tailored approach meant to simulate face-to-face CBT-I • SHUTi/Somryst – Sleep Healthy Using the Internet, originated by US researchers • Sleepio – US/UK application • Controlled trials show long-term benefit • Patients must be motivated to participate • Not found superior to face-to-face CBT-I

Ritterband LM, et al. JAMA Psych. 2017;74(1):68-75; Introducing Somryst. Pear Therapeutics. Accessed October 8, 2020. somryst.com; Lancee J et al. Sleep. 2016;39:183–91. Nonprescription Options

• Diphenhydramine, doxylamine: excessive daytime hangover, tolerance develops in 7-10 days of regular use; anticholinergic effects; discourage use • **Hydroxyzine: less anticholinergic compared with diphenhydramine/doxylamine • Melatonin: best for circadian rhythm sleep disorder, elderly patients, and youth with ADHD or ASD; well tolerated • Valerian: smelly root; widespread use in Europe; has activity at benzodiazepine (BZ) receptor; withdrawal symptoms reported after chronic use; liver toxicity reported

** Hydroxyzine typically prescription antihistamine ADHD, attention-deficit/hyperactivity disorder; ASD, autism spectrum disorder.

Wagner J, et al. Ann Pharmacother. 1998;32(6):680-691; Stevinson C, Ernst E. Sleep Med. 2000;1(2):91-99; Reid KJ, et al. Semin Neuro. 2004;24(3):315-325; Taibi DM, et al. Sleep Med Rev. 2007;11(3):209-230. Hypnotics Best Used at Lowest Effective Dose for Shortest Duration of Time Insomnia Guideline Consensus Recommendation Hypnotics by Classification

• Benzodiazepine receptor agonists (nonselective) (BZRAs) • Triazolam, temazepam, estazolam, quazepam, flurazepam • Nonbenzodiazepine (non-BZ) agents also known as “Z-hypnotics” • Zaleplon, zolpidem, eszopiclone • Antidepressants: doxepin, trazodone • Melatonin receptor agonist • Ramelteon • Dual-acting orexin receptor antagonists (DORAs) • Suvorexant, lemborexant • Emerging agents (daridorexant and seltorexant)

Liu MT. Am J Manag Care. 2020;26(4):S85-S90; Sateia MJ, et al. J Clin Sleep Med. 2017;13(2):307-349. MOA: Activation of GABA-A Receptor Through Stimulation of BZ-Receptor

• Chloride channels open • Hyperpolarization of postsynaptic membrane • Facilitates GABA, an inhibitory neurotransmitter (NT) •  Sleep consolidation

• BZRA-1 subunit selective agents or Z-hypnotics have minimal muscle relaxant, antiseizure, or anxiolytic properties

MOA, mechanism of action. Lancel M. Sleep. 1999;22(1):33-42. MOA of BZRA Hypnotics

• BZRAs bind to the BZ/chloride ionophore complex, facilitating GABA, an inhibitory NT, calming over-excited areas of the brain • BZRAs  time spent in stage 2 or “lighter sleep” and can prevent the brain from achieving stage 4 or “deep sleep” (traditional hypnotics) • “Z” hypnotics  effect on sleep architecture • Natural, nondrug-induced sleep is best, medication-induced sleep second best

Drover DR, et al. Clin Pharmacokinet. 2004;43(4):227-238. Comparing Traditional BZ Hypnotics C-IV

Drug Dose (mg) Onset (min) t1/2 (h) parent and Duration (h) metabolite Triazolam 0.125-0.5 20-30 2-3 2-5 (Halcion) Rebound insomnia; do not take longer than 7-10 days. Temazepam 7.5-30 60-120 8-20 6-10 (Restoril) Long onset but keeps asleep; no active metabolite.

Quazepam (Doral) 7.5 - 15 30-45 40 >10 Active metabolite 75 “hangover” Never used due to risk of next-day impairment

Flurazepam 15-30 30-60 3-8 >10 (Dalmane, Dalmadorm) Active metabolite 40-120 “hangover” Never used due to risk of next-day impairment.

• Duration of effect based on active metabolites, fat solubility, and single vs multiple dosing

Dopheide J, Stimmel G. Sleep disorders. In: Alldredge BK, et al, eds. Koda-Kimble & Young’s Applied Therapeutics, 10th ed. Lippincott Williams & Wilkins; 2013:1900-1920. Comparing “Z” Hypnotics: C-IV

Z-Hypnotic Usual dose Onset (min) t1/2 (h) Duration (h) • Good for situational Zaleplon insomnia; 5-10 mg 30 1.1 2-4 (Sonata) sometimes chronic insomnia Zolpidem 1.75, 3.5 20 2.4 4 (Intermezzo) sublingual • Effective short-term **Zolpidem (Ambien) 2.5 adjunct to 5-10 mg 30 4-6 and generics antidepressants Zolpidem CR 6.25 mg 30 2.8 4-7 • Hallucinations (Ambien CR) 12.5 mg reported, caution in Eszopiclone 1-3 mg 45 6 5-8 psychotic illness (Lunesta) **Most prescribed Sonata. Prescribing information. Pfizer Inc; 2019; Ambien. Prescribing information. sanofi-aventis U.S. LLC; 2019; Ambien CR. Prescribing information. sanofi-aventis U.S. LLC; 2016; Lunesta. Prescribing information. Sunovion Pharmaceuticals Inc; 2019; The Medical Letter 2012;54(1387). Clinical Comparison of BZ Receptor Active Agents Z-Hypnotic Benzodiazepine (BZ)

• 1 selectivity • Nonselective • Not anxiolytic • Anxiolytic • Not muscle relaxant • Muscle relaxant • Not antiseizure • Antiseizure • No significant impact on REM or • Suppresses REM slow-wave sleep •  slow-wave sleep • Less abuse potential • Abuse potential • CNS adverse effects (memory, balance) • CNS adverse effects (memory, balance) CNS, central nervous system. Dopheide J, Stimmel G. Sleep disorders. In: Alldredge BK, et al, eds. Koda-Kimble & Young’s Applied Therapeutics, 10th ed. Lippincott Williams & Wilkins; 2013:1900-1920. BZ-Receptor Active Hypnotics: Counseling on Common and Rare Adverse Effects Common Uncommon to Rare • Next-day impairment including grogginess or • 1998 to present – hundreds of reports of sleepiness, slowed reaction time hallucinations (visual, tactile, olfactory) • Memory problems, difficulty with new • March 2007 – complex sleep behaviors: eating, learning, confusion, increased fall risk in older driving, walking, raiding refrigerator while patients “asleep;” unaware of behaviors • Loss of coordination, dizziness, or unsteadiness • May 2019 – stronger warning on risks of • Z-hypnotics: upset stomach/diarrhea, complex sleep behaviors after 20 deaths sinusitis/phlegm; unpleasant taste with associated with complex sleep behaviors eszopiclone in patients taking Z-hypnotics

Dopheide J, Stimmel G. Sleep disorders. In: Alldredge BK, et al, eds. Koda-Kimble & Young’s Applied Therapeutics, 10th ed. Lippincott Williams & Wilkins; 2013:1900-1920; FDA requires stronger warning about rare but serious incidents related to certain prescription insomnia medicines. News release. US FDA; April 30, 2019. Accessed October 8, 2020. www.fda.gov/news-events/press-announcements/fda-requires-stronger-warnings-about-rare-serious-incidents-related-certain-prescription-insomnia Zolpidem Peak Blood Levels Higher in Women and Elderly Patients 15% of women who took 10-mg dose were impaired the next day; January 10, 2013: 3% of men, according to driving simulation tests. FDA recommends Female lower initial doses for women April Elderly 2019: FDA strengthens warning regarding avoiding Z- hypnotics in those Female with history of Young complex sleep Male behaviors Elderly Male Young

Adapted from Greenblatt DJ, Roth T. Expert Opin Pharmacother. 2012;13(6):879-893. FDA adds Boxed Warning for risk of serious injuries caused by sleepwalking with certain prescription insomnia medicines. Safety From “Zolpidem for insomnia,” Greenblatt DJ, Roth T, Expert Opinion on Pharmacotherapy, April 1, 2012; Taylor & Francis, Announcement. US FDA; April 30, 2019. Accessed October 8, 2020. https://www.fda.gov/drugs/drug-safety-and- availability/fda-adds-boxed-warning-risk-serious-injuries-caused-sleepwalking-certain-prescription-insomnia reprinted by permission of the publisher (Taylor & Francis Ltd, http://www.tandfonline.com). Trazodone

• Comparable to zolpidem short-term (≤4 weeks) trials in young adults • More effective and overall better tolerated than quetiapine in psychiatric inpatients • Long-term tolerance reports mixed • Usual dosing: 50-150 mg (25-300 mg)

• t1/2: 6-12 h, hangover possible • m-CPP metabolite can cause anxiety, insomnia, dysphoria, headache in some; tolerance can develop • Significant adverse effect profile: orthostatic hypotension, dry mouth, constipation, priapism, arrhythmia Doroudgar S, et al. Prim Care Companion CNS Disorders. 2013;15(6):1-6; Mendelson WB. J Clin Psych. 2005;66(4):469-476; Mittur A. Expert Rev Clin Pharmacol. 2011;4(2):181-190. Doxepin (Silenor) 6 mg: Safe and Effective for Chronic Insomnia in Healthy Elderly Patients

P <0.5 70 Placebo DXP 6 mg Placebo (n = 125) 60

Doxepin (n = 130) 50 4-week trial % of patients 40 reporting benefit 30

20 Available in 3mg and 10 6mg strengths 0 Helped Sleep Shortened Onset Increased Duration Got Better Sleep Adapted from Lankford A, et al. Sleep Med. 2012;13(2):133-138. Ramelteon (Rozerem)

• Melatonin MT1 and Melatonin MT2 receptor agonist • FDA approved for sleep-onset insomnia • No comparative data vs other hypnotics • No abuse potential, safe in mild to moderate sleep disordered breathing (apnea) • Dosing: 8 mg in young adults and elderly patients

• Food delays Tmax (45 min)  AUC 31%

• t1/2: 1.1-2.6 h; active metabolite 2-5 h • CYP 1A2 (major), CYP 3A4 (minor) • ADRs: dizziness, nausea, fatigue, headache ( testosterone,  prolactin,  cortisol) © 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution 3.0 License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Available at: https://www.intechopen.com/books/melatonin-the-hormone-of-darkness-and-its-therapeutic- Morin CM, Benca R. Lancet. 2012;379(9821):1129-1141. potential-and-perspectives/synthetic-melatonin-receptor-agonists-and-antagonists Orexin (hypocretin): A Wakefulness-Promoting Center in the Brain

Orexin (hypothalamus)

Orexin A or OX1 Orexin B or OX2 receptor receptor

Dense in locus Dense in coeruleus histaminergic (anxiety/panic wakefulness center areas) This Photo by Unknown Author is licensed under CC BY-SA Scammel TE, et al. Nature Med. 2007;13(2):126-128; Johnson PL, et al. Depress Anxiety. 2015;32(9):671-683. Dual-Acting Orexin Receptor Antagonists (DORAs) Suvorexant/Lemborexant • Orexin: neuropeptide that regulates wakefulness in hypocretin area of the brain; active during wakefulness • Narcolepsy correlated with damage to orexin/hypocretin or wakefulness center of the brain (DORAs contraindicated in narcolepsy) • Unique effects on sleep architecture • Increased REM sleep • Increased stage 2 sleep • No change in stage 3, 4, or slow-wave sleep • More studies needed in special populations to assess place in therapy for insomnia

Winrow CJ, Renger JJ. Br J Pharmacol. 2014;171(2):283-293. Patel KV et al. Annals of Pharmacotherapy. 2015; Vol. 49(4) 477–483. Orexin/Hypocretin Receptor Antagonists (Safety not established in patients with concomitant psychiatric diagnoses)

Drug Dose Onset t1/2 Considerations

2014 Suvorexant 10 mg, 20 mg 30 min 9-13 h 7 h left in bed; suicidal (C-IV) BZRA alternative. thoughts 2019 Lemborexant 5 mg, 10 mg <30 min 17-19 h 8 h left in bed; suicidal (C-IV) Developed as alternative to suvorexant with rapid onset. thoughts Daridorexant 25 mg, 50 mg 30 min ≈6 h Lower risk of hangover (phase 3) Nonselective, shorter half-life. due to half-life Seltorexant 10 mg, 20 mg 30 min 2-3 h May improve mood (phase 3) Selective for orexin 2 receptor; better tolerability? No cataplexy?

The Medical Letter on Drugs and Therapeutics. 2020;62(1601):97-100; Dauvilliers Y, et al. Ann Neurol. 2020;87(3):347-356; Brooks S, et. J Psychopharmacol. 2019;33(2):202-209. Orexin Receptor Antagonists: Must Counsel on Common and Rare Adverse Effects Common Uncommon to Rare • Sedation, next-day impairment including • Treatment-emergent suicidal thoughts fatigue, headache, slowed reaction time (0.4% vs 0.2% placebo) • Memory problems, decreased alertness, • Complex sleep behaviors (driving, eating, difficulty with new learning, confusion talking on phone while half asleep) • Loss of coordination, postural dizziness, or unsteadiness Caution • Do not take with alcohol or opioids due to excessive sedation/unsteadiness • Driving risk; ask prescriber about safety with other medications before taking them

FDA requires stronger warning about rare but serious incidents related to certain prescription insomnia medicines. News release. US FDA; April 30, 2019. Accessed October 8, 2020. www.fda.gov/news- events/press-announcements/fda-requires-stronger-warnings-about-rare-serious-incidents-related-certain-prescription-insomnia; Belsomra. Prescribing information. Merck Sharp & Dohme Corp; 2020; Dayvigo. Prescribing information. Eisai Inc; 2020. Who Is Likely to Abuse Hypnotics?

• Substance misuse history • Chronic, untreated anxiety disorder • Insomnia not relieved by prescribed dose of hypnotic; need to investigate other causes • Supply of hypnotic given should consider risk of abuse • Intravenous misuse in drug users reported, even with Z-hypnotics

Krystal AD. J Clin Psych. 2004;65(suppl 8):20-25; Brunelle E, et al. Addiction. 2005;100:1370-1378. Case Vignettes: Managing Insomnia

• Case 1: A 52-year-old woman complains of trouble staying asleep. She is going through perimenopause. The patient applies an estradiol, levonorgestrel transdermal patch and takes 50,000 IU of cholecalciferol weekly in addition to taking sertraline 50 mg daily for panic disorder and depression. What will you recommend for insomnia?

• Case 2: A 37-year-old healthy teacher (BMI 26 kg/m2) who is married is having trouble falling asleep and staying asleep. The patient denies substance use disorder history and drinks alcohol occasionally. The patient takes fish oil and a multivitamin daily with no other medications. Take-Home Points on Insomnia

• 30%-50% of patients have insomnia negatively impacting their quality of life • Multimodal CBT is the most effective nonpharmacologic treatment in adults • Zolpidem, eszopiclone, suvorexant, and lemborexant are the most effective hypnotic agents for insomnia in adults • Consider coexisting neuropsychiatric diagnoses before recommending hypnotic • Hypnotic use increases risk of adverse effects in all ages and has lowest effective dose for shortest duration of time optimal • Elderly patients are more susceptible to adverse effects • Particularly falls, dementia, respiratory depression • Trazodone is commonly prescribed for insomnia due to lack of abuse potential and effectiveness for trouble falling asleep/staying asleep • Melatonin is considered safe and effective for jet lag and is an option for elderly patients with insomnia and/or circadian rhythm sleep disorder, in addition to children with ADHD or ASD Pharmacy and Managed Care Considerations Douglas S. Burgoyne, PharmD, FAMCP Direct and Indirect Costs of Insomnia

• Estimates on the total cost of insomnia have ranged from $28.1 billion ($15.4 billion is 1990 US dollars [USD]) to $186.3 - $216.6 billion ($92.5 - $107.5 billion in 1988 USD) • These estimates highlight the scope of the problem • Chilcott and Shapiro estimated the annual direct costs of insomnia in the US to be $2.9 billion ($1.8 billion in 1994 USD), whereas Stoller estimated direct costs of insomnia to be $45.3 to $51.2 billion ($22.5 - $25.5 billion in 1988 USD) • Indirect costs include loss of workplace productivity via absenteeism and presenteeism as well as costs due to accidents resulting from cognitive impairment

Wickwire EM, et al. Sleep Med Rev. 2016;30:72-82; Shahly V, et al. Arch Gen Psychiatry. 2012;69(10):1054-1063; Kessler RC, et al. Sleep. 2012;35(6):825-834. Impact of Insomnia on the Workplace

• Workplace absenteeism cost estimations vary widely • Wixler estimated that insomnia-related absenteeism cost employers $9670 per year per employee • Leger estimated the cost of lost productivity due to insomnia-related absenteeism to be $112 per employee per year • Presenteeism is estimated to cost $2416 per employee annually • Corresponding to $67 billion in lost productivity per year for the entire US workforce • Insomnia increases the risk of injuries, both in and out of the workplace • Results from the American Insomnia Survey found that the average cost of insomnia- related accidents and errors was significantly higher than accidents and errors not associated with insomnia ($32,062 vs $21,914)

Wickwire EM, et al. Sleep Med Rev. 2016;30:72-82; Shahly V, et al. Arch Gen Psychiatry. 2012;69(10):1054-1063; Kessler RC, et al. Sleep. 2012;35(6):825-834. Impact on Quality of Life (QOL)

• Insomnia can have profound, negative effects on QOL • Cognitive impairment • Performance, working memory, cognitive speed, and accuracy • Increases stress and worsened mood • Depression and chronic pain • Reduces worker productivity • Increases healthcare utilization • Medications treating insomnia may also improve QOL • Studies conducted primarily with Z-hypnotics have reported improvements in health-related QOL • Insomnia is estimated to account for the largest annual loss of QALYs in the United States • 5.6 million QALYs outranking 18 other medical conditions including arthritis, depression, and hypertension QALY, quality-adjusted life-year. Bathgate CJ, Fernandez-Mendoza J. Curr Hypertens Rep. 2018;20:52; Garbarino S, et al. Int J Environ Res Public Health. 2016;13:831; Morin CM, Benca R. Lancet. 2012;379(9821):1129-1141; Wickwire EM, et al. Sleep Med Rev. 2016;30:72-82; Olfson M, et al. J Clin Psych. 2018;79(5):17m12020. Cost-Efficacy Issues of Insomnia Treatment • BZs and Z-hypnotics are inexpensive; • A model-based decision tree conducted however, inappropriate prescribing has simulations in a hypothetical cohort of likely contributed to a hidden cost Medicare beneficiaries diagnosed with burden for the US healthcare system insomnia to compare cost-effectiveness • An observational study of elderly patients in the US Medicare population seen in the emergency department after a • CBT-I had a cost of $19,442 and QALYs of fall found that 40% of patients receiving a 0.594 BZ or non-BZRA were receiving a dose • BZ or Z-hypnotics had a cost of $32,452 higher than recommended for their age and QALYs of 0.552 • In this group, the cost of emergency • No treatment had a cost of $33,853 and department services, tests, and QALYs of 0.517 hospitalization was estimated at approximately $2000 per patient

Díaz-Gutiérrez MJ, et al. Exp Gerontol. 2018;110:42-45; Tannenbaum C, et al. Drugs Aging. 2015;32(4):305-314. Healthcare Utilization (HCU)

• Patients with insomnia have higher HCU and costs, even when it is untreated • A retrospective claims-based study compared HCU in Medicare patients with insomnia and controls in the year prior to insomnia diagnosis • For patients with insomnia, all-cause cost was $63,607 higher than for controls and was driven primarily by a $60,900 higher cost of inpatient care • Emergency department costs were $1492 higher than for controls • Prescription costs were $486 higher than for controls • A study using data from a large managed care claims database compared healthcare costs of patients with depression and insomnia vs patients with depression alone • Patients with comorbid insomnia had significantly higher total direct costs ($6772 vs $5644) • Contributing factors included more outpatient visits, depression-related visits, and antidepressant prescriptions

Wickwire EM, et al. 2019; Asche CV, et al. Curr Med Res Opin. 2010;26(8):1843-1853. Treatment Guidelines

• The ACP does not recommend specific pharmacotherapy but rather that clinicians use a shared decision-making approach when determining whether to add pharmacotherapy in adults with chronic insomnia disorder in whom CBT-I alone was unsuccessful • The AASM recommends the following pharmacotherapies: • For sleep-maintenance insomnia: suvorexant, eszopiclone, zolpidem, temazepam, doxepin • For sleep-onset insomnia: eszopiclone, zaleplon, zolpidem, triazolam, temazepam, ramelteon • The AASM recommends against using trazodone, tiagabine, diphenhydramine, melatonin, tryptophan, or valerian for either sleep-onset or sleep-maintenance insomnia

Sateia MJ, et al. J Clin Sleep Med. 2017;13(2):307-349; Qaseem A, et al. Ann Intern Med. 2016;165(2):125-133. Considerations for Veterans

• The Department of Veterans Affairs guideline recommends that patients with chronic insomnia who are unable or unwilling to receive CBT-I be offered short-term use of low-dose doxepin or a non-BZ medication • All patients should be counseled about the risk for complex sleep-related behaviors before receiving a non-BZ medication • The guideline suggests against using BZs because the risk of adverse effects exceeds potential benefit • It recommends against trazodone, quetiapine, and antihistamines because of inadequate evidence of efficacy and known potential for adverse effects • Evidence was insufficient to make a recommendation for or against use of suvorexant

Mysliwiec V, et al. Ann Intern Med. 172(5):325-336. Cannabis for Insomnia

• Risks and limitations of current OTC and prescription medications have opened the door for cannabis and/or cannabidiol (CBD) in most states • Pre-existing medical programs throughout the United States (including those in Colorado) do not include sleep disturbances as a specific authorized condition • Results of a 2019 study found that the market share growth for sleep aids shrank by more than 200% with the entry of recreational cannabis dispensaries in Colorado • Cannabis appears to compete favorably with OTC sleep aids, especially those containing diphenhydramine and doxylamine, which constitute 87.4% of the market for OTC sleep aids • Cannabis access may also be associated with an increased preference for more natural sleep aids, such as melatonin and valerian • Long-term safety is unknown • Regular cannabis use for sleep, and any rebound withdrawal symptoms when use is ceased, could promote continued cannabis use and increase the likelihood of developing cannabis dependence

Babson KA, et al. Curr Psychiatry Rep. 2017;19(4):23. CBD and Sleep • Sales of OTC Sleep agents were tracked • The role of CBD on the sleep–wake cycle before and after Colorado legalized the sale • Administration of CBD has been shown to of recreational cannabis have different effects on sleep based on • OTC sleep aid’s market share had been dose: growing prior to recreational cannabis • Low-dose CBD has a stimulating effect legalization • High-dose CBD has a sedating effect • OTC aids sales dropped by more than 200% • In a study among individuals with insomnia, after dispensaries were opened results suggested that administration of 160 • It is believed that individuals use cannabis as mg/day of CBD increased total sleep time a sleep aid, although no states list sleep and decreased the frequency of arousals disturbance as a qualifying condition for the during the night, while low-dose (less than use of medical cannabis 50mg) CBD has been associated with increased wakefulness

Doremus JM, et al. Complement Ther Med. 2019;47:102207; Babson KA, et al. Curr Psychiatry Rep. 2017;19(4):23. Managed Care Considerations Medication Nonmedication = CBT-I • Potential for abuse/misuse • Beneficial, but not a pharmacy benefit • Total cost of care • Could be considered for step therapy/prior • Use in special populations authorization • Medicare/elderly patients = Beers list • Difficult to manage • Veteran and military past • Opportunity for prior authorization/step therapy • Incorporation of age into step-therapy criteria could be utilized to prevent harm from the use of BZs and non-BZRAs in elderly patients • Analyses of prior authorization programs for newer insomnia drugs have found that prior authorization is not cost-effective unless rejection rates are very high

Balkrishnan R, et al. J Clin Sleep Med. 2017;3(4):393-398. Managed Care Considerations • This is a generic category • More than 95% generic • The majority of medications are inexpensive • Many people pay cash or use a discount card program to purchase low-cost generics • Managed care organizations’ data may be even less reliable Formulary Management for Insomnia

• Formulary management is very simple • All generics are Tier 1 • Brand medications are Tier 2 or Tier 3 • Step therapy • May be required for access to brand medications • Prior authorization has not been shown to be effective in this category • Quantity limits • Best way to manage prescription quantity is 30-day supply • Some plans allow 90-day supply • Relatively safe and inexpensive Clinical Approach to Formulary • Considerations for safety • Nonmedication step therapy = CBT-I • Age • Beneficial, but not a pharmacy benefit • Beers list • Could be considered for step therapy/prior • Most agents designated to impact authorization sleep are on the Beers list • Falls and confusion are the major • Difficult to manage concerns • Medical and pharmacy systems are • Age edits should be applied to not sophisticated enough to talk with category each other…yet • Soft-edit so pharmacy can override with appropriate patient counseling • Veterans and military history • Potential for abuse and misuse • Cannabinoid use Opportunity for Pharmacist Care Management

• Pharmacists can positively influence care for insomnia • Integrated care management involves a pharmacist in the care management team • Pharmacists provide: • Enhanced medication reconciliation • Medications that overlap or may enhance feelings of drowsiness • Safety review of medications and home • Screen for fall risk • Evaluation for other comorbidities • Consider other disease states that may influence or be influenced by insomnia • Cardiovascular disease • Diabetes • PTSD • Anxiety Conclusion

• Insomnia is a significant burden on the US healthcare system and for the patients and their families affected • CBT-I seems to be effective and cost-effective for responders • Medication use (natural/OTC/prescription) is significant • The use of cannabinoids seems to be increasing as a treatment for insomnia • Safety is a major concern with all medications used to treat insomnia • Certain populations, such as elderly patients and veterans, need special consideration and management • Managed care organizations should consider safety, cost, and efficacy as they evaluate formulary placement and management strategies, such as step therapy and prior authorization Additional Resources

• National Sleep Foundation – https://www.sleepfoundation.org/ • American Academy of Sleep Medicine – https://www.AASM.org • Centers for Disease Control and Prevention – https://www.cdc.gov/sleep/index.html • National Institute of Health – https://www.nih.gov/news-events/news-releases/nih- offers-new-comprehensive-guide-healthy-sleep