Relieving the Burden of Insomnia Improving Recognition and Treatment in the Primary Care Setting

CME Relieving the Burden of Insomnia Improving Recognition and Treatment in the Primary Care Setting

Chair Paul P. Doghramji, MD Collegeville Family Practice Ursinus College Collegeville, Pennsylvania

What’s Inside 3 The Burden of Insomnia: Improving Recognition in Primary Care

8 Challenges of Treating Patients With Insomnia: The Promise of Novel Agents

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Media: Enduring Material Disclosure of Unlabeled Use Accredited Activity Release Date: January 23, 2020 This educational activity may contain discussions of published and/or Accredited Activity Expiration Date: January 22, 2021 investigational uses of agents that are not indicated by the FDA. The planners Time to Complete Activity: 30 minutes of this activity do not recommend the use of any agent outside of the labeled indications. The opinions expressed in the educational activity are those of Activity Description the faculty and do not necessarily represent the views of the planners. Please In this activity, an expert in insomnia management discusses strategies for refer to the official prescribing information for each product for discussion of improving the recognition and treatment of insomnia in the primary care approved indications, contraindications, and warnings. setting. Disclaimer Target Audience Participants have an implied responsibility to use the newly acquired This activity has been designed to meet the educational needs of primary care information to enhance patient outcomes and their own professional physicians and other clinicians involved in the management of patients with development. The information presented in this activity is not meant to serve insomnia. as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should Educational Objectives not be used by clinicians without evaluation of their patient's conditions and Upon completion of this activity, participants should be better able to: possible contraindications and/or dangers in use, review of any applicable • Describe the impact of insomnia on quality of life and risk of psychiatric and manufacturer's product information, and comparison with recommendations physical illnesses of other authorities. • Differentially diagnose insomnia from other sleep disorders • Identify tolerance and dependency issues and adverse events associated Method of Participation with available insomnia therapies There are no fees for participating in or receiving credit for this accredited • Apply the latest clinical data on novel and emerging therapies, including activity. For information on applicability and acceptance of continuing dual orexin receptor antagonists, to the treatment of patients with insomnia education credit for this activity, please consult your professional licensing board. Providership, Credit, and Support A statement of credit will be issued only upon receipt of a completed activity This CME activity is jointly provided by Medical Learning Institute, Inc. and PVI, evaluation form and will be emailed to you upon completion. You will receive PeerView Institute for Medical Education. your certificate from [email protected]. If you have questions regarding the receipt of your emailed certificate, please contact via email at This activity is supported by an educational grant from Eisai, Inc. [email protected].

Physician Continuing Medical Education About This CME Activity This activity has been planned and implemented in accordance with the PVI, PeerView Institute for Medical Education, and Medical Learning Institute, accreditation requirements and policies of the Accreditation Council for Inc. are responsible for the selection of this activity’s topics, the preparation Continuing Medical Education (ACCME) through the joint providership of editorial content, and the distribution of this activity. Our activities may of Medical Learning Institute, Inc. and PVI, PeerView Institute for Medical contain references to unapproved products or uses of these products in Education. The Medical Learning Institute, Inc. is accredited by the ACCME to certain jurisdictions. The preparation of PeerView activities is supported by provide continuing medical education for physicians. educational grants subject to written agreements that clearly stipulate and enforce the editorial independence of PVI and Medical Learning Institute, Inc. The Medical Learning Institute, Inc. designates this enduring material for a maximum of 0.5 AMA PRA Category 1 CreditsTM. Physicians should claim only the The materials presented here are used with the permission of the authors credit commensurate with the extent of their participation in the activity. and/or other sources. These materials do not necessarily reflect the views of PeerView or any of its partners, providers, and/or supporters. Faculty Disclosures Chair Paul P. Doghramji, MD Senior Family Physician Collegeville Family Practice Medical Director of Health Services Ursinus College Collegeville, Pennsylvania

Paul P. Doghramji, MD, has a financial interest/relationship or affiliation in relation to this activity in the form of: Consulting and/or Advisor for AstraZeneca; Eisai Inc.; and Jazz Pharmaceuticals, Inc.

Planning Committee Disclosures The planners from Medical Learning Institute, Inc., the accredited provider, and PeerView Institute for Medical Education, the joint provider, do not have any financial relationships with an ACCME-defined commercial interest related to the content of this accredited activity during the past 12 months unless listed below.

Content/Peer Reviewer Disclosures The following Content/Peer Reviewer has nothing to disclose:

Matthew A. Goodman, MD

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The Burden of Insomnia: Epidemiology of Insomnia1-3 Improving Recognition in Prevalence of Insomnia Proportion of Patients With Insomniab Primary Care Symptomsa in the United States Who Discuss Symptoms With HCP 2% Never 5% Never discuss

19% Rarely 33% 26% Mention during discussion A few nights per month Narrator: Welcome to this educational activity on relieving the of a different problem 69% 25% A few nights per week Specifically seek evaluation burden of insomnia. Dr. Paul P. Doghramji, Senior Family Physician 21% Every night or almost for insomnia at Collegeville Family Practice, and Medical Director of Health every night

Services at Ursinus College in Collegeville, Pennsylvania, discusses a Insomnia symptoms defined as trouble falling asleep, waking frequently at night, waking too early and unable to fall back asleep, or waking feeling unrefreshed. b Insomnia defined as having any history of difficulty sleeping. 1. https://www.sleepfoundation.org/professionals/sleep-america-polls/2005-adult-sleep-habits-and-styles. strategies for improving recognition and treatment of insomnia in Accessed December 10, 2019. 2. Bailes S et al. Fam Pract. 2009;26:294-300. 3. Ancoli-Israel S et al. Sleep. 1999;22:S347-S353. the primary care setting.

You might say, “All right, yeah, you know, sleep is important, but Insomnia: Definition and Types1,2 not that many of my patients complain of insomnia.” Well, look at this. The National Sleep Foundation—I’m proud to be on the Desired • Patients report difficulty wake time board of directors there—is a nonprofit organization in which Sleep-maintenance – Initiating sleep insomnia we gather information about sleep and disseminate information (sleep-onset insomnia) OR about sleep to the lay public and to clinicians. – Maintaining sleep (sleep-maintenance insomnia) Sleep-onset insomnia This is one of the polls that we did a couple of years back. The • Adequate opportunity and circumstances for sleep Bedtime polling question was, “How often do you have trouble getting to • Daytime impairment sleep or staying asleep or are dissatisfied with your sleep?” The numbers were surprising and quite staggering. One-third of adults 1. Sateia MJ. Chest. 2014;146:1387-1394. 2. Sateia MJ et al. J Clin Sleep Med. 2017;13:307-349. said that they have trouble with their sleep every night or almost every night. Twenty-one percent said a few nights per week Dr. Doghramji: So let’s talk about insomnia. Well actually, before they’re having trouble with their sleep. If you add this together, we talk about insomnia, let’s talk a little bit more about sleep. more than half of American adults said that they have trouble What’s sleep for? Sleep is for what I call the four R’s: rest, restore, with their sleep at least a few nights a week. We thought this was rejuvenate, and repair. unbelievable.

But you know, folks, sometimes sleep can get broken. There can be Now, you might say, “Well, you know what? I don’t see that many something wrong with sleep. Specifically, we’re going to talk today patients in my practice who have sleep problems. Not that many. about the problem of broken sleep—insomnia. Maybe now and then. I saw 20 patients today, and maybe one person had problems with sleep.” What’s insomnia? By definition and by symptom, it’s difficulty getting to sleep and/or trouble staying asleep with adequate Well, look at the pie graph on the right-hand side—the proportion opportunity and circumstances for sleep with daytime of patients with insomnia who discuss symptoms with their impairment. These are the symptoms of insomnia. That’s what healthcare providers. Seventy percent never do; they never discuss we’re going to be talking about. it. Five percent may specifically come to you and say, “Yeah, I want a treatment for some insomnia problems.” Maybe 26% will mention it during a discussion of a different problem. But clearly, the majority of patients don’t want to discuss it.

Well, you maybe have mixed emotions right now. On the one hand, you know that sleep is important, and you want to relieve the burden of insomnia. On the other hand, who wants to talk about sleep with their patients? I mean, after all, it may result in a scheduled medication that you don’t want to prescribe, right?

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That’s what we’re going to talk more about, and hopefully at the bad things can happen to you. It’s imperative, therefore, that end of this talk, you’ll feel a lot more comfortable wanting to we identify our patients who are having sleep problems and do identify your patients who have insomnia and doing something something for them that remedies the problem. good for them to help them with their four Rs—the rest, restore rejuvenate, and repair. Why? Again, just because they don’t mention it now, we no longer can say we don’t want to talk about it. We need to proactively ask our patients if they are having problems with their sleep when they The Economic Burden of Insomnia1,2 come in for office visits, especially those at higher risk.

Distribution of Direct and Indirect Costs of Insomnia Risk Factors and Contributing Medications/Substances • Estimated annual cost in 1-3 3% in Insomnia 1% the United States 0.3% Healthcare consultations 5% – Total (direct and indirect): Transportation for consultations $411 billion • Female sex 15% – Equal to 2.28% of GDP • Older age Alcohol as sleep aid Risk Factors • Comorbid conditions Prescription and OTC • Increasing nighttime sleep duration for Insomnia • Stressors (eg, unemployment, divorce) 76% medications from <6 hours to 6-7 hours could save • Shift work • Lower socioeconomic status Absenteeism $226 billion in lost productivity Presenteeism • Stimulants (eg, caffeine, • Opioids (eg, codeine, oxycodone, amphetamines, ephedrine, morphine, heroin) Medications 1. Hafner M et al. rand.org/pubs/research_briefs/RB9962.html. Accessed December 10, 2019. 2. Daley M et al. Sleep. cocaine) • Medications for cardiovascular 2009;32:55-64. and Substances • Antidepressants (eg, SSRIs, diseases (eg, diuretics) That May Contribute duloxetine, venlaxafine, MAOIs) • Medications for respiratory disorders to Insomnia • Decongestants (eg, pseudoephedrine, (eg, albuterol, theophylline) phenylephrine) • Alcohol

Well, there’s an economic burden. A recent study suggested 1. Schutte-Rodin S et al. J Clin Sleep Med. 2008;4:487-504. 2. Matheson E et al. Am Fam Physician. 2017;96:29-35. 3. Serdarevic M et al. Sleep Health. 2017;3:368-372. that [costs] due to presenteeism, absenteeism, prescription and OTC medications, alcohol as a sleep aid, transportation for consultations, and healthcare consultations could be in the billions Let’s take a look at risk factors and contributing medications and of dollars. substances for insomnia. Who are those who are at high risk for insomnia? You should be more alert to the possibility of insomnia Interestingly, just increasing nighttime sleep duration from less with those who are older; older adults are much more likely. Ask than 6 hours to 6 to 7 hours could have a massive impact in more questions to older adults about their sleep. increasing the lost dollars. There is a tendency also for insomnia problems to occur more in women than in men, those who have more comorbid conditions, Effects of Insomnia1-4 those who have more stressors in life, those who are doing shift

Impaired Risk work, and those with lower socioeconomic status. Who do we Daytime Factor Functioning Drowsy driving For ask about their sleep problems? Maybe we go and gravitate more Depression Stroke and fatal crashes toward these types of patients than just all patients in general,

Coronary artery Injuries and accidents Diabetes although ALL patients should be questioned about their sleep disease when they come in for annual check-ups. Decreased quality of life Obesity Suicide attempts

Increased presenteeism We also need to know that there are some things that patients do Overall mortality and absenteeism Hypertension or we do to them that could impact their sleep, like patients who

1. Liu Y et al. MMWR Morb Mortal Wkly Rep. 2016;65:137-141. 2. Winkelman JW. N Engl J Med. 2015;373:1437-1444. 3. https://crashstats.nhtsa.dot.gov/Api/Public/ViewPublication/812446. Accessed December 10, 2019. 4. Daley M et al. are using stimulants, antidepressants, decongestants, opioids, Sleep. 2009;32:55-64. cardiovascular medications, pulmonary medications, and also alcohol. These are some of the risk factors and contributing Now, let’s take a look more clearly, though, at the impact of aspects for insomnia. insomnia as it means to the patient. Insomnia clearly has an impact on daytime functioning, with drowsy driving causing fatal car accidents, also injuries and accidents at work, decreased quality of life, increased presenteeism, and increased absenteeism. These are all impaired daytime functioning.

But this may surprise you: if a patient doesn’t get the four Rs— the rest, restore, rejuvenate, and repair—they are much more likely to have psychiatric and medical problems. They’re much more likely to have depression, stroke, diabetes, coronary artery disease, obesity, suicide attempts and other psychiatric problems, hypertension, [and higher] overall mortality. If you don’t sleep,

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Let’s take a look at a case presentation. Angie reports difficulty Common Comorbid Conditions in Insomnia1,2 maintaining sleep. She’s a 40-year-old African American woman. She recently made partner at a law firm. Her bedtime varies • Congestive • Hypo- or • Seizure disorder • Mood disorder • Asthma • Peptic ulcer heart failure hyperthyroidism • Stroke (depression, • COPD disease • Angina • Diabetes • Parkinson disease anxiety, bipolar) • IBS between 10:00 PM all the way to midnight. She falls asleep pretty • Dyspnea • Dementia • Psychotic disorder • Reflux • Peripheral (schizophrenia) • Cholelithiasis neuropathy • Dementia easily and relatively immediately, but she wakes up at around 2:00 Endocrine Pulmonary Neurologic

• Headache Psychiatric • ADD

Cardiovascular • Multiple sclerosis • PTSD Gastrointestinal • TBI • Panic disorder AM every night. She lies in bed drifting in and out of sleep until finally, at around 5:00 in the morning, she needs to get up and get

• Fibromyalgia • BPH • Menopause • Restless legs • Rhinitis • Osteoarthritis • Nocturia • Pregnancy syndrome • Sinusitis ready for her day. • Rheumatoid • Incontinence • Periodic limb • Bruxism arthritis • Interstitial movement • Alcohol and cystitis disorder substance

• Obstructive Other abuse sleep apnea Reproductive Genitourinary • Parasomnias As a result of this, she’s forgetful, she’s fatigued. She’s slow to Sleep Disorders Musculoskeletal

1. Schutte-Rodin S et al. J Clin Sleep Med. 2008;4:487-504. 2. Riemann D et al. J Sleep Res. 2017;26:675-700. complete tasks. It’s clearly affecting her daytime functioning. Her symptoms started when she became partner 6 months ago.

I talked about comorbidities earlier, and I said that insomnia is a She drinks six cups of coffee per day—wow—but is not able to contributing factor for medical and psychiatric problems. Let’s call stay awake sometimes even during client calls. My gosh. She wants these comorbid conditions. Certain medical problems and certain something to help her sleep through the night. This is one of the psychiatric problems are much more likely to occur in patients rare 5% of patients who comes to you saying, “I want something who have insomnia. Cardiovascular disease, endocrine, neurologic, for my sleep.” psychiatric, pulmonary, gastrointestinal, musculoskeletal, genitourinary, reproductive, sleep disorders, et cetera. Taking a Thorough Insomnia History1,2

You need sleep for all parts of your body to be healthy, and when Ask Patient About there’s poor sleep, any part of your body can malfunction. When symptoms Frequency and Duration of sleep Contributing and Bedroom first started severity of symptoms perpetuating factors environment

Daytime symptoms Now, you might be thinking, “Well, in which direction does it go? Quality of sleep Trouble falling sleep Awakenings and activities (poor or (eg, time to Activities before bed (eg, number, duration) (fatigue, naps, unrefreshing) fall asleep) Does the insomnia cause these, or are these problems causing work, quality of life) insomnia? Which direction does it go?” Well, interestingly, it could Associated symptoms Contributing comorbid Disturbance in mood and behaviors conditions, Prior treatments be one direction, the other direction, or both. Let me give you an or cognitive function surrounding and medications, and responses example. during sleep and substances Include history from bed partners ! or caregivers whenever possible 1. Schutte-Rodin S et al. J Clin Sleep Med. 2008;4:487-504. 2. Riemann D et al. J Sleep Res. 2017;26:675-700. For example, neurologic headache—patients who have migraine headaches, when their migraines are out of control, they’re much more likely to have insomnia. On the other hand, if their migraines What do we do when a patient comes in like this? You take a are controlled and then all of a sudden they develop insomnia, good, thorough sleep history. You obviously ask about trouble they’re much more likely to have migraine headaches. There’s a getting to sleep and staying asleep and next-day consequences, bidirectionality there. but also let’s look at some other factors in patients like this. When did the symptoms first occur? The frequency and severity of the Let’s take a psychiatric disorder—depression. Interestingly, symptoms, the duration of sleep time total, contributing and patients who have insomnia are much more likely to have perpetuating factors—these are all important aspects of our depression, to develop depression. But also the reverse—patients patients with insomnia. who have depression are much more likely to have insomnia. You should go into other things as well like, “Tell me about your bed situation. Is it comfortable? Who else sleeps in your bed with Angie: Reports Difficulty Maintaining Sleep you? What do you do before bedtime? Do you use any kind of screens, like television or computer or laptops or those kinds of things around sleep time?” These are all the different things that we need to ask our patients. Don’t forget to ask, “What have you

ü 40-year-old African American woman been doing about your sleep problem?” ü Bedtime between 10 PM and 12 AM, falls asleep almost immediately ü Wakes around 2 AM and drifts in and out of sleep ü Forgetful, fatigued, slow to complete tasks at work ü Symptoms started when she became a partner at her law firm 6 months ago ü Drinks six cups of coffee per day but is unable to stay awake during client calls

Stock photo. Posed by model.

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There’s the DSM-5 diagnostic criteria. I’m going to go over that Angie’s Medical and Insomnia History in a few minutes with you. A couple of things that may also help

• Medical history: type 2 diabetes, • Testing within past year you with your patients are a sleep diary and an Insomnia Severity no surgeries – Normal CMP, CBC, TFT Index. Those two I’m going to show you for Angie, our patient. • Nonsmoker, drinks one to three glasses • A1c: 6.3 of wine on weekends, no caffeine intake • Stops using blue-light devices (eg, phone, after 4 PM tablet, laptop) an hour before bed • Medication: dapagliflozin/metformin • Husband reports If a patient does exhibit symptoms of depression or anxiety, there • Vital signs – Occasional snoring – BP 123/80; HR 85; RR 14 are some scales that you can use, like a PHQ-2 or a GAD-7. – No breathing pauses during sleep – Ht 5 ft 7 in; weight 145 lb; – No limb movements during sleep BMI 22.7 kg/m2 • Physical exam: anxious affect, Testing isn’t really going to be necessary for somebody with otherwise normal insomnia. Just doing the history-taking and observing the patient Symptoms have been ! gradually worsening over time is going to be enough. But in certain instances, blood testing may not be a bad idea. If a patient has restless legs syndrome, you do want to do a ferritin level, or if they have other kinds of neurologic Okay, let’s go through a couple more things about Angie’s medical disorders, you might want to do a complete set of blood tests. history and her insomnia history. She’s a diabetic, type 2. She’s had no surgery. She’s a nonsmoker, she drinks one or two or three The majority of patients are not going to need anything. If you glasses of wine on weekends. She has no caffeine after 4:00 PM, suspect periodic limb movement disorder and if you suspect but she gets her fair share before then. Her medications are those obstructive sleep apnea, you are going to need a sleep study. two that are used for diabetes, type 2 diabetes. She’s maintained a good BMI. Angie Meets the DSM-5 Diagnostic Criteria for Insomnia1

Her physical exam—she’s anxious but otherwise okay. Her lab A. Dissatisfaction with sleep quantity or quality with one or more of the following 1. Difficulty initiating sleep (children: w/o caregiver intervention) testing that was done in the past year was pretty much normal, 2. Difficulty maintaining sleep (children: w/o caregiver intervention) 3. Early morning awakening w/inability to return to sleep including an A1c, which is 6.3; she’s in pretty decent diabetic B. Significant distress or impairment control. She does stop using blue-light devices like phones, C. Occurs ≥3 nights per week D. Present ≥3 months Items B-H must tablets, and laptops an hour before bed, so she knows to do that. also be met for E. Adequate opportunity for sleep a diagnosis She’s not using any OTC sleep aids because she says, “Those are for F. Not better explained by or solely due to another sleep-wake disorder of insomnia people who have trouble falling asleep.” 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; She feels irritable, and you can see that. She’s tense, she’s on with non–sleep disorder mental comorbidity 1. https://www.ncbi.nlm.nih.gov/books/NBK519704/table/ch3.t36/. Accessed December 10, 2019. edge. She says that this is especially the case at bedtime. She gets anxious about not getting enough sleep and sometimes that may interfere with her in the middle of the night when she gets up, I said earlier that I would go over the DSM-5 diagnostic criteria for and she’s anxious about her sleep itself and that perpetuates her insomnia, and let’s do that. Insomnia is dissatisfaction with sleep insomnia. quality or quantity, with one more of the following: difficulty initiating sleep, difficulty maintaining sleep, or early morning awakening with inability to return to sleep. Diagnostic Tools and Testing to Consider in Insomnia1,2 This is the diagnostic criteria for the disorder of insomnia, but

Diagnostic Testing it must also have significant distress or impairment. It’s got to Diagnostic Testing History and If a Contributing for Other Diagnostic Criteria for Suspected Questionnaires Factor Is Suspected Suspected Sleep Medical Disorders Disorders occur three or more nights per week. It’s got to occur or [have]

• DSM-5 diagnostic • Sleep history and • 2-item PHQ-2 • Bloodwork: CMP, • Polysomnography criteria sleep diary (anxiety/ CBC, TFT, ferritin, (eg, OSA, PLMD) been going on for 3 or more months. There has to be adequate • ICSD-3 • Insomnia Severity depression) vitamin B12, CRP • Multiple sleep Index • GAD-7 (anxiety) • Other testing: EEG, latency test opportunity for sleep. It’s not better explained by or solely due • Epworth • History of ECG, CT, MRI • Maintenance of Sleepiness Scale comorbid sleep wakefulness test • Pittsburgh Sleep disorders • Home sleep apnea to another sleep-wake disorder, not attributable to medication Quality Index • Medication list test • Sleep problems should be • Actigraphy (eg, questionnaire reviewed for circadian rhythm or substance use, and not adequately explained by comorbid contributory agents disorder) • Assess caffeine, tobacco, and Order testing only if a comorbid medical or mental disorders. This is how you make the diagnosis of alcohol intake medical disorder or another sleep ! disorder is suspected insomnia, the disorder. 1. Riemann D et al. J Sleep Res. 2017;26:675-700. 2. Grander MA et al. J Clin Sleep Med. 2017;13:937-939.

So if somebody comes in with insomnia, how do you go on to assess what the patient actually has and what to do about them?

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Look at the C on the left-hand side. There is C all over the place, Angie: Insomnia Severity Index (ISI) Score1 caffeine all over. There is a little bit of exercise here and there, and

Points there’s some alcohol here and there, but you can clearly see that Question 0 1 2 3 4 SEVERITY of insomnia symptoms? Angie is really struggling to get her sleep during the sleep times Difficulty falling asleep None Mild Moderate Severe Very that she wants. 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

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

Let’s get back to Angie. With Angie, we give her an Insomnia Severity Index, and we ask her about her difficulty falling asleep. She says none. Difficulty staying asleep? Oh my God, a 4. Problem waking up too early? That’s a 4. Satisfied with current sleep pattern? Not at all, that’s a 4. Symptoms interfere with daily function? That’s a 3. Noticeable impact on quality of life? Much, that’s a 3. Worry about sleep problems? Oh, that’s a 4.

You add the whole thing up, it’s a 22. You say, “Angie, you have severe insomnia,” and she probably is going to say to you, “Doc, I told you, I’m really having a lot of problems with my sleep.” So quantifying sleep with an Insomnia Severity Index may not be a bad idea.

Angie’s Sleep Diary1

Type Day of 2 3 4 5 7 8 9 2 3 4 5 7 8 9 10 Date of 10 1 PM 6 PM 1 AM 6 AM Week Noon 11 PM Day 11 AM Midnight

6/2 Tues Work C C C A ↓ ↑ E C M C C

6/3 Wed Work C C C ↓ ↑ C M C

6/4 Thurs Work C C C C ↓ ↑ E C M C

6/5 Fri Work C C C A ↓ ↑ M C C Week 1 6/6 Sat Off C C A ↓ ↑ M C

6/7 Sun Off C C E ↓ ↑ M C C

6/8 Mon Work C C C C ↓ ↑ C M C

A: alcohol; C: caffeine; E: exercise; M: medication. ↓: going to bed; ↑: out of bed. ■: naps and nighttime sleep.

1. http://yoursleep.aasmnet.org/pdf/sleepdiary.pdf. Accessed December 10, 2019.

Another thing that you can do is give Angie a sleep diary to keep for about a week or so, especially if you’re having a little bit of difficulty with trying to understand her sleep pattern. Interesting, when you do something like this for her, she could understand her sleep pattern better and already start to work to correct certain things.

Look at this. A is for alcohol; C, caffeine; E, exercise; M, medication. Down arrow going to bed, up arrow out of bed, orange boxes are naps or nighttime sleep. Just looking at this, you can kind of see that her sleep was all over the place. It certainly is less in the evening when you want her to have the sleep, when sleep time is desired, but there’s sleep in other times as well.

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Sleep hygiene is part of something that we call cognitive behavioral therapy for insomnia. This is where a sleep coach—a cognitive behavioral therapist for insomnia—works with a patient to establish better sleep habits and get rid of undesirable thoughts to relieve their insomnia. This is typically done by a trained provider to individuals or in groups, from six to eight sessions, usually once a week or so, lasting about 45 minutes to an hour. Dr. Doghramji: We’ve talked about insomnia as a disorder that’s quite prevalent. It’s very disturbing to a patient. It can impact the It improves the time to sleep onset, decreases time awake after quality of life, and it can certainly be a risk factor for medical and sleep onset, and provides benefits for 6 to 12 months after psychiatric problems. treatment is complete, and sometimes even longer, so for many, it’s quite permanent. Basically, what does it do? Look at the fourth What’s the first thing that you do with a patient with insomnia? row there. It restructures maladaptive beliefs about consequences You educate them. You tell them how important sleep is and of insomnia, and this is a very important part of cognitive how dedicated you are to helping them get to a better night’s behavioral therapy. sleep. But in order to do so, they need to participate, and their participation starts with proper sleep hygiene, good sleep behavior.

Most important, first and foremost, is awakening at the same time every morning. This sleeping in on weekends, varying sleep time, or doing cat naps is not a good idea. We need to train the brain. The brain clock needs to be told when it’s supposed to get up in the morning, and that’s a very important thing.

The next important thing is when to go to bed. When is that supposed to happen? When the person is tired. Go to bed when you’re tired, and get up at the same time every day—weekends and weekdays as well. It’s very important to tell your patients that. Now, let’s go back to Angie. Angie is counseled on sleep hygiene But, a couple of other things. Establish daily routine activities. and referred to a certified cognitive behavioral therapist for Exercise is a very good thing. Taking walks throughout the insomnia. She returns to the office 3 months after that, and she day is a good idea, but not late at night because sometimes says, “Look, my night awakenings have decreased from every night exercise within 3 hours of bedtime can be activating and prevent to four times per week. It’s a little bit better. My daytime anxiety somebody from actually getting to sleep or staying asleep. There has improved. I’m working a little bit better during the day. I’m are a bunch of things that a patient can do as far as what we call feeling a little bit better. But, I’m anxious at bedtime, and after good sleep hygiene. awakening at night, I’m still feeling kind of tired, and I still have some trouble concentrating at work. It’s better, but it’s still there.”

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So, the symptoms have improved, but they’ve plateaued over the last couple of weeks. We’re getting better with her, but we’re not where we want to be, and perhaps it’s a consideration now to talk about medication.

Pharmacologic Treatment for Insomnia: FDA Indications and AASM Recommendations1,2

Drug Class Agent FDA Indication AASM Recommendation Schedule IV Dose Range

Triazolam3 Insomnia Onset Yes 0.125 mg – 0.25 mg Benzodiazepine Temazepam4 Insomnia Onset, maintenance Yes 7.5 mg – 30 mg

Eszopiclone5 Onset, maintenance Onset, maintenance Yes 1 mg – 3 mg

Zaleplon6 Onset Onset Yes 5 mg – 10 mg Benzodiazepine Zolpidem7 Onset Onset, maintenance Yes 5 mg – 10 mg receptor agonist Zolpidem ER7 Onset, maintenance Onset, maintenance Yes 6.25 mg – 12.5 mg

Zolpidem SL7 MOTN awakening None Yes 1.75 mg – 3.5 mg

Melatonin agonist Ramelteon8 Onset Onset No 8 mg

Histamine receptor antagonist Doxepin9 Maintenance Maintenance No 3 mg – 6 mg

Suvorexant10 Onset, maintenance – Yes 10 mg – 20 mg Orexin receptor antagonist There are some adverse reactions to these medications, and I Lemborexant11 Onset, maintenance – – 5 mg – 10 mg 1. Sateia MJ et al. J Clin Sleep Med. 2017;13:307-349. 2. Matheson E et al. Am Fam Physician. 2017;96:29-35. 3. Halcion (triazolam) Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/ want to only call your attention on this to the black box warnings. 017892s049lbl.pdf. Accessed December 9, 2019. 4. Restoril (temazepam) Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/018163s064lbl.pdf. Accessed December 9, 2019. 5. Lunesta (eszopiclone) Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/021476s030lbl.pdf. Accessed December 9, 2019. 6. Sonata (zaleplon). http://labeling.pfizer.com/ShowLabeling.aspx?id=710. Accessed December 9, 2019. 7. Ambien (zolpidem) Prescribing Information. http://products.sanofi.us/ambien/Ambien.pdf. Accessed December 9, 2019. 8. Rozerem (ramelteon) Prescribing Information. https://www.accessdata. fda.gov/drugsatfda_docs/label/2010/021782s011lbl.pdf. Accessed December 9, 2019. 9. Sinequan (doxepin) Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/016798s054,017516s023lbl.pdf. Benzodiazepines have black box warnings, benzodiazepine Accessed December 9, 2019. 10. Belsomra (suvorexant) Prescribing Information. https://www.merck.com/product/usa/pi_circulars/b/belsomra/ belsomra_pi.pdf. Accessed December 9, 2019. 11. Dayvigo (lemborexant) Prescribing Information. https://us.eisai.com/-/media/Files/Eisai/PrescribingInformation.pdf. Accessed January 15, 2019. receptor agonists have black box warnings, and the other three do not. These are FDA indications and American Academy of Sleep Medicine recommendations. On the left are the five different classes of medications: the benzodiazepines, which we’re going to talk about—triazolam and temazepam. Benzodiazepine receptor agonists—eszopiclone, zaleplon, zolpidem, zolpidem extended release, and zolpidem sublingual. Melatonin agonists—and in that category there is only one, ramelteon. Histamine receptor antagonist—again, only one there, doxepin. And [also,] orexin receptor antagonist.

The FDA indications are there, the American Academy of Sleep Medicine recommendations are next, and then the scheduling is next. A couple of things of note. These medication recommendations—as far as onset and maintenance—have to do primarily with when the medication is going to take effect and [There are a] couple of other things that you need to know about how long the medication is going to take effect. pharmacologic treatment for insomnia, and these are additional American Academy of Sleep Medicine recommendations. There is Let’s take, for example, zaleplon. The medication has rapid onset no specific guideline recommendation, or inadequate evidence, but also leaves the body very quickly, so that’s very good for for other benzodiazepines approved for insomnia, such as somebody who just has trouble getting to sleep. But let’s take estazolam, flurazepam, and quazepam, and agents used off-label another situation in which somebody has no trouble getting for insomnia—oxazepam, quetiapine, gabapentin, and paroxetine. to sleep but wakes up and can’t get back to sleep again. In that instance, doxepin—low-dose doxepin—would be a good idea But AASM clearly does not recommend for insomnia OTC because the medication is intended to help somebody just stay supplements like melatonin, L-tryptophan, and valerian. It does asleep. There are all these different indications for the different not recommend diphenhydramine, and it does not recommend medications here, and it’s important for you to go over them. trazodone and tiagabine. So AASM, American Academy of Sleep Medicine, does not recommend those for insomnia. Look also at the scheduling. Two of these medications are unscheduled, and that may be very important because there are a lot of times when our patients have other scheduled medications that they could be using, and you don’t want to add another scheduled medicine onboard. There are two that are unscheduled.

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So in choosing, what do you look for? I suggest to you the first Let’s now talk about orexin receptor antagonists. Orexin, a thing you should look for, again, is does the patient have trouble neurotransmitter, was discovered about 20 years ago or so and getting to sleep, or does the patient have trouble staying asleep, was actually discovered by two different laboratories—one or if the patient has both. Start there, and choose the medication laboratory calling it orexin, the other one calling it hypocretin from the table that I’ve just shown you. because it’s located in the lateral hypothalamus, including the perifornical area. So, hypocretin or orexin. Also, ask for a couple of other things. What has worked for you in the past? Let’s take a look at that—so, response to prior therapies. It was thought to maybe be involved in physiological roles with Comorbid conditions. If, for example, a patient has respiratory sleep and wakefulness, feeding and appetite, reward pathways, problems like COPD, you might not want to use a medication and that sort of stuff. What was very interesting about it is that we that has respiratory suppression like a benzodiazepine. Potential found that in patients with narcolepsy, they have little to no orexin. medication interactions, adverse-effect profile, patient preference, Interestingly, it was now found that orexin is a wake-promoting cost, risk for dependency—these are all factors to consider as to neurotransmitter. In order for you to be wide awake, awake like which medication you choose for your patient with insomnia. you are right now, you need orexin.

What was then discovered is that during sleep time, orexin activity is dramatically decreased. In wakefulness, orexin sends signals throughout different parts of the brain to activate and to keep it in a wake-active neuron process, but during sleep, the sleep-active neurons are active and orexin becomes relatively inactive.

So, a-ha! What can we do now? Let’s capitalize on this. Let’s see. In our patients with insomnia, maybe we can suppress orexin, reduce wakefulness, and as a result, help them get a better night’s sleep. In fact, this does translate in reality to be the case.

Let’s go back to Angie. You start Angie on eszopiclone 1 mg, which is the starting dose and is the right starting dose that the FDA recommends. One mg at bedtime, and she continues her CBT-I practices. She returns in 5 weeks, and what does she say? She says, “You know, the eszopiclone, it does make me feel drowsy at bedtime because I take it right then and I’m able to get to sleep real easily like I was, but I’m still waking up at night four times a week. It really hasn’t done as much as I wanted it to, doc.”

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[The] outcome [is] four different medications that are orexin Now, let’s take a look at lemborexant. SUNRISE 1 and SUNRISE receptor antagonists. These are all dual orexin receptor 2; SUNRISE 1 was 5 mg and 10 mg versus not just placebo but antagonists. There’s suvorexant, lemborexant, daridorexant, and also active comparator, zolpidem. It’s very interesting that, in seltorexant. These four are not all approved. that study, the 5 mg and 10 mg doses were seen to be superior in helping patients get to sleep and stay asleep. The SUNRISE 2 study—it shortens sleep latency and improves sleep maintenance.

Lemborexant was seen to have some side effects, as all medications could, but relatively minor. Some somnolence, headache, and some other kinds of side effects occurred compared with placebo.

Narrator: Based on data from SUNRISE 1 and SUNRISE 2, the US Food and Drug Administration approved lemborexant 5 mg and 10 mg on December 23, 2019 for the treatment of adult patients with insomnia characterized by difficulties with sleep onset and/or sleep maintenance.

Let me show you one interesting thing about suvorexant. This was in the phase 3 trials for suvorexant. It showed that the medication does help in wake-after-sleep onset, which means that it helps with sleep maintenance. Patients are not only able to get to sleep better, but also stay asleep very well with this medication.

Dr. Doghramji: In phase 3 updates from World Sleep Congress 2019, new data demonstrated safety and tolerability of lemborexant over a 12-month period and qualitative persistence of lemborexant effectiveness through 12 months. The mean ratings for quality of sleep and morning alertness showed improvement from baseline through 12 months with both doses of lemborexant Some side effects can occur with any medications, including this compared with placebo. Qualitative persistence of improved sleep one. There is some somnolence, headache, dizziness, et cetera. But quality and morning alertness after 12 months were also observed. as a general rule, the medication does quite well as far as overall side effects are concerned. Now, in the SUNRISE 1 study—which I said earlier was not just 5 mg and 10 mg pitted against placebo, but also against zolpidem, which was the active comparator—lemborexant treatment resulted in improvement of sleep architecture with increased time in all stages and reduction in REML compared with placebo and was superior to zolpidem for most measures. Very interesting.

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With that, I come to the end of my talk. I hope that you have found it enjoyable and informative about insomnia in your patients, to help them understand their condition, and treat them as best as possible toward their best night’s sleep. Thank you very much.

Narrator: This activity has been jointly provided by Medical Learning Institute, Inc. and PVI, PeerView Institute for Medical Education.

Okay, let’s go back to Angie. Angie starts pharmacologic therapy. You discuss with her switching to an orexin receptor antagonist, and she says she wants to continue with all the CBT-I stuff that she’s learned, but she agrees to try another pharmacologic agent.

She returns to you after 2 months, and she’s now sleeping through the night all days of the week. She’s still experiencing some occasional fogginess, but things are better. She maybe has some headaches, but again, things are better. She at this time doesn’t want to try anything else. “Things aren’t perfect, but I can function.” So, we’ve done quite well with Angie at this time with switching.

Some take-away messages. Taking a medical history combined with an insomnia history can facilitate the diagnosis of insomnia, and using tools like a sleep diary [or the] Insomnia Severity Index can certainly facilitate understanding what’s going on with the patient and what direction to then go in.

The insomnia treatment landscape continues to evolve. Suvorexant is FDA-approved for patients with sleep-onset insomnia and sleep-maintenance insomnia. Lemborexant, also a dual orexin receptor antagonist, has shown promise in recent phase 3 clinical trials designed to evaluate its safety and efficacy. Other potential orexin receptor antagonists are being evaluated in clinical trials. I suggest that the future of insomnia treatment is probably going to be primarily these orexin receptor antagonists.

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Expert commentary is based on data from recent medical literature. The materials presented here are used with the permission of the authors and/or other sources. These materials do not necessarily reflect the views of PeerView or any of its partners, providers, and/or supporters.

This CME activity is jointly provided by Medical Learning Institute, Inc. and PVI, PeerView Institute for Medical Education.

This activity is supported by an educational grant from Eisai, Inc.

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