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Lemborexant (Dayvigo): CADTH Reimbursement Review: Therapeutic area: Insomnia [Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2023 Apr.
Migraine Canada is a national federally registered charity, founded in late fall of 2018, with a mission to provide support and education as well as raise awareness about the impact of migraines. We advocate for optimal care for those living with migraines and support research to find a cure. With the help of dedicated physicians and contributors, Migraine Canada delivers evidence based, up-to-date disease and treatment information to Canadian living with migraine, including patients and caregivers, as well as healthcare professionals. We educate patients, caregivers, and healthcare professionals by researching, developing, and sharing electronic and print materials containing the most current migraine information. We drive awareness and education through our website, social media channels and forums. We have a growing community of over 2,000 individuals subscribing to our email list. We provide patient support through participation in regional on-line support groups, with more than 3,000 members on our Facebook page.
Website: www.migrainecanada.org
The information provided in this submission was collected through a Quality-of-Life online survey that was launched by Migraine Canada in late fall of 2021. It was promoted across Canada through Migraine Canada’s digital and social media channels. In total, 1,165 Canadian adults with migraine and their caregivers responded to the online survey. Of our total respondents, 19% live with low frequency migraine, 28% live with 8-14 days / month with migraine and 52% live with chronic migraine 15 or mores days. The spectrum of representation was national with the majority (68%) participating between the age of 30-59.
Migraine Canada launched a second national online survey in March 2022 to gather additional insights to support our submission and seek input from patients with experience on Dayvigo (lemborexant). It was promoted across Canada through Migraine Canada’s digital and social media channels with promotion. In total, 220 Canadians with migraine responded to the survey related directly to insomnia. Of our total respondents, 91% were female and 9% male. Similar to the quality-of-life survey, the majority of patients were between the age of 30-59 (69%).
Migraines are not just headaches but a neurological disease. Migraine impacts 1 billion people worldwide, or about 1 in 7 people. Migraine is most common between the ages of 25 and 55 but it can impact people of all ages including children (10%) but it affects three-times (25%) as many women as men (8%).
Migraines are classified according to their monthly frequency. Episodic Migraine is defined as impacting less than 15 days per month and 12% of adults living with migraine fall into this group; Chronic Migraine impacts more than 15 days per month and 2% of the adult migraine populations. Migraines often present with severe, throbbing, recurring pain, usually on one side of the head (or both sides or no pain at all). Nausea, vomiting, dizziness, extreme sensitivity to sound, light, touch, and smell, and tingling or numbness in the extremities or face are also common symptoms. About 25% of migraine sufferers also have a visual disturbance called an aura, which usually lasts less than an hour. Attacks usually last between 4 and 72 hours.
Migraine is usually categorized according to accompanying symptoms (aura, vestibular, hemiplegic) but also according to monthly frequency of attacks. Episodic migraine refers to attacks occurring 14 days or less and is now further separated in low-frequency (1-6 days) and high frequency (7-14 days). Chronic migraine is diagnosed when patients have 15 or more headache days per month. Chronic migraine is associated with increased disability and co-morbidities. It is also associated with medication overuse headache (MOH), a complication of frequent use of acute treatments that induce even more frequent and intractable headaches. The estimated prevalence of MOH varies according to countries but is usually between 0.5% and 2% of the global population (GBD 2015). Medication overuse feeds the headache cycle and patients are trapped in a vicious cycle, unable to get adequate pain relief.
There are two main states of life for a migraine patient: the active attack (ictal state) and in-between attacks (interictal state). During the attack itself, symptoms may prevent the person’s ability to accomplish their tasks, work and interact with others. The pain is at least moderate and often severe, throbbing and diffuse. The nausea and vomiting are obviously disruptive and may prevent oral medications efficiency. The sensory hypersensitivity forces many patients to isolate themselves in a dark room and stop all activities. Auras are neurological deficits that can accompany migraines (including loss of vision, speech, and sensation, even muscle strength) which can last for hours. Some migraines are also accompanied with dizziness, vertigo and loss of balance. People generally experience reduced cognition during a migraine, with slowed thinking, lack of focus, and difficulty reading and speaking. This typically disrupts most activities involving a computer or interacting with other people. A controlled migraine attack managed with effective treatment can be brief, but uncontrolled attacks may last multiple days in a row.
People living with migraine commonly live with several complications, including issues with sleep.
Issues with sleep is significant ranging from only 7% having no issues with sleep to 38% always or regularly having sleep disrupted due to their migraine.
Sleep disruption reported by patients caused by migraine over the past month was significant for respondents. Close to 20% reported 16-30 days as always or very often disrupted, followed by 19% who reported 11-15 days of disrupted sleep.
Patients rated their quality of sleep as very poor (17%), often disrupted (37%) and sometimes disrupted (30%). Only 16% rated their sleep as “good”. When as specifically if migraine impacts sleep, 84% of patients attribute their migraine as having a negative impact.
Impact of Migraine on Sleep.
When asked how often patients experience poor sleep, close to 28% reported sleep issues nightly and close to 41% experience issues 3 or more nights each week.
Quality of Sleep.
We asked respondents to rank a number on how often they had difficulty falling asleep, difficulty staying asleep, early morning ranking and difficulty functioning.
Difficulty Sleeping.
Over 90% of patients have had these symptoms lasting more than 3 months. Close to 20% have been diagnosed with insomnia by a healthcare provider. Close to 60% have informed/spoken with a healthcare professional about their sleep issues.
Symptoms Lasting More Than 3 Months and Diagnosed With Insomnia.
When asked what the outcome of the conversations, the majority of comments included being prescribed sleeping pills. Some other comments included:
“Talk about sleep hygiene/routine (which I already new/did), sleep apnea test. Trying different medications to see if it helps but so far no success”.
“Sleep is one of my triggers in my headache diary and when discussed I was offering sleeping pills which I declined as I am not keep on taking sleeping pills. The conversation ended there”.
“My doctor won’t prescribe sleeping pills. Medications are too addicting and I need to solve the issue with behavioural changes which I’ve tried and hasn’t helped”. “I was told to relax more”.
“Basically work on sleep hygiene and try medication which I was taken off by another Dr.”
“They blame migraine medication and its side effects. Regardless it’s a big issue”.
When asked how insomnia or sleep issues have negatively impacted quality of life, 86% indicated energy level was impacted, followed by 75% having cogitative functioning (ability to focus, pay attention and memory) impacted. Mood, engaging in physical exercise and ability to do household responsibilities were commonly affected and negatively impacting quality of life.
Insomnia’s Negative Impact on Day-to-Day Life?
When asked specifically if patients feel their sleep negatively impacts their migraine (frequency and intensity), 66% said yes. Approximately 24% were not sure which impacted which.
Does Sleep Negatively Impact Migraine’s Frequency and Intensity?
Some comments included:
“I haven’t been able to connect the two. My headaches are so frequent, and I rarely sleep well so I don’t know if one impact the other or if they exist independently”.
“My migraine starts during the night 90% of the time and I can’t get back to sleep”.
“Sleep is one of my triggers in my headache diary and when discussed I was offered a sleep aid which I declined as I am not keen on taking prescription pills. The conversation ended there”.
We also asked respondents if they feel their migraines are the cause of their sleep issues. 26% said yes, 25% said no and 34% weren’t sure.
Do Migraines Cause Sleep Issues/Insomnia?
Patients commented:
“Not always but is a factor when insomnia persists daily for a long period”.
“Migraines are not the main cause for the sleep issues but they do sometimes play a role”.
“I think they each have a negative impact on the other. I believe if I could get rid of my migraines, my body could adjust and eventually have good sleep patterns”.
When asked to what extent sleep problems interfere with daily functioning (ie daytime fatigue, ability to function at work/daily chores, concentration, memory, mood), over 40% had much or very much interference. Only 20% reported a little impact.
In the past two weeks, to what extent did your insomnia/sleep issues interfere with your daily functioning (e.g., daytime fatigue, ability to function at work/daily chores, concentration, memory, mood, etc.)?
Do Sleep Issues Interfere With Daily Functioning?
Patients have tried a number of different treatments and remedies. Over 42% have tried sleep hygiene behavioural therapies, followed by relaxation and mindfulness. Following non pharmacologic intervention, close to 40% have tried over the counter and prescription medications.
Remedies Tried to Improve Sleep Issues.
The majority (60%) of patients are not satisfied with how they currently manage their insomnia/sleep issues. Patient testimonials:
“Gabapentine prescription. Discontinued, too many side effects”. “Tried amitriptyline for two years, helped sleep but not the migraines”.
“Amytriptaline for 18 months helped but I gained quite a bit of weight. Beyond that nothing but the obvious – don’t drink caffeine, get fresh air, exercise, medication. Nothing helps”.
“Tried a few different medications but they made things worse”.
“I was prescribed medication but it left me feeling groggy so I stopped taking it”.
“My doctor won’t prescribe me anything because everything that works for people is addicting. So I suffer with no sleep and migraine”.
“A couple of the prescribed medications I’ve tried made feel so horrible the next day. Its like an out of body experience. Helped my sleep but side effects were to much. At least feeling absolutely exhausted is better than feeling spacey and out of it”.
“I take prescription sleeping pills nightly and take stimulant every morning”.
“Medication/meditation. Medication made me very groggy throughout the next day as I’m very sensitive”.
Overall, patients have not found an over the counter or prescription medication that works. Many commented that the sides effects from medications currently available contribute to discontinuation. A priority for people living with migraine is to find a treatment that will decrease frequency and/or intensity of their migraines.
Sleep is an important piece of the puzzle in managing migraine. Physicians treating patients with migraine encourage and emphasize the importance of lifestyle changes. Commonly referred to as SEEDS (Sleep, Exercise, Eat, Diary, Stress). Lack of sleep significantly impacts many things including tolerance, mental health and overall cognitive functioning.
Patients have made the analogy relating migraine to being in a “washing machine”. Things are going around and around with all the puzzle pieces swirling around. If patients can get one or two pieces of the puzzle under control, it would be helpful. More sleep, better sleep can help lead to better mental health, ability to have energy to exercise, eat better, etc.
People living with migraine are desperate for options that will help improve their quality of life. If patients can control the complications they experience due to their disease (migraine), its one less thing causing stress and anxiety. Sleep is a significant contributor that can’t be ignored. A medication that can help to improve sleep quality and quantity and reduce daytime insomnia would be welcome.
Medications that are not addicting would be welcome. Many physicians are hesitant to prescribe current options for this reason and many patients do not want to take current medications for fear of becoming addicted. Additional desirable outcomes for patients include less side effects (ie. somnolence, cognitive impairment). An additional outcome for patients is effectiveness over longer-term drug therapy. Many products currently available stop working.
Patient comments related to improved outcomes include:
“Finding long term success with any prescription or combinations. I either don’t sleep enough, have interrupted sleep or sleep too much. Success to me would be 7-8 hours all the time”.
“Nothing works for me. I regularly go days and weeks without sleep. I think any new medication that might help would be welcome”.
“Getting enough exercise helps immeasurable; worry makes it all worse; success – fall asleep easily without anxiety about when I will wake up”.
“Success would be consistent quality rest. No real success except taking time off to just sleep as much as my body wants”.
“I don’t remember a time when I slept consistently. I’m on enough medications that give me side effects but they work. As exhausted as I am from lack of sleep, I can’t manage the additional side effects of the sleeping pills that I’ve tried. So I don’t sleep”.
“Finding long term success with any prescription or combinations. I either don’t sleep enough, have interrupted sleep, or sleep too much. Success would be 7-8 hours regularly”.
We did not have any patients with experience on Dayvigo participate in the second survey.
Not Applicable.
Dayvigo is a first in class medication that offers a new mechanism of action to Canadian patients. There have not been new medications to help people manage insomnia in decades (since 1990’s) and the current medications that exist come with the risk of abuse, physical dependency and lack in tolerance over time.
Studies on Lemborexant support they are effective, safe and have greater benefit to risk. It meets the criteria patients have mentioned that are important to them in a new medication including fewer side effects, no rebound insomnia after discontinuation, no negative impact on cognitive functioning (ie. memory, attention) or impairment. Tolerance with Dayvigo in longer term use is also demonstrated.
Patient comments about need for new medications in Canada:
“It’s been over 3 years and I still don’t get a full night’s sleep or ever feel rested. It affects my relationships and my self-esteem greatly”.
“I’d welcome a medication that I don’t need to worry about becoming addicted to adding to my already to many health issues”.
“The medication’s I’ve tried end up not working after a while and then I tried something new and had to sort through different side effects”.
“My doctor won’t prescribe any sleeping pills because they are addicting and just tells me to manage it naturally which if that worked, I wouldn’t be telling him a literally don’t sleep. Ridiculous”.
“I just don’t manage to sleep, can’t fall asleep, can’t stay asleep. I like to find a medication that can help me sleep for 5-6 hours regularly”.
Patients in Canada deserves equitable access to all medications approved by Health Canada. There is no size fits all. Patients and clinicians need options.
To maintain the objectivity and credibility of the CADTH reimbursement review process, all participants in the drug review processes must disclose any real, potential, or perceived conflicts of interest. This Patient Group Conflict of Interest Declaration is required for participation. Declarations made do not negate or preclude the use of the patient group input. CADTH may contact your group with further questions, as needed.
Did you receive help from outside your patient group to complete this submission? If yes, please detail the help and who provided it.
This submission was summarized and written solely by the staff at Migraine Canada, free from consultation, advice, influence or financial support from any outside individual, group or company.
Did you receive help from outside your patient group to collect or analyze data used in this submission? If yes, please detail the help and who provided it.
Migraine Canada worked with a third party to create the on-line Quality of Life survey. Analysis was completed internally.
Migraine Canada independently developed and analyzed the second survey circulated for feedback on Lemborexant.
List any companies or organizations that have provided your group with financial payment over the past 2 years AND who may have direct or indirect interest in the drug under review.
Financial Disclosures for Migraine Canada.
Menopause Chicks is an online learning community for women interested in being proactive with their own health. We teach hormone health, sleep, stress and sexual health and other topics as they relate to perimenopause, menopause and post-menopause. While our reach extends 100,000+, many of our members (40,000) engage via a private online facebook group.
Menopause Chicks conducts ongoing research with its 40,000+ members. In Fall 2021, we asked members (via an online survey) to share their experiences with sleep/poor sleep. We followed up with a small online interview/focus group (November 10, 2021) honing in on specific lived experiences with poor sleep, treatments tried, treatments tried and stopped, and treatments still using. In March 22, in celebration of #WorldSleepDay, we hosted an all-day online learning event for our members with the goal of encouraging more women to have conversations with about sleep/poor sleep/the impact of poor sleep with their health team. Our group is based in Canada, the majority (50%+) of our members are Canadian. A copy of the Fall 2021 Menopause Chicks Research can be found here.
Survey responses: 1027 (68.49% Canadian), 100% female, 92% were 45+ (60% 45-54, 43% in perimenopause; 39% in postmenopause), 77% experience poor sleep more than once-per-week; the most common form of insomnia: waking up too early. 827 responders had tried prescription medication to address poor sleep.
Focus Group participants: 4 (100% Canadian).
#WorldSleepDay attendees: 500 (geography undetermined.)
Our survey showed poor sleep significantly impacted energy level, cognitive function and mood the next day. Other impacts to quality of life included: ability to engage in physical exercise, eating habits, household responsibilities, performance or attendance at work, relationships with partner, time with family and friends, ability to parent or care for aging parents and socializing.
The majority of respondents had tried one or more over-the-counter, sleep hygiene/routine, or mindfulness/medication practice in an effort to manage their insomnia. Most indicated their level of current satisfaction with insomnia treatment as “overwhelmingly dissatisfyied.”
Example of open-ended responses:
“The most challenging part of trying to navigate insomnia has been having to give up working full-time.” “I’ve tried talking to my doctor about insomnia impacts my life, but he won’t listen to me.”
“It’s so frustrating—I feel it’s hit and miss. I find a routine that works for a while, but then it stops working. I need something that will help me sleep consistently!”
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| who have lived experience with insomnia:
“It took me down really bad” – ||||||||, Time: 5:05
“When you are unable to sleep, it is miserable. I thought I was going insane, I didn’t want to live anymore, I just couldn’t thrive.” – ||||||||, Time: 9:10-11:50
“It started with a burst of anxiety and sleeplessness…I was terrified I was never going to sleep again; fearful of going to bed!” – ||||||||, Time 13:40-15:06
“Better sleep brings comfort back. Enjoying sleep again allows me to serve my family, be present for my family, do errands I want to do…be present for whatever I want to do in life.” – ||||||||, Time: 34:46-35:11
“Stress and lack of sleep led me to create Menopause Chicks…because sleep deprivation was turning me into the kind of mother I had no intention of being…it was impacting my relationship with my kids!” – |||||||| , Time: 39:41-40:50
Respondents’ Experience Addressing Insomnia.
861 respondents had tried one or more of the following: magnesium, melatonin, cannabis, antihistamines or anti-allergic medications to manage insomnia.
Of the respondents who had tried prescription medications for poor sleep, the majority had discontinued use due to dissatisfaction with how they felt the next day or fear of becoming addicted.
Example responses to open ended question: “What has been the most challenging in managing your insomnia?” “I define success if I feel rested in the morning. Nothing I have tried to-date seems to work consistently.”
“The biggest challenge is the snowball-effect on my body from sleep deprivation. I’m stressed so I don’t sleep. I don’t sleep so I become more stressed.”
“The most challenging is waking up at 3 a.m. and not being able to get back to sleep and not wanting to take anything in the middle of the night for fear of how it could impact the quality of my next day.”
Respondents had experience with Z –Drugs, Benzodiazepines, Desyrel/trazodone, Elavil/amitriptyline, Remeron/mirtazapine, Dayvigo/lemborexant, Antipsychotics/First generation, Antipsychotics/Second generation and Alpha Deta
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| who have lived experience with insomnia:
“I bought a boatload of herbals” – ||||||||, Time: 22:43-24:50
“I tried many, many different things that did not help…I do not want to hate going to bed!” – ||||||||, Time: 27:21-28:00
Respondents’ desired outcomes include: uninterrupted sleep, waking rested and feeling they can handle responsibilities of the day (work, family, etc.) They would like to see more emphasis/conversation on sleep as a key health indicator—in society and during their health appointments; many cite poor sleep as not being something their doctor ever brings up or something that never becomes personal priority (i.e. “I ‘should’ be able to handle this on my own.)
Over the years, anecdotal conversations in the Menopause Chicks community have pointed towards fear of prescription medications and how they can make women feel the following day, or they fear becoming reliant on a specific medication. There is a common understanding that sleep medications have traditionally been tested on men and often not prescribed properly for women. Members would appreciate getting updates on new developments in this area as a way of supporting their own health, but also to help shift the societal paradigm from “avoid sleeping pills at all costs” to “there are prescription options that are helpful and supportive for women.”
In our member survey, one respondent indicated they were currently taking lemborexant.
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||, we heard: (55:05 mark)
“I have had success using lemborexant in both male and female patients. One patient had been challenged with insomnia for 10 years and it was significantly impacting her quality of life, including her ability to parent and exercise. She mentioned lemborexant to me and after doing my own research, we decided to start her on the recommended dose. She called me two days later and she had slept through the night for the first time in 10 years.” ||||||||||||||||||||||||||||||||||||||||, NP.
The key values important to patients and caregivers, when it comes to the treatment of insomnia include: Does it relieve patient from the burden of “excessive awakeness”? Does it produce 7-8 hours of sleep? Is the sleep restorative that it positively influences quality of life for the patient the following day? Both patients and health professionals want more choice; more options when it comes to treating poor sleep/insomnia.
Not applicable.
Thank you for considering this input from a demographic whose health concerns are often overlooked.
Over half of women said they felt dismissed or disappointed leaving their health appointment, that their physician. That number is even higher for Indigenous women and women of colour.
3-in-10 women reported challenges accessing the health care they needed. – InHerWords.ca, BC Women’s Health Foundation
To maintain the objectivity and credibility of the CADTH reimbursement review process, all participants in the drug review processes must disclose any real, potential, or perceived conflicts of interest. This Patient Group Conflict of Interest Declaration is required for participation. Declarations made do not negate or preclude the use of the patient group input. CADTH may contact your group with further questions, as needed.
Did you receive help from outside your patient group to complete this submission? If yes, please detail the help and who provided it.
No.
After learning about CADTH, I did meet with ||||||||||||||||||||||||||||||||||||||||||||||||||||||||, CADTH in January 2022.
Did you receive help from outside your patient group to collect or analyze data used in this submission? If yes, please detail the help and who provided it.
No.
List any companies or organizations that have provided your group with financial payment over the past 2 years AND who may have direct or indirect interest in the drug under review.
Financial Disclosures for Menopause Chicks.
Mood Disorders Society of Canada (MDSC) has evolved to become one of Canada’s best-connected mental health NGOs with a demonstrated track record for forging and maintaining meaningful and sustained partnerships with the public, private and non-profit sectors throughout Canada.
MDSC has grown out of the vision and drive of a number of mental health lived experienced leaders from across Canada who in 1995 saw the need for a broad-based structure to bring consumers of mental health services together and who believe that consumers have a key role to play with regard to education and advocacy at the national level.
It was formally launched and incorporated in 2001 with the overall objective of providing people with mood disorders with a strong, cohesive voice at the national level to improve access to treatment, inform research, and shape program development and government policies with the goal of improving the quality of life for people affected by mood disorders.
The MDSC’s overall objective is to provide people with mood disorders with a strong, cohesive voice at the national level by:
Website: https://mdsc.ca/
Information used to compile this submission was gathered via the following: Mood Disorders Society of Canada (MDSC) conducted a national Sleep and Mental Health survey to understand sleep behaviours and how sleep problems such insomnia impact our mental health, and how mental health issues can also impact our sleep.
MDSC hired the independent research firm Narrative Research to conduct the survey and analyse the results, Our research objectives included:
The online survey of the general population was conducted with a random sample of 1,200 respondents across Canada. In addition, MDSC shared a survey link through its network (notably on social media), resulting in 49 additional surveys being completed. Quotas were applied to the general population survey based on age, gender and region, while the survey results were also weighted on those characteristics. In addition to the questions included on the general population survey, the network survey included a few more questions, resulting in an average completion time of 22 minutes. The average survey length for the general population survey was 18 minutes. The survey was in field from September 21 to October 7, 2021.
Two in ten respondents mention having been formerly diagnosed by a health professional with a sleep disorder. Regardless of having been diagnosed with a sleep disorder, insomnia is prevalent among respondents, with more than half who say that they have experienced insomnia over the past year, specifically difficulty falling asleep or staying asleep, or waking up too early and not being able to get back to sleep. Again, those reportedly suffering from insomnia are more likely to be dissatisfied or neutral about their sleep pattern. They are also most likely to include females, and those with household incomes of less than $50k per year.
Some demographics of the 1,249 completed respondents.
Age:
16 to 29 = 13%
30 to 49 = 39%
50+ = 48%
Gender:
Girl/Woman = 54%
Boy/ Man = 45%
27% of respondents are retired, 44% employed, 9% employed part-time, 5% self-employed, 9% unemployed, with 3% currently identifying as students.
Income levels were:
Under $27,000 – 10%
$27,001 - $41,000 = 15%
$41,001 - $50,000 = 9%
$50,001- $100,000 = 36%
$101,000 or more = 22%
Prefer not to say = 8%
MDSC also gathered information for this submission through individual interviews with three patients who have been struggling living with insomnia, and who have tried a variety of treatments and therapies. We also interviewed several family members to gain further insight.
We spoke at great length with two clinicians. One a family physician and one a psychiatrist.
Additional experience and perspectives was garnered through our reviewing patient and family member input and comments/ shared experiences through our MDSC online Discussion Forum which is hosted on the MDSC website and is a portal for in-depth online discussions.
MDSC has very large number of dedicated followers and our organization has with more than 87,000 social media followers. We have extensive website visitors as well, along with our main mdsc.ca website, our depressionhurts.ca website alone has 500 visitors per day and is extremely active. Our national mental health campaign, Defeat Depression, holds mental health walks from coast to coast with over thousands of people taking part. We also have a national online discussion support chat line that has over 2,800 discussion threads and over 35,000 posts
It is through the above context and our 20+ years of ongoing collective efforts of direct engagement with patients and representing the lived experiences of the patient community that we bring to this submission. It is the goal of our organization to be their voice in this process.
The impacts on a person with insomnia often have wide ranging consequences. According to the results of our national sleep and mental health survey, dealing with serious sleep problems causes distress for most respondents to varying degrees, most significantly for those with a formally diagnosed sleep or mental health disorder, and those reporting insomnia. The issues identified are mostly related to difficulties sleeping, such as having trouble falling asleep or staying asleep, with resulting consequences of feeling tired or having little energy. There is an across the board understanding that sleep has a direct and significant impact on most aspects related to a person’s overall health, including vitality, mental health, intellectual functions, productivity, and body pains/aches. The results of the national survey also clearly indicate sleep issues are seen as having important consequences on society, and there remains a need for increased public education.
One quarter of the survey respondents indicate that they snore loudly, that is loud enough to be heard through closed doors or resulting in their bed-partner elbowing them for snoring at night. This is most prevalent among those self- reporting insomnia, males, Atlantic Canadian respondents and non-white individuals. One in seven report that someone observed them stop breathing or chocking/gasping during their sleep.
Respondents with a formal sleep disorder diagnosis are more likely to report having insomnia, snore loudly and have stopped breathing or chocked/gasped during their sleep. In addition, a diagnosis of a sleep disorder, insomnia and snoring are more common among those who have been formerly diagnosed with mental illness. Also determined was that 60% of respondents stated there was a stigma associated with the illness. Stigma is very real and people can delay getting a diagnosis and seeking treatment due to a fear of what friends, family may think, in addition to their own self- stigma.
During one discussion, the individual informed me that stress and anxiety have a great influence on the quality of their sleep, and they felt that these two factors were the primary reason of their sleep problem. They also identified a drastic increase in their levels of both stress and anxiety since the covid-19 pandemic began.
Following this meeting, in a further discussion, a family member also detailed how they had seen a significant change in their partners’ ability to “turn off” the anxiety (primarily caused by news exposure and work pressures) and linked stressors that have had a profound negative affect on their sleep. The family member stated that the usual pattern seemed to be their partner would go 4-6 days with broken sleep consisting of roughly 4-6 hours of sleep on good nights, interspersed with periods of getting out of bed and moving to the living room, unable to turn off the thinking and unable to fall asleep. On occasion total sleep was even less. This in itself has caused the other partner to have broken sleep during most of these nights as well. During these periods it was mentioned that the family member was feeling stressed, temperamental and emotionally and physically drained.
Respondents in the survey who have a formal sleep disorder or mental health diagnosis, and those who experienced insomnia in the past year, expressed they feel much more likely that sleep impacts how they interact with their spouse/partner or their children. With those respondents between 16 and 49 years of age in a relationship are more likely to say that sleep impacts their relationships to some degree. The impact of sleep on someone’s relationship with their children is also considered more important among parents and guardians 16-49 years old than among those who are older.
It was indicated in the survey responses that 86% of respondents indicated some level of dissatisfaction in their sleep patterns. Of these, 77% stated the sleep problems had at least a little to very much interfering with their daily functions. Within this 7 per cent group, 42% identified their cognitive functions were impacted, 38% stated their household chores were affected, 38% identified with physical exercise being impacted and 28% stated with work was impacted.
One person being interviewed stated sleep is a major factor in mood disorders, and getting enough sleep is very important for wellness maintenance. There was a solid understanding on the connection between mental health and sleep. Our survey results show has an impact on most physical and mental functions.
Respondents were asked how much actual sleep time they got on a daily basis over the past two weeks. For respondents who identified as being unemployed, retired, on short or long-term disability, and those who did not disclose their occupational status reportedly slept an average of 7 hours per night. Respondents who are employed, a student, or volunteer full-time reported sleeping an average of 6 hours before days when they work/have class/volunteer, while they slept an average of 7 hours on other nights. Of the respondents who have identified as having experienced insomnia over the past year, or with a formal sleep disorder diagnosis, and those with a mental health diagnosis, slept an average of one hour less per night compared to other respondents.
As an additional indicator of the ramifications of sleep problems and insomnia, one-third of respondents who are working, studying or volunteering full time have missed time off work, school or volunteer activities due to sleep problems in the past year, and report an average of eight missed days. Those respondents who have a mental health diagnosis (11 days) or a sleep disorder diagnosis (10 days). Looking at the entire responses, the average lost productivity due to sleep issues averages three days in the past year.
Survey respondents who identified as having experienced insomnia during the past year (n=673-676) were asked extra questions about sleep medication and treatments. One quarter of respondents are clearly dissatisfied. More than one quarter of respondents have used prescribed medication in the past to help with their sleep. Past usage of such medication is far more common among those who have been diagnosed with a sleep disorder (57%), people who have experienced insomnia (39%) and those with a mental health diagnosis (62%).
62% report having taken prescribed sleeping medication in the past two weeks, either at least three times a week (35%), once or twice a week (17%), or less than once a week (10%). Respondents who have received a sleep disorder diagnosis are more likely to have taken prescribed sleep medication in the past two weeks with 81% responding affirmative.
On average, the longest period of time that respondents have been using prescribed sleep medications at least three times a week was 59 months (nearly five years). Respondents who have taken prescribed sleep medication mostly saw a positive impact on their sleep from taking these medications and to a lesser extent, on their mental health.
In a separate MDSC national mental health survey conducted in September, 2021, 45% of respondents identified Improving Access to Medications and Treatment as their number 1 election issue for the Government of Canada, with 94% of them identifying it as important. It was the number one priority specified by respondents.
From the clinician in-person (Zoom) interviews:
Clinician #1 (Family physician, over 30 years’ practice, prior, pharmacist. Patient case load of 2,200)
This physician went into great detail on working with hundreds of patients with insomnia, and treated the full spectrum of patients, right from the newly presenting to those who have struggled with insomnia for decades. The challenge he expressed was trying to find the treatment which was safe, stable and tolerated.
During the interview this physician stated that in the years past there was a higher tendency to prescribe benzodiazepines or Z-drugs for insomnia, however there were several key areas of concern, from dependencies to next morning drowsiness.
Clinician #2 (Psychiatrist, over 25 years’ practice)
This Psychiatrist described his many years of working with patients who had among other mental health issues, comorbid issues of insomnia which was compounding recovery and their wellness. He described how sleep was one of the pillars of health and was a key area that needed to be balanced in order to move forward with the patients lives. He went into great details on a treatment pathway many had taken, again reiterating what I had heard previously by clinician #1 and two patients, seemed like there was earlier usage of medications such as trazodone and other benzodiazepines, but there was always the real concern of issuing opioids, dependencies and using these medications.
One instance involved a patient who was dealing with migraines and insomnia. This person was on trazodone daily and a further 15 mg of zopiclone to deal with the insomnia. The patient was always feeling sluggish and mornings were very challenging to get motivated and active. So, when the new treatment Lemborexant became available the patient was weaned off the previous medication and then tried Lemborexant. The result was the patient told the clinician “this is incredible”. The difference was quite profound to them, and they were then getting 7-8 hours of sleep a night.
Another patient who was living with PTSD and had insomnia as a symptom, this person was also finding it difficult to manage their insomnia and had tried for years to get in into a livable situation. Once they began using Lemborexant, they found it to be extremely helpful, and changed the way they were able to live.
It is important to also point out from both these clinicians I heard very aligned experiences, that there has been concern for working with patients who have multiple issues that they are trying to address. For instance, both described the caution needed when dealing with a patient who presented with pain, mental illness and symptoms of insomnia. That in the past there was less options for treatments, which led to more use of opioids as part of the treatments, and this was a concern. Both went into how much having Lemborexant as one of the new tools in their toolbox was extremely helpful
Also both were very aware of how when they are working with patients who have insomnia one of the predominate issues facing many patients is equitable access. While this treatment may not seem, for those who are either unemployed or underemployed, if they are not covered for the treatment regiment, there is a real barrier to access. While we are only talking about a couple dollars a day, if you are on social assistance, or have a wage job, this cost is a real obstacle.
Recently in particular, the pandemic and the economic havoc that has ensued (employment slowdowns, re-structuring, business closures etc.) there are people who are falling between the cracks for coverage. As seen in the demographics of survey participants,34% are earning under $50,000 per year. MDSC has heard directly from patients consistently throughout the years that if you are not employed in an occupation that has a solid benefits plan with sufficient drug coverage, often, covering these expenditures is a severe challenge. One person recently stated it clearly “... I was laid off in July but the company I worked for allowed us to prepay for benefits for 3 further months in an agreement with Manulife. I was on the CERB until it ended and then transitioned over to EI. I get the full amount on EI available, but with rent and basic living expenses it leaves very little for anything else. I have only a few weeks left of medication and the costs are very high...”
We need to realize that many lower income occupations do not come with drug coverage. Additionally, if you are unemployed, or under-employed, and if your medications are not covered within provincial health care plans, you must pay out of pocket. It is why we hear often from patients about not being able to afford the medication they need to recover and maintain their wellness. They either cannot afford the medication or if they do buy it, they will skip doses and try to stretch the prescription out to last two or more months at a time.
MDSC strongly believes that it is crucial that patients are informed of, have access to and have choice of medications that work for them. Patients need to be able to decide on the medication that they feel works for their illness, with the side effects that are acceptable to their lives. What is very well known is that medications can affect one person differently then the way it may impact another person. That is why often, it takes a period of time, and trying different treatments for the patient to find the treatment that works for them. They need to be able to make informed decisions on which side effects they are best able to accept. The goal being to take the treatments that help them best manage the particular illness they are dealing with, in a manner which does not expose them to additional side effects that may cause other issues for them to then have to cope with.
Our position is the unwavering importance that treatment coverage must be available to everyone, regardless of their economic status. It should be a health related right, either through their employer and a quality drug plan, when available, or when a person is not covered through private coverage, due to reasons such as being unemployed or disabled, or any other similar situation, they need to be covered within provincial and territorial health care plans to have access to the treatments that work best for them. Anything less is barrier to equal access, a barrier to health, and detrimental to the success of Canadian society.
Patients, family members, and caregivers believe strongly that access to treatment should not be limited to only those with private drug plan coverage, while those who work for employers who do not have drug coverage do not get access to the medication for their individual illness. Our position is that accessing the medications to treat illness should be fully equitable for all those who are ill.
Of the three individuals who we interviewed and identified as having taken Lemborexant (Dayvigo) three stated they had private health coverage, with one stating as having some private coverage but relied on the provincial health care coverage mainly. None had detailed any experience in clinical trials.
We asked specifically what a meaningful, successful outcome for a good sleep medication would be. We were looking for what they felt was the key values and also asked if they felt they were receiving this now. All there stated what was important to them was to be able to trust that they could fix their sleep problems so that they would be able to enjoy their days again. Especially when it came to interacting with family members and work colleagues. They also all stated to be more productive at work. Minimizing any side effects are a prominent concern. Two identified their being able to not becoming anxious or stressed because they would worry about not being able to count on normal sleep.
Patient #1
“I am finding I am seeing the ability to be able to level off my irregular sleeping patterns, and trust that I will be able to feel rested when I go to work the next day”
“Not having to only rely on waiting until near midnight each night before I finally drift off to sleep, only to waken by 3”
Patient #2
Expressed their feelings of to not become dependent on the medication over the long term. They have been looking for a medication that was gentle on their stomach and not overpowering, which they claimed to feel with this medication.
They stated while it “was too soon to see any pronounced impact, they did not have the feeling of next morning dullness and drowsiness” which they have had in the past.
Patient #3
This patient stated she had tried several different medications in the past, and all seemed to lose their effectiveness after several weeks, leading to either having to take more dosage, which resulted in her feeling hung over the next day. She expressed she has tried Dayvigo, which was working for her without any major side effects.
“Less time laying there tossing and turning now”.
Of these three:
Clinician #1 (Family physician, over 30 years’ practice, prior pharmacist. Patient case load of 2,200)
The physician informed me that the introduction of Lemborexant has been a real game changer and that it was “something so totally different”. He stated he treats the full spectrum of patients, and in doing so there is always the goal of ensuring the cure is not worse than the disease. He has been prescribing Lemborexant over the past year and a half and he is fully impressed with the outcomes. He articulated that with this new treatment he is not worried about issues such as next day sedation. He went on to detail how while treating the full range of patients, he saw an across-the-board positive outcome throughout. Patients who respond well, respond very well. Another key benefit was the quickness of the medication, patients describe taking the medication 20 minutes before bed, they could take it while doing the dishes, or on the couch and get the result 20 minutes later while going to bed. He expressed no concern with attentiveness the next morning, there were no experiences of next day sedation which could impact things like driving, work attendance etc.
He went on to describe a patient who had not informed him that she had been quietly struggling with insomnia for 20 years. He prescribed Lemborexant, and received a call two days later from this patient who was completely thrilled with the fact she was able to now sleep, and stated there was no after effect of impact at all.
Another keynote was that this medication worked well even if the patient was on multiple medications. He indicated that he was able to wean a person off other higher doses of medications once they were able to use Lemborexant to address their insomnia.
Clinician #2 (Psychiatrist, over 25 years’ practice)
As described a little earlier in this submission, this clinician informed me of numerous patients that had been on other medications and he migrated some of them over to Lemborexant. He stated he had good success with this medication one patient went on to state how impressed they were with the treatment telling him…“this is incredible”. and they were then getting 7-8 hours of sleep a night.
One of the real noticeable things the psychiatrist told me about was how they felt confident when prescribing Lemborexant, in that there would not be a rebound in the insomnia, and they would be able to start and stop the treatment if/ when needed. They also went on to let me know that even if a patient missed a day, they would not see any negative issue. There was not experiences with next day sedation
Not applicable.
Mood Disorders Society of Canada (MDSC) is proud to represent and speak on behalf of patients across Canada. Through the course of our business, we engage with patients, family members and caregivers every day on an on- going basis.
A significant component of recovery and wellness maintenance includes access to medications. Finding the right medication that works for the individual can take many months (if you are fortunate) or many years for the patient. During this phase, we need to recognize that the family members connected to the patient are also going through this process.
We know that getting good, consistent, quality sleep is a crucial part of your overall wellness. While many of us tend to delay addressing sleep problems, we often find ourselves reaching a point where it makes itself known to us as being a problem, usually in a manner which is quite noticeable.
Sleep is one of the foundational blocks of our wellness, and it affects all areas of our health and wellness. It eliminates toxins and repairs our bodies, regulates blood sugar, mood and stress, boosts immunity and energizes nerve cells and muscles. Without proper sleep, we quickly can see negative impacts such as drowsiness, daytime fatigue, irritability and headaches, difficulty focusing or paying attention, lack of the ability to complete intricate tasks, and invariably, leads to increased tendencies to make wrong decisions, such as poor unhealthy food choices.
As a society, we have become more pressured to over perform, to place business and success at the forefront of all of our priorities. Coupled with increased media exposure and the pandemic, we have seen a dramatic increase in sleep problems and insomnia. Over the past 18 months, many are re-evaluating priorities and are realizing they are experiencing some imbalances. Many Canadians are now eager to see normalcy return in to their daily realities. This is why finding the right treatment options will support patients return to a healthier life.
We must make sure medications are made available and they can access, their medications if they are not covered by private health care plans. This is crucial to enable patients the ability to maintain work, interact with their family and friends and feel like they are contributing to society.
From our discussions with both patients and clinician, it is vitally important to ensure coverage for this medication. While the cost is negligible, it is so important that barriers do not exist in accessing this new treatment.
To maintain the objectivity and credibility of the CADTH reimbursement review process, all participants in the drug review processes must disclose any real, potential, or perceived conflicts of interest. This Patient Group Conflict of Interest Declaration is required for participation. Declarations made do not negate or preclude the use of the patient group input. CADTH may contact your group with further questions, as needed.
Did you receive help from outside your patient group to complete this submission? If yes, please detail the help and who provided it.
No.
Did you receive help from outside your patient group to collect or analyze data used in this submission? If yes, please detail the help and who provided it.
No.
List any companies or organizations that have provided your group with financial payment over the past 2 years AND who may have direct or indirect interest in the drug under review.
Financial Disclosures for Mood Disorders Society of Canada.
National advisory board comprising Canadian physicians including family physicians and psychiatrists with interest and experience in the management of insomnia.
Advisory board meetings, literature reviews, conferences, discussions with colleagues, clinical experience, patient testimonials.
Describe the current treatment paradigm for the disease.
According to the Public Health Agency of Canada, 1 in 2 adults have trouble falling asleep or staying asleep, while 1 in 3 have difficulty staying awake during the day. Approximately 13% of Canadians meet formal diagnostic criteria for insomnia disorder. The prevalence of insomnia in Canada is further increased in the presence of chronic conditions including hypertension (19%); asthma (21%); diabetes (22%), cancer (23%); back problems (23%); arthritis (24%) migraine (26%); heart disease (26%); peptic ulcer (28%); and stroke (29%). Up to 2/3 of patients with chronic pain conditions also experience sleep disorders. The prevalence of insomnia disorder and the incidence of new cases of insomnia disorder have increased worldwide since the beginning of the COVID-19 pandemic. Canada has one of the highest rates of insomnia disorder since the beginning of the COVID-19 pandemic, second only to the United States.
There has been a paradigm shift in the assessment and treatment of insomnia disorder beginning with the establishment of formal criteria in DSM-5 (2013); the recognition of sleep having a restorative function on multiple aspects of health; the changing focus of insomnia treatments from medications that increase sleepiness to those that reduce alertness; and the importance of CBTi and sleep hygiene in the treatment of insomnia disorder. However, there remain many barriers to the effective management of insomnia disorder including a lack of medical education at all levels concerning insomnia from neurobiology to comorbidities, limited access to services, poor availability of resources, misconceptions about sleep needs, misinformation about self-medication with cannabis, alcohol, and OTC medications as well as the widespread use of off- label and inappropriate medications. In fact, a Canadian study of OTC use has shown a trajectory of increasing use over time in more than I in 5 individuals, and suggested clinical intervention could pre-empt vulnerability to counter- productive self-medication.
Despite the high prevalence of insomnia disorder, there are no Canadian guidelines or evidence-based recommendations. Further, there is no mention of sleep health in any of the current Canadian guidelines for the management of hypertension, diabetes, dementia or obesity – all recognized comorbidities. In fact, ironically, the only guidance relates the the risks of existing treatment (Canadian Coalition for Seniors Mental Health Canadian Guidelines on Benzodiazepine Receptor Agonist Use Disorder Among Older Adults 2019; Pottie, K., et al., Deprescribing benzodiazepine receptor agonists: Evidence-based clinical practice guideline. Can Fam Physician, 2018. 64(5): p. 339-351; Choosing Wisely: https://choosingwiselycanada.org/geriatrics/).
The pharmacological management of insomnia disorder represents a significant challenge in current clinical practice in Canada. The two major classes of approved and reimbursed medications for short-term use are the benzodiazepines (BZPs) [triazolam, flurazepam, nitrazepam, temazepam] and Z- drugs [zopiclone, zolpidem, eszopiclone]. However, in reality these medications are used for much longer periods than recommended and in a potentially dangerous and harmful way e.g, in combination with inappropriate medications such as opioids (OTC and prescription), antihistaminic compounds including OTC cold and flu treatments, or substances such as alcohol and cannabis; and in an unsafe way e.g., driving or operating machinery within 12 hrs of ingestion.
It is well recognized that chronic use of BZPs and Z-drugs is physically and psychologically harmful, due to their addictive potential as well as the common side effects of cognitive and physical impairment. These drugs increase fall risk, especially in the elderly, as well as contributing to next day physical and cognitive impairment. In the opioid pandemic over the last few years, there has been a heightened awareness of the increased morbidity and mortality risk when these medication classes are prescribed in combination with opioids. This realization has significantly reduced prescribing of both of these medications, and led to situations where patients are denied treatment for treating their sleep disorder and pain disorder. According to Canadian Institute of Health Information and Canadian Centre on Substance Use and Addiction hospitalization due to opioid poisoning was most common to co-occur with use of BZPs (19% in 2014- 2015); fatal overdose with opioid was significantly increased with concurrent use of BZPs; and in Ontario for 2015, BZPs were present in post-mortem toxicology reports in half of all opioid related deaths.Compounded sedation and thus risk of death also occurs with other neuropathic pain medications e.g., gabapentin and pregabalin commonly used in conditions such as diabetes and peripheral vascular disease.
The BZPs and Z-drugs mode of action (MOA) is primarily through GABAA receptor agonism and their effect on sleep is through their sedative action. The third class of approved hypnotic is a tricyclic antidepressant that is also sedative due to is antihistaminic activity. Essentially due to their MOA, BZPs and Z-drugs lead to physical dependence, withdrawal and rebound insomnia concerns: 10 – 30% chronic BZD and Z-drug users are physically dependent; 50% BZD and Z- drug users suffer from withdrawal symptoms; 5 – 58% of BZD and Z-drug users develop rebound insomnia, after 2-4 weeks of treatment.
However, with the increasing understanding of the neurobiology of sleep there is a consequent changing focus of insomnia treatments from sedative medications to those that reduce wakefulness e.g., very recent data suggests that compared with healthy controls, patients with primary insomnia exhibited significantly decreased functional connectivity density (FCD) in the left medial frontal gyrus and increased FCD in the left supplementary motor area (JI B, et al.
Neuropsychiatric Disease and Treatment 2022:18 1–10). Consequently, the introduction of an agent with a novel MOA heralds a paradigm shift in the ability to address some of the fundamental dysfunctions in insomnia disorder.
What are the most important goals that an ideal treatment would address?
Insomnia increases the risks of physical (stroke, type 2 diabetes, hypertension, MI, cancer, CHF) and psychiatric comorbidity (depression, anxiety, dementia), as well as overall mortality (OR:1.93 – 2.14). Further, overall mortality risk increases with the number of insomnia symptoms. Insomnia has a debilitating impact on an individual’s health and functional ability on a functional basis.
The economic burden of insomnia in Canada is substantial e.g., $6.6 billion annually and $5010 per person annually in Quebec in 2009, and with 5 weeks of work lost per year due to presenteeism, 1 week lost per year lost due to absenteeism and double the accident rate (not including driving accidents).
Approximately, 74% of Canadians drive to work each day. In Motor Vehicle Accident (MVA) based deaths 11.2% drivers tested positive for sedative-hypnotic prescription drugs post-mortem, while MVA-related accident-based hospitalizations increased from 5.6 to 6.5x within 2 weeks after filling a BZD prescription. Further, 73% of Canadians with insomnia did not feel productive at work and 31% made an error at work with 12% actually falling asleep at work.
Concomitant disease burden and drug savings due to improved management of insomnia.
Considering the treatment goals in Section 4, please describe goals (needs) that are not being met by currently available treatments.
As a result of lack of safe on-label pharmacological options for treating insomnia disorder, physicians have resorted to off-label use of sedating drugs including antidepressants, antipsychotics, and anticonvulsant medications. These classes of medications however have their own inherent long list of harmful side effects. Most worrisome are daytime sedation, anticholinergic side effects, and significant weight gain leading to the many health consequences associated with obesity. The American Academy of Sleep Medicine and Choose Wisely Canada clearly state that these alternatives have potential harm that outweighs the benefit and strongly caution against the use of these medications for treating sleep disorders.
Because of the lack of safe and effective prescription treatment options, many patients have resorted to self-treatment with alcohol and cannabis not infrequently combined with OTCs (sedating antihistamines, diphenhydramine, cold medications). It cannot be overemphasized the harm that overuse of these products are causing to both mental and physical health of patients. This is causing yet another health care crisis in our society and the economic and social costs are quickly mounting.
Which patients have the greatest unmet need for an intervention such as the drug under review?
A CADTH review of interventions for the management of insomnia found the use of sedative drugs is frequently for longer durations than the evidence supports; important points summarized as follows:
The elderly are extremely vulnerable to inappropriate prescribing with 20 -53% in LTC in Canada being prescribed antipsychotic medication without an underlying psychiatric diagnosis. BZPs are in the top 10 drug classes prescribed to seniors with BZP & Z-drugs rate of use increasing with age.
Several Canadian guidelines recommend to optimize the safety and quality of life of older adults through the appropriate use and prescribing of medications, and the deprescribing of inappropriate medications which includes prioritizing the reduction of sedative hypnotics and encouraging policy makers to reimburse alternative interventions (pharmacological & non-pharmacological) that are proven safe and effective. Yet in reality, safety is compromised by the current reimbursement plans e.g., reimbursement criteria in Ontario encourages trial of BZPs and off-label use of trazodone. The latter is the most common medication in the “Other antidepressants” drug class — used by 25.8% of seniors living in LTC. Trazodone, even at low-dose, has been shown to have the same fall risk as BZPs in nursing homes in Ontario. The increase in trazodone and quetiapine users has exceeded the decrease in BZPs users in LTC in Ontario, while in Quebec, 82.5% of trazodone prescriptions are for the off-label use of insomnia.
Of note, the effect of BZPs on postural stability is 3x worse than a person with blood alcohol legal limit for impaired driving and 52-90% increase risk of hip fractures due to BZD and Z-drug use, respectively. In 2015 the costs of hospitalization, emergency department and outpatient visit costs due to inappropriate BZP use in Canada were $3,076 per elderly patient per year.
Four of the top 5 drugs identified by deprescribing guidelines across Canada include BZPs, atypical antipsychotics, typical antipsychotics and zopiclone (with BZDs ranked 1st). These guidelines recommend to deprescribe BZPs and Z-drugs if used more than 4 weeks in adults and in elderly independent of duration of use and not to use BZPs or other sedative-hypnotics in older adults as first choice for insomnia. Yet 34% of family physicians prescribe sedative or hypnotic medications for more than a year.
An Alberta study in 2015 found that the overall prevalence of BZP and Z-drug use was 10% overall, increased with age and was consistently highest among females, and with 20% using both classes of drug and 10% having 3 or more prescribers. Days of consecutive use were highest among the elderly. Further, in Canada, drug plan cost wasted due to excessive dosing and excessive duration of use of BZPs and Z-drugs accounts for 9% and 59% respectively.
American and Canadian guidelines do not recommend trazodone or low-dose antipsychotics for sleep. However, in hospital settings antipsychotics and trazodone are used widely for insomnia even in vulnerable populations of children or elderly. An Ontario study found that 11.5% of children and adolescents in an inpatient treatment unit were being prescribed quetiapine, and in 81%% this was for either insomnia or insomnia and another reason (66% continued on quetiapine after discharge). A Nova Scotia study of hospitalized seniors in 16 different hospitals reported a point prevalence of 34.6%.
The above Canadian data highlight the urgent and dire need to pursue safe and effective interventions for the treatment of insomnia disorder. The wealth of clinical trial data coupled with the significant clinical experience of the group is consistent and emphasizes the place of lemborexant in the modern treatment algorithm for insomnia disorder.
How would the drug under review fit into the current treatment paradigm?
Lemborexant is a dual-acting orexin antagonist and representative of a new class of rationally developed medications for sleep disorders. The MOA is unique and novel compared to all existing treatments and involves modulation of an endogenous neurotransmitter system. The data reviewed indicate broad benefit that include a positive effect on sleep architecture, lack of hangover and cognitive effects as well as increased continuous positive airway pressure (CPAP) compliance reported in patients with obstructive sleep apnea (OSA) and likely downstream cost benefit associated with CPAP compliance.
Insomnia disorder frequently becomes a persistent condition thus earlier identification and intervention is key. In view of the positive efficacy: safety ratio of lemborexant compared with existing alternatives, this agent should be considered as part of first-line treatment. Earlier use of a safe and effective agent with a MOA that has the potential to ameliorate the course of the illness is therefore likely to shift the current treatment paradigm in terms of a focus on earlier use. If lemborexant is used early, there is the greatest potential for improving outcomes in the treatment of insomnia disorder in Canada. It is the opinion of the group that lemborexant that it works quickly, keeps working (no tolerance) and often continues to improve in its action.
Please indicate whether or not it would be appropriate to recommend that patients try other treatments before initiating treatment with the drug under review. Please provide a rationale from your perspective.
From a clinical perspective, it is important to choose the drug with the optimal risk: benefit [short and long-term] for the patient based on individual and disease characteristics. Existing therapies whether indicated or off-label comport unacceptable risk or are completely inappropriate (see response to 6.3 for further details). Therefore, it makes clinical sense to use the best agent as first-line treatment and avoid the harms associated with the drugs currently being used. It is the opinion of the group that lemborexant is the best and most effective agent now available in Canada.
How would this drug affect the sequencing of therapies for the target condition?
Current approved and non-approved therapies typically include Z-drugs, BZPs, antihistamines and antipsychotics. The risks of BZPs include habituation, tolerance and dependence and diversion to cognitive impairment, daytime sedation, memory and motor deficits, delirium, rebound insomnia. The risks of Z- drugs include habituation, tolerance and dependence, diversion, cognitive impairment, daytime sedation, rebound insomnia and complex sleep behaviors. Efficacy diminishes as early as in 4 weeks due to tolerance. In clinical practice not only are these drugs continued for much longer periods than indicated in the product monograph but doses are frequently escalated despite Health Canada alerts recommending reduction in dose to reduce next day impairment.
Antihistamines and antipsychotics are inappropriate and are associated with a multitude of physical health risks (cardiac, metabolic, neurological).
It is the opinion of the group that lemborexant should be offered as a first-line option to potentially prevent chronicity and refraction and reduce likelihood of physical and psychiatric comorbidities. See 7.1 for additional comments from the group.
Which patients would be best suited for treatment with the drug under review?
Given the prevalence of sleep disorders, it is probable that most patients presenting with these complaints in routine practice would benefit from treatment. Further, because of the high rates of comorbidity, both physical and psychiatric, insomnia disorder is a condition that requires assessment and treatment. See 7.1 for additional comments from the group.
How would patients best suited for treatment with the drug under review be identified?
Given the prevalence of s disorders patients are likely to present in routine clinical practice from family practice to specialist clinics. Appropriate clinical assessment is always required. In specialist and sleep clinics it is more likely that rating scales will be utilized but are not necessary for diagnosis. Identification of contributory/confounding factors is part of the clinical assessment. Pre- symptomatic does not really apply to this condition. The criteria for insomnia disorder are now formally defined in DSM-5. See 7.1 for additional comments from the group.
Which patients would be least suitable for treatment with the drug under review?
Patients that have a history of complex sleep behaviors; primary sleep disorders; genetic conditions such as Smith- Magenis syndrome; non-adherence; and treatment refraction. Patients unable or unwilling to implement sleep hygiene strategies. Lemborexant is contraindicated in patients with severe hepatic disease, and there are interactions with diltiazem and modafinil.
Is it possible to identify those patients who are most likely to exhibit a response to treatment with the drug under review?
It is likely that many patients with insomnia disorder would exhibit a positive response to lemborexant, and especially if medication naïve. Thus, the treatment should be a first-line pharmacotherapy choice before harmful alternatives such as Z-drugs and BZPs, to avoid risk of iatrogenic treatment refraction, physical harm including falls and dependence. Given the prevalence of insomnia disorder such patients presenting to physicians should be assessed for treatment.
What outcomes are used to determine whether a patient is responding to treatment in clinical practice?
Response in clinical practice is typically assessed by qualitative improvement in sleep (sleep diaries), day time alertness and functioning through self-report and collateral. Scales used in clinical practice include the with Insomnia Severity Index [ISI] and the Epworth Sleepiness Scale (ESS) which are both short questionnaires. Comorbidities are assessed with Patient Health Questionnaire [PHQ-9] and General Anxiety Disorder [GAD-7] as well as Clinically Useful Depression Outcome scale (CUDOS). The Sheehan Disability Scale (SDS) is used to assess functionality.
What would be considered a clinically meaningful response to treatment?
A clinically meaningful response to treatment would involve qualitative and quantitative improvement in sleep (sleep efficacy), daytime alertness and function, reduction in concomitant medications; improvement in associated relevant conditions, and patient satisfaction.
How often should treatment response be assessed?
Treatment response should be assessed at patient visits through self-report of sleep (supplemented by collateral where possible) and daytime functioning; supplemented with the use of rating scales in specialist clinics.
Side effects of treatment should also be assessed at patient visits. The frequency of adverse effects and side effect profile of lemborexant are both well established and favorable. It is not envisaged that there would be the need for any additional monitoring as it relates to this treatment (ie: blood tests or other interventions).
What factors should be considered when deciding to discontinue treatment?
Discontinuing or switching medications is something that should always be done cautiously and collaboratively taking into account previous treatment history and with a clear rationale. This may include poor or limited response, side effects, or drug-drug interactions. Alternative treatments should be carefully considered in terms of risk: benefit, cost and acceptability. Rebound insomnia is reported with almost all existing treatments but particularly GABA A agonists, and contributes to dependence and difficulty in switching from BZPs and Z-drugs. Lemborexant, given its MOA, is less likely to be associated with rebound insomnia and this is consistent with the clinical experience of the group. Guidance is also provided through the Canadian SwitchRx website.
What settings are appropriate for treatment with the drug under review?
Settings would include family practice, specialist community clinics (general psychiatric, sleep disorders, PTSD/veterans, addictions, women’s health, occupational medicine, neurology), hospital inpatients and outpatients.
For non-oncology drugs, is a specialist required to diagnose, treat, and monitor patients who might receive the drug under review?
Given that sleep disorders are prevalent and managed by many different specialities relevant reviewers should potentially include psychiatrists and family physicians, as well as pulmonologists and neurologists.
Is there any additional information you feel is pertinent to this review?
The group have significant experience in dealing with sleep disorders and the management of complex patients. In discussions, clinicians have shared stories of lemborexant imparting life-changing outcomes for patients by improving cognition, minimizing polypharmacy, enabling significant weight loss, and reducing suicidal and homicidal ideation. Please see comments from the group as follows:
Dr. Walter Chow, a family physician from Victoria, BC, stated that the increasing prevalence of insomnia needs to be recognized, especially with the COVID-19 pandemic and its associated stressors.
Dr. Pierre Chue, a psychiatrist from Edmonton, AB, identified that safe and effective treatments for insomnia are lacking, specifically non-addictive medications.
Dr. Alain Sotto, a family physician from Toronto, ON, noted that many workplace accidents are caused by next-day impairment associated with use of benzodiazepines and Z-drugs—which is particularly important for patients who work as pilots, train engineers, etc. “I actually give a copy of the Health Canada warning to my patients, which states they should NOT drive for 12 hours after taking zopiclone 7.5 mg—all my patients are shocked that it’s actually written.”
Dr. Pieter Strauss, a psychiatrist from Abbotsford, BC, stated the need for insomnia to be viewed as a primary problem; moreover, clinicians should inquire about sleep at every patient visit.
Dr. Roger McIntyre, a psychiatrist from Toronto, ON, observed that, attitudinally, insomnia is often perceived as a diagnosis of later consideration rather than a diagnosis of priority consideration.
Dr. Tom Janzen, a family physician from London, ON, added that clinicians are taught that insomnia is a symptom of other conditions, yet a lack of healthy sleep can lead to other comorbidities.
Dr. Kaplan posited that treatments should be adjusted based on whether a patient is experiencing primary or comorbid insomnia.
Dr. McIntyre remarked that hypnotic medications are prescribed with impunity in Canada; therefore, safety index is a major unmet need in this space.
Dr. Chow emphasized that many clinicians are fearful of regulatory college oversight of benzodiazepines and Z-drugs prescribing practices; this can cause primary care clinicians to avoid prescribing these drugs entirely.
Dr. Alan Lowe, a psychiatrist from North York, ON, noted a lack of patient education; patients should better understand insomnia and the treatment options that are available beyond medications, such as cognitive behavioural therapy for insomnia (CBT-I). He added that patients who are educated about insomnia are less likely to self-medicate with substances such as alcohol and marijuana.
Dr. Kaplan noted that non-pharmacological therapies, such as CBT-I, generally lack availability and accessibility.
Dr. Michael Mak, a psychiatrist from Toronto, ON, acknowledged that patients with insomnia often require immediate treatment; consequently, clinicians need improved access to pharmacotherapy and CBT-I.
Dr. Ruzica Jokic, a psychiatrist from Kingston, ON, commented on the ambiguity of treatment duration recommendations in the presence of medical and psychiatric comorbidities.
Dr. Chue noted that patients often take concomitant medications and substances (e.g. alcohol, cannabis), which pose risks when combined with benzodiazepines and Z-drugs.
Dr. Boivin elaborated that understanding the safety of intermittent use of hypnotic medications is crucial, especially for shift work and atypical work schedules.
Dr. Jokic detailed concerns with long-term benzodiazepine and Z-drug use among the elderly due to comorbid conditions and negative effects on cognition, suggesting that clinicians move away from prescribing these drugs in this population.
Dr. Chow stated, “Elderly patients have that increased fall risk and are very sensitive to anticholinergic medications, especially in conjunction with the polypharmacy that they're already getting. So, in my experience, they do very well with lemborexant. And in some patients who still need their previous insomnia medication, I've been able to reduce doses drastically to a level where I'm more comfortable that I'm not adding more harm than good by trying to get them a good night's sleep.” Similarly, Dr. Chow identified increased fall risk and anticholinergic sensitivity—particularly with polypharmacy—as considerations specific to the elderly. Moreover, his elderly patients have fared well on lemborexant, as it has allowed for drastic reductions of other insomnia medications for a harm-reduction approach.
Dr. Boivin added that patients often use insomnia medications nightly for years, despite established recommendations for the shortest possible duration.
Dr. Kaplan commented that discontinuing benzodiazepines and Z-drugs is extremely difficult, as patients with tolerance experience withdrawal.
Dr. Janzen commented that the lemborexant MoA has unique properties compared to past substances.
Dr. Chue underscored that lemborexant may benefit from the current trend of emphasizing “natural” therapies (e.g. melatonin, marijuana) and that benzodiazepine and Z-drugs significantly impair cognition, emotion, and memory, which makes it difficult for patients to benefit from behavioural treatment and cognitive therapy. Conversely, lemborexant's lack of cognitive impairment allows for a combination of pharmacotherapy and an enhanced response to behavioural or cognitive therapy. “I see a lot of PTSD patients who are prescribed up to their ears with benzodiazepines and other Z-drugs to reduce some of that hypervigilance, arousal, and anxiety. Yet those very drugs actually impact negatively on the other interventions that we are trying to implement with this very difficult and damaged population.”
Dr. Kaplan highlighted that, unlike benzodiazepines and Z-drugs, lemborexant improves sleep architecture—including sleep stages 3, 4, and REM—which leads to improved recovery of both body and brain.
Dr. Jokic and Dr. Lowe emphasized that lemborexant improves daytime functioning and overall quality of life. Notably, patients with OSA are more compliant with their CPAP therapy since lemborexant helps with middle and late insomnia; this reduces downstream issues with CPAP non-compliance, such as increased risk of cardiovascular disease and/or psychiatric disorders.
From his occupational medicine practice, Dr. Sotto identified that business executives who travel extensively for work could benefit substantially from lemborexant. Currently, these patients use zopiclone 7.5 mg; however, they are often deterred by the associated 12-hour impairment after ingestion. Dr. Sotto highlighted the need for personalized therapy to meet the demands of each patient.
Dr. Boivin added that there is interest in lemborexant use to improve sleep-wake cycles in patients with circadian rhythm disorders—notably, shift workers, patients with psychiatric disorders, and patients with fibromyalgia.
Dr. Sotto highlighted that patients taking lemborexant 5 mg cannot drive for 7-9 hours compared to 12 hours with zopiclone; this is a significant difference that clinicians should balance against the needs of each patient’s lifestyle.
Dr. Strauss stated that many patients with insomnia are unaware of their degree of impairment from lack of sleep and fatigue. This may be due to comorbid anxiety and depression that prevents them from adequately addressing sleep or use of medications that cause severe daytime sedation. “I've seen with the patients that I've switched over or started treating de novo with lemborexant, how people say they are woken up and how they're suddenly finding themselves capable and that executive tasks take a shorter time. And I've already started seeing that self-confidence improves as a result of that.”
Dr. Lowe highlighted the uniqueness of lemborexant because, in addition to other sleep stages, it increases REM, which is important in many psychiatric conditions where REM and slow-wave sleep (SWS) are suppressed.
Dr. Lowe reported good results from lemborexant treatment—used in combination with other psychotropic agents—among his patients with chronic psychiatric conditions. Patients convey waking up more refreshed, which allows other psychotropic agents to be reduced.
Dr. Chue alluded to the link between insomnia and the development of significant inflammatory markers over time, including an increased risk of cancer. Therefore, insomnia is not only a disease process in and of itself, but also worsens other conditions and pathologies.
Dr. Boivin identified daytime functioning as the most important factor for successful insomnia management, rather than time-to-sleep onset and total sleep time. She acknowledged that patient reporting is subjective; however, patients' perception of their sleep is very important and a key goal of CBT-I.
Dr. Boivin further emphasized that the significance of overall patient functioning, which involves obtaining a history of their daily activities, asking how they feel about their sleep (e.g. are they anxious if they wake up in the night?), and asking how they function throughout the day.
Dr. Chow suggested that short- and long-term safety of a pharmacological treatment is important, particularly from a clinician's perspective.
Dr. Kaplan noted that successful insomnia management may improve other comorbid conditions in which insomnia is a secondary concern.
Dr. Sotto stated that the driving test data from the lemborexant safety study provided valuable information for patient use, as well as an indicator of next-day functioning.
Dr. Sotto identified the necessity of counselling for successful insomnia management, emphasizing that this is especially important for patients who have been taking benzodiazepines and Z-drugs. Patients require education that being “knocked out” by a GABA agonist does not equate to high quality sleep.
Dr. Jokic added that patients should be informed that they should observe improvements in thinking, attention, and concentration and, thus, work performance with better quality sleep.
Dr. Sotto stated, “The comment I wanted to bring to your list is I think we need to put patient counselling. Most people think that when you take a sleep drug, especially if they've been on benzos or Z-drugs, they think they're going to get hit on the head and knocked out. And that is a really bad misconception.
Lemborexant doesn't do that—it doesn’t block your GABA receptor. So you have to explain to the patient, you've been on Z-drugs for 10 years, I'm going to give you lemborexant, don't expect to get knocked out, it's not how it works. And once you educate them, I think that's really where the rubber meets the road.”
Dr. Jokic added that patients should be informed that they should observe improvements in thinking, attention, and concentration and, thus, work performance with better quality sleep.
Dr. Chue stated, “And if they're sleeping better then it's an opportunity to start looking at reduction in the medications that we've been utilizing to try and improve sleep or sedate. So, that can take some refining over time, depending on the number of medications and overall complexity.”
Dr. Mak responded that any pharmacologically-naïve patients or those who wish to move away from benzodiazepines or Z-drugs are ideal for lemborexant.
Dr. Kaplan emphasized that all patients with insomnia should be considered for lemborexant.
Dr. Sotto noted, “Perimenopausal women come in, they haven’t slept, they’re anxious, they’re flashing, they’re hot. They just come in as a disaster, and we do them a terrible disservice because we’re not treating their lack of sleep. So, I think they’re a prime example where lemborexant would be great.”
Dr. Lowe identified that patients with refractory insomnia and those with late insomnia should be considered for lemborexant.
In addition to patients who report sleep issues, Dr. Kaplan remarked that clinicians should also consider lemborexant for patients on long-term benzodiazepines or Z-drugs—oftentimes, these individuals do not recognize that they are impaired. To this end, Dr. Kaplan stated that he is proactively discussing lemborexant with all his patients on benzodiazepines or Z-drugs.
Dr. Mak added that patients waitlisted for CBT-I could be treated with lemborexant.
Dr. Lowe suggested that patients who are self-medicating with alcohol and/or marijuana would be good candidates for lemborexant.
Dr. Chow commented that he greets every patient in his clinical practice by asking them how they are managing through the COVID-19 pandemic and, if they are struggling, he asks them how they are sleeping. This simple introduction uncovers many patients with insomnia.
Dr. Kaplan underscored that all patients with chronic pain should be asked about their sleep quality, as poor sleep can worsen pain and vice versa. Additionally, many medications used for chronic pain are sedating, though that does not necessarily equate to high quality sleep. Moreover, combining benzodiazepines or Z-drugs with opioids for chronic pain treatment greatly increases the risk of overdose; he urged clinicians to balance pain severity against the risk of opioid misuse. Dr. Kaplan urged psychiatrists to consider a patient’s chronic pain medications when prescribing psychiatric medications, such as benzodiazepines or Z-drugs. Dr. Kaplan expressed excitement about lemborexant as it can help patients with chronic pain sleep without it being a sedative, which substantially decreases the risk of overdose. He recommends that this be a major point of emphasis for lemborexant use.
Dr. Kaplan expressed excitement about lemborexant as it can help patients with chronic pain sleep without it being a sedative, which substantially decreases the risk of overdose. He recommends that this be a major point of emphasis for lemborexant use.
Dr. Jokic concurred with Dr. Kaplan, noting that lemborexant can be combined safely with pregabalin for the treatment of fibromyalgia.
Dr. Sotto: given the effect improper sleep can have on other comorbidities, lemborexant is both life-sustaining and lifesaving and, therefore, should be covered.
Dr. Janzen commented that payors need to be informed of the population benefits of a successful insomnia medication to improve comorbidity burden (e.g. anxiety, depression, psychosis) and safety (e.g. preventing hip fractures). Additionally, it is necessary to outline to payors that by treating even a small percentage of people with insomnia, the risks associated with the current insomnia treatment options can be reduced significantly.
Dr. Lowe remarked that if payors wish to save costs, they need to fund medications that are safe, efficacious, and improve functional outcomes. In his practice, Dr. Lowe has begun observing improved CPAP compliance, which indirectly reduces costs (e.g. costs from cardiovascular events).
Dr. Sotto argued that, given the effect improper sleep can have on other comorbidities, lemborexant is both life-sustaining and lifesaving and, therefore, should be covered.
Dr. Kaplan noted a major benefit of lemborexant amongst his patients with chronic pain is that they now have a safe option for sleep that can be taken in combination with opioids; this is extremely important as sleep is necessary for pain management. “So, for me, lemborexant is revolutionary. Instead of using a medication with sleep as a side effect, we can use a medication that’s going to help their actual sleep.”
Dr. Jokic reported her patients with mood disorders feel less foggy, can think more clearly, are more active during the day, and can concentrate. However, it is difficult to objectively measure quality of life in clinical practice, so she relies on subjective patient-reported outcomes to assess daytime functioning and quality of life. “And for me, the biggest success is that people are actually re-engaging— going back to work, going back to school—and that is something that we can objectively measure with some scales that affect daytime function.”
Dr. Mak noted that he has had success switching long-term users of benzodiazepines and Z-drugs to lemborexant, particularly patients over 65 years or those with newly developed movement disorders.
Dr. Chow reported success with cross-titration. Patients who have been on high- dose benzodiazepines or Z-drugs for many years require a slower taper period. Furthermore, a broken sleep-and-wake switch justifies using reduced doses of sleep switch medications. Moreover, temporary co-administration of hypnotic medications and lemborexant during cross-titration has been proven by SwitchRx but should be individualized for each patient.
Dr. Jokic added that none of her patients taking lemborexant and benzodiazepines or Z-drugs in parallel have experienced any worsening of daytime functioning.
Dr. Chow stated, “I find with typical antipsychotics the taper is usually over a matter of weeks. With benzos and Z-drug hardcore users, it's a matter of months, sometimes taking down only by 10% every few weeks. I have been much more successful at harm reduction and getting them down on the doses of those less favourable medications, and lemborexant has really been able to help with that.”
Dr. Kaplan highlighted the issue of caffeine addiction in patients with insomnia, noting that lemborexant can help reduce this dependency. Many patients claim they need coffee to wake up; however, coffee carries health risks (e.g. atrial fibrillation).
Dr. Jokic reported that patients with treatment-resistant mood disorders describe improvements with lemborexant—they can read a book, can compose a sentence without losing their train of thought, and do not need reminders everywhere.
Dr. Kaplan added that patients who are sleeping better often report improved mood as measured by PHQ-9.
Dr. Kaplan added a personal story, stating that he travelled a lot prior to the pandemic. He has tried benzodiazepines and Z-drugs, which resulted in severe next-day sedation and impairment, so he is interested to see how lemborexant will improve travel.
Dr. Kaplan noted a major benefit of lemborexant amongst his patients with chronic pain is that they now have a safe option for sleep that can be taken in combination with opioids; this is extremely important as sleep is necessary for pain management. “So, for me, lemborexant is revolutionary. Instead of using a medication with sleep as a side effect, we can use a medication that’s going to help their actual sleep.”
Dr. Chow highlighted positive feedback from his patients, including that they fall asleep quicker, feel more refreshed and clear-headed in the morning, and do not need coffee to get rid of morning brain fog. Patients do not explicitly state that they fall less; however, Dr. Chow posits that this can be extrapolated.
Dr. Kaplan agreed that requiring less coffee is a subtle—but vital—indication of improvement.
Dr. Jokic reported her patients with mood disorders feel less foggy, can think more clearly, are more active during the day, and can concentrate. However, it is difficult to objectively measure quality of life in clinical practice, so she relies on subjective patient-reported outcomes to assess daytime functioning and quality of life. “And for me, the biggest success is that people are actually re-engaging— going back to work, going back to school—and that is something that we can objectively measure with some scales that affect daytime function.”
Dr. Mak noted that he has had success switching long-term users of benzodiazepines and Z-drugs to lemborexant, particularly patients over 65 years or those with newly developed movement disorders.
Dr. Strauss shared an anecdote of a patient who used trazodone for 20 years for sleep as part of her management for generalized anxiety disorder (GAD), social anxiety, PTSD, and major depressive disorder (MDD). Additionally, she had a history of comorbid alcohol dependence but had been abstinent for four years. The patient was morbidly obese with a poor quality of life. Dr. Strauss noted that initial attempts to switch this patient to lemborexant resulted in physical withdrawal (e.g. shivers, tremors, nausea). A second attempt was made with a more gradual trazodone taper. Lemborexant has been life-changing for this patient—she is social, feels more confident, is more cognitively capable, and lost 30 pounds from increased activity levels.
Dr. Chow shared a story of an elderly patient who previously used zopiclone nightly and lorazepam as needed. With oversight from the College of Physicians, the patient was gradually weaned from benzodiazepines and Z-drugs to amitriptyline, trazodone, and quetiapine as needed. The patient was also on tamsulosin and finasteride for urinary retention symptoms. The patient was cross-titrated off trazodone, quetiapine, and amitriptyline, in addition to stopping tamsulosin and finasteride due to urinary improvements. Dr. Chow commented that this highlights the anticholinergic side effects of many medications used in the elderly. With lemborexant, the patient went from five medications to one—a cost saving from the payor’s perspective.
Dr. Jokic recounted a high-functioning 60-year-old with severe depression with psychotic features requiring polypharmacy, including mirtazapine, olanzapine, and duloxetine. The patient encountered significant issues getting restorative sleep and experienced profound cognitive dysfunction. Dr. Jokic stopped mirtazapine, decreased the olanzapine dose, and added lemborexant. The patient’s functioning improved significantly; in addition to losing 20 pounds, they reported being able to exercise, read, and volunteer.
Dr. Lowe added that he sees patients with severe psychiatric disorders and OSA similar to Dr. Jokic's case. He has observed great success reducing symptoms of suicidal and homicidal ideation among this population with lemborexant treatment.
Dr. Chow commented that he provided lemborexant samples to his dentist; after three days of lemborexant use, they reported no impairments and felt clear-headed.
Dr. Boivin shared that she has provided lemborexant samples to her postmenopausal friends with sleep problems, and they have reported positive effects.
To maintain the objectivity and credibility of the CADTH drug review programs, all participants in the drug review processes must disclose any real, potential, or perceived conflicts of interest. This conflict of interest declaration is required for participation. Declarations made do not negate or preclude the use of the clinician group input. CADTH may contact your group with further questions, as needed. Please see the Procedures for CADTH Drug Reimbursement Reviews (section 6.3) for further details.
Did you receive help from outside your clinician group to complete this submission? If yes, please detail the help and who provided it.
Eisai provided clinical trial data specific to lemborexant; organized the advisory panel with physicians nationwide and provided a summary of the discussions. Beyond the data provided, Eisai has not influenced the opinions provided in this submission, which remains entirely that of the contributory authors/advisory board members.
Did you receive help from outside your clinician group to collect or analyze any information used in this submission? If yes, please detail the help and who provided it.
See above.
List any companies or organizations that have provided your group with financial payment over the past two years AND who may have direct or indirect interest in the drug under review. Please note that this is required for each clinician that contributed to the input — please add more tables as needed (copy and paste). It is preferred for all declarations to be included in a single document.
Name: Dr. Pierre Chue
Position: Professor of Psychiatry, University of Alberta
Date: March 18, 2022
COI Declaration for National Advisory Board — Clinician 1.
Name: Dr. Walter K. Chow
Position: B.Sc. (Pharmacy), MD. Family Physician
Date: March 2022
COI Declaration for National Advisory Board — Clinician 2.
Name: Dr. Kyle O. Lee
Position: Family Physician
Date: March 21, 2022
COI Declaration for National Advisory Board — Clinician 3.
Name: Albert Ng
Position: Physician
Date: March 18, 2022
COI Declaration for National Advisory Board — Clinician 4.
Name: Tom Janzen, Parkwood Institute, London, Ontario
Position: Physician on Assessment Unit Mental Health and CMIO
Date: March 21, 2022
COI Declaration for National Advisory Board — Clinician 5.
Name: Dr. Christine Palmay
Position: Consultant, Slide Deck – Sleep During Midlife Years and Beyond
Date: March 18, 2022
COI Declaration for National Advisory Board — Clinician 6.
Name: Lionel Noronha
Position: Family Physician
Date: March 18, 2022
COI Declaration for National Advisory Board — Clinician 7.
This clinician group is comprised of a network of senior clinicians across Canada who are specialists in or have a very strong interest in the treatment of sleep disorders. The group includes nationally and internationally known experts in sleep disorders, insomnia, mood, anxiety and attention deficit hyperactivity disorder (ADHD), who are extremely active in continuing medical education to public and professional audiences worldwide.
There are over 300 years of multi-disciplinary clinical experience among these clinicians that spans not only sleep medicine and insomnia, but general practice, psychology, psychiatry, neurology and respirology. All have significant experience with the evolution, strengths, and weaknesses of treatments in insomnia disorder with and without multiple comorbidities, as well as a keen awareness of the longstanding gaps in treatment options for our patients.
Clinicians in the group also represent a wide variety of treatment settings, including hospital, community, and private outpatient settings. All have academic appointments or university affiliations, and many are heavily involved in national and international research, clinical trials, as well as guideline development in insomnia and many of its major comorbid disorders. The group also includes feedback and research studies from the first recipient of the CIHR Distinguished Scientist Award for Insomnia Research. (CM)
The information gathered for this submission was compiled from:
Please note that there are three separate document files with this submission:
Insomnia disorder has been shown to be an independent clinical entity with clear diagnostic criteria. (1) It has a very significant prevalence in Canada (over 13% with the disorder and 30-40% with symptoms) that is linked to medical and psychiatric illness as well as significant morbidity and health system costs. (2-4) Recent data put the estimated cost to the province of Quebec from insomnia alone at $6.6 billion yearly. (4) Insomnia disorder has also clearly shown to have a bidirectional relationship with multiple common comorbid medical and psychiatric comorbidities such as major depressive disorder (MDD) and chronic pain. (5) and the treatment of insomnia has been shown to improve these comorbid conditions. (6,7)
The first line therapy for insomnia disorder is cognitive behavior therapy (CBT-I), a short-term, sleep-focused, non-drug treatment. This includes sleep hygiene education, cognitive therapy, relaxation therapy, stimulus control and sleep restriction. The most critical parts of CBT-I appear to be the behavioral sleep scheduling procedures, including stimulus control and sleep restriction. (8,9) However, in the Canadian context delivering this treatment is severely limited by lack of publicly funded access and training, as well as the limited number of adequately trained health-care providers competent to deliver treatment. Although it is quite efficacious with few adverse effects, and great leaps have been made to deliver this service through telemedicine strategies and digital therapeutics, many patients cannot or choose not to do CBT-I as it takes significant effort and motivation. Up to 30% of patients also drop out of CBT-I therapy before finishing (10) and 30-35% of patients do not respond even after a full course of CBT-I treatment. (9,11) There may also be specific subtypes of insomnia that pharmacotherapy may be better suited for. (12, 13)
Hence, the current practical standard of care for community clinicians for the management of insomnia disorder in Canada is largely pharmacotherapy. Unfortunately, this currently consists of a small range of drugs with limited evidence of efficacy, effectiveness, safety warnings, or that are used off label. This leads to the lack of or inconsistent treatment of insomnia disorder. Thus newer, safer and well tolerated pharmacotherapeutic agents with good evidence are very necessary in the treatment paradigm for insomnia disorder.
Traditionally, the classes of drugs that are indicated by Health Canada for pharmacotherapy for insomnia have included the benzodiazepines and the benzodiazepine receptor agonists (BzRA) zopiclone, zolpidem, zaleplon and eszopiclone, which have a similar but more specific mechanism of action. Although there can be subtle differences between the BzRA in their subunit binding patterns, all the above drugs work as sleep promoters through the Gamma aminobutyric acid (GABA-A) receptor agonism. More recently, two agents that block wake promoting neurotransmitters have been indicated, doxepin, an antidepressant that selectively blocks histamine at very low doses, and the drug currently under review, the novel dual orexin receptor antagonist (DORA) lemborexant.
Though effective, there are significant challenges to treatment of insomnia disorder with the benzodiazepines and to a lesser degree the BzRA. They can confer a significant risk of adverse effects, such as delirium, falls, motor vehicle accidents, respiratory depression, cognitive impairment, memory issues as well as abuse, dependence, tolerance, and withdrawal symptoms with long-term use particularly in the elderly or medically ill. (14, 15) Insomnia disorder is also mostly a long-term chronic illness (16), yet treatment guidelines, as well as large groups such Choosing Wisely and deprescribing.org recommend against the use of these drugs in the long term. (8, 17-19)
And though the evidence does not completely support this, Health Canada monographs and regulatory colleges in many provinces have put punitive dispensing restrictions and excess monitoring on the benzodiazepines and BzRA, (20-25) making clinicians even more hesitant to treat insomnia disorder with them. Despite a better safety profile and promising data, low dose doxepin has not been proven to be widely successful in its clinical use and only has an indication for sleep maintenance. (26)
Because of these limitations, numerous drugs without Health Canada approval are routinely used in the treatment of insomnia and are often a first line treatment for many Canadian clinicians. Commonly used ones that have mixed recommendations include the hormone melatonin and the sedating antidepressant trazodone. (27,28) Many other off label agents are also utilized, and these include sedating antidepressants (mirtazapine, amitriptyline), other members of the benzodiazepine class (lorazepam, clonazepam), alpha-2 delta ligand anticonvulsants (gabapentin and pregabalin) and even the mostly inappropriate usage of low dose atypical antipsychotics (quetiapine, olanzapine, risperidone). Though guidelines indicate that these can be useful in insomnia disorder cases with significant comorbid illness or certain subpopulations, (27) evidence is scant and these are not recommended treatments. (8,17,18)
Poorly regulated over the counter (OTC) preparations containing doxylamine, dimenhydrinate and diphenhydramine are also used frequently in Canada (3) and can also lead to tolerance, dependence, falls and very deleterious cognitive side effects, especially in the elderly. (29-31) Surveys also indicate a high use of other substances such as alcohol and cannabis for insomnia. (32) Outside of very rare usage of cannabis for sleep difficulties associated with significant comorbidities, (33) the use of cannabis for insomnia disorder can be a dangerous practice, yet it is common and heavily promoted by the legalized retail and medical cannabis industry. All the above factors lead to a confusing landscape and at times mistreatment for Canadian patients suffering from insomnia disorder.
The underlying disease mechanisms of insomnia disorder are still being investigated and are complex and multifactorial. No pharmacological treatment appears to modify the disease mechanisms, and all medication treatment at this point should be considered symptomatic. However, early prompt treatment may reduce further chronicity and disability of insomnia disorder. (27) CBT-I directly targets the perpetuating factors contributing to the chronicity of the disorder and may thus be considered to partially modify the underlying mechanisms. (34) Other off label treatments may facilitate a reduction and improve insomnia symptoms by treating the underlying comorbidity and CBT-I has been shown to do this as well. (7, 35)
Current treatment guidelines for insomnia disorder are centered around 2 primary goals, to improve sleep continuity [i.e., nocturnal symptoms such as improving sleep onset, sleep maintenance by reducing awakenings and increasing the total sleep time (TST)] and to improve related daytime function through decreases in fatigue, impaired attention/concentration, disrupted mood, lack of motivation as well as impaired social and professional life impairments. (17).
By definition, treatment of insomnia disorder would not provoke adverse effects such as next day cognitive impairment, unsteadiness or behavioral abnormality occurring during sleep. Simply improving nocturnal symptoms is not adequate if not achieving an improvement overall daytime function. Normal sleep architecture should be preserved and restored as much as possible as well.
Insomnia is related to many adverse health consequences including depression, cardiovascular disease, hypertension, obesity, and neurodegenerative disease. (36-38) Optimal management of insomnia should also have a significant positive impact on burden on these diseases, overall occupational function, and health related quality of life.
Considering the treatment goals, please describe goals (needs) that are not being met by currently available treatments.
Insomnia is a multifactorial complex disease, and it is well known that not all patients respond to all treatments. Unfortunately given the currently indicated treatments, it has long been a “one size fits all” approach for the Canadian clinician which has not previously considered the variety of insomnia symptom types, mechanisms, and associated comorbidities.
As mentioned previously, CBT-I is an excellent first line treatment, but is often not accessible or acceptable to the patient and has a limited response rate even when used optimally. Hence pharmacotherapy will still be commonly used by Canadian clinicians either in tandem, after, or instead of this first line treatment. Many of the currently approved medications have potential side effects that limit their use in several populations. Long term efficacy is often undocumented and only 3 agents, lemborexant, eszopiclone and zolpidem have data of 6 months or more. (39-41)
Even when used properly as per the current evidence, current treatments such as benzodiazepines and to some extent the BzRA, commonly show a significant lack of response, tachyphylaxis and tolerance in clinical practice. Clinicians have not had a safe and endorsed treatment for chronic insomnia so prescribing scheduled drugs for lengths of time and at doses that guidelines and monographs mainly do not support, using off label agents or even trivializing and not treating insomnia occurs frequently. Given this and the wide use of OTC and substances by patients for sleep, it is quite clear outcomes are not being met in insomnia disorder. Treatments with better evidence on key outcomes with improved tolerability and safety are critical. Compliance with medication is typically not an issue, however both psychological and physical dependency with certain agents can be problematic.
Which patients have the greatest unmet need for an intervention such as the drug under review?
As noted above, could be argued that the majority of patients with insomnia disorder have an unmet need. Insomnia disorder is very common and presents frequently to the primary care physician. Almost one-third of visits to a family practice network were related to a sleep complaint and 11% met the criteria for insomnia disorder, (42) which is remarkably consistent with the Canadian population prevalence data of 30-35% for a sleep complaint and more than 13% for the disorder. (3) Equitable access to another accessible, tolerable, and efficacious approved treatment such as lemborexant is simply necessary to continue to give further options for the Canadian clinician to address this common and disabling complaint.
Particular groups of patients with a greater unmet need would include.
How would the drug under review fit into the current treatment paradigm?
As noted above, lemborexant is a DORA (Dual Orexin Receptor Antagonist) which is a unique, novel, and more specific mechanism of action. It is part of a new evolving paradigm of medications with high pharmacological specificity to offer improved safety, efficacy, and more targeted symptom outcomes in insomnia disorder.
This competitive and transient dual orexin receptor antagonism targets a completely different cerebral network in comparison to other medications used both on and off label for insomnia. It directly and specifically targets the mechanism of high wakefulness and hyperarousal during the night which may be more related to the underlying disease process of insomnia disorder. It does this in a precise fashion without almost any other effect on other neurotransmitter areas. (67) This is in direct contrast to most other indicated agents that promote inhibitory neurotransmitters and/or crudely and non-specifically suppress indirect arousal mechanisms. It also appears to increase total sleep time in a more natural fashion by increasing REM sleep. (68) The clinical significance of this is unclear, but it may promote better memory and emotion regulation (69) and is direct contrast to the majority of commonly used sleep promoting drugs. (70)
Lemborexant is clearly a first line therapy for all patients with insomnia disorder that are offered pharmacotherapy. It has clinical trial data in comorbid and elderly populations demonstrating excellent efficacy/tolerability, a very low side effect profile, (39, 50, 71) no apparent tolerance, withdrawal, or dependence, (61) and limited overall next day effects even on driving. (72, 73) Lemborexant also demonstrates limited drug interactions and no change in dosing or adverse events is suggested in wide age and weight groups. (74, 75) Even though the FDA classified it as a schedule IV drug, there is no compelling evidence of abuse potential in theory (55) or seen in clinical trials. As noted earlier, Health Canada has not classified it as a controlled substance.
There is also clear response with lemborexant in severe insomnia, (76) and a reduction of next day fatigue. (77) Also, a recent meta-analysis evaluating a number of insomnia treatments indirectly indicated that lemborexant had the highest probability of being the best treatment for 3 of the 4 outcomes measured objectively by polysomnography. These were a measure of sleep onset, latency to persistent sleep (LPS), and two measures of overall sleep quality, the amount of time spent in bed in sleep, or sleep efficiency (SE) as well as total sleep time (TST). (78)
Our clinical experience has also mostly matched the above trial data and our group would also clearly consider lemborexant among one of the first agents to be used in insomnia disorder pharmacotherapy for all Canadian clinicians.
Although the unique mechanism of lemborexant would complement other insomnia pharmacotherapy, combination pharmacotherapy for insomnia disorder would be off label and saved for more resistant or comorbid patients. However, our group have found clinically that even though the other agent can’t often be discontinued, the dose can be lowered, lowering the risk profile. Pharmacotherapy can often complement CBT-I and may facilitate earlier insomnia remission (79,80). Extrapolation from other studies would the support concomitant use of lemborexant and CBT-I, given its unique mechanism of action and the lack of tolerance, rebound, and withdrawal. We have also seen clinically that the unique mechanism of lemborexant also complements other pharmacological treatments for common comorbid conditions such as depression and bipolar disorder by not interfering with the mechanism of action and not increasing side effects.
The availability and usage of lemborexant has already caused a shift towards better treatment of insomnia disorder in the current treatment paradigm. We have already seen fewer patients who are resorting to less proven riskier medications, cannabis, OTC medication and alcohol to help their symptoms. Lemborexant could also be considered benzodiazepine and BzRa “sparing” as previously clinicians would have no choice but to use these medications long term in an off-label fashion to treat the patient constantly having to weigh the risks of the agent versus treatment of the disorder.
Earlier, safer treatment of insomnia disorder has also been seen with the first line use of lemborexant which may reduce chronicity and the aforementioned consequences of the disease. More equitable access for lemborexant would further this paradigm shift. We also believe this is sustainable to the Canadian health care system because the agent is priced very competitively in this country for a new first in class agent with a unique mechanism, especially given the significant economic burden of insomnia. This group has had many patients who have had no qualms for paying out of pocket for lemborexant given the marked improvement in their functioning, cognition and limited next day side effects.
Please indicate whether or not it would be appropriate to recommend that patients try other treatments before initiating treatment with the drug under review. Please provide a rationale from your perspective.
Patients should always be offered or trialed on some form of CBT-I, or at the very least stimulus control and sleep restriction as a first line treatment, as this is an efficacious non-drug long term intervention with very few adverse effects. After this, given that major comorbidities have been assessed and treated, as noted above lemborexant would be a first choice pharmacotherapeutic treatment for all insomnia patients given the data on efficacy, tolerability, safety and potential unique mechanism of action that may be disease modifying.
The BzRA, especially eszopiclone, which has a wide variety of efficacy and safety data in multiple populations superior to the other insomnia medications (81,82) could be considered for short term/acute insomnia or second line treatment for chronic insomnia. Doxepin could be considered in the elderly if sleep maintenance is an issue. (49) Trazodone and melatonin have some guideline support and could be considered. (27,28) Other off label treatments could still be considered if there is a major comorbid condition to be treated (27), failure of the above treatments, or if financial access to newer agents is an issue.
How would this drug affect the sequencing of therapies for the target condition?
As mentioned above, lemborexant has allowed us to use treatments such as benzodiazepines, BzRa and off label treatments such as trazodone and mirtazapine later in therapy. The safety and tolerability profile of lemborexant and the DORA class clearly differs from those of more traditional sleep-promoting drugs. (83)
If lemborexant fails, the risk benefit ratio of other agents is more defensible for patients and clinicians. This drug could be used as a subsequent line of therapy if the patient is stable on current treatment and has been offered CBT-I initially or concomitantly. Off label combination use with other agents for sleep has proven to be useful clinically with lemborexant as well.
Which patients would be best suited for treatment with the drug under review?
Data formally identifying of subgroups that will preferably respond to lemborexant is still unclear. As this drug acts in a mechanism to “turn off the wake signal”, clinically it is hypothesized that it may work well for patients suffering states of hyperarousal, such as those with chronic pain, mood, anxiety, or trauma related conditions. The anxiety and trauma aspects may be particularly important due to the level of collective global societal traumas experienced during the COVID-19 pandemic and the significantly increased rates of insomnia disorder (more than 25% in one recent Quebec study) in Canada. (84)
Many of the other groups that would be clinically well suited to lemborexant have a great unmet need for treatments and have been outlined above in question 5.2. To reiterate this would include:
Actual disease characteristics that would indicate suitability for lemborexant treatment would be chronicity of disease given it is one of only two indicated sleep agents that has efficacy data for up to 12 months (40, 61). Given the reduction of hyperarousal by lemborexant, we have also found clinically that patients that have disorders of the arousal system (such as insomnia disorder comorbid with anxiety depression, bipolar disorders, ADHD, post-traumatic stress disorder (PTSD), and chronic pain syndromes appear to respond better.
How would patients best suited for treatment with the drug under review be identified?
The diagnosis of insomnia disorder is made with history taking, clinical examination and judgment. Although there are clear criteria, insomnia disorder is also a longitudinal illness often accompanied by many comorbid, sleep, medical and/or psychiatric disorders. (96, 97) The insomnia complaint can often be a risk factor, separate disorder or symptom of its major comorbidities as almost ¾ of patients have at least one major comorbidity. (1, 42) Patient reporting of subjective symptoms can be prone to selection and/or recall bias, hindering the diagnosis. Depending on training and experience there can be much variability in expert opinion on the interpretation of the contribution of insomnia disorder in a particular patient’s overall case. Subsequent over or under attribution to comorbid conditions often occurs.
There are no laboratory tests to diagnose insomnia disorder, however validated diagnostic tools have been developed such as the Insomnia Severity Index to assist diagnosis and treatment monitoring (98,99). There are also other scales to establish the likelihood of other sleep disorders that include the STOPBANG and Berlin questionnaire (sleep apnea), IRLS (restless legs syndrome) and the MEQ (circadian rhythm disorders). (100) Common comorbidities such as depression, anxiety, bipolar disorder, and ADHD need to be screened for as well and tools such as the PHQ-9, (depression) GAD-7, (anxiety), MDQ (bipolar disorder) and the ASRS (ADHD) can be used. (100) However, these are all subjective scales that lack specificity to create a diagnosis and there is variability in usage and stringent comorbidity screening. This does not preclude the treatment of insomnia, especially with CBT-I, but not assessing comorbidities can potentially greatly reduce the effectiveness of pharmacotherapy. Simple monitoring with sleep diaries and movement-based technologies is also popular clinically.
Often a polysomnogram or sleep study (PSG) is used to rule out other sleep disorders but is not recommended routinely for insomnia workup (97). Full PSG testing is superior in this facet, but not widely accessible in many parts of the country without cost or significant wait times. Home PSG testing is notoriously inaccurate in the setting of insomnia disorder and the overutilization of this can interfere with an insomnia workup and incorrectly judge the contribution of a breathing related sleep disorder, jeopardizing the order in which the insomnia disorder is treated.
Insomnia disorder is not challenging to diagnose properly in clinical practice, but a major issue is the lack of understanding of how its many medical, sleep and mental health comorbidities interact to ensure proper treatment. Misattribution often occurs in clinical practice, and it can take many years and the right consultations to clarify the correct diagnosis and comorbidities. System issues in diagnostic and treatment difficulties are related to a lack of primary care training, full PSG and insomnia specialist support in parts of Canada. The population of many provinces outside of Ontario often only have one or two centers that treat insomnia patients.
It is unclear if there is an insomnia prodrome, but early and prompt intervention with CBT-I or short-term medications in the acute phase intuitively can lessen disability in the future. (101)
Which patients would be least suitable for treatment with the drug under review?
Those who have not responded to multiple attempts with other agents (lemborexant may be tried, but expectations would be guarded) and who have not had formal behavioral sleep medicine interventions. Patients with a high degree of untreated comorbidity, pediatric patients as there are no data, or narcolepsy type illnesses that already lack orexin would not be suitable. Patients with nightmare disorder or REM sleep behaviour disorder may be less suitable, given that lemborexant has been seen to increase REM more than other classes of agents, (68) but clinically this has not always seen to be the case.
There is also no data for lemborexant in the transient insomnia patient that requires as needed sleep medication and the mechanism of action would likely be more suited to a chronic insomnia that requires regular pharmacotherapy.
Nonetheless, many of this group have found clinical success in off label as needed use, especially in shift workers.
Is it possible to identify those patients who are most likely to exhibit a response to treatment with the drug under review?
This sort of response specificity has remained elusive in insomnia disorder, although further work with more specific agents such as lemborexant as well as insomnia phenotypes may eventually change this. Since the mechanism of action of lemborexant is to transiently inhibit the wake and arousal system, intuitively patients who have this disruption may respond better. As previously noted, clinically this group has seen better responses in many areas where arousal is disrupted such as patients with insomnia and MDD, anxiety ADHD, PTSD, and fibromyalgia. The elderly may also have a type of insomnia that responds to the orexin blocking mechanism of action (52). The group has also seen that those without long term benzodiazepine or BzRA use may do somewhat better, indicating again the potential suitability of lemborexant as a first line therapy.
What outcomes are used to determine whether a patient is responding to treatment in clinical practice?
Outcomes used in clinical trials include objective measures of sleep on the PSG such as LPS, TST, wake after sleep onset (WASO) as well as similar variables calculated by subjective patient sleep diary measures. TST is thought to be most correlated to self-report next day function. (102)
The Insomnia Severity Index (ISI) is the most frequently used patient reported outcome to document treatment response and remission from insomnia in clinical trials. This scale correlates well with outcomes used in clinical practice which would be self-reports of improvement insomnia symptoms, sleep quality, nighttime wakening, amount of sleep, next day fatigue, and ultimately improvement in daytime functioning and quality of life. (99)
What would be considered a clinically meaningful response to treatment?
There has been significant lack of standardization of clinically meaningful outcome measures in insomnia clinical trials (103), and there may be a mismatch between subjective and objective definitions of response and remission. (104) However, when using the ISI, which is a 7-item patient-report scale with a maximum score of 28, a cutoff score above 8 or 10 have both been used insomnia disturbance, a score of below 8 is used to indicate absence of insomnia, and a score greater than 14 suggests moderate to severe insomnia (98, 99). In clinical trials of both CBT-I and pharmacologic agents, a change in the total ISI score of 7 or greater indicates a clinically meaningful improvement of insomnia symptom severity, whereas an absolute value on the total ISI score of below 8 points indicates a remission from insomnia. (99)
Although there can be great variability, commonly used definitions of objective response are a LPS or WASO of below 30 min, sleep efficiency over 80% as well as an increase of TST over 30 minutes. Lemborexant is equivalent or above clinically significant effect sizes for subjective and objective variables compared to other indicated pharmacotherapeutic agents for sleep (78, 105)
The magnitude of response to treatment can vary greatly by physician in insomnia disorder. Factors include recognition of insomnia disorder as a separate dimension that requires treatment, training in treatment modalities for insomnia, the ability to assess, screen and get major comorbidities treated, adherence to guideline-based therapy, therapeutic rapport with patient, as well as the availability of full PSG and CBT-I resources.
How often should treatment response be assessed?
This will depend on the severity. When treatment is initiated, response should be assessed every 2-4 weeks to monitor response, especially if concomitant CBT-I is being pursued or the medication is being tapered. If a patient remains stable, review every 3-6 months would be warranted. (27) Because of the lack of tolerance, long term side effects or apparent tachyphylaxis with lemborexant, assessment of treatment response in chronic insomnia may not need to be as frequent as it is with other agents such as benzodiazepines or BzRa drugs where the side effects and risks clearly worsen with age. (14)
What factors should be considered when deciding to discontinue treatment?
Factors to be considered include both level and stability of response and the key outcome how the sleep leads to improved next day function. Lack of response in this area would lead to discontinuing treatment. Conversely, a very positive response may also lead to consideration of discontinuing treatment if concomitant CBT-I has been used or if the response is longstanding and stable. Lemborexant has no evidence of physical withdrawal and can be stopped quickly making it much easier to discontinue treatment compared to the benzodiazepines and to a lesser extent BzRA. Stopping these drugs quickly can lead to numerous deleterious psychological effects and even seizures. (14) Other factors to consider in discontinuing lemborexant are uncommon adverse events such as excessive next day fatigue, disturbing dreams and rarely sleep paralysis. Off label additional treatment may be needed in resistant patients, but because of the unique mechanism of lemborexant that will be often in combination therapy with a traditional insomnia agent rather than instead of.
What settings are appropriate for treatment with the drug under review?
This is an oral tablet that does not need supervision. It can be taken in all settings (hospital inpatient/outpatient, community settings or at home by the patient)
For non-oncology drugs, is a specialist required to diagnose, treat, and monitor patients who might receive the drug under review?
No, as noted above, insomnia is an extremely common disorder. It presents in some fashion to most clinical specialties. Lemborexant is a safe, tolerable agent that is can easily be used by any physician that needs to treat insomnia with pharmacotherapy. Most commonly this would be the community family physician, psychiatrist, or sleep specialist. Given its favourable efficacy and safety in the elderly as well as evidence that it may help sleep in neurodegenerative conditions, geriatric physicians, hospitalists and internal medicine specialists may initiate treatment as well.
Lemborexant is a very safe, effective, and tolerable first line agent suitable for a wide age range of people years who suffer from insomnia, which is a serious and common condition that can lead to significant morbidity, mortality and health system costs if not adequately treated. This group strongly believes that the data for lemborexant accurately reflect our clinical experience and it has become a much needed and valuable 1st line pharmacotherapy for insomnia disorder in a wide variety of settings. It is easy to prescribe and is competitively priced for a first in class agent with this level of efficacy and safety.
Lemborexant has been found to be very helpful alone or in combination to treat those with severe chronic refractory insomnia associated with medical and psychiatric comorbidities. Patients often will report “the most natural sleep I have had,” “felt the most rested I have ever felt,” and “finally I have gotten the sleep I have been wanting for so long.” Significant improvements in function and return to work from disability has been seen a number of times. Clinicians themselves suffering with insomnia have also been started on this agent and reported similar benefits.
More equitable access to this agent will allow better and earlier treatment of insomnia disorder and help reduce the current byzantine pantheon of off label medication, OTC and chemical usage of treatments for insomnia disorder that has far more deleterious effects on the patient and the health care system both directly and indirectly.
To maintain the objectivity and credibility of the CADTH drug review programs, all participants in the drug review processes must disclose any real, potential, or perceived conflicts of interest. This conflict of interest declaration is required for participation. Declarations made do not negate or preclude the use of the clinician group input. CADTH may contact your group with further questions, as needed. Please see the Procedures for CADTH Drug Reimbursement Reviews (section 6.3) for further details.
No.
Did you receive help from outside your clinician group to complete this submission?
No.
Did you receive help from outside your clinician group to collect or analyze any information used in this submission.
Not applicable.
List any companies or organizations that have provided your group with financial payment over the past two years AND who may have direct or indirect interest in the drug under review. Please note that this is required for each clinician who contributed to the input — please add more tables as needed (copy and paste). It is preferred for all declarations to be included in a single document.
Name: Pierre Blier, MD, PhD
Position: Professor, Department of Psychiatry, University of Ottawa
Date: March 17, 2022
COI Declaration for CCSSP — Clinician 1.
Name: Thien Thanh Dang Vu
Position: Neurologist, Professor
Date: March 2, 2022
COI Declaration for CCSSP — Clinician 2.
Name: Alex Desautels
Position: Clinical assistant professor, University of Montreal; Medical Director, Center for Advanced Research in Sleep Medicine Hôpital du Sacré-Coeur de Montréal
Date: March 9, 2022
COI Declaration for CCSSP — Clinician 3.
Name: Raymond Gottschalk
Position: Consultant
Date: March 24, 2022
COI Declaration for CCSSP — Clinician 4.
Name: Jeffrey Habert, MD, CCFP, FCFP
Position: Assistant Professor, University of Toronto, Department of Family and Community Medicine
Date: 12/03/2022
COI Declaration for CCSSP — Clinician 5.
Name: Martin Katzman
Position: Professor; Clinical Director
Date: March 25, 2022
COI Declaration for CCSSP — Clinician 6.
Name: Atul Khullar, MD, MSc, FRCPC, DABPN, DABSM, DABOM
Position: Clinical Associate Professor, University of Alberta Dept of Psychiatry
Date: Feb 8, 2022
COI Declaration for CCSSP — Clinician 7.
Name: Serge Lessard
Position: Medical director introspect research centre
Date: March 22, 2022
COI Declaration for CCSSP — Clinician 8.
Name: Alan Lowe
Position: Assistant Professor, University of Toronto; Psychiatry Staff, North York General Hospital
Date: March 2022
COI Declaration for CCSSP — Clinician 9.
Name: Michael Mak
Position: Psychiatrist
Date: March 19, 2022
COI Declaration for CCSSP — Clinician 10.
Name: Roger McIntyre
Position: Psychiatrist
Date: March 19, 2022
COI Declaration for CCSSP — Clinician 11.
Name: Charles Morin
Position: Professor of Psychology, Director, Sleep Research Center, and Canada Research; Chair in Behavioural Sleep Medicine, Université Laval
Date: March 22, 2022
COI Declaration for CCSSP — Clinician 12.
Name: Roumen Milev
Date: March 2, 2022
COI Declaration for CCSSP — Clinician 13.
Name: Charles H. Samuels
Position: Medical Director, Centre for Sleep and Human Performance
Date: March 9, 2022
COI Declaration for CCSSP — Clinician 14.
Name: Jennifer Swainson
Position: Associate Clinical Professor Dept of Psychiatry University of Alberta; Psychiatrist, Misericordia Community Hospital
Date: Feb 15, 2022
COI Declaration for CCSSP — Clinician 15.
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