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Between mid-February and mid-March 2020, the number of sleep prescriptions in the United States rose by 14.8%. The increase may be due to the pandemic, says Manoj Malhotra, MD. Based on his experience, he says “the current environment, with myriads of shifts in our day-to-day lives, is a perfect storm for sleep challenges.”

In this Mental Health Minute, Malhotra explains how to distinguish between a general lack of sleep and chronic insomnia, and how to treat the latter.

 is vice president, United States medical affairs for the neurology business group at Eisai.

Have you seen more patients with sleep problems during the pandemic? 

Share comments with your colleagues by emailing 

. Comments may be shared online pending review and editing for style.

Key considerations for healthcare providers seeking to manage their patients’ insomnia.  

The COVID-19 Pandemic Is a Perfect Storm for Sleep Challenges

The US Food and Drug Administration (FDA) recently accepted the new drug application (NDA) for Idorsia’s investigational dual orexin receptor antagonist, daridorexant, designed for the treatment of 

“I’m very happy that this first regulatory hurdle is behind us,” said Jean-Paul Clozel, MD, Chief Executive Officer of Idorsia. “This was a huge NDA and the team has done an excellent job in preparing the dossier, on which the FDA can judge the properties and merits of daridorexant. We now stand-by to work with the FDA to answer any questions that might arise concerning the effect of daridorexant on sleep, daytime functioning, and its safety profile.”

Daridorexant targets overactive wakefulness associated with insomnia by blocking the activity of orexin, has a rapid onset, and lasts long enough to cover the night without any next-morning residual sleepiness. According to data from the phase 3 registration program, daridorexant is the first insomnia treatment to show statistically significant and clinically meaningful improvements in daytime functioning, sustained over time, as well as sleep during the night.

“While we designed daridorexant to have the optimal profile for a sleep medicine, I am none-the-less stunned by the results. Once approved, by providing daridorexant to the millions of patients with insomnia, Idorsia will have a major impact on this medical, social, and economic problem,” Clozel said. “It has struck me particularly in these times of confinement that we are living through, that sleep problems are a major issue and require an extremely safe and effective drug that can be used by the many. With these results Idorsia is entering into a new era; less than 3 years since its creation, Idorsia is taking a huge step forward in delivering on the vision to become a fully-fledged biopharmaceutical company.”

Adverse events included headache, somnolence, fatigue, dizziness, and nausea, although the incidence of somnolence was low and did not increase with daridorexant 50 mg when compared with placebo.

Idorsia submitted the NDA on January 8, 2021 and anticipates a US launch in the first half of 2022, should approval be received.

1. Idorsia Pharmaceuticals. FDA accepts the new drug application for review of Idorsia’s daridorexant for the treatment of adult patients with insomnia. 

https://www.globenewswire.com/news-release/2021/03/10/2190042/0/de/FDA-accepts-the-new-drug-application-for-review-of-Idorsia-s-daridorexant-for-the-treatment-of-adult-patients-with-insomnia.html

2. Idorsia Pharmaceuticals. Idorsia announces positive results in the first Phase 3 study of daridorexant with improved overall sleep and daytime performance of patients with insomnia. News release. April 20, 2020. 

https://www.idorsia.com/media/news-details?newsId=2284972

This investigational dual orexin receptor antagonist improved sleep overnight and daytime functioning. 

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holds a doctorate in psychology and is the founder of Pro Recovery Rx, a supplement line dedicated to supporting brain health for individuals in addiction recovery. She also teaches a class called NeuroHealth Coach, which helps professionals integrate brain health into their daily lives.

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The US Food and Drug Administration (FDA) has accepted Avadel Pharmaceuticals New Drug Application (NDA) for FT218 for review. FT218 is a formulation of sodium oxybate that uses Avadel’s MicroPump™ controlled-release (CR) technology for the treatment of severe daytime sleepiness and cataplexy in adults with narcolepsy.

“The FDA’s acceptance of our NDA for once-nightly FT218 and assignment of a PDUFA target action date of October 15th represents another important milestone on the path towards receiving approval. We are confident in our regulatory filing strategy and we look forward to working with the Agency in our pursuit of bringing this important treatment to patients,” Greg Divis, Chief Executive Officer of Avadel, said to the press. “If approved, FT218 will be the first and only once-nightly oxybate medication, a significant advancement to the twice-nightly regimen that has been required for nearly 20 years.”

Avadel’s NDA submission is supported by positive data from the phase 3 REST-ON study, completed under a Special Protocol Assessment (SPA) agreement with the FDA. In the first half of 2021, Avadel intends to present data from the study for the 3 primary endpoints, a number of secondary endpoints, and post-hoc analyses at upcoming conferences.

“It’s important to remember that FT218 was granted Orphan Drug Designation by the FDA based on the plausible hypothesis that it may be clinically superior to the twice-nightly formulation of sodium oxybate already approved by the Agency for the same indication. If the FDA approves FT218 and grants Orphan Drug Exclusivity, then we would be awarded a seven-year period of market exclusivity in the US,” said Divis.

The FDA assigned the NDA a Prescription Drug User Fee Act (PDUFA) target action date of October 15, 2021.

Additionally, 4 phase studies from the FT218 pharmacokinetic program will be published in the article, “Pharmacokinetics of FT218, a Once-Nightly Sodium Oxybate Formulation in Healthy Adults,” in 

“These data should instill confidence in clinicians and patients regarding the robust phase 1 development program for FT218, with the demonstration of predictable blood levels of the active ingredient with a single dose, and a low residual amount of active drug remaining when a patient would awaken,” David Seiden, MD, lead author and senior medical director of clinical development and medical affairs at Avadel Pharmaceuticals, told the press. “As a sleep medicine physician and researcher, I am pleased that we have leveraged our proven technology to move toward the goal of patients potentially having access to a once-nightly sodium oxybate treatment.”

1. Avadel Pharmaceuticals. Avadel Pharmaceuticals announces FDA acceptance of New Drug Application for FT218 in adults with narcolepsy for the treatment of excessive daytime sleepiness and cataplexy. News release. March 1, 2021. 

https://www.globenewswire.com/news-release/2021/03/01/2184208/0/en/Avadel-Pharmaceuticals-Announces-FDA-Acceptance-of-New-Drug-Application-for-FT218-in-Adults-with-Narcolepsy-for-the-Treatment-of-Excessive-Daytime-Sleepiness-and-Cataplexy.html

2. Avadel Pharmaceuticals. Avadel Pharmaceuticals announces publication of once-nightly FT218 pharmacokinetic studies. News release. March 2, 2021. 

https://investors.avadel.com/news-releases/news-release-details/avadel-pharmaceuticals-announces-publication-once-nightly-ft218

If approved, this formulation of sodium oxybate will be the first once-nightly oxybate treatment for daytime sleepiness. 

Sleepiness Treatment Under FDA Review 

Thomas So, PharmD, discusses getting a better night's sleep, even during the pandemic. 

is Manager at the Meducation Group at First Databank (FDB). 

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Andrew Krystal, MD, discusses his recent publication, 

Cost-effectiveness of digital CBT (Sleepio) for insomnia: A Markov simulation model in the United States

is a psychiatrist who cares for adults with all types of sleep disorders, with particular expertise in insomnia. He also treats patients who have mood and anxiety spectrum disorders in addition to sleep disorders. An internationally renowned expert on sleep and mood disorders, he has more than 25 years of experience in patient care and research. He is president of the Sleep Research Society and a member of the American Academy of Sleep Medicine, American Psychiatric Association and American College of Neuropsychopharmacology. He serves on the examination committee of the American Board of Sleep Medicine, which allows medical professionals to pursue certification in sleep medicine.

How cost-effective is fully automated digital cognitive behavioral therapy (CBT) intervention for insomnia?

Digital Cognitive Behavior Therapy for Insomnia 

At the recent Virtual SLEEP 2020 Meeting, Eisai gave 2 presentations. One of these was on lemborexant, which was recently launched in the US for the treatment of adult patients with insomnia, characterized by difficulties with sleep onset and/or sleep maintenance.

In these presentations, data on the following topics were shared:

1. Long-term results evaluating lemborexant efficacy and safety in adults ages 65 and older, in measures of time to sleep onset, sleep efficacy, and sleep maintenance.

2. Efficacy and safety results of lemborexant in female subjects of perimenopausal age from SUNRISE 2.

3. An open-label pilot study evaluating the ability of patients with insomnia disorder to directly transition from zolpidem to lemborexant. 

4. The impact of lemborexant on fatigue severity.

is the International Project Team Lead for the lemborexant clinical development program at Eisai. 

The International Project Team Lead for the lemborexant clinical development program shares insights from their presentations at the Virtual SLEEP 2020 Meeting. 

An Inside Look at 2 Presentations from the Virtual SLEEP 2020 Meeting

If you were to poll physicians and ask which specialty usually takes the lead in the management of chronic pain, no doubt an overwhelming majority would say anesthesiology, with a smaller number saying neurology and physiatry. However, probably few would say psychiatry.

It is odd considering the recent revision of the 

 by the International Association for the Study of Pain, the leading worldwide organization for medical professionals involved in the field of pain: “Pain is always a subjective experience that is influenced to varying degrees by biological, psychological, and social factors.”

 This appears to be almost precisely with what psychiatry deals.

We already know that there is a high degree of comorbidity between 

 with chronic pain and, although it is commonly thought that the mental disorders are always secondary to the pain, research has shown that pain is a common presenting symptom of these disorders.

The papers in this Special Report discuss 2 other problems that frequently occur in those with chronic pain: 

 (PTSD). We have known about the relationship between sleep disorders and chronic pain for years; however, the relationship between pain and PTSD is a more recent finding.

As with depressive and anxiety disorders, it is usually thought that if a sleep disorder is present in a person with chronic pain, the sleep issue is always secondary to the pain. However, this oversimplifies the relationship. The interaction between pain and sleep disorders is often a 2-way street, with each exacerbating the other. Both the pain and the sleep disorder need to be addressed.

Of course, the presence of any type of pain can impair sleep. Patients with peripheral diabetic neuropathic pain often report worse pain in their lower extremities during the night when they are trying to sleep. Those who suffer from complex regional pain syndrome in their lower extremities may complain that it is it painful to have sheets touch their skin due to allodynia, in which stimuli that do not usually cause pain do so. Patients with back pain often report problems with sleep due to pain although, curiously, laying down is the position they usually find most comfortable. In fact, if the pain is worse lying down, it is considered a red flag indicative of serious underlying pathology.

Similarly, disruption in normal sleep cycles can cause pain. More than 45 years ago, research found disruptive sleep in some healthy individuals precipitated the symptoms of fibromyalgia and resulted in widespread pain.

There are few studies on the treatment of comorbid pain and sleep disorders. Although both are commonly treated with medications, there is limited research on using pharmacologic agents when both problems are present. Most of the studies have looked at pregabalin in patients with fibromyalgia.

Opioids and benzodiazepines, medications that are frequently prescribed for patients with chronic pain, may actually exacerbate pain because they can cause hyperalgesia (eg, lower pain threshold). These agents can also exacerbate sleep disorders because of their disruption of normal sleep architecture. Sadly, many lay people and medical professionals mistakenly believe that the sedative side effects of these medications mean they will be beneficial for sleep.

There is much less research on chronic pain and PTSD, although there has been a growing interest in the past few years. 

A limiting factor of the data is that much of the research involves veterans. Due to the nature of our recent wars, many veterans suffer from painful injuries caused by explosions. They frequently suffer from traumatic brain injuries (TBI) of varying severity. In fact, both pain and sleep disorders have both been associated with TBI.

 Of course, few civilians who suffer PTSD have similar experiences, so the role TBI may play in the development of comorbid PTSD and chronic pain remains to be determined. 

In addition, research has shown that PTSD may not only be associated with both pain and sleep disorders, but also play a role in acute pain becoming chronic pain.

Since we have yet to identify a markedly efficacious treatment for PTSD, adding chronic pain as a factor further complicates care decisions. Furthermore, although there has been much speculation as to which factors predispose people to develop PTSD and chronic pain separately, we still have no final answer, and we have limited ability to predict who is at increased likelihood for developing both.

For all 3 problems—PTSD, sleep disorders, and chronic pain—psychologically based therapies appear to be among the most promising treatments. They also do not carry the same risks of exacerbating another condition as do medications.

Since psychiatrists often treat PTSD and even sleep, there is little doubt they will see patients with comorbid chronic pain. Unless psychiatrists also are knowledgeable about pain and its management, we will not be able to provide optimal care for our patients.

 is in private practice in Philadelphia.

This article was originally posted on October 21, 2020, and has since been updated. Scroll down for the 

 of the full print issue in which it appeared. -Ed

The revised International Association for the Study of Pain definition of pain: concepts, challenges, and compromises.

2. Moldofsky H, Scarisbrick P, England R, et al. Musculoskeletal symptoms and non-REM sleep disturbance in patients with “fibrositis syndrome” and health subjects. 

3. Husak AK, Bair MJ. Chronic pain and sleep disturbances: a pragmatic review of their relationships, comorbidities, and treatments. 

4. Lavigne G, Khoury S, Chauny JM, et al. Pain and sleep in post-concussion/mild traumatic brain injury. 

5. Burns JW, Janssen, Lillis T, et al. The transition from acute to persistent pain: the identification of distinct trajectories among women presenting to an emergency department. 

Pain may not often be considered within the realm of psychiatry; however, chronic pain's relationships with sleep disorders and PTSD make it an issue psychiatrists can—and should—address.  

Psychiatry’s Role in the Management of Chronic Pain

Pain has a substantial impact on sleep, and an insufficient amount of restful sleep can increase pain susceptibility. Brief bouts of pain—such as pain due to a traumatic injury or a short-lived medical issue—can cause almost immediate adverse effects on daytime functioning and alertness. The symptoms can begin to manifest as soon as the day after a night of inadequate sleep. Chronic pain can lead to prolonged sleep deprivation that can have physical, emotional, and behavioral complications. For example, in the rheumatologic literature, it has long been noted that there is an association between chronic musculoskeletal pain, sleep disruption, and depression.

 More recent research attempts to elucidate the contributing factors and address treatment planning.

 is a benefit of effective pain management. A pain management strategy may also require dedicated attention to sleep quality and sleep quantity. Evaluation of sleep disturbances in the context of chronic pain requires a comprehensive assessment of subjective symptoms and objective tests, such as sleep questionnaires and an 

. Treatment of sleep issues caused by chronic pain is individualized and multifaceted and must take the chronic pain condition, the specific sleep disturbance, and the psychiatric sequalae into account.

Sleep disturbances caused by chronic pain

It is estimated that between 50% to 80% of those living with chronic pain experience sleep disruption. For example, a study revealed 53% of participants with chronic pain met criteria for insomnia, while only 3% of the pain-free controls met the criteria.

 There is also a potential a dose-response link between the intensity of pain and its impact on sleep.

Insomnia is the most commonly noted sleep disorder associated with chronic pain. A large meta-analysis noted a high prevalence of other sleep disruptions as well, with the 3 most common being insomnia at 72%, restless leg syndrome with a prevalence of 32%, and obstructive sleep apnea with a prevalence of 32%.

 It is notable that the 3 most commonly observed sleep disorders added up to greater than 100%, underscoring the fact that chronic pain can be associated with more than 1 type of sleep disturbance at a time (

There are several mechanisms by which pain interferes with sleep. Pain is an obvious distraction that makes it hard to fall asleep and can lead to waking up at night, especially when pain medication wears off. However, pain also interferes with the physiology of sleep in targeted ways that go beyond the conscious distraction caused by the discomfort. There is a variability in chronic pain diagnoses, and the distinctive types of pain syndromes affect sleep differently. Furthermore, the impact of chronic pain on sleep appears to be multidimensional. Research into various pain syndromes and their physiological impact on sleep provide a range of insights into the ways that pain interferes with sleep.

For example, acute post-surgical pain also has quantifiable effects on sleep, including a measurable decrease in the time spent in the 

 (REM) of sleep. Changes are noted not only after general anesthesia, but also after regional anesthesia.

 This observation suggests that the pain itself (rather than the general anesthetic wearing off) is at least a contributing factor to post-operative pain-associated sleep disturbances.

Fibromyalgia is frequently associated with sleep disturbances.

 Patients with fibromyalgia have reduced short-wave sleep and abnormal α-rhythms, with episodes of wakefulness during non-REM sleep.

 Daytime fatigue and non-restorative sleep are common complaints among patients who have fibromyalgia, and these polysomnogram findings are consistent with inadequate sleep quality, even when patients might seem to have slept for an adequate number of hours.

Neuropathic pain is also associated with sleep disturbances, and there is a strong bidirectional relationship between sleep disturbances and neuropathic features of pain.

Sleep disturbances are common among patients who have chronic, recurrent headaches. Common headache types, including tension headaches and migraines, often have associated symptoms besides pain, including sleep disturbances.

 As with fibromyalgia, the amount of time spent sleeping is not necessarily diminished in patients who have headache-associated sleep disturbances. Instead, it is the restorative effects of sleep that are impacted by chronic headache pain, rather than the total amount of sleep per night. The features of sleep disturbances can also vary with different types of headaches.

Sleep disturbance also can affect a person’s response to pain. As sleep stages are compromised, daytime pain increases through a process of hyperalgesia, in which lower pain stimuli result in higher pain perception and greater pain-associated impairment than would be expected otherwise.

According to research in patients with fibromyalgia, sleep deprivation impairs pain-inhibition pathways that normally help control pain.

 Studies also suggest that sleep deprivation can lead to systemic inflammation that can amplify pain.

 The evidence does not suggest that sleep deprivation can independently cause pain; rather, sleep deprivation may amplify the perception of pain that is already occurring as a result of underlying causes.

It is important to note that, while there is a strong association between sleep disorders and chronic pain and mood disorders, it is very difficult to determine which of these has a stronger impact on the others.

Psychiatric consequences of pain-related sleep disturbances

A number of psychiatric sequelae can complicate pain-induced sleep disturbances. There is a strong relationship between chronic pain that is associated with sleep disturbances and subsequent diagnoses of depression and anxiety.

 Other psychiatric issues, such as delusions, hallucinations, or mania are not commonly noted with pain-induced sleep disturbances.

Studies looking at neuropathic pain suggest that inflammation may be associated with psychiatric changes and behavioral alterations.

 However, experts are not completely sure whether there may be other contributory factors as well, and future research regarding the etiology of psychiatric disturbances in pain-induced sleep disturbances may answer some of the currently unanswered questions about these complex relationships.

Regardless of the exact molecular cause, psychiatric diagnoses of anxiety or depression can cause severe patient distress and may also lead to behavioral changes. These issues must be addressed in the clinical setting so that patients can have access to symptom relief and an improved quality of life.

Because of the bidirectional relationship between pain and sleep disturbances, experts recommend evaluating patients who have chronic pain for undiagnosed sleep disorders.

 Evaluation can include commonly used sleep questionnaires, such as the Mini Sleep Questionnaire (MSQ), the Pittsburgh Sleep Quality Index (PSQI), and the Epworth Sleepiness Scale. Objective measures include polysomnogram, Multiple Sleep Latency Test (MSLT), and Maintenance of Wakefulness Test (MWT). Additionally, screening tests for depression and anxiety are often necessary as well. Key components of the evaluation include diagnosing the sequelae of pain in addition to diagnosing the pain syndrome.

The treatment of pain has far reaching effects beyond pain control. Yet, managing pain-related sleep disturbance is not based on pain management alone. Interventions directly aimed at treating sleep disturbance are associated with a better outcome than interventions aimed at only treating the pain.

Currently, very little research has been done on the optimal treatment of sleep disorders in patients with chronic pain, and there is a lack of formal guidelines for approaching the problem. Research is emerging, however, and some experts recommend tailoring sleep care to the specific patient, rather than using a general approach to managing sleep disturbances for patients in whom chronic pain is believed to be the cause of the sleep problem.

 Some authors even suggest that chronic pain is a triad that includes pain, sleep disturbance, and depression.

There are a number of different treatment approaches for pain-associated sleep disturbances, including cognitive behavioral therapy, medication, and respiratory support during sleep for patients who need it.

 Treatment of chronic pain should always take sleep issues into consideration. Opioids, for instance, can alter sleep architecture, and while there are many disadvantages to long-term use of opioids for treating chronic pain, there are rare situations in which they are prescribed. This treatment can be especially problematic for patients who have respiratory sleep disorders, like sleep apnea. Given the complicated balance involved in chronic pain management, opioids might still be an appropriate part of the treatment plan for certain patients who have respiratory side effects. In these cases, the use of respiratory assistance, such as continuous positive airways pressure (CPAP) during sleep, may be an effective solution.

The overall approach to pain management that is complicated by sleep and psychiatric issues requires a tailored plan. It might or might not involve treatments for more than 1 diagnosis of the pain/sleep disturbance/depression triad. For instance, antidepressants might help with pain control and with mood stabilization. And anticonvulsants may help with pain control while also improving sleep.

 But, despite these obvious potential overlaps in treatment, some patients might benefit from optimal treatment approaches tailored to each diagnosis, even if completely separate treatments for each condition are required to achieve control of symptoms. Pharmacological interventions often must be selected based on the targeted symptoms. Even conservative management approaches, such as counseling, cognitive behavioral therapy, and physical therapy are most effective when they are symptom-specific, because the conservative approaches for treating each condition are not identical.

is Associate Editor Humanities in Neurology, Clinical Assistant Professor Case Western Reserve University School of Medicine, Div. of Medical Education, and Editor in Chief Emeritus of 

This article was originally posted on September 21, 2020, and has since been updated. Scroll down for the 

1. Moldofsky H. The significance of the sleeping-waking brain for the understanding of widespread musculoskeletal pain and fatigue in fibromyalgia syndrome and allied syndromes. 

2. Cheatle MD, Foster S, Pinkett A, et al. Assessing and Managing Sleep Disturbance in Patients with Chronic Pain. 

3. Mathias JL, Cant ML, Burke ALJ. Sleep disturbances and sleep disorders in adults living with chronic pain: a meta-analysis. 

4. Dette F, Cassel W, Urban F, et al. Occurrence of rapid eye movement sleep deprivation after surgery under regional anesthesia. 

5. Choy EH. The role of sleep in pain and fibromyalgia. 

6. Stocks J, Tang NK, Walsh DA, et al. Bidirectional association between disturbed sleep and neuropathic pain symptoms: a prospective cohort study in post-total joint replacement participants. 

7. Fernández-de-Las-Peñas C, Fernández-Muñoz JJ, Palacios-Ceña M, et al. Sleep disturbances in tension-type headache and migraine. 

8. Kundermann B, Krieg JC, Schreiber W, Lautenbacher S. The effect of sleep deprivation on pain. 

9. Marshansky S, Mayer P, Rizzo D, Baltzan M, Denis R, Lavigne GJ. Sleep, chronic pain, and opioid risk for apnea. 

Prog Neuropsychopharmacol Biol Psychiatry

10. Nicholson B, Verma S. Comorbidities in chronic neuropathic pain. 

11. Nijs J, Mairesse O, Neu D, et al. Sleep disturbances in chronic pain: neurobiology, assessment, and treatment in physical therapist practice. 

Sleep disturbance and chronic pain work together to cause misery for patients, with one exacerbating the other. Here: Tips to address both and bring peace to patients.

Sleep Disorders