Current and Emerging Therapies for Insomnia

Up to 10% of the US adult population will experience chronic insomnia, with women and elderly individuals at particularly high risk. Cognitive behavioral therapy is the core treatment for insomnia. When cognitive behavioral therapy is not enough, medications can help patients overcome the barriers and learned behaviors that prevent a good night’s sleep. Benzodiazepines and nonbenzodiazepine GABA-A receptor agonists are the traditional medications used to treat insomnia. More recently, orexin inhibitors have been introduced that may have fewer adverse effects, including the development of dependence. To date, only suvorexant and lemborexant have been approved for the treatment of insomnia. However, several other agents are in later stages of development. This article will review the available pharmacotherapeutic options for treating insomnia.

Am J Manag Care. 2020;26:S85-S90. https://doi.org/10.37765/ajmc.2020.43007Introduction

Insomnia is a condition of unsatisfactory sleep in terms of sleep onset, sleep maintenance, or early waking.^1-5 It impairs daytime well-being and subjective abilities and functioning. Insomnia is pervasive in the United States and other Western societies. Insomnia can occur over either a short period of time (acute) or a longer period (chronic). This article will discuss chronic insomnia primarily.

Chronic insomnia is associated with numerous adverse effects (AEs) on a person’s well-being, including fatigue, poor cognitive function, mood disturbance, and distress or interference with personal functioning.^1-7 Older adults more often have difficulty maintaining sleep (wake time after sleep onset [WASO]), whereas younger adults report more difficulty falling asleep (sleep onset latency [SOL]).

Guideline Recommendations for the Treatment of Insomnia

Insomnia can be treated with pharmacologic and nonpharmacologic approaches, individually or in combination. Several groups have published guidelines for the management of insomnia, including:

• American Academy of Sleep Medicine (AASM) (2017)¹
• American College of Physicians (ACP) (2016)²
• Agency for Healthcare Research and Quality (AHRQ) (US Department of Health and Human Services) (2017)³
• British Association for Psychopharmacology (2019)⁵

Clinical Assessment

The diagnosis of insomnia is usually based on patient self-reporting. Insomnia may be a condition in and of itself or a symptom of another underlying medical or behavioral condition.^1-5 The patient evaluation of comorbid conditions should exclude:

• Medical conditions (eg, obstructive sleep apnea [OSA], pulmonary disease, heart failure, chronic pain, restless legs syndrome, hyperthyroidism)
• Psychiatric disorders (eg, depression, anxiety, posttraumatic stress disorder)
• Substance abuse/misuse (eg, alcohol, caffeine, drug and herbal stimulants)
• Behavioral contributions (eg, excessive screen time, exercise, or fluids before bed; poor sleep hygiene)
• Other factors contributing to sleep disruption (eg, circadian rhythm sleep-wake disorders)

Many individuals may experience insomnia and comorbid disorder(s) concurrently. For instance, insomnia may lead to anxiety about insomnia, which could further exacerbate sleep fragmentation. Questionnaires, at-home sleep logs, and actigraphy can all be helpful tools for the assessment of insomnia in the absence of other apparent etiologies.

Treatment Guidance

The guidelines vary in their recommendations of specific pharmacologic treatments. However, they follow a general approach^1-5,8:

• Evaluate insomnia characteristics. Determine how sleep is deficient. Optimize treatment for any comorbid disorders.
• Initiate treatment with cognitive behavioral therapy (CBT) with/without relaxation therapy.
• If no effect, consider adding additional nonpharmacologic modalities.
• If still no improvement, reconsider diagnosis. Reevaluate, especially for occult comorbid disorders.
• If still no improvement, combine CBT with evidence-based pharmacology.
• If still no improvement, introduce alternative therapies (eg, valerian, melatonin).

The ACP does not recommend specific pharmacotherapy, but rather that clinicians use a shared decision-making approach when determining whether to add pharmacotherapy in adults with chronic insomnia disorder in whom cognitive behavioral therapy for insomnia (CBTI) alone was unsuccessful.²

The AASM recommends the following pharmacotherapies¹:

• For sleep maintenance insomnia: suvorexant, eszopiclone, zolpidem, temazepam, doxepin
• For sleep onset insomnia: eszopiclone, zaleplon, zolpidem, triazolam, temazepam, ramelteon

The AASM recommends against using trazodone, tiagabine, diphenhydramine, melatonin, tryptophan, or valerian for either sleep-onset or sleep-maintenance insomnia.¹

The AHRQ does not make recommendations but notes the following from a systematic review of 169 randomized controlled trials and 12 observational studies³:

• In the general adult population: Eszopiclone improves global outcomes, SOL, and total sleep time (TST) as well as reduces WASO. Zolpidem improves global outcomes, sleep latency, TST, and sleep quality; it may reduce WASO. Zaleplon improves sleep quality but likely has no effect on TST. Suvorexant improves global outcomes, sleep latency, and TST as well as reduces WASO. Ramelteon improves global outcomes and sleep quality but likely has no effect on other sleep outcomes. Doxepin may improve some global outcomes. Other antidepressants noted in the AHRQ review (trazodone, amitriptylline, and mirtazapine) are not approved for the treatment of insomnia.
• In the older adult (≥55 years) population: Eszopiclone may improve some outcomes. Zolpidem and ramelteon may improve SOL. Doxepin improves TST and may improve other sleep and global outcomes.

Current Treatment Options

Treatment Goals

The goals of treatment are to improve sleep quality and related poor daytime functioning while reducing distress and anxiety related to sleep fragmentation.^2,8 Patients should be reevaluated at least every 6 months. Management is highly personalized, and treatments may need to be switched and/or combined. Successive treatment failures may suggest an unrecognized underlying comorbidity.

Pharmacologic Interventions

Nonpharmacologic interventions may help many individuals with insomnia, but many people will not overcome their insomnia without assistance from medications. Withdrawal from CBTI is as high as 40% before midtreatment.⁹ Over-the-counter (OTC) medications are not recommended by the AASM due to lack of efficacy and safety data.¹ The choice of prescription medication should be based on treatment goals and patient-specific characteristics.

Measures of Sleep Function/Dysfunction

Specific outcomes for sleep research generally include measures of WASO, sleep latency, number of awakenings, TST, and sleep efficiency.⁸ People with insomnia have average sleep latency and WASO greater than 30 minutes, sleep efficiency less than 85%, and/or TST shorter than 6.5 hours.⁸ Psychological measures of sleep include patient-reported outcomes and psychological assessment scales that describe sleep-related psychological distress, daytime function, quality of life, and sleep quality.

OTC Medications

A patient’s first attempt to control insomnia often involves the use of OTC medications. Alcohol is commonly used but its effects are of short duration, and it can adversely affect sleep quality.¹⁰ The use of alcohol can disrupt sleep homeostasis and carries the potential for abuse and dependency.¹¹ Persons with alcohol use disorder may experience profound insomnia as a result of chronic, excessive alcohol consumption.

The most common antihistamines in OTC products are diphenhydramine and doxylamine.¹² With antihistamines, the possibility exists for next-day sedating effects and some individuals develop paradoxical reactions such as agitation and anxiety. Antihistamines are associated with dry mouth, blurred vision, increased heart rate, difficulty urinating, memory problems, and confusion. According to the American Geriatrics Society Beers Criteria, antihistamines should be avoided in elderly patients due to the increased risk of cognitive impairment, falls, and motor vehicle accidents.^1,13 Diphenhydramine inhibits cytochrome P450 2D6 (CYP2D6), which can cause drug interactions with a diverse collection of medications.¹⁴

Many herbal preparations and supplements for insomnia are available on the market, although most lack sufficient evidence demonstrating a sleep benefit.¹⁵ Herbal preparations carry a risk of possible unknown drug interactions as well as of contamination from nonstandardized production and quality control, which may result in variable concentrations of active ingredients among brands and lots.^16,17 Valerian is a common herbal sleep aid for chronic insomnia.¹⁸ Its effects are gradual, and abrupt discontinuation is associated with withdrawal symptoms similar to those caused by benzodiazepines.¹⁹ Melatonin is produced in the pineal gland in response to circadian signaling.²⁰ The rise in melatonin level facilitates sleep onset, and study results have shown a small effect on sleep latency but not on other sleep measures.^21,22

Prescription Medications

The medications that are available specifically for treatment of insomnia target receptors that contribute to the regulation of the sleep and wake cycle: γ-aminobutyric acid (GABA-A), melatonin, histamine, and orexin/hypocretin receptors.^9,12,23 With the exceptions of doxepin and ramelteon, most approved medications for insomnia are Schedule IV controlled substances, owing to the potential for abuse.

Many people with insomnia experience it for extended periods of time, often for more than 1 year. In studies of up to 12 months in length in elderly patients, doxepin, eszopiclone, ramelteon, suvorexant, zaleplon, and zolpidem retained their efficacy without tolerance, abuse, withdrawal effects, or any new AEs developing.²⁴

GABA-A agonists

The GABA-A receptor is a chloride ion channel widespread in the central nervous system (CNS). When activated, GABA-A allows passage of chloride ions into the cell, resulting in hyperpolarization and decreased likelihood of action potential transmission. Facilitation of GABA-A results in sedative, anxiolytic, muscle-relaxant, and hypnotic effects.

Benzodiazepines are GABA-A agonists indicated for people with difficulty with sleep onset, difficulty with sleep onset and sleep maintenance, or middle-of-the-night awakenings with difficulty returning to sleep. Benzodiazepines are associated with rapid development of tolerance as well as risk of abuse or dependency, cognitive impairment, and rebound insomnia after discontinuation.²⁵ Tolerance can lead to dose escalation, and use of benzodiazepines for as little as 3 to 4 weeks is associated with withdrawal symptoms if stopped abruptly. This drug class is not recommended for use in elderly patients as listed by Beers Criteria.^18,26 In spite of this, benzodiazepines are used frequently in older patients, and up to one-third of elderly patients who take benzodiazepines use them on a long-term basis.¹⁸ Long-term use is associated with ataxia, sedation, greater risk of falls and fractures, cognitive decline, and dependency. An increased risk of sedation, respiratory depression, coma, and death is associated with combined use of benzodiazepines and opioids.²⁷

Nonbenzodiazepine GABA-A agonists (“Z-drugs” or “nonbenzodiazepines”) are effective for people with sleep-onset and sleep-maintenance difficulties, and they are among the drugs most commonly prescribed for insomnia. Eszopiclone is useful in managing insomnia with comorbid depression or generalized anxiety disorder. However, nonbenzodiazepines are not considered to be “safer” than benzodiazepines as both have a risk of tolerance, daytime somnolence, anterograde amnesia, slowness of mental processes and body movements, and, when combined with other sedative drugs (eg, opioids), overdose.²⁸ Complex behaviors, such as sleep driving, sleep eating, and sleep walking, have been reported by persons using nonbenzodiazepines. Nonbenzodiazepines have adverse effects similar to benzodiazepines (eg, falls, fractures, delirium) and as a result are also included in the Beers Criteria list of drugs that should be avoided in elderly patients.^18,26 Nonbenzodiazepine use in elderly patients offers minimal improvement in sleep latency and duration and is associated with increased hospitalization as well as emergency department visits.

Sedating antidepressants

Histamine in the CNS potently promotes wakefulness. Doxepin, at doses of 25 mg to 300 mg, is a tricyclic antidepressant with serotonin and norepinephrine reuptake inhibition as well as antihistamine and anticholinergic activity. At low doses (3-6 mg), it is a pure H₁ receptor antagonist. Doxepin should not be coadministered with monoamine oxidase inhibitors.^29,30

Trazodone does not carry an indication for insomnia but has been used in patients with primary or secondary insomnia at doses of 50 mg to 100 mg. It is a serotonin antagonist and reuptake inhibitor that also has moderate antihistamine and low anticholinergic activity. In a systematic review, trazodone was effective in decreasing sleep latency and increasing sleep duration and quality of sleep. The most common adverse effects of trazodone were drowsiness, headache, and orthostatic hypotension. Postural hypotension is a concern, particularly in elderly patients who are at risk of falls and injury.^29,31

Melatonin receptor agonist

Ramelteon is a melatonin receptor agonist, targeting melatonin receptors 1 and 2 preferentially over receptor 3. Melatonin acts in the hypothalamus, causing sedation, and regulates sleep-wake cycles. Ramelteon marginally reduces sleep latency but does not increase TST. Melatonin receptor agonists carry a low risk of dependency and would be appropriate in patients with substance use disorders.⁵ High-fat meals can delay absorption, and the potential for drug interactions is moderately high.

Orexin Receptor Antagonists

The orexin/hypocretin receptor is central to the regulation of sleep-wake cycles, arousal, and appetite.³² A medication that acts as an antagonist to the orexin receptor could induce sleepiness and sustain longer periods of sleep, which could be helpful for the treatment of insomnia.³³

Suvorexant

Suvorexant is a dual-orexin receptor antagonist (DORA) that was approved in 2014 for the treatment of insomnia. Suvorexant suppresses the wake drive by blocking both the orexin-1 and orexin-2 receptors. Compared with another DORA, almorexant, suvorexant demonstrated a more balanced sleep architecture profile due to its promotion of both rapid eye movement (REM) and non-REM sleep, whereas almorexant primarily increases REM sleep. Suvorexant has been shown to increase time spent in each stage of sleep and to increase TST.³³

Suvorexant was studied in 3 clinical trials in patients with insomnia characterized by difficulties with sleep onset and sleep maintenance. In study 1 and study 2, suvorexant was superior to placebo for sleep latency, assessed objectively by polysomnography and subjectively by patient estimation. Suvorexant was also superior to placebo for sleep maintenance, assessed objectively by polysomnography and subjectively as patient-estimated TST.

In a 1-month crossover study (study 3), adults (aged 18-64 years) were treated with placebo and suvorexant. Suvorexant 10 mg and 20 mg were superior to placebo for sleep latency and sleep maintenance, assessed objectively by polysomnography. Higher doses of suvorexant were found to have similar efficacy to lower doses but were associated with significantly higher incidence of AEs.

In clinical trials, the most common AE (reported in ≥5% of patients treated with suvorexant and at least twice the placebo rate) in patients with insomnia treated with suvorexant 15 mg or 20 mg was somnolence (suvorexant 7% vs placebo 3%). The AE profile in elderly patients was generally consistent with that in nonelderly patients. The discontinuation rate due to AEs for patients treated with suvorexant 15 mg or 20 mg was 3% compared with 5% for placebo.

Individuals with narcolepsy lack most or all orexin receptors in the hypothalamus and should not receive suvorexant. Before increasing the dose, it should be considered that obese patients and women have reduced clearance compared with leaner people and men.³⁴

Lemborexant

Lemborexant is a DORA that was approved in late December 2019 for the treatment of insomnia characterized by difficulties with sleep onset and/or sleep maintenance in adults.^35,36 Lemborexant has a half-life of approximately 17 to 19 hours; it decreases wakefulness and promotes non-REM sleep with no effect on REM sleep.³³ Lemborexant was studied in the SUNRISE 1 and SUNRISE 2 trials.³⁷ In the SUNRISE studies, lemborexant significantly improved objective and subjective measures of sleep onset and sleep maintenance compared with placebo. These were 1-month and 6-month, placebo-controlled trials, respectively, with the primary end point of sleep latency and secondary end points of sleep efficiency and WASO. Comparator arms were 10 mg and 5 mg lemborexant versus placebo. Both trials achieved their primary end point.

The most common AE (reported in ≥5% of patients treated with lemborexant and at least twice the rate of placebo) in both SUNRISE 1 and SUNRISE 2 was somnolence (lemborexant 10 mg, 10%; lemborexant 5 mg, 7%; placebo, 1%).³⁸ Treatment discontinuation was highest in the 10-mg lemborexant group compared with the other groups (8.3%, 4.1%, and 3.8%, respectively).³⁹ No respiratory concerns were noted in the trials. Patients with mild OSA did not experience worsening sleep apnea, as measured by changes in apnea-hypopnea index or peripheral oxygen saturation.⁴⁰

Other Orexin Inhibitors in Phase 3 Clinical Trials

Daridorexant (nemorexant)

Daridorexant (nemorexant) is a DORA with a half-life of approximately 6 hours. Phase 2 study results have shown a dose-dependent effect on reducing WASO and latency to sleep onset. The most common AEs reported were headache, somnolence, diarrhea, and fatigue.^41,42

Seltorexant

Unlike other orexin inhibitors that antagonize both orexin-1 and orexin-2 receptors, seltorexant is a selective orexin-2 receptor antagonist. This unique mechanism of action may offer hypnotic effects while preserving normal sleep architecture and reduced risk for cataplexy. Seltorexin has a half-life of 2 to 3 hours.⁴³ In its phase 2 clinical trials, seltorexant was shown to improve sleep induction and prolong sleep duration. It is also being studied for the treatment of hyperarousal-related insomnia in patients with depression. The most common AEs reported were headache, dizziness, and somnolence.^44-46

Pharmacologic Treatment Failure

A specific insomnia medication will not be effective for everyone, so a personalized approach to management is needed.^4,8 Comorbid conditions should be suspected in patients who repeatedly have limited or only transient improvements with medication and CBT. Polypharmacy is a significant concern, particularly in elderly patients. In the ambulatory setting, approximately one-third to two-thirds of elderly patients use 5 or more daily prescription medications, in addition to about half using OTC medications and dietary supplements.⁴⁷ In the nursing home setting, up to 40% of residents are using 9 or more daily medications. Polypharmacy is associated with increased healthcare costs and increased risk of AEs (eg, drug interactions, falls, cognitive impairment). Pharmacists can be instrumental in reducing polypharmacy.⁴⁸

Pharmacotherapy for Specific Populations

As people age, sleep timing advances (ie, earlier bedtimes and rise times), and falling asleep becomes more difficult.^18,24 Elderly people may have a disrupted sleep architecture, with less REM sleep and more stage I and stage II non-REM sleep. They frequently have comorbidities and reduced cognitive function. Older adults often have insomnia, and many medications are not suitable for use in this population. CBT is the first choice of treatment but may require longer periods of time to have an effect. Medication choice should be tailored to the patient’s needs^18,24:

• Patients with sleep-onset disturbance may have better results with a hypnotic that has a short half-life.
• Patients with sleep-maintenance difficulties may benefit more from a hypnotic with a longer half-life but should avoid hypnotics with a very long half-life to reduce the occurrence of next-day sedation.
• Comorbidities (medical, psychological), drug interactions, and polypharmacy will need careful attention.
• Caution should be used when initiating complex medication regimens, and downward adjustments should be considered.^8,12

Conclusions

Chronic insomnia is a prevalent and difficult-to-treat condition.¹ Difficulty falling asleep or maintaining sleep leads to daytime struggles, such as fatigue, mood disturbances, and decreased ability and desire to work or socialize. Women and elderly patients are at particular risk of chronic insomnia. Treatment should be tailored to the individual needs of the patient, and patients may need to switch medications to find the one that alleviates their symptoms best. Guidelines are discordant and vague, which is likely a reflection of the individual nature of insomnia and the difficulty of developing a one-size-fits-all algorithm.^1-3,8 

Author affiliation: Mei T. Liu, PharmD, BCPP, is a clinical assistant professor, Department of Pharmacy Practice and Administration, Ernest Mario School of Pharmacy, Rutgers, the State University of New Jersey, Piscataway, NJ; and a clinical psychiatric pharmacist, Department of Pharmacy, Penn Medicine Princeton House Behavioral Health, Princeton, NJ.

Funding source: This activity is supported by an educational grant from Eisai.

Author disclosure: Dr Liu has no relevant financial relationships with commercial interests to disclose.

Authorship information: Substantial contributions to the intellectual content including concept and design, analysis and interpretation of data, drafting of the manuscript, and critical revision of the manuscript for important intellectual content.

Address correspondence to: mei.liu@pharmacy.rutgers.edu.

Medical writing and editorial support provided by: David Modrak, PhD, and Patrick Stone.

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