Shopping Cart

INTRODUCTION

To want and try to sleep but be unable to is a frustrating disorder that occurs in up to one-half of the population acutely and up to 10% of people chronically.^1-3 Insomnia is the most common sleep disturbance in adults, occurring more in females and increasing in incidence with age.^1-3 Insomnia is described by the American Academy of Sleep Medicine (AASM) and the European Sleep Research Society (ESRS) as a subjective difficulty in falling or staying asleep, early awakening, sleep consolidation, or poor sleep quality despite the appropriate opportunity for sleep that results in daytime impairment.⁴ Insomnia is considered chronic when it occurs at least 3 times per week for at least 3 months.^1-3

The impact of insomnia on functional status is wide reaching. While there are no specific or dominant features associated with insomnia, patients typically experience at least one symptom of daytime dysfunction due to nighttime insomnia.^3,4 These include fatigue or malaise; impairment of attention; concentration or memory; mood disturbance or irritability; impulsivity, aggression, or hyperactivity; decreased academic, occupational, or interpersonal performance; reduced energy, initiative, and motivation; or tendency toward errors and accidents.^2,3,5,6 In older adults, resulting daytime cognitive and attention deficiencies may be misidentified as dementia or other forms of cognitive impairment.⁷

Consequences associated with insomnia include work absenteeism or tardiness, occupational and car accidents, development of psychiatric disorders, depression, alcoholism relapse, cardiovascular disease, or adverse effects (AEs) in patients with chronic pain.^1-4 In geriatrics, insomnia is correlated with dementia and mortality.⁷ Additionally, less than 6 hours of sleep on average a night is associated with an increased risk for type 2 diabetes, obesity, cortical atrophy, dementia, stroke, depression, anxiety, and mortality.^2,3,8 The economic burden in the United States is estimated to be as high as $116 billion per year.^1,7

Unfortunately, there are substantial gaps in our knowledge about insomnia. Many of the agents historically used to treat sleep disturbances lack rigorous clinical studies. The known abuse potential with benzodiazepines (BDZs) and hypnotics have increased use of other medications less likely to be abused but without significant evidence of efficacy.⁵ Many have only been studied for short periods (12 weeks or less), and this is concerning because up to 70% of patients continue using a prescription medication for insomnia 1 year after diagnosis and not always with significant improvements in symptoms.⁹ Additionally, few robust studies compare different treatment options.⁹ As a result, clinicians must use what evidence is available along with drug-specific knowledge to identify optimal treatment regimens.

MEDICAL CONDITIONS ASSOCIATED WITH SLEEP DISTURBANCES AND INSOMNIA

Insomnia is categorized into 3 groups: primary insomnias, insomnia associated with other sleep disorders, and insomnia due to medical comorbidities, psychiatric disorders, or medication/substance use (Table 1).^3,4 Unfortunately, the pathophysiology of insomnia is not well understood, and it can be hard to differentiate among these types of insomnia in practice.³

A wide variety of comorbidities and differential diagnoses are associated with insomnia, and the relationship is often bidirectional. Patients should be referred for a thorough physical examination to evaluate any comorbidities and optimize their management.⁴ At times, treating somatic causes of insomnia may alleviate its symptoms.² It is important to identify sleep-disordered breathing before initiating medications, as they can worsen symptoms or lead to complications.⁷ Additionally, almost all mental health disorders have been associated with sleep disturbances, but patients may not have reported symptoms of psychiatric or cognitive disorders to their clinician.²

Evaluating Causes of Sleep Disturbance

The diagnosis of insomnia is often made clinically based on patient-reported complaints.³ It is important to obtain a history that evaluates sleep and wake function, common medical and psychiatric conditions, medication use, and other variables that affect sleep. Since insomnia can manifest in a variety of abnormalities regarding sleep, understanding the primary complaints or symptoms is important to help direct further evaluation and management.^2-4 The assessment of these symptoms should not be isolated to generalized symptoms but should include day-to-day variability.⁴ While no specific quantities for these parameters are diagnostic of insomnia, patients with insomnia often report an average sleep latency of at least 30 minutes, total sleep time (TST) of less than 6.5 hours, wake time after sleep onset (WASO) of 30 minutes or more, and sleep efficiency of less than 85%.⁴

A variety of tests are used to aid the diagnosis or monitoring of insomnia. At a minimum, patients should be assessed with a general questionnaire regarding medical conditions and health, psychiatric comorbidities, and medication use, the Epworth Sleepiness Scale (ESS) or other validated sleepiness assessment instrument, and a 2-week sleep log that provides information regarding day-to-day changes in sleep variables.^2-4 Sleep logs should track daily bedtimes, sleep latency, nighttime awakenings, WASO, sleep duration, sleep efficiency, naps, daytime impairment, and use of medications, caffeine, and alcohol within each 24-hour period.^2-4

A good sleep history is one of the essential necessities for diagnosis.³ Sleep logs provide information on sleep variables in an objective fashion. The 3P model was designed to help clinicians focus the sleep history.¹⁰ The first P stands for factors predisposing patients to insomnia, such as genetic or personal traits that cause hyperarousal. The second P stands for precipitating factors that trigger the insomnia cycle, such as positive or stressful life events. The third P stands for perpetuating factors that enable insomnia to continue, even if the precipitating factor is removed or resolved. Quantitative and qualitative descriptions of the patient’s occupational and work environment and responsibilities; lifestyle and exposure to light, drugs, alcohol, nicotine, or caffeine; travel; daytime dysfunction; and comorbidities should be obtained initially and throughout management.⁴ When evaluating the patient’s sleep history, information from a bed partner may provide valuable information on factors that the patient may not be as aware of such as periodic limb movements or periods of apnea during sleep.^2,3 Evaluating daytime activities and function is useful in assessing potential contributors to and consequences of insomnia. Patients are often more fatigued than sleepy.^2,4 However, daytime napping can decrease evening sleep drive and should be explored as a potential factor exacerbating insomnia.^3,4

Patients may also complain of mood disorders and cognitive difficulties. It is not unusual for patients to experience irritability, anxiety, loss of interest, depression, inattention, and mild memory difficulty.^2,4 The combination of these consequences may lead to interpersonal difficulties and avoidance of normal daytime activities, including work, exercise, and social events. This can turn into a cyclic pattern because minimal daytime functioning can in turn exacerbate insomnia.⁴

Assessment of sleep hygiene is another important evaluation component. To confirm insomnia diagnosis, patients should still experience symptoms despite a dark, quiet sleep environment and a regular bedtime routine.³ Many patients display presleep behaviors that contribute to or complicate insomnia. Patients may participate in activities in the bed or sleep environment that are not compatible with sleep. Eating, computer, or tablet use, talking on the telephone or use of mobile devices, and watching television should occur away from the primary sleeping area.^2,4 Interestingly, ambient light should be considered a nonpharmacologic disease interaction because too much exposure in the evening reduces physiologic melatonin production.¹¹

Evaluation of insomnia requires detailed assessment using subjective questionnaires and instruments.^3,4 The ESS is one of the most commonly used questionnaires in clinical practice to evaluate daytime sleepiness. The 8-item questionnaire assesses the likelihood of falling asleep while performing activities such as reading, riding in a car, or watching television.¹² The ESS is not specific to insomnia, and scores of 10 or higher indicate daytime sleep–related dysfunction.¹² While the ESS measures the impact of insomnia on patient functioning, it does not evaluate sleep latency, maintenance, or quality.

The Pittsburgh Sleep Quality Index (PSQI) assesses a patient’s self-perceived sleep quality.^13,14 The 19-question subjective questionnaire evaluates sleep quality over the past month using 7 subscales that assess average bed and wake-up time, sleep latency, duration, quality, efficiency, contributors to poor sleep, sleep medication use, and daytime dysfunction.^13,14 Scores greater than 5 suggest sleep disturbances.^13,14

The Insomnia Severity Index (ISI) has 7 self-rated questions that assess difficulty falling or staying asleep and early awakenings for the previous 2 weeks, satisfaction with sleep pattern, and impact of sleep difficulties on quality of life, stress, and daily functioning.¹⁵ Scores of 8–14 indicate subthreshold insomnia, 15–21 indicate moderate insomnia, and 22–28 indicate severe insomnia. The ISI may be helpful for evaluating response to therapy; reductions in score of 8 or more points can indicate improvement in symptoms.¹⁵

A polysomnography (PSG), or sleep study, is not routinely indicated to diagnose insomnia but is recommended in the suspicion of breathing or movement disorders, unclear initial diagnosis, treatment failure, or arousals associated with violence or harmful behavior.^2-4 Actigraphy is a device worn on the wrist that records movement and uses an algorithm to estimate sleep and wake periods.³ It may be used in combination with a light sensor to estimate sleep latency from the times the lights are turned out.³ Actigraphy can be useful when patients have unreliable sleep logs or possible circadian disorders.³ Certain laboratory tests may be obtained to determine if there is a somatic cause of the insomnia; these include electrolytes; thyroid, liver, and kidney function; hemoglobin; ferritin; vitamin B₁₂; and C-reactive protein.²

DRUG–DISEASE INTERACTIONS

The use of numerous medications and nutrients affects sleep or daytime symptoms. Likewise, the withdrawal of substances such as alcohol, BDZs, or opioids may also cause sleep disturbances.³ Common medications affecting sleep are listed in Table 2. It is especially important to make sure that use of both prescription and over-the-counter (OTC) medications is delineated.

For some patients, it may be possible to interchange a stimulating medication for another medication to address sleep issues. For example, it may be reasonable to change paroxetine to mirtazapine in a patient with co-existing depression. Dosing schedules should be arranged to minimize the impact on sleep and doses of stimulating medications and caffeine intake should cease in the early afternoon at the latest.⁴

The effects of some medications on sleep are not as widely recognized. For instance, beta-blockers, calcium channel blockers, and nonsteroidal anti-inflammatory drugs reduce endogenous melatonin levels.^3,16 The literature is inconclusive about the clinical impact of this reduction on sleep, but adjustments in agent and dosing schedules could potentially aid in symptom management.³

OVERVIEW OF TREATMENT FOR INSOMNIA

General Approach to Care

When appropriate management of a precipitating cause of insomnia does not resolve symptoms or when a precipitating cause cannot be addressed or identified, treatment of insomnia symptoms is warranted. Cognitive behavioral therapy for insomnia (CBT-I) is the standard of care and recommended by the AAMS, ESRS, and the American College of Physicians as first-line therapy for chronic insomnia.^1,2,4,6 If insomnia complaints do not resolve with CBT-I alone, medication can be initiated, but CBT-I should be continued alongside pharmacotherapy in the treatment plan.^1,2,4,6 CBT-I positively affects both insomnia and comorbid symptoms. Though effects may not be seen immediately, results are long lasting and superior to those seen with medications even 6–12 months after CBT-I has been discontinued.^2,6

CBT-I commonly consists of psychoeducation, sleep hygiene counseling, relaxation training, stimulus control therapy, sleep restriction therapy, and cognitive therapy.² Discussion about sleep hygiene is an essential part of the management of insomnia.⁶ Patients should be counseled to limit activities in the bed and bedroom to those most compatible with sleep, go to bed only when sleepy and get out of bed if unable to fall asleep, maintain consistent morning wake times, use the bedroom only for sleep, and avoid daytime napping.^2,3 This helps eliminate a conditioned response that associates the sleep environment with arousal, re-associates the bed and bedroom with sleep, and supports a more consistent sleep schedule.^2,3 Counseling on adapting environmental factors, including temperature, noise, and light control, to support sleep hygiene should occur.² Certain behavioral strategies can be used to improve sleep duration and efficiency. One such strategy is sleep restriction, which involves initially limiting the sleep window and time in bed to the reported average nightly sleep time, with a recommended minimum window of 4 to 6 hours.^2,3 The goal is to match the patient’s time in bed with reported sleep duration.³ The time in bed is adjusted weekly based on response and sleep efficiency until the patient reaches an optimal sleep duration.² Sleep restriction may not be appropriate in patients with certain comorbidities; it has been shown to decrease seizure threshold, increase pain sensitivity, and stimulate mania in bipolar disorder.³ Exercise is encouraged but should not occur within 3 hours prior to bedtime.⁷

Few comparative studies of medication efficacy for insomnia are available.¹ In 2017, the AAMS published guidelines for the treatment of chronic insomnia in adults.¹ The AAMS recommends that medication selection be based on available evidence in combination with patient-specific factors, including optimal pharmacokinetic parameters, safety and interaction profiles, and history of medication response. Every recommendation is rated weak in strength.¹ Initial prescriptions should be limited and even when medications are effective, patients should follow up with their provider within 3 to 4 weeks.⁷ Improvement in symptoms may occur for 7 to 10 days after initiation of or changes in medication.⁷ When medications are helping, patients may be advised to decrease therapy by 1 dose per week until only intermittent dosing is required.⁷

Herbal Compounds, Supplements, and OTC Medications

Up to 60% of the agents used for sleep difficulties are OTC supplements, herbal products, or nonprescription medications.⁹ Evidence for use of most of these products for insomnia is inconclusive or weak, and none are recommended for routine use.^1,2,9

The most well-known herbal product is valerian, a plant-derived extract that modulates gamma-aminobutyric acid type A (GABA_A) receptors to produce calming effects.^1,6 Hypnotic effects are produced after 2 to 3 weeks of dosing with 600 mg daily.⁷ The AAMS guidelines recommend against valerian use because evidence suggests its benefits equal the risks and some patients have experienced liver toxicity.^1,2,7 Two meta-analyses suggest valerian may produce a small improvement in sleep quality, but most studies have shown minimal to no improvement on sleep.^17-19 Chamomile, kava, and wuling have also been used to treat sleep complaints but have yet to show clinically significant improvement in sleep parameters in studies.¹⁹

Diphenhydramine is an OTC antihistamine often used to self-treat sleep problems, but it is specifically not recommended by AAMS or ESRS.^1,2 Diphenhydramine has not shown positive effects on sleep onset, TST, or sleep efficiency on a consistent basis.^3,6 Even when helpful effects occur, tolerance develops after 1 to 2 weeks of continued use.⁶ The risk of dose-dependent AEs, including anticholinergic effects, outweigh any benefits for chronic insomnia. At best, diphenhydramine may be helpful for acute insomnia in otherwise healthy adults associated with allergies or upper airway infections, but overall, its use should be limited and discouraged.³

Melatonin and Melatonin Agonists

Melatonin, a core regulator of the circadian rhythm, is a natural hormone released during dark periods of each 24-hour period.^3,11,20 It binds to the melatonin1 (MT₁) and melatonin 2 (MT₂) receptors, but exact mechanism of melatonin and melatonin agonists for enabling sleep has not been fully determined.^3,5

Melatonin is available as an OTC supplement with pharmacokinetics comparable to the endogenous hormone.⁵ It should be taken 30 minutes before bedtime, but effects may not be seen for up to 4 hours after administration in some patients, and food can delay its absorption.^3,7 Timing of dosing should be individualized during the hours between dinner and the goal bedtime. The ideal dose for efficacy has not been established; doses in studies varied from 0.15 mg to 15 mg daily.²⁰

Melatonin has a modest benefit on sleep latency and quality.^3,21-24 The quality of evidence for the hypnotic effects of melatonin is low, the overall clinical effect size is small, and its routine use is not recommended in available guidelines.^1,2,21-23 The limited availability of clinical studies may be related to its endogenous nature, which means it cannot be patented and therefore may not provide the same incentives for evaluation that other medications provide.¹¹

Interestingly, studies involving patients aged 55 years and older have shown more positive outcomes than those including patients of all ages.⁵ Endogenous production of melatonin decreases with age, making this agent an attractive option in older adults with sleep difficulties.⁵ Though limited, data suggest melatonin’s efficacy in older adults is higher in those who are also using BDZs.¹¹ BDZs may either alter the receptor effect of melatonin or somehow inhibit melatonin release, but these mechanisms need to be explored in appropriate studies before a firm association is established.¹¹

Melatonin is a relatively safe medication; it has a short half-life of 30–50 minutes and does not produce a hangover effect.^11,21-24 Additionally, melatonin is without abuse potential and can be beneficial for patients prone to substance abuse.³ In fact, one study found patients receiving melatonin were significantly more likely to discontinue BDZs compared with placebo.²⁴ Its most common AEs are daytime sleepiness, headache, and dizziness, each occurring in less than 2% of patients.²⁰ Because melatonin is involved in the regulation of reproduction, use of higher doses in women of child-bearing age is a theoretical concern.^3,11

The melatonin agonist ramelteon is approved by the U.S. Food and Drug Administration (FDA) for insomnia associated with sleep latency.⁵ Unlike melatonin, ramelteon is recommended by the guidelines for sleep-onset insomnia.¹ Ramelteon is a more potent agonist of the MT₁ and MT₂ receptors than melatonin with a long duration of action.^3,5 It decreases sleep latency while improving TST and sleep quality when administered 30 minutes before bedtime.^{5-7,23,25–27} Ramelteon’s effects are maintained for at least 1 year, and it may be a reasonable option in patients requiring long-term treatment.²⁵

Because high-fat meals can substantially increase bioavailability, ramelteon should be taken on an empty stomach.⁵ The 8 mg dose is very well tolerated and may be safer than zolpidem 10 mg, particularly in older patients.⁷ Ramelteon is not known to have an abuse potential, possesses a good safety profile, and has no known rebound or withdrawal effects.⁶ Its most common AEs are headache, fatigue, and nausea, but some older men may see a small but potentially significant decrease in free testosterone.^7,25 Collectively, ramelteon is a reasonable early option when nonpharmacologic interventions alone are unsuccessful.⁶

Benzodiazepines

Benzodiazepines (BZDs) have been marketed for decades for insomnia.²⁷ They promote sleep by increasing the effect of GABA binding on the GABA_A receptor.^3,5,16 Based on the amount and quality of available evidence, current guidelines recommend only 2 BDZs — triazolam for sleep latency and temazepam for sleep latency and maintenance — but studies have evaluated other agents.¹

BDZs are effective for short-term (4 weeks or less) treatment of insomnia in low doses taken approximately 30 minutes before bedtime.^1,2,7 As a class, BDZs possess myorelaxant and anxiolytic effects, which may be helpful in patients suffering with coexisting pain or anxiety.³ Tolerance can develop quickly with long-term BDZ use; subjective sleep quality may be at or below baseline after just 24 weeks.¹⁶ Intermittent dosing may be preferable to daily therapy to minimize unwanted effects and delay the development of tolerance.⁷

The biggest limitation to BDZ use is the associated safety risks. These drugs cause psychomotor impairment, and their potential for abuse is well documented.^3,6 The longest study for insomnia involved temazepam use for 8 weeks, during which dependence was not observed.³ Still, physical dependence is a well-known effect with BDZs and can occur with just a few days of use.⁶ The AEs result from broad central nervous system (CNS) inhibitory activity and tend to be dose-dependent.³ Other potential AEs include next-day hangover effects, cognitive or memory impairment, tolerance, accidents, rebound insomnia, and withdrawal effects.^5,6 The negative cognitive effects seen with long-term use may still be present up to 6 months after discontinuation.²

Most concerning, the intermittent and regular use of BDZ has been shown to increase mortality.² While these effects can occur in patients of any age, they are more pronounced in aging patients.⁷ Almost one-third of older adults use long-term BDZs, which is associated with cognitive decline, falls, and fractures.⁷ Regular assessment of medication indication, efficacy, and safety may help mitigate such negative consequences.⁷

It is critical that patients understand that BDZs should not be abruptly stopped after long-term use due to the propensity for withdrawal, which can be severe.⁶ To discontinue a BDZ, a gradual taper of the dose by 5%–10% every 1 to 2 weeks is advised.⁶

Nonbenzodiazepine Hypnotics

Benzodiazepine receptor agonists (BZRAs), sometimes referred to as “Z-drugs,” are the most frequently prescribed medications for insomnia.^1,27 The class was developed in an attempt to maximize the benefits of BDZs while lessening the impact of AEs.²⁷ They have a chemical structure different from BDZs but act through a similar mechanism.³ Because their affinity for GABA_A is primarily to the α₁ receptor subunit, which has the largest hypnotic effects, BZRAs produce more specific actions and fewer AEs. They are effective for short-term (4 weeks or less) treatment of insomnia.^1,3,7 All 3 agents within the class are recommended by AAMS to improve sleep latency, but only zolpidem and eszopiclone are recommended for sleep maintenance.¹ BZRAs produce positive treatment responses in approximately 76% of patients and remissions in almost 48% of patients.^2,28 BZRAs should be taken immediately before bedtime, and when possible, intermittent versus daily therapy is preferable.⁷ It is unclear how well or how long improvement in sleep is maintained after therapy cessation, but studies suggest that patients who have taken BZRAs for extended periods of time do continue to see some benefits after the medication is discontinued.²⁷

Unfortunately, head-to-head evaluations of the BZRAs are limited. A small study over 2 weeks did not show differences in efficacy or safety between zolpidem or zaleplon.²⁹ Several unique characteristics of the BZRAs can help individualize a regimen for a patient. Zolpidem is the most frequently prescribed BZRA and has been studied the most in older adults.²⁷ It is available in multiple formulations, each designed to address a specific insomnia need. The original immediate-release (IR) tablet is best suited for managing difficulties with sleep latency but is effective for other insomnia difficulties as well.²⁷ Extended-release (ER) zolpidem may help manage fragmented sleep or early awakenings, but its effects can last for more than 9 hours, necessitating a delay in activities that require alertness to late morning or afternoon.^7,27 While studies do indicate a longer TST with the ER formulation, a significant increase in TST has also been seen with the IR tablet; use of the IR tablet may minimize or circumvent next-day effects from the ER formulation.²⁷

Zolpidem is also available in an oral spray and a sublingual tablet to manage awakenings and difficulty returning to sleep in the middle of the night.²⁷ Similar to the ER formulation, sublingual or oral spray zolpidem should not be taken unless the patient has at least 7 to 8 hours of time in bed remaining.⁷ Impact on sleep parameters with zolpidem appear more pronounced earlier in therapy, suggesting the possibility of tolerance with long-term use.⁷

Zaleplon has similar characteristics to zolpidem and is available as a 5 mg and 10 mg capsule for sleep latency and improves sleep maintenance.^29-31 Sleep latency is best maintained at 1 month with the 10 mg dose; there are no significant differences between doses on sleep maintenance.^30-32 Cessation of zaleplon, at least at higher doses, can result in rebound insomnia, although this effect may be more pronounced in younger than older adults.^29-32

Eszopiclone is the only agent in the class approved for long-term use, despite the others having been studied for similar amounts of time.^16,33 It produced significant improvement in sleep at all time points through 6 months, indicating that tolerance during this time may not be as problematic.³³

Small studies suggest zaleplon may be helpful in treating insomnia and improving daytime sleep in shift workers without significant impairments on psychomotor or cognitive performance when awakened.³² Zolpidem and zaleplon have been studied in small trials at simulated high altitudes where respiratory function, daytime cognition, and sleep function can be negatively affected in those unaccustomed the environment; study participants had improvement in respiratory and sleep function and no worsened daytime cognition compared with those receiving placebo who experienced worsening of all three outcomes.³²

Like BDZs, BZRAs can cause a wide range of AEs and consequences. Many AEs are similar to the BDZs, including psychomotor impairment, decreased balance/falls, daytime drowsiness, cognitive effects, and misuse or abuse.^3,5,27 Some patients may experience short-term rebound insomnia when BZRAs are stopped. ^6,27 Supratherapeutic doses can cause withdrawal symptoms when discontinued; these range from mild (e.g., headache) to severe (e.g., seizures).^6,27

BZRAs also have unique AEs associated with their use. Zaleplon and eszopiclone have a bitter taste that may complicate administration in patients with sensory or swallowing difficulties.^2,7,33 Zolpidem and zaleplon can negatively affect next-day cognition.² Eszopiclone and zolpidem may increase the risk of minor infections.^2,7,29,33 Zolpidem in particular has several concerning AEs, including risk of hip fracture, angioedema, higher risk of traumatic brain injury, suicide attempts and completion, unconscious sleep behaviors (e.g., sleepwalking, driving, shopping, eating, and sex while asleep) and impaired driving.^2,6,7,27 All BZRAs are Schedule IV medications with known abuse potential. Prescriptions should be objectively reviewed to ensure efficacy is optimized and the risk of misuse or diversion is minimized.⁶

Antidepressants

The sedating antidepressants improve sleep by antagonizing wake-promoting monoamines such as histamine, serotonin, acetylcholine, and noradrenaline.^2,16 The most commonly used antidepressants used are doxepin, trazodone, mirtazapine, and amitriptyline. The antidepressants are not prone to abuse, but their efficacy data are not as strong as for BDZs or BZRAs.^2,3 In addition, studies supporting their long-term use are lacking.²

Antidepressant doses used for insomnia are often lower than what is needed for depression; in some cases the beneficial effects on sleep may be lost at doses necessary to treat depression.^2,3 However, antidepressants may be useful for patients with coexisting depression or other mental disorders and can significantly decrease the need for BDZs.³⁴ Practically, their pharmacokinetic profiles require administration earlier in the evening than other agents, at least 2 hours before bedtime.³⁴

Doxepin is a tricyclic antidepressant and the only selective histamine₁ (H₁) antagonist recommended in guidelines and approved by FDA for use in patients with insomnia caused by lack of sleep maintenance.^1-3 Originally developed for use as an antidepressant at doses of 75–150 mg daily, its specificity as a H₁ antagonist increases at doses less than 10 mg.^3,5,6 Doses used in insomnia are 3–6 mg.^3,5,7,25 Its effects appear to be greatest at the end of the night without increasing morning impairment, making doxepin a good option for those with early awakenings and difficulty falling back asleep.^3,7 This may be particularly helpful in older adults whose sleep is most disturbed in early morning hours.⁷

Food, especially high-fat meals, delays absorption of doxepin; to prevent next-day effects, doxepin should not be taken within 3 hours of food.^5,7 Doxepin is well tolerated; at the 3 mg dose, AEs are similar to placebo and include nausea, headache, dizziness, and somnolence.^3,6,7,25 Still, caution is advised in patients with decreased kidney function, glaucoma, urinary obstruction, or cognitive impairment. ^3,7 It should not be used in patients with severe sleep apnea.⁷ Additionally, doxepin’s histamine blockade can be helpful in patients with co-existing environmental allergies. Doxepin is 80% protein bound, and smaller doses may be required in patients with decreased serum albumin levels.⁵ Reduced doses should also be considered in patients taking concurrent CYP2C19 or CYP2D6 inhibitors — including cimetidine and or sertraline — as these can increase plasma doxepin concentrations.^5,6 Doxepin has not been well studied against other therapies for insomnia, making it difficult to determine its exact role in therapy. However, doxepin does not appear to have an abuse potential and may be helpful in patients for whom that would be of concern.³

Amitriptyline is another tricyclic antidepressant that exerts its hypnotic effects via potent H₁ antagonism.¹⁶ The guidelines do not include amitriptyline and its current role in insomnia management is unclear.¹ Amitriptyline has been studied for insomnia only in patients with depression, and overall efficacy data to support its use is lacking.^6,16 Amitriptyline use is limited by an extensive number of AEs, particularly anticholinergic effects. At low doses, it is less selective and exhibits more anticholinergic activity as part of is sedating effects.¹⁶ Subsequently, it should be explicitly avoided in older adults, for whom safer alternatives exist.

Trazodone is one of the most widely prescribed agents for insomnia.⁵ Trazodone’s hypnotic effect is complex and involves multiple mechanisms including H₁ antagonism, partial agonism of 5-hydroxytryptamine (5-HT, or serotonin) type 1A (5-HT_1A) receptors, and antagonism of 5-HT_2A, 5-HT_1C, and postsynaptic α₁-adrenergic receptors.⁵

Despite its high rate of use, trazodone has not been robustly studied for insomnia, and its use is not recommended by the guidelines based on studies of 50 mg.^1,2 A 2-week trial showed no significant improvements with trazodone 50 mg versus placebo.^3,35 This same trial indicated that sleep latency was significantly longer with trazodone compared to zolpidem, with no significant difference in sleep duration between the groups.³⁵ Two studies of trazodone in patients with depression failed to show significant efficacy.⁵ On the other hand, a 2015 retrospective analysis showed trazadone was as effective as mirtazapine at low doses, with a higher proportion of patients responding to doses as low as 25 mg without any significant safety concerns or complaints.³⁶

AEs of trazodone include dizziness, drowsiness, headache, orthostatic hypotension, dry mouth, nausea, and vomiting.⁶ The terminal half-life is prolonged with higher doses, especially in older patients, which may inadvertently prolong any unwanted effects.⁶ However, trazodone’s lack of anticholinergic effects can be a strength when selecting therapy for older adults.⁶ Therefore, if trazodone is used for insomnia, therapy can be initiated at low doses; if improvement in sleep does not occur, a change in therapy should be considered rather than increasing the medication dose. Trazodone may also be useful for insomnia secondary to stimulating antidepressants such as fluoxetine or bupropion in patients with co-existing depression.^5,36 All males should be counseled on the risk of priapism.^3,5,6

Trazodone is metabolized by CYP3A4 and CYP2D6, and dose adjustments may be required when it is used concurrently with inhibitors of these enzymes.^5,6 Trazodone has a lower risk for abuse compared with BDZs.^5,6

Mirtazapine has selective histamine and α₂-adrenergic antagonism that causes sedation, particularly at lower doses.^3,14 The guidelines do not comment for or against mirtazapine use in insomnia. It has not been well studied in primary insomnia, but in patients with secondary insomnia, its effects are greatest on sleep maintenance.^3,5,6,14,37 The beneficial effects on sleep are greater at 7.5 mg and decrease as the dose increases.^6,36 Mirtazapine is also known to increase appetite and may be used as an appetite stimulant in some patients as well. It should be administered in the evening or at bedtime, regardless of indication, due to its sedative effects. Like doxepin, mirtazapine is highly protein bound, and lower doses may be warranted in older patients.^5,38 Patients should be advised that beneficial effects may not occur for up to 4 days in patients of all types and as long as 6 days in older adults.^6,38

Overall, mirtazapine is well-tolerated. In addition to sedation and increased appetite, AEs include dry mouth and constipation.³ Daytime somnolence often resolves with continued use.³⁷ Mirtazapine’s safety profile makes it an attractive option for insomnia in older adults, even in the absence of depression or other mental disorders. Still, mirtazapine use is limited in certain comorbidities. More than one-fourth of patients taking mirtazapine experience restless-leg syndrome, and the drug can induce nightmares and cause weight gain, which can be problematic in those with obesity and/or obstructive sleep apnea (OSA).³⁴ When discontinued, mirtazapine should be tapered over 2 to 4 weeks to avoid withdrawal effects associated with abrupt cessation.³⁸

Dual Orexin Receptor Antagonists

Orexins are two peptides (orexin A and B) that come from neurons in the lateral hypothalamus and promote wakefulness and arousal.³ Orexin plays an essential role in the sleep cycle by regulating rapid eye movement (REM) sleep and maintaining alertness. The neurons are active during wake periods and inactive during sleep.⁸ Dual orexin receptor antagonists (DORAs) block the arousal mediated by orexins without affecting a person’s ability to wake up when aroused by external stimuli.^8,39 Unlike medications that affect GABA, DORAs promote time spent in both non-REM and REM sleep.⁴⁰

Suvorexant was the first DORA approved by FDA for insomnia. It blocks both orexin receptors.^3,5 Overall, suvorexant’s efficacy in insomnia is similar to BDZs, ramelteon, and sedating antidepressants.⁵ Suvorexant decreases sleep latency, increases TST, and improves sleep maintenance, but the guidelines recommend it only for sleep maintenance.^1,3 Suvorexant’s distinguishing feature is that it continues to be effective in the last third of the night without significant morning sedation.³ The drug binds to and releases from the receptor slowly, which accounts for longer effects than its pharmacokinetic profile would suggest.¹

Suvorexant has been studied for time periods up to 1 year without substantial rebound insomnia or withdrawal effects.^1,3,6-7,40 Dosing should occur at the lowest effective dose of 5 to 20 mg daily, approximately 30 minutes prior to bedtime, and only when the patient has at least 7 hours remaining before wake time.^7,41 Suvorexant should not be taken with food to avoid a delay in peak effects of up to 90 minutes.^6,40 Patients should be counseled that it may take up to 3 days before full effects are seen.⁴¹ Although there is no precise recommendation, lower doses are advised in patients with obesity (body mass index >30 kg/m²) and females; approximately 15%–25% more drug exposure and slower clearance occurs than in those with lower body mass indexes and in males.^16,40

Suvorexant doses should not exceed 10 mg in patients taking moderate CYP3A4 inhibitors or other CNS depressants, and the drug should be avoided in patients taking strong CYP3A4 inhibitors or with severe liver impairment.^6,16,40 Doses of 30 to 40 mg were studied in phase 3 trials but were associated with more safety issues, including next-day driving impairment.^40,41 Other AEs at high suvorexant doses include hallucinations, sleep paralysis, unconscious nighttime behaviors, and narcolepsy-like effects.⁵ In approved doses, suvorexant AEs include somnolence, headache, dizziness, dry mouth, abnormal dreams, and nasopharyngitis.^7,16,40

Most AEs present early in treatment, and patients may develop a tolerance to some of these with continued medication use.^40,42 Suvorexant use in older adults does not significantly impair balance, memory, or cause residual daytime effects.^6,7 Concomitant administration with other hypnotic agents is overall well tolerated, but as would be expected, more daytime somnolence can be expected.⁴² When added to ramelteon in patients with acute stroke, significantly better outcomes were observed, including less difficulty staying asleep, less daytime somnolence, less delirium, and shorter hospital stays compared with those who received ramelteon and a BZRA.⁴³ Suvorexant has not been well studied in patients with sleep apnea; if used, patients should be closely using by the apnea-hypopnea index.^7,40

Suvorexant is classified as a Schedule IV medication.⁴¹ Its abuse potential is similar to that of zolpidem but with less self-harm, less perceptual changes, and fewer hallucinations.^3,40,41

Lemborexant

Lemborexant is approved by FDA for patients with insomnia associated with sleep onset or maintenance.⁸ The 5 mg dose, which can be titrated up to 10 mg, can be taken immediately before bed, but it is important that the patient has at least 7 hours before a planned wake-up time.⁸ The reason for the time requirement is due to impairments in balance, attention, and memory at 4 hours post-dose that do not appear to be present at 8-hour post-dose.³⁹

Unlike suvorexant, lemborexant does not appear to be affected by obesity. However, it should not be dosed higher than 5 mg per night in patients with moderate liver impairment or those taking weak CYP3A4 inhibitors.⁸ Because of the risk of clinically significant changes in plasma concentrations, lemborexant should be avoided in patients with severe liver impairment or on moderate-to-strong CYP3A4 inhibitors or inducers.⁸

In older adults, lemborexant 5 mg and 10 mg doses were significantly better than placebo and zolpidem for improving sleep latency, sleep efficiency, and WASO, with benefits seen as soon as the first dose.^8,45,46 Lemborexant’s efficacy and safety has been evaluated in studies lasting up to 1 year with beneficial impacts on sleep parameters seen early and maintained throughout therapy.^8,44,45

Lemborexant is overall well tolerated, with the most common AEs being somnolence, headache, and nightmares and abnormal dreams, though the incidence of these effects was similar to placebo.⁸ Lemborexant does not seem to induce withdrawal and is not associated with rebound insomnia.^8,44 It does not appear to induce oxygen desaturation or increase nighttime OSA in patients with mild OSA after 8 days of 10 mg dosing, but its safety in this population has only been evaluated in a small study. While lemborexant might be cautiously considered in mild OSA, its use should be reserved in patients with more severe OSA until additional data are available.^8,46

While extremely rare, lemborexant may induce sleep paralysis or hypnagogic or hypnopompic hallucinations during sleep/wakefulness transitions.⁸ It may also cause rare symptoms similar to mild cataplexy such brief periods of leg weakness, but unlike with narcolepsy, these symptoms are not triggered by strong emotion.⁸ It is worth noting that lemborexant has been evaluated in older adults in multiple studies, providing an evidence-based efficacy and safety profile for a patient population particularly sensitive to pathophysiologic and pharmacologic effects associated with insomnia and its historical therapeutic options.^8,45 Finally, lemborexant’s abuse potential appears to be similar to suvorexant and zolpidem.⁸

THE PHARMACISTS’ ROLE IN MANAGING INSOMNIA

The majority of patients suffering from insomnia manage their symptoms with nonprescription agents.⁵ While those with occasional insomnia may find relief with self-care, it is not an effective approach to chronic insomnia. Though patients may consider OTC products safer than those requiring a prescription, many OTC agents pose clinically important safety concerns. Diphenhydramine for example is included in numerous OTC sleep aids or may be taken alone when self-treating insomnia. However, its use has not been shown to produce significant improvements in sleep.²⁵ Its notorious anticholinergic profile and age-related altered pharmacokinetics provide a negative risk versus benefit ratio, particularly in older adults.⁶

When pharmacists are approached for medication recommendations for insomnia, it is important to inquire about symptom duration and severity and to refer patients meeting the definition of chronic insomnia for appropriate diagnosis. Some OTC agents, such as melatonin, may be a viable option for certain patients, but it is essential that patients understand that they need to inform their primary care and other healthcare providers of their symptoms and self-management. It is also pertinent to recognize that many patients will not achieve effective management of their symptoms through self-care alone. These patients should be encouraged to be formally assessed for insomnia and any related comorbidities through appropriate diagnostic methods.

When the diagnosis of insomnia has been made, pharmacists can help in optimal treatment selection by identifying an effective regimen individualized to the patient’s pharmacokinetics, comorbidities, concurrent medications, preferences, and insurance coverage. For example, because DORAs are newer agents, they may be cost-prohibitive for some patients. Emphasizing appropriate dosing, including timing and coadministration of food, can help maximize medication effectiveness while decreasing negative effects. Patients should be counseled to allow up to 10 days to see effects after starting therapy and to contact their prescriber if symptoms have not improved by that time.⁷

Pharmacists can aid in the management of AEs by increasing awareness via counseling and routine monitoring at patient encounters. Pharmacists have more interactions with many patients than other clinicians and may be able to recognize complications early enough to prevent long-term or severe consequences. Pharmacists should also remember to continuously screen for drug-drug interactions. Some OTC products can have profound effects on insomnia therapies. For example, cimetidine increases plasma zaleplon concentration by 85%.³² Many of the medications have clinically significant drug-drug interactions involving CYP450 enzymes.

Several drug-disease interactions or considerations influence pharmacotherapy recommendations, including avoiding BDZs or BZRAs in those with histories of substance abuse and using DORAs with caution in those with chronic respiratory conditions. For patients requiring long-term pharmacotherapy, especially older adults, medications that have been studied longer and in higher numbers of these patients, such as the DORAs, could be recommended.⁶

Pharmacists should be aware of how long patients have been using agents for insomnia. It is important to help set expectations so patients understand that these medications should not become lifelong therapies. Most medications have only been studied for short periods of time in insomnia, and regular reevaluations are necessary to determine if there is a continued need for pharmacologic intervention and to assess response to therapy. It is equally important to reconcile medication use with a known purpose. For example, the number of BZRAs prescriptions is up to 21 times higher than the number of patient reports of sleepiness and 5 times higher than the number of insomnia diagnoses.⁶ Finally, many medications for insomnia are controlled substances with known abuse potential. Vigilant medication reconciliation based on indications not only helps improve efficacy and safety but helps to minimize misuse and diversion.

Overall, the management of insomnia is complex and complicated by a lack of efficacy data for many medications, variable safety profiles, drug-drug and drug-disease interactions, concerns for symptom rebound, medication withdrawal, and diversion or misuse potentials. Many of these concerns can be addressed with appropriate attention and an individualized approach. Patients may seek to treat their symptoms with OTC products, but often these are often not effective for chronic insomnia without other nonpharmacologic interventions or pharmacologic agents. Recognizing when a patient needs accelerated treatment, reinforcement of nonpharmacologic approaches, and monitoring of medication response and safety are the core principles of good pharmaceutical care for this unfortunate but common condition.

REFERENCES

1. Sateia MJ, Buysse DJ, Krystal AD, et al. Clinical practice guideline for the pharmacologic treatment of chronic insomnia in adults: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med. 2017;13:307–349.
2. Riemann D, Baglioni C, Bassetti C, et al. European guideline for the diagnosis and treatment of insomnia. J Sleep Res. 2017;26:675–700.
3. Krystal AD, Prather AA, Ashbrook LH. The assessment and management of insomnia: an update. World Psychiatry. 2019;18:337–352.
4. Schutte-Rodin S, Broch L, Buysse D, et al. Clinical guideline for the evaluation and management of chronic insomnia in adults. J Clin Sleep Med. 2008;4:487–504.
5. Atkin T, Comai S, Gobbi G. Drugs for insomnia beyond benzodiazepines: pharmacology, clinical applications, and discovery. Pharmacol Rev. 2018;70:197–245.
6. Schroeck JL, Ford J, Conway EL, et al. Review of safety and efficacy of sleep medicines. Clin Ther. 2016;38:2340–2372.
7. Abad VC, Guilleminault C. Insomnia in elderly patients: recommendations for pharmacological management. Drugs & Aging. 2018;35:791–817.
8. Scott LJ. Lemorexant: first approval. Drugs. 2020:doi:10.1007/s40265-020-01276-1.
9. Rios P, Cardoso R, Morra D, et al. Comparative effectiveness and safety of pharmacological and non-pharmacological interventions for insomnia: an overview of reviews. Systematic Reviews. 2019;8:281.
10. Spielman AJ, Caruso LS, Glovinsky PB. A behavioral perspective on insomnia treatment. Psychiatr Clin North Am. 1987;10(4):541–553.
11. Olde Rikkert MG, Rigaud AS. Melatonin in elderly patients with insomnia. A systematic review. Z Gerontol Geriatr. 2001;34:491–497.
12. Johns MW. Reliability and factor analysis of the Epworth Sleepiness Scale. Sleep. 1992;15:376–381.
13. Buysse DJ, Reynolds DF, Monk TH, et al. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res. 1989;28:193–213.
14. Wang D, Li Z, Li L, Hao W. Real-world, open-label study to evaluate the effectiveness of mirtazapine on sleep quality in outpatients with major depressive disorder. Asia Pac Psychiatry. 2014;6:152–160.
15. Morin CM, Belleville G, Belanger L, et al The Insomnia Severity Index: psychometric indicators to detect insomnia cases and evaluate treatment response. Sleep. 2011;34:601–608.
16. Dujardin S, Pijpers A, Pevernagie D. Prescription drugs used in insomnia. Sleep Med Clin. 2020;15:133–145.
17. Bent S, Padula A, Moore D, Patterson M, et al. Valerian for sleep: a systematic review and meta-analysis. Am J Med. 2006;119:1005–1012.
18. Fernandez-San-Martin MI, Massa-Font, R, Palacios-Soler L, et al. Effectiveness of valerian on insomnia; a meta-analysis of randomized placebo-controlled trials. Sleep Med. 2010;11:505–511.
19. Leach MJ, Page AT. Herbal medicine for insomnia: a systematic review and meta-analysis. Sleep Med Rev. 2015;24:1–12.
20. Besag FMC, Vasey MJ, Lao KSJ, Wong ICK. Adverse events associated with melatonin for the treatment of primary or secondary sleep disorders: a systematic review. CNS Drugs. 2019;33:1167–1186.
21. Buscemi N, Vandermeer B, Hooton N, et al. The efficacy and safety of exogenous melatonin for primary sleep disorders, a meta-analysis. J Gen Intern Med. 2005;20:1151–1158.
22. Ferracioli-Oda E, Qawasmi A, Bloch MH. Meta-analysis: melatonin for the treatment of primary sleep disorders. PLoS ONE. 2013;8:e63773.
23. Kuriyama A, Honda M, Hayashino Y. Remelteon for the treatment of insomnia in adults: a systematic review and meta-analysis. Sleep Med. 2014;15:385–392.
24. Garzon C, Guerrero JM, Aramburu O, et al. Effect of melatonin administration on sleep, behavioral disorders, and hypnotic drug discontinuation in the elderly: a randomized, double-blind, placebo-controlled study. Aging Clin Exp Res. 2009;21:38–42.
25. Sys J, Cleynenbreugel SV Deschodt M, et al. Efficacy and safety of non-benzodiazepine and non-Z-drug hypnotic medication for insomnia in older people: a systematic literature review. Eur J Clin Pharmacol.2020;76:363–381.
26. Liu J, Wang LN. Ramelteon in the treatment of chronic insomnia: systematic review and meta-analysis. Int J Clin Prac. 2012;66:867–873.
27. Machado FV, Louzada LL, Cross NE, et al. More than a quarter century of the most prescribed sleeping pill: systematic review of zolpidem use by older adults. Exp Gerontol.2020;136:110962.
28. Pillai V, Roth T, Roehrs T, et al. Effectiveness of benzodiazepine receptor agonists in the treatment of insomnia: an examination of response and remission rates. Sleep. 2017;40:zsw044.
29. Huang YS, Hsu SC, Liu SI, et al. A double-blind, randomized, comparative study to evaluate the efficacy and safety of zaleplon versus zolpidem in shortening sleep latency in primary insomnia. Chang Gung Med J. 2011;34:50–56.
30. Fry J, Scharf M, Mangano R, et al. Zaleplon improves sleep without producing rebound effects in outpatients with insomnia. Int Clin Psychopharmacol. 2000;15:141–152.
31. Hedner J, Yaeche R, Emilien G, et al. Zaleplon shortens subjective sleep latency and improves subjective sleep quality in elderly patients with insomnia. Int J Geriatr Psychiatry. 2000;15:704–712.
32. Ebbens MM, Verster JC. Clinical evaluation of zaleplon in the treatment of insomnia. Nat Sci Sleep. 2010;20:115–126.
33. Liang L, Huang Y, Xu R, et al. Eszopiclone for the treatment of primary insomnia: a systematic review and meta-analysis of double-blind, randomized, placebo-controlled trials. Sleep Med. 2019;62:6–13.
34. Wichniak A, Wierzbicka A, Walecka M et al. Effects of antidepressants on sleep. Curr Psychiatry Rep. 2017;19:63.
35. Walsh JK, Erman M, Erwin CW, et al. Subjective hypnotic efficacy of trazodone and zolpidem in DSM-III-R-primary insomnia. Hum Psychopharmacol. 1998;13:191–198.
36. Savarese M, Carnicelli M, Cardinali V, et al. Subjective hypnotic efficacy of trazodone and mirtazapine in patients with chronic insomnia: a retrospective, comparative study. Arch Ital Biol. 2015;153:231–238.
37. Winokur A, Sateia MJ, Hayes B, et al. Acute effects of mirtazapine on sleep continuity and sleep architecture in depressed patients: a pilot study. Biol Psychiatry. 2000;48:75–78.
38. Anttila SAK, Leinonen EVJ. A review of the pharmacological and clinical profile of mirtazapine. CNS Drug Rev. 2001;7:249–264.
39. Murphy P, Kumar D, Zammit G, et al. Safety of lemborexant versus placebo and zolpidem: effects on auditory awakening threshold, postural stability, and cognitive performance in healthy older participants in the middle of the night and upon morning awakening. J Clin Sleep Med. 2020;16:765–773.
40. Norman JL, Anderson SL. Novel class of medications, orexin receptor antagonists, in the treatment of insomnia — critical appraisal of suvorexant. Nat Sci Sleep. 2016;14:239–247.
41. Sutton EL. Profile of suvorexant in the management of insomnia. Drug Des Devel Ther. 2015;9:6035–6042.
42. Sano H, Asai Y, Miyazaki M, et al. Safety profile and clinical course of patients with insomnia administered suvorexant by initial treatment status in a post-marketing survey. Expert Opin Drug Saf. 2019;18:1109–1118.
43. Kawada K, Ohta T, Tanaka K, et al. Addition of suvorexant to ramelteon therapy for improved sleep quality with reduced delirium risk in acute stroke patients. J Stroke Cerebrovasc Dis. 2019;28:142–148.
44. Rosenberg R, Murphy P, Xammit G, et al. Comparison of lemborexant with placebo and zolpidem tartrate extended release for the treatment of older adults with insomnia disorder: a phase 3 randomized clinical trial. JAMA Netw Open. 2019;2:e1919254.
45. Moline M, Karppa M, Yardley J et al. 165 Impact of lemborexant on insomnia disease severity and fatigue: results from the 6-month placebo-controlled period of the phase 3 SUNRISE-2 study. CNS Spectr. 2020;25:305–306.
46. Cheng JY, Filippov G, Moline M, et al. Respiratory safety of lemborexant in healthy adult and elderly subjects with mild obstructive sleep apnea: a randomized double-blind, placebo-controlled, crossover study. J Sleep Res. 2020;29:e13021.

Back to Top