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INTRODUCTION — Insomnia was previously viewed as a sleep disturbance that was secondary to a medical condition, psychiatric illness, sleep disorder, or medication, and would improve with treatment of the underlying disorder . However, evidence over the past 20 years indicates that this view is incorrect.
It is now recognized that insomnia is often an independent disorder [2,3]. Insomnia may occur in the absence of coexisting conditions and, when coexisting conditions exist, may persist despite successful treatment of the coexisting condition. Treatment directed at the insomnia and the comorbidity may be necessary. Since insomnia can precipitate, exacerbate, or prolong comorbid conditions, treatment of insomnia may improve comorbidities [4-7].
Treatment of insomnia is described in this topic review. The definition, types, epidemiology, clinical features, consequences, and diagnostic evaluation of insomnia are reviewed elsewhere. (See "Overview of insomnia" and "Clinical features and diagnosis of insomnia".)
GENERAL APPROACH — All patients with insomnia should receive therapy for any medical condition, psychiatric illness, substance abuse, or sleep disorder that may be precipitating or exacerbating the insomnia (table 1). They should also receive basic behavioral counseling about sleep hygiene (table 2) and stimulus control (table 3).
For patients who continue to have insomnia that is sufficiently burdensome to warrant other interventions, treatment options include behavioral therapy, medication, or both:
●Behavioral therapies beyond sleep hygiene and stimulus control include relaxation, sleep restriction therapy, cognitive therapy, and cognitive behavioral therapy for insomnia (CBT-I) . These therapies are not available in all medical centers. (See 'Behavioral therapy' below.)
●Approved medications used to treat insomnia include benzodiazepines, nonbenzodiazepine sedatives, melatonin agonists, antidepressants, and orexin antagonists. (See 'Medications' below.)
●Combination therapy involves initially prescribing both CBT-I and a medication (usually for six to eight weeks), then tapering the medication off or to an as-needed schedule while continuing CBT-I (see 'Combination therapy' below). The use of medication prior to the initiation of behavioral therapy appears to be less effective .
The choice of treatment should be individualized according to the patient's values and preferences, the availability of advanced behavioral therapies, the severity and impact of the insomnia, and the potential benefits versus the risks, costs, and inconveniences. For most patients, we suggest CBT-I rather than medication as initial therapy, recognizing that both approaches are effective in short-term studies, but that medications have a higher risk of side effects and have been inadequately evaluated for use for longer than a year. However, access to behavioral therapy may be limited in some regions and for some patients groups. A preference for CBT-I or other behavioral therapies over medication as initial therapy has been endorsed in clinical practice guidelines of the American Academy of Sleep Medicine  and the American College of Physicians [8,11].
Treatment decisions must also factor in the potential health risks of untreated chronic insomnia, which include decreased quality of life, increased risk for psychiatric comorbidities and substance abuse, decreased performance, and the association between chronic insomnia and risk of cardiovascular morbidity and all-cause mortality. (See "Overview of insomnia", section on 'Consequences'.)
In clinical practice, initial treatment typically involves sleep hygiene instruction and stimulus control procedures. If follow-up indicates that further treatment is needed, then more formal CBT-I alone or in combination with a medication may be used for six weeks. For patients who respond to therapy (ie, report both improved sleep at night and improvement of daytime deficits), the medication can be tapered or used as needed while continuing the CBT-I. Patients whose symptoms recur after discontinuation of therapy may require re-evaluation for referral for polysomnography or additional CBT-I, with or without pharmacologic therapy. An exception to this approach is patients who have short-term insomnia due to a self-limited stressor; such patients may benefit from short-term medication alone.
BEHAVIORAL THERAPY — Behavioral therapies for insomnia include sleep hygiene education, stimulus control, relaxation, sleep restriction therapy, cognitive therapy, and cognitive behavioral therapy . Patients whose insomnia has been successfully treated by behavioral therapy are likely to report decreased daytime symptoms and improvement of daytime function, quality of life, and comorbidities. Behavioral therapy is well tolerated and has a low risk of adverse effects, but it is not readily available in many places.
Behavioral therapy beyond an introduction to sleep hygiene and stimulus control is typically implemented over a series of approximately 6 to 10 sessions. The evidence suggests that the success of the therapy is related to the experience of the individual implementing it .
●Sleep as long as necessary to feel rested (usually seven to eight hours for adults) and then get out of bed
●Maintain a regular sleep schedule, particularly a regular wake-up time in the morning
●Try not to force sleep
●Avoid caffeinated beverages after lunch
●Avoid alcohol near bedtime (eg, late afternoon and evening)
●Avoid smoking or other nicotine intake, particularly during the evening
●Adjust the bedroom environment as needed to decrease stimuli (eg, reduce ambient light, turn off the television or radio)
●Avoid prolonged use of light-emitting screens (laptops, tablets, smartphones, ebooks) before bedtime 
●Resolve concerns or worries before bedtime
●Exercise regularly for at least 20 minutes, preferably more than four to five hours prior to bedtime [15,16]
●Avoid daytime naps, especially if they are longer than 20 to 30 minutes or occur late in the day
Sleep hygiene counseling alone has not been directly compared with no intervention or a sham intervention. However, numerous clinical trials have used sleep hygiene counseling alone as the control intervention and showed some improvement in sleep but less than that seen with pharmacotherapy or cognitive behavioral therapy [17-19].
Stimulus control — Patients with insomnia may associate their bed and bedroom with the fear of not sleeping or other arousing events, rather than the more pleasurable anticipation of sleep. The longer one stays in bed trying to sleep, the stronger the association becomes. This perpetuates the difficulty falling asleep.
Stimulus control therapy is a strategy whose purpose is to disrupt this association by enhancing the likelihood of sleep (table 3) . Patients should not go to bed until they are sleepy and should use the bed primarily for sleep (and not for reading, watching television, eating, or worrying). They should not spend more than 20 minutes in bed awake. If they are awake after 20 minutes, they should leave the bedroom and engage in a relaxing activity, such as reading or listening to soothing music. Patients should not engage in activities that stimulate them or reward them for being awake in the middle of the night, such as eating or watching television. In addition, they should not return to bed until they are tired and feel ready to sleep. If they return to bed and still cannot sleep within 20 minutes, the process should be repeated. An alarm should be set to wake the patient at the same time every morning, including weekends. Daytime naps are not allowed.
Patients may not improve immediately. However, accumulating sleepiness will facilitate sleep during successive nights.
Stimulus control therapy has improved sleep in randomized trials and its effects may be long lasting [21-23]. One study suggested that stimulus control therapy is more effective among patients who are not already taking medications for insomnia .
Relaxation — Relaxation therapy may be implemented before each sleep period. There are two common techniques for relaxation therapy: progressive muscle relaxation and the relaxation response.
●Progressive relaxation is based upon the theory that an individual can learn to relax one muscle at a time until the entire body is relaxed. Beginning with the muscles in the face, the muscles are contracted gently for one to two seconds and then relaxed. This is repeated several times. The same technique is used for other muscle groups, usually in the following sequence: jaw and neck, upper arms, lower arms, fingers, chest, abdomen, buttocks, thighs, calves, and feet. This cycle is repeated for approximately 45 minutes, if necessary.
●The relaxation response begins by lying or sitting comfortably. The eyes are closed and relaxation is allowed to spread throughout the body. A relaxed, abdominal breathing pattern is established. Thoughts are redirected away from everyday thoughts and toward a neutral mental focusing device, such as a peaceful word or image.
One trial randomly assigned 57 patients with insomnia to receive progressive relaxation therapy or no therapy . Progressive relaxation therapy improved measures of sleep, but not daytime function. Another randomized trial similarly found improvement in sleep measures among patients who received relaxation therapy compared with a sham therapy, but the improvement was modest and smaller than that achieved with cognitive behavioral therapy . Slow-paced breathing prior to sleep onset as a means of reducing vagal activity has been shown to improve sleep parameters .
Sleep restriction therapy — Some patients with insomnia stay in bed longer to try to make up for lost sleep. This causes a circadian shift and a reduction in the homeostatic drive that makes sleep onset the following night more difficult and results in the need to stay in bed even longer. Sleep restriction therapy counteracts this tendency by limiting the total time allowed in bed, including naps and other sleep periods outside of bed, in order to increase the drive to sleep . This consolidates sleep and improves sleep efficiency (the percentage of time in bed that the patient is asleep).
Sleep restriction therapy begins by decreasing the time spent in bed to the same amount of time that the patient reports sleeping (usually determined from sleep diaries or logs completed by the patient), but not less than five hours per night (table 4). On a daily basis, the patient reports the amount of sleep obtained the previous night and the amount of time spent in bed. The clinician then computes the sleep efficiency, which is the reported time asleep divided by the reported time in bed. The time in bed is increased by 15 to 30 minutes once the sleep efficiency exceeds 85 percent. This process is repeated until the patient reports improved sleep without residual daytime sleepiness. However, total time in bed for some patients can remain at six hours or less for long periods of time. Naps are not permitted.
To improve compliance, the rationale for the therapy needs to be carefully explained to patients and some care needs to be used to determine and schedule the time in bed in a manner that maximizes the ability to sleep and is acceptable to the patient. Older patients tend to have more difficulty maintaining sleep even when restricted; therefore, they are given more lenient criteria.
A 2014 systematic review identified four randomized trials of sleep restriction therapy as a stand-alone therapy versus another intervention or control for chronic insomnia . The weighted effect sizes for improvement in subjective sleep variables were medium to large and comparable to those achieved with cognitive behavioral interventions in other meta-analyses [30,31]. In the largest individual study, 179 older adults with primary insomnia were randomly assigned to six weeks of sleep restriction therapy, stimulus control therapy, a multicomponent behavioral intervention, or wait-list control . All treatments resulted in significant improvements in diary-reported sleep outcomes compared with control, and there was no advantage to a multicomponent intervention over a single component intervention. Effect sizes were generally moderate to large and maintained at 3 and 12 months post-treatment.
Potential adverse effects of sleep restriction therapy include increased daytime sleepiness and decreased reaction times, as well as possible exacerbation of bipolar disorder. (See 'Adverse effects' below.)
Cognitive therapy — Patients who are awake at night commonly become concerned that they will perform poorly the next day if they do not obtain adequate sleep. This worry can exacerbate their difficulty falling asleep, creating a vicious cycle of wakefulness and concern. A person may begin to blame all negative events in their life on poor sleep. During cognitive therapy, a person works with a therapist to deal with anxiety and catastrophic thinking, while establishing realistic expectations related to insomnia and the need for sleep.
Cognitive behavioral therapy — Cognitive behavioral therapy for insomnia (CBT-I) is a strategy that combines several of the previously described approaches over several weeks . A sample eight-session CBT-I program may include an introductory sleep education session, followed by two sessions that focus on stimulus control and sleep restriction. These may be followed by two sessions that focus on cognitive therapy and then a session on sleep hygiene. Finally, there may be a session that reviews and integrates the previous session and a session that addresses future problems, such as stress and relapse . Patients are encouraged to complete sleep logs as they learn and apply the various strategies. This allows improvement to be measured.
The advantage of the educational nature of CBT-I is that it provides patients with tools to apply in the future. Disadvantages of CBT-I include the duration of therapy and the relatively few clinicians who are skilled at all of its components. The benefit of CBT-I may be reduced when it is administered by less experienced clinicians .
CBT-I has proven efficacious in moderate- to high-quality randomized trials [1,35,36]. A 2015 meta-analysis identified 20 randomized trials of CBT-I for chronic insomnia in over 1100 participants; CBT-I approaches incorporated at least three of the following: cognitive therapy, stimulus control, sleep restriction, sleep hygiene, and relaxation . Compared with inactive control conditions, CBT-I improved sleep on a variety of outcome measures, including sleep onset latency (improved by 19 minutes), wake time after sleep onset (decreased by 26 minutes), and sleep efficiency (improved by 10 percent). The benefits of CBT-I appeared to persist beyond the active treatment period. Separate meta-analyses of trials in patients with insomnia comorbid with medical, sleep, or psychiatric disorders have found similar results [37,38].
Several randomized studies have suggested that alternative delivery methods such as telephone-based CBT-I [39,40] and internet-based CBT-I [41-46] may be effective treatment options that could overcome some of the access and economic barriers that exist for traditional CBT-I. As an example, one trial recruited 303 patients with chronic insomnia via the internet and randomly assigned them to receive a six-week interactive, fully automated web-based CBT-I program or a control condition (access to an educational website) . At six weeks, patients assigned to CBT-I showed greater improvement in subjective sleep measures, including 41 percent who achieved remission of insomnia (Insomnia Severity Index <8). Remission rates also favored the intervention at one year (57 versus 27 percent), although subjective total sleep times were similar between groups.
Despite these results, larger studies are needed that directly compare alternative delivery methods with face-to-face CBT-I . In a small trial comparing face-to-face and guided online CBT-I with a wait-list control in 90 patients with insomnia, both delivery methods performed significantly better than the wait-list control, but face-to-face CBT-I was associated with larger treatment effects and better depression and anxiety outcomes than online delivery .
CBT-I is particularly recommended for use in patients where medications are contraindicated or may be more likely to produce side effects, such as in older adults, pregnant women, or patients with renal, hepatic, or pulmonary disease.
Other approaches — Other behavioral therapies that may emerge as useful in the treatment of insomnia include mindfulness meditation [49-52] and exercise training . However, a small randomized trial comparing tai chi with CBT-I in older adults found that CBT-I was associated with greater and more sustained improvement in sleep quality, fatigue, and depressive symptoms than tai chi .
Adverse effects — Adverse effects of behavioral therapy have not been well described, but one area of caution relates to sleep restriction. Sleep restriction decreases sleep latency and increases sleep efficiency by causing sleep deprivation (ie, total sleep time is decreased, not increased). In one study, subjects reported increased sleepiness and had slower reaction times during a four-week treatment period that then returned to baseline three months later, when time in bed had increased to about seven hours . These effects are similar to those seen during chronic partial sleep deprivation and suggest that patients using this therapy should be carefully monitored and instructed to avoid hazardous activity and driving when time in bed has been significantly reduced. Sleep restriction should be used with caution in patients with underlying bipolar disorder, since sleep deprivation can trigger manic episodes .
MEDICATIONS — Medications or classes of medications that are approved to treat insomnia include benzodiazepines, nonbenzodiazepine hypnotics, melatonin agonists, doxepin, and suvorexant . The potential benefits of pharmacologic therapy on sleep quality and daytime function are balanced against the risk of side effects as well as physical and psychological addiction with long-term use. These risks may be increased in certain clinical settings:
●Pregnancy – Sedative-hypnotics may increase the risk of fetal malformations if used during the first trimester.
●Alcohol consumption – Sedative-hypnotics should not be combined with alcohol because there is a risk of excessive sedation and respiratory suppression whenever central nervous system suppressants are combined.
●Renal or hepatic disease – Most sedative-hypnotic medications undergo hepatic and renal clearance. Metabolic clearance may be delayed in patients who have renal or hepatic disease, leading to accumulation and excessive sedation.
●Pulmonary disease or sleep apnea – Many sedative-hypnotics are respiratory suppressants that can worsen obstructive sleep apnea or hypoventilation.
●Nighttime decision makers – Sedative-hypnotics should not be taken by individuals who may be called upon to make important decisions during the night (eg, clinicians on-call or single parents responsible for the care of young children) because they can cause excess sedation and impair decision-making.
●Older adults – The risk of adverse effects is increased in older adults, especially those who are older than 75 years. This is a consequence of multiple comorbidities and central nervous system changes associated with aging. (See 'Older adults' below.)
Choice of an agent — Randomized trials directly comparing the effect of different medications on insomnia are rare. Indirect comparisons of benzodiazepines and nonbenzodiazepines suggest that these classes of medication have a similar impact on sleep onset latency (ie, they decrease objective sleep onset latency by approximately 10 minutes and subjective sleep onset latency by 15 to 20 minutes) . However, the benzodiazepines are more likely to prolong total sleep time, perhaps because they tend to have longer half-lives [58,59].
In one of the few trials that directly compared different medications, 382 patients with primary insomnia received each of six interventions in random order for two nights each, with a three- to seven-day wash-out period in between . The agents included placebo, eszopiclone (1, 2, 2.5, and 3 mg), and zolpidem (10 mg). Compared with placebo, eszopiclone at doses of 2.5 and 3 mg decreased the median wake time after sleep onset, but zolpidem and eszopiclone at doses of 1 and 2 mg did not. The wake time after sleep onset refers to the amount of time that the patient is awake between sleep onset and the final morning arising time. There were no differences in any of the objective sleep outcomes when eszopiclone (2 and 3 mg) and zolpidem were compared directly.
Most clinicians select a sedative-hypnotic on the basis of the type of insomnia (ie, sleep onset or sleep maintenance) and the duration of effect:
●For patients with sleep onset insomnia, a short-acting medication is a reasonable choice for an initial trial of pharmacologic therapy. This may improve the insomnia with less residual somnolence the following morning. Examples of short-acting medications (duration of effect ≤8 hours) include zaleplon, zolpidem, triazolam, lorazepam, and ramelteon.
●For patients with sleep maintenance insomnia, a longer-acting medication is preferable for an initial trial of pharmacologic therapy. Examples of longer-acting medications include zolpidem extended release, eszopiclone, temazepam, estazolam, low dose doxepin, and suvorexant. However, these medications may increase the risk for hangover sedation and patients must be warned about this possibility.
●For patients with awakening in the middle of the night, both zaleplon and a specific sublingual tablet form of zolpidem have been developed for use during the night, with the constraint that there will be at least four hours of time in bed remaining after administration.
Other issues to be considered when prescribing a medication for insomnia include cost and adverse effects. The benzodiazepines and older nonbenzodiazepines (specifically, zaleplon and zolpidem) tend to be less expensive than the other nonbenzodiazepines and ramelteon. The adverse effects are discussed below. (See 'Risks and side effects' below.)
Benzodiazepines — Benzodiazepines are a class of sleep promoting medications that bind to several gamma-aminobutyric acid (GABA) type A receptor subtypes . They reduce the time to the onset of sleep, prolong stage 2 sleep, prolong total sleep time, and may slightly reduce the relative amount of rapid eye movement (REM) sleep . In addition, they decrease anxiety, impair memory, and have anticonvulsive properties.
Benzodiazepines commonly used for the treatment of insomnia include triazolam, estazolam, lorazepam, temazepam, flurazepam, and quazepam. A primary difference among these medications is their duration of action. Triazolam is short-acting; estazolam, lorazepam, and temazepam are intermediate-acting; flurazepam and quazepam are long-acting (table 5) . Diazepam is also long-acting, but is generally not used to treat insomnia because it has a long duration of effect and can lead to the accumulation of active metabolites. The long-acting benzodiazepines should be avoided in older adults because there is increased risk for adverse effects in this patient population .
Meta-analyses of randomized, placebo-controlled trials indicate that benzodiazepines decrease sleep latency and the number of awakenings, while improving sleep duration and sleep quality [58,59,64,65]. Typical changes associated with these medications include decreases in the duration to sleep onset by approximately 10 minutes and increases in the total sleep time of 30 to 60 minutes [58,59].
The side effects of benzodiazepines are described below. (See 'Risks and side effects' below.)
Nonbenzodiazepines — Nonbenzodiazepine benzodiazepine receptor agonists have a structure that is different from the benzodiazepines and includes more targeted action at one GABA type A receptor. A consequence of their greater specificity is less anxiolytic and anticonvulsant activity.
Nonbenzodiazepines appear to improve both subjective and objective sleep outcomes. Specifically, meta-analyses of randomized, placebo-controlled trials indicate that nonbenzodiazepines decrease sleep latency and the number of awakenings, while improving sleep duration and sleep quality [57-59,64-66]. Nonbenzodiazepines have increased adverse events compared with placebo.
●Zaleplon has a very short half-life of about one hour. As a result, it is effective for patients who have difficulty falling asleep (ie, sleep onset insomnia), but may not be effective for patients who have difficulty maintaining sleep (ie, sleep maintenance insomnia) . Due to the very short half-life, the potential for hangover sleepiness is minimal after normal sleep periods. Occasional side effects include headache, dizziness, nausea, abdominal pain, and somnolence . Zaleplon is not indicated for long-term use.
●Zolpidem has a half-life of approximately 1.5 to 2.4 hours. It is indicated for the short-term treatment of insomnia characterized by difficulty with sleep initiation . The most common side effects are headache, dizziness, and somnolence, which can in turn lead to falls. Zolpidem is not approved for long-term use.
Zolpidem is also available in a dissolvable tablet and as an oral spray for patients who have difficulty swallowing a pill. A dissolvable tablet (1.75 to 3.5 mg) can be taken in the middle of the night for sleep maintenance insomnia, with the requirement that at least four hours be available to sleep after administration and at least five hours be available prior to driving. In January of 2013, the US Food and Drug Administration (FDA) issued a safety announcement recommending use of a lower dose in women than had been previously recommended . This should also be considered in men. (See 'Dosing precautions' below.)
●Zolpidem extended release also has a half-life of about 1.5 to 2.4 hours, but is released over a longer duration. It was developed to improve both sleep onset insomnia and sleep maintenance insomnia while avoiding hangover effects, although it has never been directly compared with regular zolpidem . Side effects of zolpidem extended release are relatively few, with the most common being headache, somnolence, and dizziness, which can in turn lead to falls . In January of 2013, the FDA recommended use of a lower dose in women than had been previously recommended . This lower dose should also be considered for men. In a follow-up safety announcement, the FDA added a warning that patients should not drive or engage in other activities that require complete mental alertness the day after taking zolpidem extended release because zolpidem levels can remain high enough the next day to impair these activities .
Sleep may be worse during the first night following discontinuation of this medicine. Zolpidem extended release is not limited to short-term use and there is little evidence for abuse or dependence in most patients. In theory, however, such medications could be habit forming with long-term use. (See 'Adverse effects of nonbenzodiazepines' below.)
●Eszopiclone has the longest half-life of the approved nonbenzodiazepines, approximately five to seven hours. This may extend to nine hours in older adult patients. Eszopiclone is effective for both sleep onset insomnia and sleep maintenance insomnia . Patients taking eszopiclone may report an unpleasant metallic taste. Other reported side effects are shared with nonbenzodiazepines as a class (headache, dizziness, parasomnias, next-day impairment in some patients) [61,73]. (See 'Adverse effects of nonbenzodiazepines' below.)
Sleep may be worse on the first night after discontinuation of this medication. Eszopiclone is not limited to short-term use and there is little evidence for abuse or dependence in most patients. In theory, however, such medications could be habit forming with long-term use.
Most clinical trials evaluated short-term therapy (eg, seven days), although a few longer clinical trials have been performed. In one randomized trial, patients treated with eszopiclone for six months had improved quality of life, decreased work limitation, and improved sleep compared with placebo . This persisted throughout the trial and the subsequent six month open label extension. In another randomized trial of 1018 patients with insomnia, zolpidem extended release taken for up to six months improved sleep onset, sleep maintenance, morning sleepiness, next-day concentration, and work performance compared with placebo [75,76].
Adverse effects associated with the nonbenzodiazepines are similar to those associated with benzodiazepines. This is discussed below. (See 'Risks and side effects' below.)
Melatonin agonists — Ramelteon is a melatonin agonist. In randomized trials, short-term use of ramelteon is associated with improvement in some sleep parameters in patients with insomnia, but the effect size is relatively small.
A 2014 meta-analysis that included 11 trials and over 5700 patients found that ramelteon was associated with significant improvement in subjective sleep latency (-4.6 minutes) and total sleep time (7.3 minutes) compared with placebo but no significant difference in other parameters, including subjective total sleep time, number of awakenings, and wakefulness after sleep onset . Although most studies examined short-term treatment and outcome in middle-aged adults , a small number of individual trials have demonstrated persistence of subjective benefit for at least six months, and improvement in older adults [78-82]. Subjective efficacy extended to one year in an open label trial .
Although ramelteon is approved in the United States and Japan, the European Medicines Agency (EMA) concluded in 2008 that there was inadequate evidence that the drug was effective for insomnia . It did not approve ramelteon for use. Tasimelteon is a second melatonin agonist that has been approved in the United States for treatment of non-24-hour sleep-wake disorder, a circadian sleep-wake rhythm disorder that occurs primarily in blind individuals [85,86].
Ramelteon binds to melatonin receptors expressed in the suprachiasmatic nucleus with much higher affinity than melatonin itself and has a half-life of 1.5 to 5 hours [87,88]. Ramelteon is metabolized by the liver and should be used with caution in patients with hepatic insufficiency. It is contraindicated in patients taking fluvoxamine, since fluvoxamine may decrease the metabolism of ramelteon . Ramelteon is more effective in treating sleep onset insomnia compared with sleep maintenance insomnia.
Adverse effects associated with melatonin agonists are generally milder than those associated with benzodiazepines and nonbenzodiazepines. The most common adverse effect is somnolence. (See 'Adverse effects of melatonin agonists' below.)
Orexin receptor antagonists — Orexin receptor antagonists are a novel class of drugs in development for the treatment of insomnia. Orexin A and orexin B are hypothalamic neuropeptides that play a key role in promoting wakefulness and regulating the sleep-wake cycle . Suvorexant, an oral dual orexin receptor antagonist with a 12-hour half-life, was approved by the FDA in August 2014 .
The efficacy of suvorexant was demonstrated in a multicenter international trial of 781 patients with primary insomnia who were randomly assigned to receive nightly suvorexant or placebo in a 2:1 ratio for one year, followed by a two-month randomized discontinuation phase . The dose of suvorexant used was 40 mg for patients <65 years of age and 30 mg for patients ≥65 years. At one month, patients treated with suvorexant had improved subjective total sleep time (39 versus 16 minutes; difference 23 minutes, 95% CI 16-29) and subjective time to sleep onset (-18 versus -8 minutes, 95% CI -15 to -5) compared with placebo. Two-thirds of patients in each arm completed one year of treatment; improvements in subjective sleep persisted at one year. The most common adverse effect was somnolence, which was more common in patients treated with suvorexant than placebo (13 versus 3 percent). There was a trend toward rebound insomnia with discontinuation of suvorexant. A smaller trial showed similar results with short-term treatment and evidence of a dose-response gradient in both efficacy and side effects with doses ranging from 10 to 80 mg nightly .
In next-day driving performance testing, some men and women treated with 20 mg of suvorexant had impaired driving performance, including 5 out of 52 subjects who stopped testing early due to somnolence, and the FDA has approved suvorexant at a maximum dose of 20 mg per night [91,94]. Treatment should be initiated at the lowest dose (5 mg), so that the lowest effective dose can be determined. Suvorexant is metabolized by cytochrome P450 3A4 (CYP3A4), and there is potential for increased toxicity when used in combination with CYP3A4 inhibitors (table 7). The recommended dose of suvorexant is 5 mg in patients taking moderate CYP3A4 inhibitors, and it is not recommended for use in combination with strong CYP3A4 inhibitors. Due to the potential for dependence and abuse, it is a schedule C-IV controlled substance. The most common side effect is daytime somnolence. Like other sedatives, it has the potential to worsen sleep-disordered breathing in vulnerable patients. (See 'Adverse effects of orexin antagonists' below.)
The role for this drug in the treatment of insomnia remains to be determined, as suvorexant and other similar drugs in development have not yet been compared directly with other therapies for insomnia. Development of almorexant, another orexin receptor antagonist, was halted in 2011 for reasons that have not been made publicly available .
Other medications — Numerous other medications have a sedating effect, but are not recommended for routine use in patients with insomnia. These include antidepressants, diphenhydramine, antipsychotics, and barbiturates.
Antidepressants — One antidepressant, doxepin, has been approved by the FDA at doses of 3 and 6 mg primarily for the treatment of insomnia. Other antidepressants (eg, amitriptyline, trazodone) are sedating because of central anticholinergic or antihistaminergic activity. Such antidepressants may be useful in the management of patients who have insomnia associated with depression, although they are not approved by the FDA for treatment of insomnia.
Sedating antidepressants have also been evaluated in patients with insomnia who are not depressed in a few studies:
●In a trial that randomly assigned 240 older adult patients with insomnia to receive low dose doxepin (1 or 3 mg) or placebo for 12 weeks, patients who received the 3 mg dose of doxepin had a reduction of wake time after sleep onset, increased total sleep time, increased sleep efficiency, and increased self-reported sleep quality when compared with placebo. Patients who received the 1 mg dose of doxepin had inconsistent improvement of some outcomes measures at several time points .
●Another trial randomly assigned 306 nondepressed patients with insomnia to receive trazodone, zolpidem, or placebo for two weeks . After one week of therapy, trazodone improved subjective sleep latency, sleep duration, wake time after sleep onset, and number of awakenings, compared with placebo. However, after two weeks, the trazodone group did not differ significantly from the placebo group.
Despite their sleep-promoting effects, the routine use of sedating antidepressants other than low dose doxepin to treat insomnia in patients who are not depressed has not been recommended because the sedating effect tends to be short-lived and other side effects are common [1,98].
Diphenhydramine — Many over-the-counter sleep aids contain diphenhydramine (a sedating antihistamine) or a combination of diphenhydramine plus pain relievers. There is little evidence that diphenhydramine improves insomnia and it may cause sedation the next day (due to its long half-life). Additional side effects include decreased alertness, diminished cognitive function, delirium, dry mouth, blurred vision, urinary retention, constipation, and increased intraocular pressure . Routine use of diphenhydramine to treat insomnia is not recommended.
Antipsychotics — Antipsychotics have been used to treat insomnia. However, there are few trials that demonstrate effectiveness of these medications and all have potentially significant adverse effects. The routine use of antipsychotics to treat insomnia in patients without psychosis is not recommended .
Barbiturates — Barbiturates have similarly been used to treat insomnia. However, all have potentially significant adverse effects. Routine use of barbiturates to treat insomnia is not recommended .
Over-the-counter — Herbal products, hormones, and alcoholic beverages have been used as sleep aids by patients with insomnia but there are sparse data upon which to evaluate their efficacy. These agents are not regulated by the FDA.
●Herbal products – A variety of herbal products are purported to be useful for insomnia. There is little evidence from randomized controlled trials about the efficacy of many herbals, however, and for those that have been well studied (eg, valerian), there is little evidence of benefit. A meta-analysis that included 14 randomized trials in over 1600 patients found no significant difference between any herbal medicine and placebo on any of 13 clinical efficacy measures of insomnia . The majority of the trials (11 out of 14) studied valerian; chamomile, kava, and wuling were studied in one trial each. Unlike the other herbals studied, valerian was associated with a greater number of adverse events per person compared with placebo. Valerian may also produce hepatotoxic effects . Contamination with undesirable substances poses a problem for many such natural remedies. (See "Overview of herbal medicine and dietary supplements".)
●Melatonin – Melatonin is a hormone that is normally secreted by the pineal gland. It does not appear to be beneficial as a treatment for insomnia in most patients with two exceptions: it may be useful in patients who have delayed sleep-wake phase syndrome (a circadian sleep-wake rhythm disorder) and in a subgroup of patients with low melatonin levels [1,100-105]. It appears to be safe when used short-term (three months or less) . (See "Classification of sleep disorders", section on 'Circadian rhythm sleep-wake disorders'.)
●Alcohol – Alcohol is commonly self-prescribed as a sleep aid because it decreases the time required to fall asleep, at least in the short-term. However, alcohol can promote sleep disturbances later in the night and promotes upper airway instability and sleep apnea. These negative effects, coupled with the significant risk of dependence and interaction with other medications, preclude the use of alcohol to treat insomnia . (See "Insomnia in patients with a substance use disorder", section on 'Alcohol'.)
Risks and side effects
Common to all hypnotics — The most common adverse effects associated with the benzodiazepines and nonbenzodiazepines are residual daytime sedation, drowsiness, dizziness, lightheadedness, cognitive impairment, motor incoordination, and dependence [1,58,59,64]. In addition, most hypnotics are respiratory suppressants that can worsen obstructive sleep apnea or hypoventilation.
Long-term use may be habit forming and rebound insomnia may occur when some short-acting medications are discontinued. Less common adverse effects include complex sleep-related behaviors (eg, sleep walking, driving, making telephone calls, eating, or having sex while not fully awake), anterograde amnesia (particularly with triazolam or when used with alcohol), aggressive behavior, and severe allergic reaction [62,107]. Lethal overdose is rare , unless there is concurrent use of alcohol or another central nervous system depressant.
Adverse effects of nonbenzodiazepines — Generally speaking, the adverse effects associated with the nonbenzodiazepines are similar to those associated with the benzodiazepines, but their frequency and severity may be less [58,59]. This is probably related to their shorter half-lives, although as discussed below, next-morning impairment has been increasingly recognized with higher doses and in certain patient populations. (See 'Dosing precautions' below.)
Most of the complex sleep-related behaviors that have been reported in patients taking nonbenzodiazepines were related to zolpidem, but it is unknown whether this reflects the widespread use of zolpidem or an association between the agent and the side effect . In one study, zolpidem accounted for 12 percent of all emergency department visits for adverse drug events related to psychiatric medication in the United States over the period of 2009 to 2011, and 21 percent of all such visits involving adults ≥65 years of age . Other side effects that have been reported in patients taking nonbenzodiazepines include an unpleasant taste (eszopiclone) and hallucinations (zolpidem).
The incidence of infection (eg, upper respiratory, otitis media, urinary tract, conjunctivitis, others) may also be increased among patients taking a nonbenzodiazepine, according to one meta-analysis . Two subsequent studies, one in humans and one in mice, have also reported an increased risk of pneumonia associated with benzodiazepines and the nonbenzodiazepine zopiclone, possibly related to modification of GABA type A activity during infection [111,112]. A study in mice suggested that this risk could extend to all hypnotics that act at this site .
Dosing precautions — Dosing recommendations for hypnotic medications have traditionally been based on group statistical effects rather than individual responses. However, there has been increasing recognition that variability in nonbenzodiazepine metabolism may affect next-morning drug levels and side effects. The safety announcements reviewed below suggest that clinicians should have increased sensitivity to next-day residual effects when prescribing any of the drugs in this class and should educate patients accordingly.
●In 2013, the FDA published a safety communication that the recommended dose for zolpidem be set at the lowest dose (5 mg for all except zolpidem extended release, which is now 6.25 mg) for women and also be considered for men . In addition, a new warning was issued for zolpidem extended release, advising that individuals refrain from driving or other activities that require mental alertness the day after taking the drug . These recommendations were based on studies showing that blood levels of zolpidem above about 50 ng/mL appeared capable of impairing driving sufficiently to increase the risk of an accident. This blood level was found in about 15 percent of women and 3 percent of men eight hours after administration of 10 mg of zolpidem. Eight hours after use of the extended-release formulation of zolpidem, 33 percent of women and 25 percent of men still had this elevated blood level.
Additional recommendations were not made for older adults, who have previously been advised to use the lowest doses of these medications, but additional care is warranted for these patients. (See 'Older adults' below.)
●In 2014, a similar safety communication was issued for eszopiclone, based on data that the 2 and 3 mg doses may be associated with impairment of driving skills, memory, and coordination lasting more than 11 hours without subjective awareness in some patients . A starting dose of 1 mg is now recommended in all patients.
Adverse effects of melatonin agonists — Ramelteon has fewer side effects than the nonbenzodiazepines or benzodiazepines . It is not associated with hypnotic side effects (eg, next day residual performance deficits), withdrawal, or rebound insomnia, and it does not appear to be habit forming [82,114]. Ramelteon has little abuse potential and is not a scheduled substance with the United States Drug Enforcement Administration (DEA), unlike most other drugs used to treat insomnia. The most common side effects are somnolence, dizziness, nausea, fatigue, and headache [1,62]. Elevated prolactin levels and decreased testosterone levels may occur, but routine monitoring of either is not indicated in the absence of other clinical indications.
Adverse effects of orexin antagonists — The most common adverse effects of suvorexant are daytime somnolence and headache. As with other hypnotics, next-day driving may be impaired due to the long half-life of the drug . Other potential side effects include sleepwalking, REM sleep behavior disorder, suicidal ideation, and the emergence of sleep paralysis, hypnogogic hallucinations, and mild cataplexy (as seen in narcolepsy). Suvorexant is metabolized by cytochrome P450 3A4 (CYP3A4), and there is potential for increased toxicity when used in combination with CYP3A4 inhibitors (table 7).
Limited data suggest that suvorexant has relatively minor effects on the severity of sleep-disordered breathing in vulnerable patients [116,117], although like other sedatives, it should be used cautiously in these patients until there is more experience with the drug. In a sleep laboratory study, 26 patients with mild to moderate obstructive sleep apnea were given 40 mg of suvorexant or placebo for four consecutive nights in a crossover design, and the mean apnea-hypopnea index (AHI) increased by a mean of 2.7 (95% CI 0.2-5.1) after multiple doses of suvorexant . The AHI rose by ≥5 events per hour in eight patients (range 5 to 20) and decreased by ≥5 events in three patients.
Older adults — Older adults have a particularly high risk of adverse effects from hypnotic drugs, including excessive sedation, cognitive impairment, delirium, night wandering, agitation, postoperative confusion, balance problems, and impaired performance of daily activities [118-120]. An increased risk of falls with severe consequences, including traumatic brain injury and hip fracture, has been observed in association with both benzodiazepines and nonbenzodiazepines such as zolpidem [119,121].
In a meta-analysis of 24 randomized trials (2417 patients) that evaluated the impact of pharmacotherapy in adults older than 60 years with insomnia, there was an improvement of sleep quality, total sleep time, and frequency of nighttime awakening . However, the magnitude of these benefits was relatively small compared with the two- to fivefold increase in adverse cognitive or psychomotor events. This suggests that additional caution is necessary when deciding whether pharmacotherapy is indicated for an older patient with insomnia.
Mortality — Several observational studies have found an association between use or prescription of hypnotic drugs and all-cause mortality and/or cancer, with adjusted hazard ratios ranging from 1.1 to 4.5 [123-128]. The association has been observed in the general adult population [123-125,127,128], postmenopausal women , and in patients with schizophrenia . Other studies in older adults have failed to find a significant association between hypnotic use and mortality after adjusting for potential confounders [130,131].
One of the larger studies suggested that hypnotic drugs (including frequently prescribed agents such as zolpidem and temazepam) were associated with an increased risk of both cancer and death, even at prescription levels of less than 18 doses per year over a 2.5-year duration . Another large retrospective case-control study included over 34,000 patients age 16 years and older first prescribed an anxiolytic or hypnotic drug or both between 1998 and 2001, matched by age, gender, and primary care practice with nearly 70,000 controls . Over an average follow-up period of 7.6 years, prescription of anxiolytic and hypnotic drugs was associated with a twofold increased hazard of death after adjusting for a wide range of potential confounders, including medical and psychiatric comorbidities, sleep disorders, and other drugs. After excluding deaths during the first year of follow-up, this effect translated to four excess deaths per 100 people followed over a seven-year period.
It is important to emphasize, however, that this evidence is observational and, therefore, does not indicate causality. Chronic insomnia has been associated with a variety of medical and psychiatric comorbidities, many of which are associated with premature mortality, and it is difficult to exclude residual confounding by indication or other unmeasured factors. A prospective investigation of long-term hypnotic use compared with placebo and behavioral treatment is needed.
Drug interactions — Concurrent use of any sleeping medication and alcohol (or another central nervous system depressant) increases the risk of central nervous system depression and, therefore, is contraindicated.
Most benzodiazepines (except lorazepam, oxazepam, and temazepam) and nonbenzodiazepines are metabolized by the CYP3A4 system . Inhibitors of the CYP3A4 system (eg, clarithromycin) increase the risk of toxicity related to benzodiazepines and nonbenzodiazepines, while inducers of the CYP3A4 system (eg, rifampin) may decrease the effectiveness of benzodiazepines and nonbenzodiazepines.
Ramelteon is metabolized by the CYP1A2 system and, to a lesser extent, the CYP2C9 and CYP3A4 systems . Fluvoxamine is a potent inhibitor of the CYP1A2 system and should not be used with ramelteon because it markedly increases serum concentrations of ramelteon. Other inhibitors of the CYP1A2 (eg, ciprofloxacin), CYP2C9, or CYP3A4 systems may also increase the risk of ramelteon toxicity, while inducers of the CYP systems (eg, rifampin) may decrease the effectiveness of ramelteon.
Suvorexant is metabolized by the CYP3A system and should not be administered in combination with strong inhibitors of CYP3A (eg, ketoconazole, many antiretroviral drugs) (table 7). Conversely, suvorexant effects can be decreased when co-administered with strong CYP3A inducers (eg, rifampin, carbamazepine, phenytoin).
COMBINATION THERAPY — Combination therapy involves prescribing both cognitive behavioral therapy for insomnia (CBT-I) and a medication, usually for six to eight weeks. The medication is then tapered off or to an as-needed schedule, while continuing the CBT-I.
Two trials from the same investigators illustrate the effects of combination therapy:
●The first trial randomly assigned 78 patients with persistent insomnia to receive CBT-I alone, temazepam alone, CBT-I plus temazepam, or placebo for eight weeks . At the end of the treatment phase, all of the therapies had significantly decreased the wake time after sleep onset compared with placebo, although there were no significant differences when the treatment groups were compared with each other. Two years following the completion of treatment, only the CBT-I alone group had maintained its reduction in the wake time after initial sleep onset.
●The second trial randomly assigned 160 patients with persistent insomnia to receive CBT-I plus zolpidem or CBT-I alone for six weeks . Both groups had decreased sleep onset latency, decreased wake time after sleep onset, and increased sleep efficiency when compared with baseline after six weeks. However, there was no significant difference in the remission rate when the groups were compared with each other (44 versus 39 percent). The patients then underwent secondary randomization. Patients in the CBT-I alone group were randomly assigned to no treatment or maintenance CBT-I, while patients in the CBT-I plus zolpidem group were randomly assigned to either maintenance CBT-I or maintenance CBT-I plus as-needed zolpidem. The improvement of sleep latency, wake time after sleep onset, and sleep efficiency was maintained in all groups at six months, when compared with baseline. The remission rate was higher at six months among the groups that had received CBT-I plus zolpidem during the initial six weeks of the trial, than among the groups that had initially received CBT-I alone (56 versus 43 percent).
Taken together, the evidence indicates that CBT-I alone, drug therapy alone, and combination therapy all improve measures of insomnia (eg, wake time after sleep onset) within weeks of initiating the therapy. Continuing CBT-I alone after the completion of initial therapy appears to be the best option for maintaining improvement long-term. CBT-I also increases the likelihood that the medication can eventually be tapered .
If sleep restriction therapy is combined with hypnotic medication, clinicians should be aware that the combination of chronic partial sleep deprivation and medication hangover could significantly increase daytime sleepiness and behavioral risk. (See 'Adverse effects' above.)
The evidence is insufficient to justify combination therapy as routine initial management for insomnia patients. Many patients will improve with CBT-I alone, without pharmacologic therapy.
FOLLOW-UP — If the treatment is successful, patients will report both improved sleep at night and improvement of daytime deficits. Discontinuation of the medication should be considered in any patient who is receiving pharmacologic therapy alone or combination therapy.
Patients who have little improvement during the initial trial of cognitive behavioral therapy, pharmacologic therapy, or combination therapy may have other causes of poor sleep. Adherence with the prescribed therapy should be confirmed and then additional diagnostic evaluation performed. Such patients often require referral to a sleep disorders center to be evaluated for sleep apnea or other underlying causes. Such an evaluation is indicated earlier (ie, prior to the failure of routine therapy) if there is clinical suspicion that sleep apnea or another etiology exists. (See "Clinical features and diagnosis of insomnia", section on 'Other sleep disorders'.)
Other patients may respond initially to pharmacologic therapy but later relapse while still taking the same drug. In such cases, clinical re-evaluation is warranted to determine whether there are lifestyle changes or other new factors that may be exacerbating the insomnia. There are limited data on tolerance and cross-tolerance among various medications used to treat insomnia, but some amount of tolerance likely exists for the benzodiazepines and nonbenzodiazepine receptor agonists [135-137].
Treatment decisions in patients with possible tolerance must be individualized, taking into account factors such as side effects, duration of therapy, prior therapies, and availability of alternative options, such as behavioral therapy. If lifestyle changes and other exacerbating factors have been ruled out, we consider the following approaches:
●In a patient who complains of loss of efficacy from a short-acting nonbenzodiazepine, such as zolpidem, we suggest a trial of a longer-acting drug, such as eszopiclone, or switch to medication from a different class, such as low-dose doxepin.
●Some patients may benefit from a drug holiday, after which time they may again respond to the initial drug therapy.
●Institution of behavioral therapy can help transition some patients away from long-term use of a benzodiazepine or nonbenzodiazepine receptor agonist. (See 'Behavioral therapy' above.)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Insomnia (The Basics)")
●Beyond the Basics topics (see "Patient education: Insomnia (Beyond the Basics)" and "Patient education: Insomnia treatments (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●All patients with insomnia should receive therapy for any medical condition, psychiatric illness, substance abuse, or sleep disorder that may be precipitating or exacerbating the insomnia. They should also receive general behavioral suggestions, particularly advice regarding sleep hygiene (table 2) and stimulus control (table 3). (See 'General approach' above.)
●For patients who continue to have insomnia that is severe enough to require an intervention, we suggest cognitive behavioral therapy for insomnia (CBT-I) as the initial therapy rather than medication (Grade 2B). An alternative type of behavioral therapy is reasonable if CBT-I is not available. (See 'General approach' above and 'Behavioral therapy' above.)
●For patients whose insomnia continues to be severe enough to require an intervention despite CBT-I, we suggest the addition of a medication to CBT-I rather than changing to a strategy of medication alone (Grade 2B). (See 'General approach' above and 'Medications' above.)
●For patients who require medication for sleep maintenance insomnia, we suggest a longer-acting medication rather than a short-acting agent (Grade 2C). Alternatively, a formulation of zolpidem has been approved for use in the middle of the night. Patients should be warned about the risk for daytime drowsiness, impaired driving, dizziness, and lightheadedness. (See 'Choice of an agent' above.)
●Patients given behavioral plus pharmacologic therapy should continue behavioral therapy for six to eight weeks. In patients who respond to therapy, the medication can be tapered while continuing the behavioral therapy. Patients whose symptoms recur may require evaluation in a sleep disorders center, prior to the institution of long-term therapy. (See 'General approach' above and 'Follow-up' above.)
●Long-term treatment with medication alone is not the optimal treatment strategy for patients with insomnia. (See 'Risks and side effects' above.)
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