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Overview of the treatment of insomnia in adults

Overview of the treatment of insomnia in adults
Author:
John W Winkelman, MD, PhD
Section Editor:
Ruth Benca, MD, PhD
Deputy Editor:
April F Eichler, MD, MPH
Literature review current through: Feb 2022. | This topic last updated: Oct 05, 2021.

INTRODUCTION — Insomnia is one of the most common symptoms for which adults seek medical advice. Although sleep is a strong and highly regulated biologic drive, the ability to fall asleep at the desired time and maintain sleep without excessive waking is fragile and influenced by multiple factors. Identification of these factors is at the core of insomnia treatment.

Management of insomnia requires a stepwise approach, beginning with attempts to eliminate or at least minimize contributing factors and comorbid illnesses that interfere with optimal sleep. Insomnia often responds only partially to treatment of individual sleep-impairing influences, however, and many patients require medication directed towards sleep itself. Successful behavioral and pharmacologic approaches to insomnia can only be devised once all contributing factors are recognized and addressed.

The topic is an overview of the approach to management of acute and chronic insomnia in adults. Specific medications and behavioral therapies for insomnia are reviewed in more detail separately. (See "Pharmacotherapy for insomnia in adults" and "Cognitive behavioral therapy for insomnia in adults".)

INITIAL ASSESSMENT AND COUNSELING — Insomnia etiology is best conceptualized as a combination of predisposing, precipitating, and perpetuating factors that vary over time. Each of these factors should be assessed to formulate an individualized treatment plan.

Predisposing and precipitating factors — The sleep history should include an examination of the social, medical, and psychiatric events that may have been relevant when insomnia began. Common predisposing and precipitating factors include an individual's underlying reactivity to sleep disturbance when under stress, medical and psychiatric conditions, and genetic factors (table 1) [1,2]. (See "Evaluation and diagnosis of insomnia in adults", section on 'Common comorbidities'.)

Such events and comorbidities are important for treatment because:

Insomnia precipitated by a symptom such as pain, nocturia, or shortness of breath is unlikely to improve without maximal treatment of the medical disorder. (See 'Pain' below.)

Sleep disorders other than insomnia (eg, obstructive sleep apnea [OSA], restless legs syndrome [RLS]) may present with insomnia but are unlikely to improve without treatment directed at the specific sleep disorder. Suspected OSA is an indication for in-laboratory polysomnography or home sleep apnea testing. (See 'Patients with comorbid sleep disorders' below and "Clinical presentation and diagnosis of obstructive sleep apnea in adults", section on 'Diagnostic evaluation'.)

Psychiatric disorders and insomnia have a bidirectional relationship, and concomitant treatment for both disorders is often necessary to hasten recovery and increase the likelihood of sustained response. (See 'Patients with comorbid psychiatric disorders' below.)

A history of childhood trauma or chaotic home environment at night (even in the absence of posttraumatic stress disorder [PTSD]) may increase vulnerability to sleeplessness as an adult. Awareness of this history is valuable as it may shed light on etiology and help identify targets of cognitive therapy.

Medication side effects — Medications used to treat a comorbid condition may themselves precipitate insomnia through stimulation of arousal centers or other central nervous system effects (eg, stimulants, glucocorticoids, some antidepressants), nocturia (eg, diuretics), or respiratory suppression (eg, opioids) (table 2). Use of medications with the potential to disrupt sleep has been associated with an increased risk of insomnia on a population level [3] and is commonly overlooked as a contributing factor.

Stimulants – The major determinants of whether stimulants such as methylphenidate or modafinil will interfere with sleep are dose and effective half-life. Many stimulants have effective half-lives greater than 10 hours and can therefore interfere with both sleep onset and sleep maintenance. Lowering the dose, choosing a shorter-acting agent, and administering the medication earlier in the day may attenuate the sleep disturbance.

Antidepressants – Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are associated with treatment-induced insomnia in approximately 20 percent of patients. While morning dosing is commonly recommended to mitigate sleep disturbances, it is not clear that this reduces the risk of incident insomnia. Lowering the dose may be of value. Sometimes, the sleep disruptive effects of antidepressants are transient, and temporary use of a sedating medication may be indicated to address this side effect.

Glucocorticoids – Oral or inhaled glucocorticoids commonly produce insomnia [4]. Lowering the dose and administering the medication earlier in the day may attenuate the sleep disturbance. If sleeplessness does not improve over time, co-administration of a sedating medication is a common approach.

Opioids – Although opioids are sedating, chronic use can lead to increased sleep fragmentation and nocturnal awakenings related to changes in sleep architecture and respiratory control. Polysomnography is required to diagnose sleep-disordered breathing due to chronic opioids, as central apneas or irregular breathing patterns may not be apparent to the patient or a bed partner. Lowering or eliminating the opioid dose and positive airway pressure therapy are the primary treatment strategies. (See "Sleep-disordered breathing in patients chronically using opioids".)

Perpetuating factors — Behavioral and cognitive compensatory responses to sleeplessness, some of which can be maladaptive for sleep, may further disturb sleep onset and maintenance and perpetuate insomnia.

Many patients with insomnia have poor sleep habits, unrealistic expectations of sleep, or inappropriate attributions about the association of daytime symptoms and nocturnal sleep. When these counterproductive processes are substantial, they need to be addressed, either alone or in addition to other therapeutic strategies.

Determine consistency of timing of bedtime and wake time and amount of time allotted to attempts to sleep. A sleep diary (table 3A-B), filled out by the patient for at least two weeks, is an essential component of the evaluation and is often informative for both patient and clinician. Regular timing of bedtime and, particularly, wake time (seven days per week) is essential for those with insomnia. The amount of time from initial attempts to sleep to final wake time should be reduced to the estimated total sleep time.

Ask if the patient is actually sleepy at bedtime. Attempts to sleep should occur only when sleepy (similar to attempts to empty the bowel or bladder).

Ask about napping and dozing during the day or evening, which should be avoided to maximize sleep drive at night.

Determine the level of anxiety regarding sleeplessness, both in the evening before bed as well as while awake in bed attempting to sleep. If substantial anxiety is present ("insomnia phobia"), methods to reduce anxiety should be instituted. (See 'Overview of cognitive behavioral therapy' below.)

Ask about clock-watching while in bed.

Ask about nocturnal environmental disturbances (children, pets, bed partner, electronics).

Determine if expectations of sleep onset time, number of awakenings, and total sleep time are realistic for age, and, if not, educate about appropriate expectations (figure 1). (See "Insufficient sleep: Definition, epidemiology, and adverse outcomes", section on 'How much sleep do we need?'.)

Assess perceived consequences of sleeplessness and attributions of daytime function and health to sleep. Educate about appropriate attributions of the effects of insomnia.

Maladaptive habits and attitudes that may perpetuate sleeplessness are the target of the cognitive component of cognitive behavioral therapy for insomnia (CBT-I) and should be addressed in all patients with chronic insomnia. However, it should be noted that by the time patients present to a clinician, it is often difficult to determine if such compensations are the most important cause of the insomnia or simply an inappropriate response to it.

Sleep habits and attitudes — Healthy sleep habits and attitudes are essential to improve and maintain good sleep (table 4). These habits and attitudes should be reviewed with all patients as part of the initial assessment to reinforce healthy approaches and identify targets for intervention. (See "Cognitive behavioral therapy for insomnia in adults", section on 'Sleep hygiene'.)

APPROACH TO ACUTE INSOMNIA — Short-term insomnia (lasting less than one month) is a common form of insomnia and usually results from psychologic or physiologic stress. Patients with acute insomnia can usually identify the immediate precipitant to the insomnia. The clinical approach to acute insomnia is twofold:

Discuss the role that the stressor is playing in disturbing sleep, and assess the level of distress. Education can provide some control or at least acceptance of the temporary sleeplessness. For patients with mild or manageable levels of distress, we provide reassurance and a plan for follow up if symptoms do not improve.

When the insomnia is severe or associated with substantial distress, we offer short-term use of an insomnia medication to help address immediate interference with daytime function and to control escalating anxiety about sleep. Selection of a medication is individualized using the same principles as those for chronic insomnia medication selection. (See "Pharmacotherapy for insomnia in adults", section on 'Our approach'.)

The goal of pharmacologic therapy in this setting is to minimize the additional psychologic and physical stress that sleeplessness produces. In addition, treatment of short-term insomnia may reduce the development of dysfunctional cognitive and behavioral responses to sleeplessness that could otherwise increase the risk of more chronic insomnia.

Follow-up in two to four weeks is encouraged to reassess additional causes of insomnia, current sleep-related symptoms, anxiety about sleep, and to reinforce good sleep habits. If insomnia is persistent, evaluation and treatment with cognitive behavioral therapy for insomnia (CBT-I) is encouraged. (See 'Overview of cognitive behavioral therapy' below.)

APPROACH TO CHRONIC INSOMNIA — Cognitive behavioral therapy (CBT) and pharmacotherapy are the main treatment options for chronic insomnia that persists despite appropriate identification and management of precipitating and perpetuating factors.

Choice of initial therapy — CBT for insomnia (CBT-I) is preferred as first-line therapy for chronic insomnia in most patients. CBT-I is not effective for all patients and is not accessible to many, however, either due to lack of therapists or to limitations of insurance or time. In such cases, long-term use of medications is an acceptable approach if the patient is thoroughly evaluated beforehand, is followed regularly during the course of treatment, and continues to respond positively to the medication [5].

Several prospective studies have assessed the comparative efficacy of CBT-I, medications, and combination therapy as an initial approach. In short-term trials, CBT-I alone and CBT-I in combination with medications demonstrate relatively equivalent outcomes, and both are superior to medication alone [6-8]. Longer-term outcome studies (12 to 24 months) also demonstrate superior efficacy of CBT-I alone or in combination with medication compared with medication-alone approaches [9]. CBT-I without medication has the advantage that it does not expose patients to side effects and potential drug interactions, and it provides patients with lifelong skills should insomnia recur [5,10,11]. 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 [11], the British Association for Psychopharmacology [12], the American College of Physicians [10,13], and the European Sleep Research Society [14]. (See 'Society guideline links' below.)

If rapid response is needed for clinical reasons (eg, deterioration in daytime function or excessive anxiety regarding sleeplessness, which may interfere with the ability to follow sleep restriction and stimulus control aspects of CBT-I), a combination approach can be used initially (given the faster response with medication approaches), with a plan to taper the medication over time (eg, six to eight weeks). (See 'Follow-up and monitoring' below.)

There are no reliable predictors of treatment response to CBT-I or medications [15]. One might predict that deviations from optimal thoughts and behaviors would provide greater opportunity for benefit from CBT-I; however, counterproductive beliefs and behaviors may have developed as a consequence of more severe sleep disturbance, more disorganized lifestyle, or underlying anxiety disorder and therefore may actually be markers of treatment resistance. One study suggested that greater distress at baseline or prolonged times to fall asleep may predict beneficial response to CBT-I, whereas short total sleep time (<6 hours) may predict poor response [16,17].

Predictors of treatment success with medications for insomnia are also poorly characterized. In one meta-analysis of nonbenzodiazepine benzodiazepine receptor agonists (BZRAs), younger age and female sex were associated with greater improvements in sleep onset latency [18]. Anecdotally, previous nonresponse to high doses of hypnotics or substantial discrepancy between self-reported and objectively recorded total sleep time (referred to as paradoxical insomnia) are indicators of poor future response to medications.

Overview of cognitive behavioral therapy — Cognitive behavioral therapy for insomnia (CBT-I) is the preferred form of treatment for chronic insomnia in adults and has been endorsed as first-line therapy by multiple societies and guideline panels [5,10,12,13,19,20].

CBT-I is a multicomponent approach to chronic insomnia that addresses common thoughts and behaviors that interfere with optimal sleep. It is traditionally delivered in face-to-face individual or group settings, over four to eight sessions; remote delivery (online or telephone) can also be effective but supporting data are less robust.

The behavioral components of CBT-I include:

Establishment of a stable bedtime and wake time seven days per week

Reduction in time in bed to approximate the total hours of estimated sleep (sleep restriction) (table 5)

Encouragement to use the bed only for sleep and sex; try to sleep only when sleepy; and get out of bed if anxiety occurs while unable to sleep (stimulus control) (table 6)

Sleep hygiene, which includes avoidance of substances that interfere with sleep, avoidance of naps to maximize sleep drive, and optimization of the comfort of the sleep environment (table 4)

The cognitive approaches of CBT-I address:

Anxious and catastrophic thoughts that are associated with sleeplessness

Inappropriate expectations about hours of sleep

Misattributions regarding the effects of sleeplessness

Relaxation through progressive muscle relaxation, mindfulness, and meditation (table 7)

CBT-I and other behavioral approaches to chronic insomnia are reviewed in more detail separately. (See "Cognitive behavioral therapy for insomnia in adults".)

Overview of pharmacotherapy — The choice among various medications for insomnia is individualized based on a variety of factors, including patient age and comorbidities, type of insomnia complaint, side effect profiles, cost, and clinician and patient preference (algorithm 1). The choice of therapy, specific drugs, side effects, and risks are reviewed separately. (See "Pharmacotherapy for insomnia in adults", section on 'Drug selection'.)

Briefly, medications with regulatory approval for insomnia treatment span multiple classes and agents that can be categorized based on their mechanism of action or original indication: benzodiazepine receptor agonists (BZRAs, including benzodiazepines and nonbenzodiazepine BZRAs, such as zolpidem), histamine receptor antagonists (eg, low-dose doxepin), melatonin receptor agonists (eg, ramelteon), and dual orexin receptor antagonists (table 8A-C).

Use of other sedating medications for insomnia should be considered for patients who do not have an adequate therapeutic response to first-line medications with regulatory approval for insomnia, when a different mechanism of action is desired, or when there is a specific reason to avoid BZRAs. Medications with sedating effects, such as trazodone and gabapentin, when used at much lower doses than those studies and approved for other indications, may represent a relatively safe alternative to BZRAs in selected patients, even if the evidence base for efficacy is not as robust. For such patients who have not responded to CBT-I, the risks of untreated insomnia also factor into decision making.

FOLLOW-UP AND MONITORING

Response assessment — Insomnia is a clinical diagnosis, and therefore treatment response is based on history and patient self-report. A sleep diary (table 3A-B) is a valuable supplement to the history, as some patients may remember only the nights when they slept poorly.

Consumer wearable devices that report sleep parameters are increasingly popular and may be of some value, but only to compare sleep before and after treatment, as their accuracy for absolute sleep metrics is often poor. (See "Actigraphy in the evaluation of sleep disorders", section on 'Consumer wearable devices'.)

Follow-up after the first month of medication use is indicated if continued treatment is planned. Thereafter, follow-up at least every six months is recommended.

Poor response to initial therapy — In patients who fail insomnia treatment, it is important to discuss expectations of sleep, particularly in those with advanced age and comorbidities. In the presence of unreasonable expectations, all treatments have a high likelihood of failure.

Examination of sleep diaries for timing of sleep and duration of time in bed may demonstrate conditions that make optimal sleep unlikely (eg, excess time in bed, variable bedtimes or wake times) or that sleep has in fact improved. (See 'Perpetuating factors' above.)

Cognitive behavioral therapy for insomnia (CBT-I) requires discipline, perseverance, and a belief that counterintuitive behaviors (eg, reduction in time in bed, getting out of bed when not asleep) can be therapeutic. These factors contribute to suboptimal adherence to, and benefit from, CBT-I in some patients. In such cases, a trial of medication is often reasonable as second-line therapy. Maintenance of as many of the components of CBT-I as possible remains important over time.

When medication treatments fail, clinicians should determine whether failure is due to lack of efficacy or treatment-emergent side effects. Both of these limitations can often be addressed by altering the dose, timing, or specific medication that is prescribed. This topic is reviewed in more detail separately. (See "Pharmacotherapy for insomnia in adults", section on 'Patients with inadequate response'.)

Tapering medications — Attempts to discontinue sedative medications are a valuable but difficult task, as patients may be reluctant to fix what is not broken and are very anxious about the return of sleeplessness. A supportive discussion about the patient's concerns and about the probability of successful discontinuation is recommended.

The duration of insomnia prior to medication treatment is the best predictor of the likelihood of continued need for medication. Nonetheless, approximately 75 percent of those with insomnia have symptoms for less than one year [21]. Conveying this message may be reassuring when patients are considering whether medication remains necessary.

CBT-I treatment is encouraged prior to medication taper to reinforce optimal sleep habits and manage dysfunctional thoughts that may arise during the process. In general, a slow reduction in medication dose is the best approach, with roughly 25 percent reduction in the original dose each week [22].

Reasons for subspecialty referral — Referral to a subspecialist is appropriate under the following circumstances:

There is suspicion that a relevant comorbidity (medical, psychiatric, or sleep) is an important contributor to the insomnia and requires further expertise and management in that context.

A patient is not responding to treatments that are generally effective for insomnia.

TREATMENT CONSIDERATIONS FOR SPECIFIC POPULATIONS

Patients with comorbid psychiatric disorders — Approximately half of patients with chronic insomnia have a psychiatric disorder, and the majority of those with a psychiatric disorder have insomnia. Although it is worthwhile examining the temporal relationship between the sleep disturbance and the psychiatric illness, establishing a clear causal relationship between the two is often difficult if not impossible. The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), defines insomnia disorder as a distinct entity, encouraging independent diagnosis and treatment of insomnia in the context of psychiatric illness [23].

In the context of an untreated psychiatric disorder with substantial insomnia, treatment should be directed towards both sets of symptoms. Concurrent treatment of insomnia with a medication such as eszopiclone in patients undergoing initial treatment of mood and anxiety disorders has been shown to enhance response time and overall efficacy for the underlying psychiatric illness [24,25].

Treatments that address both sets of symptoms (eg, sedating antidepressants) are often considered when insomnia is a prominent feature of a mood or anxiety disorder. However, the short-term advantages of this approach need to be weighed against the potential side effects (eg, weight gain with mirtazapine, dry mouth with most drugs, daytime sedation), in light of the fact that long-term use of the medication for the psychiatric disorder may be required. In addition, the doses of sedating antidepressants used for insomnia are not usually therapeutic from the standpoint of the mood disorder.

Mood and anxiety disorders — Treatment of mood and anxiety disorders with either pharmacotherapy or psychotherapy produces improvements in insomnia in most patients. However, persistent or treatment-emergent insomnia occurs even after improvement of the psychiatric illness in many patients. Sleep disturbance is the most common persistent symptom in treated depression and is a risk factor for recurrence of a mood episode in euthymic bipolar patients [26,27].

Treatment of insomnia in this context should be directed towards the presumed causes of the sleep disturbance, assessing the roles of persistent mood disorder, a comorbid sleep, medical or psychiatric disorder, behavioral factors, and the antidepressant medication itself [28]. (See 'Predisposing and precipitating factors' above and 'Perpetuating factors' above.)

The value of cognitive behavioral therapy for insomnia (CBT-I) in patients with mood disorders is unsettled. Initial studies suggested that adding this approach to psychiatric medications improved both sleep disturbance and the underlying depression or bipolar disorder [29,30]. However, subsequent studies, while confirming the benefits of CBT-I for insomnia in this context, have shown mixed results on outcomes related to psychiatric illness [31,32]. There are no controlled data on the use of CBT-I in anxiety disorders comorbid with insomnia.

Posttraumatic stress disorder — Insomnia is nearly universal in patients with posttraumatic stress disorder (PTSD), consistent with the hypervigilance and nightmares that are diagnostic criteria for the disorder. Insomnia is also one of the most common persistent symptoms after evidence-based treatment for PTSD [33]. Consistent with general guidelines, CBT-I is considered first-line therapy for insomnia treatment in PTSD, and one controlled study demonstrated benefit of CBT-I for multiple sleep outcomes compared with a waitlist control group [34]. (See "Psychotherapy and psychosocial interventions for posttraumatic stress disorder in adults".)

No controlled trials have specifically examined the use of pharmacotherapy to address insomnia in PTSD. However, the most commonly used medications for PTSD with insomnia are trazodone and nonbenzodiazepine benzodiazepine receptor agonists (BZRAs). Treatment of nightmares is discussed separately. (See "Nightmares and nightmare disorder in adults".)

Psychotic disorders — Insomnia is common and often multifactorial in patients with schizophrenia, both prior to and with treatment of the psychotic illness. Contributing factors may include the underlying psychotic disorder, erratic sleep schedules, comorbidity with other sleep disorders (eg, sleep apnea), and comorbid psychiatric (eg, substance abuse/dependence) or medical illness.

Clinicians will often use sedating antipsychotics in such patients, either switching from an existing agent or as an adjunctive medication. Unfortunately, these medications have a propensity for weight gain and metabolic disturbances.

Small controlled trials support the use of CBT-I or eszopiclone in the treatment of insomnia in schizophrenia [35,36]. In the eszopiclone trial, eight weeks of nightly treatment was associated with improvement in overall insomnia severity in patients with clinically stable schizophrenia [36].

Substance use disorders — Substance use disorder, like many other psychiatric disorders, has a bidirectional relationship with insomnia. Insomnia is a risk factor for substance abuse and occurs with increased frequency during active use and in early or late recovery [37,38]. Insomnia is also a risk factor for relapse.

As in other patients with chronic insomnia, use of CBT-I is preferred, particularly as patients with a substance use disorder may have "forgotten" how to initiate sleep without a sedative. Mastering CBT-I may provide confidence that sleep can be achieved using the body's own sleep drive [39,40]. Because CBT-I may take more time to become effective than medications, use of pharmacotherapy early in sobriety may be beneficial in selected patients. Gabapentin, trazodone, and quetiapine are commonly used in this setting. BZRAs are generally avoided due to concerns about relapse, dependence, and the combined toxicity of BZRAs with alcohol and other substances.

The evaluation and treatment of insomnia in patients with a substance use disorder is reviewed in more detail separately. (See "Insomnia in patients with a substance use disorder".)

Older adults — The prevalence of insomnia is reduced in older adults compared with younger adults, possibly because of decreased expectations of sleep, more flexible sleep hours, or changing role expectations [41]. Nonetheless, difficulties with sleep initiation and achievement of restorative sleep become more prominent with age [21].

Treatment of insomnia in older adults requires careful attention to the role of medical, neurologic, sleep, and psychiatric comorbidities. Vulnerability to side effects increases with age, and medications for insomnia often exacerbate existing age-related impairments such as gait instability, sedation, cognitive dysfunction, urinary and bowel dysfunction, and cardiac arrhythmias. Older adults may have slower drug metabolism, and thus maximum and next-day serum concentrations will be increased.

Due to these concerns, CBT-I is the treatment of choice in older adults with chronic insomnia. CBT-I has shown efficacy in a number of studies in older adults, both in individual and group settings [32,42]. CBT-I is well tolerated. When sleep restriction is used as part of CBT-I, attention to next-day sleepiness is warranted. Other nonpharmacologic interventions that may help sleep in older adults include exercise and tai chi [43-46]. (See "Cognitive behavioral therapy for insomnia in adults" and "Physical activity and exercise in older adults".)

Pharmacotherapy in older adults with persistent insomnia should be individualized with increased awareness of the potential for drug interactions, altered metabolism, and side effects. (See "Pharmacotherapy for insomnia in adults", section on 'Special populations'.)

Hospitalized patients — Insomnia, whether acute or chronic, is commonly encountered in hospitalized patients. Sleep disturbances in the hospital are often multifactorial, and the initial approach should focus on optimizing the sleeping environment, treating the underlying medical illness, minimizing stimulating or sleep-related side effects of concomitant medications, and using nonpharmacologic strategies to improve sleep. When pharmacotherapy is deemed necessary, selection of an agent should be individualized based on symptom severity, age, comorbidities, side effects, and drug-drug interactions. (See "Poor sleep in the hospital: Contributing factors and interventions".)

Dementia and other neurodegenerative disorders — Many neurologic disorders are associated with insomnia, either as a result of dysfunction in central nervous system pathways that regulate sleep or as a consequence of pain, immobility, or respiratory dysfunction.

Alzheimer disease – Insomnia is very common in Alzheimer disease (AD) and can manifest with disturbances in circadian timing of sleep, frequent awakenings, and nocturnal restlessness. Nonpharmacologic therapies are the mainstay of treatment. First-line approaches include treatment of comorbid medical and sleep disorders, adjustment of potentially sleep-disruptive medications, and behavioral approaches such as stability of the light-dark cycle and enhancement of social and physical activity during the day.

There are no reliably beneficial medication treatments for insomnia in patients with AD, and the risk of side effects is increased. Controlled trials have failed to show benefit of melatonin or ramelteon in either moderate to severe AD or mild to moderate AD [47]. In one small trial, trazodone (50 mg) had modest benefit at two weeks in patients with moderate to severe AD [48]. The dual orexin receptor antagonist suvorexant was found to be more effective than placebo in a four-week trial in patients with mild probable AD (and not in those with more severe impairment), and the main side effect was somnolence (4.2 versus 1.4 percent) [49]. (See "Pharmacotherapy for insomnia in adults", section on 'Special populations'.)

Evaluation and management of sleep disturbances and sleep disorders in patients with AD and other forms of dementia are reviewed in more detail separately. (See "Sleep-wake disturbances and sleep disorders in patients with dementia".)

Parkinson disease – Insomnia is also very common in Parkinson disease (PD), with primary motor symptoms of tremor, bradykinesia, and rigidity leading to impairments in sleep maintenance. Nonmotor symptoms such as depression, hallucinations, and nocturia can also contribute. Overnight wearing off of dopaminergic medications or, conversely, the activating effects of dopaminergic medications, may produce insomnia and complicate optimal medical management. (See "Clinical manifestations of Parkinson disease", section on 'Sleep disorders'.)

Initial management of insomnia in PD is directed towards addressing these potential disease-related etiologies. If insomnia persists, sedative medications can be used with caution, starting at low doses given increased vulnerability to cognitive and motor side effects. According to the Movement Disorder Society Taskforce Guidelines, controlled-release carbidopa-levodopa, eszopiclone, and melatonin all have low-level evidence supporting their use in PD-related insomnia [50].

Concussion and traumatic brain injury — Insomnia is reported by more than half of patients with traumatic brain injury and is especially common among those with milder injuries, including concussion. Circadian rhythm disturbances are also common and can be misattributed to insomnia. The approach to insomnia and other sleep disturbances in patients with traumatic brain injury is reviewed separately. (See "Sleep-wake disorders in patients with traumatic brain injury".)

Patients with comorbid sleep disorders

Obstructive sleep apnea — Insomnia and obstructive sleep apnea (OSA) are distinct sleep disorders that typically require independent treatment; however, they commonly co-occur. Approximately 15 percent of patients with insomnia have moderate to severe OSA, with higher rates in males, older adults, those who snore, and patients with metabolic syndrome, obesity, or daytime sleepiness [51]. Undiagnosed OSA is common among patients with insomnia complaints [52]. Comorbid insomnia also interferes with adherence to continuous positive airway pressure (CPAP).

There are a limited number of controlled trials of medications or CBT-I for treatment of insomnia in OSA, and the existing studies usually address untreated OSA. Concerns about exacerbation of respiratory status with use of BZRAs have limited their use in this context; however, short-term trials have demonstrated that BZRAs do not worsen untreated sleep apnea [53,54].

Patients with mild to moderate sleep apnea benefit from insomnia treatment to a similar degree as those without sleep apnea [55]. Patients with insomnia may struggle more to adjust to sleep apnea treatments such as positive airway pressure (PAP) therapy than those without insomnia [56,57].

Limited prospective data suggest that CBT-I is an effective strategy in patients with insomnia and moderate to severe OSA [58-60]. Patients should be monitored closely for increased daytime sleepiness in the initial period of bedtime restriction therapy, if used. (See "Cognitive behavioral therapy for insomnia in adults", section on 'Precautions'.)

Short-term use of sedating medications appears to be safe as a means to improve CPAP adherence and potentially address underlying insomnia in patients with mild-moderate OSA [53]. In one trial, eszopiclone reduced the severity of sleep-disordered breathing and improved sleep during one to two nights of use [61,62]. CPAP treatment adherence and rates of CPAP discontinuation over the first two weeks of treatment also improved, although other studies have shown mixed results. (See "Assessing and managing nonadherence with continuous positive airway pressure (CPAP) for adults with obstructive sleep apnea", section on 'Pharmacological therapy'.)

Restless legs syndrome — Insomnia is nearly universal in patients presenting for treatment of restless legs syndrome (RLS). A single question such as "Do your legs bother you at night?" should be asked of all patients with insomnia to screen for RLS. As with other insomnia comorbidities, addressing RLS is an important component of successful therapy for sleeplessness.

Anecdotally, alpha-2-delta ligands (eg, gabapentin, pregabalin) are preferred as initial agents when sleep disturbances are prominent, given their sedating properties and benefit for RLS itself [63]. Serotonergic agents (eg, trazodone, mirtazapine) may exacerbate RLS symptoms and should generally be avoided. (See "Management of restless legs syndrome and periodic limb movement disorder in adults".)

Of note, patients with RLS may be at increased risk for complex sleep-related behaviors with use of BZRAs such as zolpidem. Emergence of a sleep-related eating disorder in particular is sometimes a clue that a patient has underlying RLS that was not previously recognized. (See "Disorders of arousal from non-rapid eye movement sleep in adults", section on 'Sleep-related eating disorder'.)

Patients with comorbid medical conditions — Sleep disturbance is associated with a wide range of medical conditions. Cumulative number of medical conditions (multimorbidity) predicts rates of sleep disturbance as well as use of sedating medications, independent of age [64,65]. Optimal management of these conditions often improves sleep; however, insomnia may persist even with resolution of the medical condition or with partial, but maximal, medical management.

As bidirectional relationships exist among many medical conditions and insomnia, addressing insomnia may improve both the patient's medical status and their quality of life. Considerations in some of the more common medical comorbid conditions are reviewed in the sections below.

Pain — Pain is one of the most common causes of both acute and chronic insomnia. Sources of pain that may be especially likely to disrupt sleep are gastroesophageal, headache, musculoskeletal, and neuropathic.

Management of the pain is the primary method to improve sleep, and medications directed towards sleep should be reserved until maximal pain control is established. However, as sleeplessness most likely increases pain intensity and frequency, insomnia treatment is an important goal in optimal pain relief.

Many insomnia therapies (eg, CBT, sedating antidepressants, BZRAs, gabapentin/pregabalin) have overlapping indications for various pain syndromes and are reasonable choices in patients with pain for whom a secondary sleep benefit is desired [66].

Chronic lung disease — Over 25 percent of patients with chronic obstructive pulmonary disease (COPD) have insomnia disorder [67]. Contributing factors include cough, dyspnea, medication use, comorbid sleep-related breathing disorders, and medical and psychiatric comorbidities.

Polysomnography (PSG) to exclude a sleep-related breathing disorder should be performed in patients who have more severe overnight oxygen desaturation (or those with cyclical/sawtooth oxygenation), morning headaches after oxygen administration, obesity, or gastroesophageal reflux disease [68]. (See "Sleep-related breathing disorders in COPD".)

Studies on the treatment of insomnia in patients with COPD are limited. In the absence of sleep apnea identified on PSG, CBT-I is encouraged as first-line therapy. Medications are generally reserved for patients who have failed CBT-I, based on concerns about increased vulnerability to adverse effects on respiratory drive, diaphragmatic endurance, and oxygen saturation. Sedating antidepressants, melatonin, and gabapentin may be safer choices than BZRAs in most patients. BZRAs can be used in patients with normocapnic COPD, followed by overnight oximetry monitoring. In a systematic review of five small studies, BZRAs improved objective sleep measures but not subjective sleep in patients with COPD [69].

Renal failure — Insomnia is highly prevalent in patients with chronic kidney disease (CKD). Contributing factors may include pruritus, pain, nocturnal leg cramps, RLS, sleep apnea, comorbid medical illnesses, circadian rhythm alterations, and poor sleep hygiene. Overnight polysomnography should be performed if a sleep-related breathing disorder is suspected based on clinical symptoms (eg, excessive daytime sleepiness, snoring, witnessed apneas during sleep) and risk factors such as obesity and end-stage kidney disease (ESKD). (See "Sleep disorders in end-stage kidney disease", section on 'Sleep apnea'.)

There are no controlled data on CBT-I in patients with CKD, but supportive evidence in the general population is likely generalizable to these patients, who are at increased risk for altered drug clearance and adverse drug effects. Optimization of renal replacement therapy is an important consideration in patients with ESKD. (See "Sleep disorders in end-stage kidney disease", section on 'Treatment'.)

A few small studies have examined pharmacotherapy in patients with CKD. In short-term placebo-controlled studies, zolpidem, zaleplon, and clonazepam all improved sleep quality [70]. Melatonin improved sleep measures in a short-term, but not a one-year, study [71]. When medications are prescribed for sleep, initial low doses and slow upward taper are recommended. Drugs that are renally eliminated should be avoided (eg, gabapentin).

Pregnancy — Sleep disturbance increases during the course of pregnancy, affecting one-quarter of women in the first trimester to over two-thirds by the end of the third trimester [72]. Common causes of insomnia also change over time, from nausea, urinary frequency, and backache early in pregnancy to fetal movements, heartburn, leg cramps, RLS, and physical limitations in achieving a comfortable position by the end of pregnancy. Although many women have disturbed sleep, most do not identify it as a disorder, possibly because they have prepared for it or recognize that it is time limited. Nevertheless, some women do have more severe insomnia or are more severely disturbed by nighttime awakenings or daytime dysfunction.

RLS is important to recognize as it occurs with increased frequency as pregnancy progresses and often interferes with initiation of sleep. Often, the simple prompt "Do your legs bother you when you are lying down at night?" will facilitate diagnosis during pregnancy. Treatment options include iron supplementation, nonpharmacologic therapies, and medications in selected patients. (See "Restless legs syndrome during pregnancy and lactation".)

There are few controlled data on treatment of insomnia in pregnancy [73]. Nonpharmacologic therapies are the safest option and are preferred over pharmacotherapy by most women and couples [74-76]. Several randomized trials support the efficacy of CBT-I in pregnancy using in-person or digital delivery methods [77-80].

Over-the-counter sedating antihistamines such as doxylamine or diphenhydramine can be used in women who desire medication and have no alternative causes of sleeplessness that can be addressed more effectively (eg, RLS, gastroesophageal reflux) [81,82]. Other pharmacologic options, including BZRAs and sedating antidepressants, should generally be avoided as potential risks likely outweigh benefits. (See "Prenatal care: Patient education, health promotion, and safety of commonly used drugs", section on 'Difficulty sleeping'.)

Menopause — Women in the menopausal transition commonly report insomnia. Factors associated with insomnia include vasomotor symptoms (hot flashes and night sweats), reproductive hormonal changes themselves, an increase in obstructive sleep apnea prevalence, and increased risk of comorbid mood and medical disorders. (See "Clinical manifestations and diagnosis of menopause", section on 'Sleep disturbance'.)

Similar to the general population, CBT-I is an effective treatment for menopausal insomnia, both in women with and without nocturnal hot flashes. In one trial, six-session individual CBT-I delivered by telephone was effective for both overall insomnia severity and difficulty falling and staying asleep (but not for total sleep time) in menopausal insomnia with hot flashes [83]. In another trial, face-to-face multimodality CBT-I and single-modality sleep-restriction therapy (SRT) were each more effective than sleep hygiene education among 150 postmenopausal women with menopause-related chronic insomnia [84,85]. The degree of improvement on sleep outcome measures as well as depression and maladaptive thinking tended to be greatest with CBT-I, and there was trend towards greater insomnia remission rates with CBT-I over SRT.

For women with hot flashes and sleep disturbances, improvements in sleep have also been observed with a range of pharmacotherapies including menopausal hormone therapy, venlafaxine, gabapentin, fluoxetine, eszopiclone, and escitalopram [86,87]. (See "Menopausal hot flashes", section on 'Management'.)

Yoga and exercise may be beneficial for sleep in women in the menopausal transition, although the effect size is likely to be small [88,89].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Insomnia in adults".)

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

Pretreatment assessment – Insomnia often has multiple etiologies (table 2). All patients should be evaluated for predisposing and precipitating factors (eg, depression, anxiety, pain), concomitant medications that may be interfering with sleep, and maladaptive cognitive and behavioral responses to sleeplessness that may be perpetuating insomnia (table 4). (See 'Initial assessment and counseling' above.)

Short-term insomnia – Short-term insomnia (less than one month) usually results from psychologic or physiologic stress and is often self-limited. (See 'Approach to acute insomnia' above.)

For patients with mild or manageable levels of distress, we provide education, reassurance, and a plan for clinical follow-up. If insomnia persists at follow-up, we reassess level of distress and proceed as for chronic insomnia below.  

When acute insomnia is severe or associated with substantial distress, we offer short-term use of an insomnia medication to help address immediate interference with daytime function and to control escalating anxiety about sleep (algorithm 1). Medication selection is reviewed separately. (See "Pharmacotherapy for insomnia in adults", section on 'Drug selection'.)

Chronic insomnia – Patients with chronic insomnia have persistent sleep difficulties that last months to years and often follow a waxing and waning course. Cognitive behavioral therapy (CBT) and pharmacotherapy are the main treatment options when symptoms persist despite management of precipitating and perpetuating factors.

In most patients with chronic insomnia, we suggest cognitive behavioral therapy for insomnia (CBT-I) as first-line therapy, rather than medication (Grade 2B). Short-term use of a medication in combination with CBT-I is reasonable in patients with severe distress (eg, deterioration in daytime function or excessive anxiety regarding sleeplessness, which may interfere with the ability to follow sleep restriction and stimulus control aspects of CBT-I). (See 'Choice of initial therapy' above and 'Overview of cognitive behavioral therapy' above.)

When pharmacotherapy is used for insomnia, selection of medication should be individualized based on patient age and comorbidities, the type of insomnia complaint, side effect profiles, cost, and clinician and patient preference (algorithm 1). Selection of a specific medication is reviewed separately. (See "Pharmacotherapy for insomnia in adults", section on 'Drug selection'.)

Follow-up – Little data are available on the efficacy and safety of long-term pharmacotherapy for insomnia other than for nonbenzodiazepine BZRAs. The risk of side effects must be assessed both prior to, and regularly during the course of, medication management of insomnia. (See 'Follow-up and monitoring' above.)

Special populations – Special populations in whom additional treatment considerations arise include older adults, patients with comorbid psychiatric, neurologic, and sleep disorders, and those with medical comorbidities and conditions. (See 'Treatment considerations for specific populations' above.)

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Topic 97867 Version 16.0

References

1 : Risk factors for incident chronic insomnia: a general population prospective study.

2 : Sleep system sensitization: evidence for changing roles of etiological factors in insomnia.

3 : Trends in the use of medications with insomnia side effects and the implications for insomnia among US adults.

4 : The impact of glucocorticoids and statins on sleep quality.

5 : Clinical Practice Guideline for the Pharmacologic Treatment of Chronic Insomnia in Adults: An American Academy of Sleep Medicine Clinical Practice Guideline.

6 : Behavioral and pharmacological therapies for late-life insomnia: a randomized controlled trial.

7 : Cognitive behavior therapy and pharmacotherapy for insomnia: a randomized controlled trial and direct comparison.

8 : Cognitive behavioral therapy, singly and combined with medication, for persistent insomnia: a randomized controlled trial.

9 : Long-Term Maintenance of Therapeutic Gains Associated With Cognitive-Behavioral Therapy for Insomnia Delivered Alone or Combined With Zolpidem.

10 : Management of Chronic Insomnia Disorder in Adults: A Clinical Practice Guideline From the American College of Physicians.

11 : Clinical guideline for the evaluation and management of chronic insomnia in adults.

12 : British Association for Psychopharmacology consensus statement on evidence-based treatment of insomnia, parasomnias and circadian rhythm disorders.

13 : Psychological and Behavioral Interventions for Managing Insomnia Disorder: An Evidence Report for a Clinical Practice Guideline by the American College of Physicians.

14 : European guideline for the diagnosis and treatment of insomnia.

15 : Adherence to cognitive behavioral therapy for insomnia: a systematic review.

16 : Predictors of treatment response to brief behavioral treatment of insomnia (BBTI) in older adults.

17 : Insomnia Patients with Objective Short Sleep Duration have a Blunted Response to Cognitive Behavioral Therapy for Insomnia.

18 : Effectiveness of non-benzodiazepine hypnotics in treatment of adult insomnia: meta-analysis of data submitted to the Food and Drug Administration.

19 : Behavioral and psychological treatments for chronic insomnia disorder in adults: an American Academy of Sleep Medicine clinical practice guideline.

20 : Endorsement of European guideline for the diagnosis and treatment of insomnia by the World Sleep Society.

21 : Sleep problems, comorbid mental disorders, and role functioning in the national comorbidity survey replication.

22 : Management of Hypnotic Discontinuation in Chronic Insomnia.

23 : Management of Hypnotic Discontinuation in Chronic Insomnia.

24 : Eszopiclone co-administered with fluoxetine in patients with insomnia coexisting with major depressive disorder.

25 : Eszopiclone coadministered with escitalopram in patients with insomnia and comorbid generalized anxiety disorder.

26 : Residual symptoms in depressed outpatients who respond by 50% but do not remit to antidepressant medication.

27 : Sleep disturbance in euthymic bipolar patients.

28 : Insomnia and somnolence associated with second-generation antidepressants during the treatment of major depression: a meta-analysis.

29 : Cognitive behavioral therapy for insomnia enhances depression outcome in patients with comorbid major depressive disorder and insomnia.

30 : Treating insomnia improves mood state, sleep, and functioning in bipolar disorder: a pilot randomized controlled trial.

31 : Efficacy of Cognitive-Behavioral Therapy for Insomnia Combined With Antidepressant Pharmacotherapy in Patients With Comorbid Depression and Insomnia: A Randomized Controlled Trial.

32 : Cognitive behavior therapy for older adults with insomnia and depression: a randomized controlled trial in community mental health services.

33 : Persistence of sleep disturbances following cognitive-behavior therapy for posttraumatic stress disorder.

34 : Cognitive behavioral therapy for insomnia in posttraumatic stress disorder: a randomized controlled trial.

35 : Efficacy of cognitive behavioural therapy for sleep improvement in patients with persistent delusions and hallucinations (BEST): a prospective, assessor-blind, randomised controlled pilot trial.

36 : The impact of eszopiclone on sleep and cognition in patients with schizophrenia and insomnia: a double-blind, randomized, placebo-controlled trial.

37 : A longitudinal study of insomnia and other sleep complaints in adolescents with and without alcohol use disorders.

38 : The sleep of abstinent pure primary alcoholic patients: natural course and relationship to relapse.

39 : Randomized controlled trial of brief cognitive-behavioural interventions for insomnia in recovering alcoholics.

40 : Cognitive-behavioral therapy for insomnia in alcohol dependent patients: a randomized controlled pilot trial.

41 : Prevalence and perceived health associated with insomnia based on DSM-IV-TR; International Statistical Classification of Diseases and Related Health Problems, Tenth Revision; and Research Diagnostic Criteria/International Classification of Sleep Disorders, Second Edition criteria: results from the America Insomnia Survey.

42 : Insomnia (primary) in older people: non-drug treatments.

43 : Effects of Tai Chi or Exercise on Sleep in Older Adults With Insomnia: A Randomized Clinical Trial.

44 : Improving sleep quality in older adults with moderate sleep complaints: A randomized controlled trial of Tai Chi Chih.

45 : Cognitive behavioral therapy vs. Tai Chi for late life insomnia and inflammatory risk: a randomized controlled comparative efficacy trial.

46 : Exercise training improves sleep quality in middle-aged and older adults with sleep problems: a systematic review.

47 : Pharmacotherapies for sleep disturbances in dementia.

48 : Trazodone improves sleep parameters in Alzheimer disease patients: a randomized, double-blind, and placebo-controlled study.

49 : Polysomnographic assessment of suvorexant in patients with probable Alzheimer's disease dementia and insomnia: a randomized trial.

50 : The Movement Disorder Society Evidence-Based Medicine Review Update: Treatments for the non-motor symptoms of Parkinson's disease.

51 : Prevalence and risk factors of moderate to severe obstructive sleep apnea syndrome in insomnia sufferers: a study on 1311 subjects.

52 : Prevalence and symptoms of occult sleep disordered breathing among older veterans with insomnia.

53 : Effects of opioid, hypnotic and sedating medications on sleep-disordered breathing in adults with obstructive sleep apnoea.

54 : Effect of 1 month of zopiclone on obstructive sleep apnoea severity and symptoms: a randomised controlled trial.

55 : Efficacy of Cognitive Behavioral Therapy for Insomnia in Older Adults With Occult Sleep-Disordered Breathing.

56 : Comorbid insomnia symptoms predict lower 6-month adherence to CPAP in US veterans with obstructive sleep apnea.

57 : Sleep maintenance insomnia complaints predict poor CPAP adherence: A clinical case series.

58 : Developing a successful treatment for co-morbid insomnia and sleep apnoea.

59 : A randomized controlled trial of CBT-I and PAP for obstructive sleep apnea and comorbid insomnia: main outcomes from the MATRICS study.

60 : Randomized controlled trial of an integrated approach to treating insomnia and improving the use of positive airway pressure therapy in veterans with comorbid insomnia disorder and obstructive sleep apnea.

61 : Effects of a short course of eszopiclone on continuous positive airway pressure adherence: a randomized trial.

62 : Eszopiclone improves overnight polysomnography and continuous positive airway pressure titration: a prospective, randomized, placebo-controlled trial.

63 : Comparison of pregabalin with pramipexole for restless legs syndrome.

64 : Chronic conditions and sleep problems among adults aged 50 years or over in nine countries: a multi-country study.

65 : Multimorbidity and use of hypnotic and anxiolytic drugs: cross-sectional and follow-up study in primary healthcare in Iceland.

66 : Effect of Telephone Cognitive Behavioral Therapy for Insomnia in Older Adults With Osteoarthritis Pain: A Randomized Clinical Trial.

67 : Insomnia in patients with COPD.

68 : The overlaps of asthma or COPD with OSA: A focused review.

69 : The effect of benzodiazepines on insomnia in patients with chronic obstructive pulmonary disease: a meta-analysis of treatment efficacy and safety.

70 : Sleep Disorders, Restless Legs Syndrome, and Uremic Pruritus: Diagnosis and Treatment of Common Symptoms in Dialysis Patients.

71 : Long-term effects of melatonin on quality of life and sleep in haemodialysis patients (Melody study): a randomized controlled trial.

72 : Sleep disturbance in pregnancy. A subjective survey.

73 : Interventions for sleep problems during pregnancy: A systematic review.

74 : A review of sleep-promoting medications used in pregnancy.

75 : Couples' treatment preferences for insomnia experienced during pregnancy.

76 : Insomnia Treatment Preferences During Pregnancy.

77 : Cognitive Behavioral Therapy for Prenatal Insomnia: A Randomized Controlled Trial.

78 : Sleeping for Two: An Open-Pilot Study of Cognitive Behavioral Therapy for Insomnia in Pregnancy.

79 : Efficacy of Digital Cognitive Behavioral Therapy for the Treatment of Insomnia Symptoms Among Pregnant Women: A Randomized Clinical Trial.

80 : A randomized controlled trial of digital cognitive behavioral therapy for insomnia in pregnant women.

81 : Sleep Pharmacotherapy for Common Sleep Disorders in Pregnancy and Lactation.

82 : Insomnia treatment in the third trimester of pregnancy reduces postpartum depression symptoms: a randomized clinical trial.

83 : Telephone-Based Cognitive Behavioral Therapy for Insomnia in Perimenopausal and Postmenopausal Women With Vasomotor Symptoms: A MsFLASH Randomized Clinical Trial.

84 : Treating chronic insomnia in postmenopausal women: a randomized clinical trial comparing cognitive-behavioral therapy for insomnia, sleep restriction therapy, and sleep hygiene education.

85 : Treating insomnia improves depression, maladaptive thinking, and hyperarousal in postmenopausal women: comparing cognitive-behavioral therapy for insomnia (CBTI), sleep restriction therapy, and sleep hygiene education.

86 : Treatment of chronic insomnia disorder in menopause: evaluation of literature.

87 : Pharmacologic and hormonal treatments for menopausal sleep disturbances: A network meta-analysis of 43 randomized controlled trials and 32,271 menopausal women.

88 : Efficacy of yoga for vasomotor symptoms: a randomized controlled trial.

89 : Efficacy of exercise for menopausal symptoms: a randomized controlled trial.