Approach

Your Organizational Guidance

ebpracticenet urges you to prioritize the following organizational guidance:

Aanpak van slaapklachten en insomnie (slapeloosheid) bij volwassenen in de eerste lijnPublished by: Werkgroep Ontwikkeling Richtlijnen Eerste Lijn (Worel)Last published: 2018Prise en charge des problèmes de sommeil et de l’insomnie chez l’adulte en première lignePublished by: Groupe de Travail Développement de recommmandations de première ligneLast published: 2018

It is important to identify and optimize management of any comorbid medical conditions (e.g., chronic pain, hot flashes, hyperthyroidism, bladder disturbance, obstructive sleep apnea, periodic limb movement disorder, or restless legs syndrome) or psychiatric disorders (e.g., mood disorders, anxiety disorders, substance use disorder, acute stress, or trauma) that may be contributing to chronic insomnia.[78]

Review the patient's usual medications to establish whether they include drugs that may cause or worsen insomnia, such as stimulants, antidepressants, corticosteroids, diuretics, or sedatives; if so, consider whether it is possible to lower the dosage and/or utilize the medication at another time of the day in order to reduce the impact on sleep.

Management of acute insomnia

Acute insomnia lasts less than 3 months and often occurs in response to an identifiable stressor.[1][2] Acute insomnia is very common and often transient, and does not always require treatment.[112] Note that current diagnostic classifications do not have quantitative severity criteria for insomnia disorder; it is up to the clinician to judge what is severe enough to treat.[7]

In the first instance, identify potential stressors that may be disturbing sleep (e.g., work-related stress or relationship difficulties) and encourage the patient to address these where possible. Enquire about maladaptive coping strategies such as daytime napping or use of stimulants, and offer advice on avoidance of these as well as on general sleep hygiene measures.[112] Aims of short-term treatment for acute insomnia include reducing alarming thoughts associated with sleeplessness, in order to protect against the development of counterproductive cognitive, emotional, and behavioral responses to sleeplessness that are risk factors for transient insomnia to evolve into a chronic condition.

Nonpharmacologic therapies for acute insomnia

Cognitive behavioral therapy for insomnia (CBT-I) is a first-line approach for acute insomnia. CBT-I has been shown to be effective for chronic insomnia.[113]​ Evidence for its use in acute insomnia is limited but promising.​[4][5][6]​​​ One randomized controlled trial investigated the effect of a 1-week internet-delivered course of CBT-I on patients with acute insomnia. After 12 weeks, the incidence of progression to chronic insomnia was significantly lower in the CBT-I group compared with controls (33.3% vs. 65.8%).[4] Further small trials have suggested that a single 60- to 70-minute session of CBT-I for acute insomnia is effective in reducing insomnia severity.​[5][6]

Depending on the assessment of the problem, a provider may identify the relevant component of CBT-I for a particular patient. This requires an understanding of the CBT-I key principles, which encompass:[114]

  • Learning approaches to downregulate arousal and become more adept at inducing a state of relaxation. There is no evidence that any one approach, such as progressive muscle relaxation, self-hypnosis, meditation, or mindfulness, is more effective. Each approach requires practice. Mindfulness explicitly engenders a cognitive mindset that addresses another key element of CBT-I, namely letting go of the need to predict what is going to happen and remaining in the moment. This permissive approach, encouraging curiosity rather than fostering an expectation of a desired outcome, is intended to remove performance anxiety surrounding sleep.

  • Cognitive restructuring, where a person embraces the reality that sleep is out of control and so the focus is on surrendering to whatever happens regarding sleep. The need for control is redirected toward removing impediments to sleep, such as managing sleep hygiene, engaging in stimulus control to reduce the time in bed when not sleeping, and avoiding time cues.

  • Avoiding time cues, because checking the time can become arousing owing to invoking worry about time spent awake, limited opportunities for sleep, and concern over daytime function.[115]

  • Reducing the time in bed if not sleeping by creating a buffer zone to go to if uncomfortable, or frustrated in bed, in order for the patient to reset their emotional and physiologic state by doing a soothing, relaxing activity out of bed. The person is instructed to return to bed when they feel sleepy. Caution is needed to manage the patient's expectation that sleep will occur, because if sleep is expected and does not occur, this can lead to counterproductive frustration, rather than acceptance that CBT-I is a training program designed to reduce the time in bed not sleeping and will require repeated implementation for benefits to accrue. This process can be repeated, all the time removing the expectation for sleep to occur on demand and replacing it with a focus on relaxation. Acceptance and commitment therapy aims to break the vicious cycle of trying to control sleep. Control in this setting, meaning adopting the expectation that sleep should occur, has been proposed to inhibit the automatic expression of sleep and so worsen the sleep difficulty. This approach employs mindfulness to displace the expectation of sleep.

  • Sleep restriction may be necessary if a person is spending excessive time in bed without sleeping. This is addressed by understanding sleep efficiency, which relates to the percentage of time in bed sleeping rather than being awake.[116]​ This may initially seem counterintuitive to the patient who is spending more time in bed to compensate for less sleep and so requires an understanding of the rationale for this approach, which is to increase the likelihood of sleep by reducing the opportunity to sleep, and starts with setting a firm wake up time.

  • Identifying and changing negative cognitions that engender alarm. This involves giving examples of how such cognitions create alarm so a person can review their thoughts related to not sleeping and alter those that are self-defeating. Changing such maladaptive beliefs regarding sleep has been shown to bring about a significant change in insomnia severity.[117]

Sleep hygiene and a discussion of relaxation techniques to reduce arousal and redirect attention from the desire for sleep to becoming comfortable in bed and accepting that sleep onset is out of control are appropriate interventions and draw upon key principles of CBT-I. These are appropriate nonpharmacologic treatment options for acute insomnia, especially in patients who prefer not to use medications, or who have suboptimal response to hypnotics.[118][119][120][121][122][123][124][125][126][127][128][129]​​ Evidence for most nonpharmacologic therapies for insomnia (excluding CBT-I) is limited, and insufficient to determine the relative efficacy of different nonpharmacologic treatments.[130]​ There is insufficient evidence that sleep hygiene techniques alone are an effective treatment for insomnia, although they may be helpful when combined with other specific interventions.[131]

Pharmacotherapy for acute insomnia

Despite a lack of controlled study evidence in acute insomnia, the same hypnotics with an evidence base for use in chronic insomnia are considered to be first line for acute insomnia.

Short-term use of a hypnotic is an appropriate option to consider in patients with acute insomnia that is severe or associated with substantial distress, when a rapid amelioration of symptoms is desirable, and/or in settings where there is limited or no access to behavioral treatments, if the patient is unable or unwilling to participate in behavioral therapy, or if behavioral therapy has been tried and found to be ineffective.​[106]​​​​[111]

The key to selecting an appropriate evidence-based hypnotic is the determination of whether a patient is experiencing sleep initiation difficulty, sleep maintenance difficulty, or both sleep initiation and maintenance difficulty.

  • For patients with sleep-onset difficulties, nonbenzodiazepine benzodiazepine receptor agonists (e.g., zolpidem, zaleplon, eszopiclone), dual orexin receptor antagonists (e.g., suvorexant, lemborexant, daridorexant), or ramelteon (a melatonin receptor agonist) are all reasonable first-line choices.[106] Phase 3 trials have shown these agents to improve subjectively and objectively (polysomnography [PSG]) determined sleep outcomes and decrease sleep onset latency (SOL) compared with placebo.[132][133]

  • For patients with difficulty maintaining sleep or early awakening, first-line choices include the nonbenzodiazepine benzodiazepine receptor agonists with longer half-lives (i.e., zolpidem and eszopiclone), doxepin (a tricyclic antidepressant with antihistamine properties), or a dual orexin receptor antagonist.[106] These drugs all have capacity to decrease wake after sleep onset and increase total sleep time.[106]

  • For patients with a combined difficulty with both initiating sleep and maintaining sleep, zolpidem and eszopiclone, and dual orexin receptor antagonists, all appear to be effective choices.

See sections below for a more detailed discussion of these drugs including pharmacology, evidence for their use, and safety considerations.

No hypnotics are indicated for use in pregnant women. Clinicians considering offering a pharmacologic treatment for acute insomnia during pregnancy should seek specialist input (e.g., from a psychiatrist with expertise in prescribing during pregnancy, or from an obstetrician) due to the risks associated with common hypnotics during pregnancy.

Follow up patients with acute insomnia after 2-4 weeks to establish whether insomnia is persistent; for persistent insomnia meeting diagnostic criteria for chronic insomnia, follow guidance on management of chronic insomnia.[111]

Management of chronic insomnia

Insomnia lasting 3 months or longer is considered chronic.[1]​​[2]

Treatment options for patients whose chronic insomnia does not respond to treatment of comorbid conditions include CBT-I, sleep hygiene approaches, or pharmacotherapy. It is important to take an individualized approach to treatment, based on the patient's preferences, the severity of their insomnia, the risks versus benefits of treatment, and the availability of specialist treatment options such as cognitive behavioral therapy.

For most patients, initial treatment with a behavioral therapy such as CBT-I, if available, is likely to provide the best balance between efficacy and safety.​[130][134][135]​​ However, CBT-I alone is not an effective strategy for all patients: for example, where there is no or restricted access to this service, an inability or unwillingness to participate in therapy, or lack of response to treatment. In this scenario, pharmacologic treatment may be indicated.[106]

For insomnia during pregnancy (when the risk:benefit ratio typically shifts in favor of nonpharmacologic options where possible), there is a limited evidence base for treatment; CBT-I (both face-to-face and online) appears to be a safe, effective, and acceptable first-line option.[136][137] If a pharmacologic agent is required during pregnancy, seek specialist input.

Nonpharmacologic therapies for chronic insomnia

CBT-I, a multicomponent nonpharmacologic therapy, has been shown to effectively treat insomnia over the long term but requires patient commitment, sustained adherence, and practitioner training.[118][130][138][139][140]​ CBT-I results in significant symptom improvement even after 12 months, and may be of benefit either alone or in combination with a hypnotic.[119] CBT-I also appears to be effective in primary care and community settings.[141][142]​ However, in practice, patients are infrequently referred for CBT-I due to barriers to uptake, particularly in primary care; such barriers include limited physician access to CBT-I and behavioral sleep medicine specialists, and patient barriers such as lack of knowledge, inaccurate treatment beliefs, and accessibility difficulties.[143]

CBT-I is effective when employed under the guidance of a clinician, either in face-to-face individual or group settings, or via internet-based CBT-I (sometimes called digital CBT-I or dCBT-I). There is an increasing evidence base in favor of dCBT-I suggesting that it is comparable to in-person CBT-I in effectiveness.[113][118][144]​​[145]​​ dCBT-I has the potential to increase patient access to CBT-I, thus offering patients and clinicians an increased choice among evidence-based treatments (CBT-I or pharmacotherapy) for insomnia.[134][146]

Behavioral interventions targeted to the underlying conditions have been shown to be effective in treating insomnia comorbid with other conditions, such as Alzheimer disease and post-traumatic stress disorder (PTSD).[147][148][149]​​​​ There is some evidence to suggest that CBT-I reduces symptoms of comorbid depression in patients with insomnia, particularly when carried out face-to face.[150][151][152]​​​​ Treating insomnia using CBT-I has been shown to improve quality of life, prevent depression, and possibly improve cardiometabolic biomarkers such as C-reactive protein and hemoglobin A1c (HbA1c).[29][153]​​​[154]

Evidence for other (i.e., not CBT-I) nonpharmacologic therapies for insomnia is limited, and insufficient to determine the relative efficacy of the different treatments.[130] If CBT-I is not available or not wanted, sleep hygiene, cognitive restructuring, and relaxation techniques are appropriate nonpharmacologic treatment options for insomnia, especially in patients who prefer not to use medications, or who have suboptimal response to hypnotics.[118][119][120][121][122][123][124][125][126][127][128][129]

Sleep hygiene involves developing habits conducive to sleep, such as:

  • avoiding stimulants, including nicotine and caffeine (as well as foods containing caffeine), for several hours before bedtime

  • avoiding alcohol around bedtime

  • avoiding blue-light-emitting digital devices (e.g., smart-phones/computers) close to bedtime

  • establishing a regular bedtime and rise time; avoiding excessive time in bed trying to sleep

  • avoiding extended daytime naps

  • accepting that sleep onset is involuntary and out of a person's control

  • adopting a more permissive approach to sleep by controlling and removing impediments but accepting sleep will happen but not on demand, only trying to sleep when sleepy

  • taking regular exercise, especially in the late afternoon or early evening

  • allowing adequate time to unwind before going to bed

  • ensuring the environment is conducive to sleep - making certain the bed and bedding are comfortable, the room is dark and quiet, and temperature and humidity are controlled; and

  • avoiding clock-watching during the sleep period.

There is insufficient evidence that sleep hygiene techniques alone are an effective treatment for insomnia, although they may be helpful when combined with other specific interventions.[131] The results of one meta-analysis suggest that sleep hygiene education is substantially less effective than CBT-I, but that it is associated with a small to moderate improvement of symptoms of insomnia; it is unclear from current data whether sleep hygiene education might have a role in a stepped care model for insomnia.[155]

Relaxation techniques include progressive relaxation, guided imagery and meditation, and biofeedback. Stimulus control therapy and sleep-restriction therapy are also effective and recommended techniques for the management of chronic insomnia.​[131][138]

Nonpharmacologic treatments are beneficial when employed under the guidance of a clinician, either in face-to-face individual or group settings, or via internet-based CBT-I. The effects of self-help treatments such as exercise are small to moderate.[156][157][158]

Complementary, herbal, or alternative treatments have been considered for the treatment of insomnia, but studies do not support their use, or further investigation is required to determine their efficacy.[159][160][161][162][163][164][165][166][167]

Pharmacologic therapies for chronic insomnia

Short-term and potentially longer-term provision of a hypnotic is an appropriate second-line option for patients with chronic insomnia. CBT-I should be offered first line, but if the insomnia has become severe and the patient is in distress, or they are unable or unwilling to accept CBT-I, or have not responded to CBT-I, consider prescribing a hypnotic.

A greater evidence basis supports individual hypnotic agents for treating chronic insomnia than for acute insomnia. An essential element in choosing a particular evidence-based hypnotic agent is first determining whether the patient is experiencing sleep initiation difficulty, sleep maintenance difficulty, or both sleep initiation and sleep maintenance difficulty.[106]

  • For patients with sleep-onset difficulty alone, hypnotics demonstrating established capacity to reduce sleep onset latency and confer reasonable safety include nonbenzodiazepine benzodiazepine receptor agonists and ramelteon.[106] Dual orexin receptor antagonists are also reasonable choices, based on phase 3 trials.[132][133][168][169][170][171][172]

  • For patients with sleep maintenance difficulty alone, the nonbenzodiazepine benzodiazepine receptor agonists with longer half-lives (i.e., zolpidem and eszopiclone), doxepin (a tricyclic antidepressant with antihistamine properties), and the dual orexin receptor agonist suvorexant demonstrate acceptable efficacy and safety.[106] Lemborexant and daridorexant show favorable profiles based on sponsored phase 3 trials. All of these hypnotics have evidence of efficacy in decreasing wakefulness after sleep onset (WASO), increasing sleep efficiency (SE), and increasing total sleep time (TST).[106]

  • For patients with a combined difficulty with both initiating sleep and maintaining sleep, zolpidem and eszopiclone, and dual orexin receptor antagonists, all appear to be effective choices.

Nonbenzodiazepine benzodiazepine receptor agonists

  • Nonbenzodiazepine benzodiazepine receptor agonists (e.g., zolpidem, zaleplon, eszopiclone) are also known as "Z drugs." These drugs attach preferentially to the alpha subunit of the GABA A receptor.[173] They exert their effects by enhancing the central nervous system GABAergic activity, resulting in inhibition of excitatory neurons.

  • Though they act in a pharmacologically similar manner to classic benzodiazepines, their half-lives are much shorter. Due to their short half-lives, nonbenzodiazepine benzodiazepine receptor agonists are unlikely to produce sedation and impairment of function (at therapeutic doses) during active daytime hours starting 7-8 hours post dose.[174] Doses can be adjusted downward or upward easily to allow for immediate improvement in sleep or to diminish adverse effects.

  • Nonbenzodiazepine benzodiazepine receptor agonists are now generally considered to be safer than traditional benzodiazepines, but there continues to be some controversy about this issue, and whether any liability difference is based largely on their favorable half-life properties or due to a class-related pharmacodynamic difference.[175]

  • All of these drugs show established efficacy in reducing sleep onset latency (SOL), and for zolpidem and eszopiclone, in reducing WASO, and increasing TST and sleep quality (SQ), based on both objective (PSG) and subjective measures (sleep diary) in short-term studies.[106]

Dual orexin receptor antagonists

  • Dual orexin receptor antagonists (e.g., suvorexant, lemborexant, daridorexant) promote sleep by blocking attachment of the wakefulness instigating neuropeptides orexin A and B to orexin receptors 1 and 2.

  • Accumulating evidence supports their efficacy in decreasing SOL, WASO, and TST based on objective (PSG) and subjective measures.[132][133][168][169][170][171]​ Longer-term studies are lacking for these agents.

Ramelteon

  • A melatonin receptor agonist that has been shown to reduce sleep onset latency but is likely ineffective for sleep maintenance.[106][176]​​[177]

There exists no clear evidence to support the superiority of one recommended class of hypnotic over another.[178][179]​​​ Choice of drug should be tailored to the insomnia phenotype and consideration of its safety and tolerability. Advise that patients take their medication about 30 minutes before sleep, optimally between the hours of 9 pm and 1 am, and remain in bed at least 7-8 hours before arising. Patients should try to avoid getting up and walking in the middle of the night, and avoid driving until tolerability of the medication is established.

Hypnotics may be used alone or in conjunction with nonpharmacologic therapies. One review of randomized controlled trials suggests that targeted and time-limited insertion of zolpidem within a course of CBT-I may allow certain patients to successfully complete their CBT-I without detriment to their long-term CBT-I related outcomes.[180]​ However, just a few controlled studies address this topic regarding combined or adjunctive behavioral and pharmacologic treatments.[181]​ Thus, the evidence at present for this approach should be considered weak.

Sedating antihistamines, such as diphenhydramine and doxylamine, are sometimes used to treat insomnia, but evidence for their safety and efficacy is limited.[106][182]​​[183]​ Use of these agents should be avoided.

Special patient populations

Pregnancy

  • No hypnotics are indicated for use in pregnant women. Behavioral treatments are the preferred option, but if hypnotics may be indicated based on a risk:benefit determination, they should be prescribed preferably along with specialist input and a collaborative management approach with a psychiatrist and/or obstetrician with expertise in prescribing these agents during pregnancy.

Older adults

  • Treating older patients with hypnotics presents a challenge because older patients are more prone to medication-related adverse events, yet there exists little quality evidence to support acceptable harm versus efficacy profiles in choosing between agents. Older patients often have comorbid medical conditions, and take other medications, conferring an increased risk for disease-drug and drug-drug interactions with the hypnotic agent.

  • One of the most concerning adverse events that occurs at greater frequency for older patients is that of falls. The American Geriatric Society (AGS) BEERs criteria for potentially inappropriate medication prescribing in older adults places all benzodiazepines and nonbenzodiazepine benzodiazepine receptor agonists on its list of medications to avoid due to an increased risk of accidents and falls.[184]

  • It can be assumed, because dual orexin receptor antagonists have been around for a much shorter period than nonbenzodiazepine benzodiazepine receptor agonists, that insufficient real-world data exist for other hypnotics when compared with nonbenzodiazepine benzodiazepine receptor agonists. Some controlled trials and subgroup analyses indicate a favorable risk:benefit profile for dual orexin receptor antagonists in older patients.[185]​ A minority of patients experience somnolence as an adverse effect.​[170][186]​​​​ One controlled trial compared lemborexant, zolpidem, and placebo in adults ages 55 years and older with insomnia. Lemborexant and zolpidem showed largely comparable efficacy; however, falls and mild sleep paralysis events occurred only in the lemborexant arm. The falls were not considered to be treatment-related.[187]

  • Current data are insufficient to determine whether dual orexin receptor antagonists offer a more favorable risk:benefit profile in older adults than nonbenzodiazepine benzodiazepine receptor agonists. No definitive evidence supports an increased risk for one recommended class of hypnotic over the other. The authors do not recommend avoiding nonbenzodiazepine benzodiazepine receptor agonists as a class for older adults. Nonbenzodiazepine benzodiazepine receptor agonists have uniquely short half-lives that allow for targeted dosing, a potential pharmacologic advantage not yet tested in the real world versus longer half-life agents such as dual orexin receptor antagonists. An individualized risk versus benefit profile should be determined that takes into account pertinent clinical factors, including coexisting comorbidity, medications, potential for drug-drug interactions, psychosocial factors, and patient values and preferences.

Considerations for pharmacologic therapy in patients with comorbid conditions

Depression or anxiety

  • Hypnotics have been shown to be efficacious in treating insomnia comorbid with anxiety and depression.[188][189][190][191][192]​ One controlled study of selective serotonin-reuptake inhibitor (SSRI)-treated depressed patients with insomnia demonstrated a decrease in suicidality with zolpidem compared with placebo.[193]

  • Sedating antidepressants, such as mirtazapine or paroxetine, may be an appropriate choice for those with active depression and insomnia.[194]​ The efficacy and safety of mirtazapine (a tetracyclic antidepressant) for insomnia has not been established, and there is a risk of daytime sedation and metabolic adverse effects. Paroxetine, an SSRI, produces potentially anticholinergic adverse effects and a substantial potential for drug-drug interactions due to its potent ability to inhibit cytochrome CYP2D6. Clinical judgment regarding the use of mirtazapine or paroxetine monotherapy for patients with depression, versus combined treatment with a nonsedating antidepressant and a hypnotic, must be made on an individualized case-by-case basis, which includes consideration of patient preference. Consult a specialist for guidance on selecting a suitable antidepressant or anxiolytic in these patients. One controlled study demonstrated that effective treatment of major depressive disorder with an SSRI allowed for seamless discontinuation of coadministered eszopiclone within 8 weeks.[195]

  • Trazodone is a widely prescribed hypnotic at doses generally lower than those established as effective for depression.[182] The American Academy of Sleep Medicine advises that this drug’s harms outweigh its benefits.[106]​ Severe discontinuation-related adverse events have been reported.

  • The dose of doxepin should not be escalated above approved doses for insomnia in order to try to approximate doses potentially effective for depression.

Dementia

  • Little evidence exists to help guide pharmacologic treatment options for patients with dementia and comorbid insomnia.[196] The authors recommend a similar approach to that recommended for hypnotic prescribing in older adults, first considering behavioral options for insomnia.

  • Sedating antidepressants and antipsychotics are commonly used for this condition despite considerable concerns regarding the use of these unproven medications for primary insomnia in such a vulnerable group of patients. Antipsychotics carry a warning for increased mortality in patients with dementia.[197]​ In addition, they confer a substantial risk for drug-induced parkinsonism, increasing the risk for falls. No reliable evidence supports that these medications should be used in place of established hypnotics that are proven relatively safe and effective in the general population for uncomplicated insomnia (i.e., no psychosis or severe agitation).

  • Treating Alzheimer disease optimally with a combination of an acetylcholinesterase inhibitor and memantine can help to alleviate sleep disturbance.[198][199]​​​​ Behavioral and environmental modifications that allow for circadian realignment may be most helpful.[200][201]​​​

  • Although trazodone has shown some efficacy for insomnia in patients with dementia, concerns exist regarding its long half-life, risk of falls, propensity for drug-drug interactions (e.g., with serotonergic drugs), cardiovascular activity (e.g., orthostatic hypotension), and daytime sedation.[202][203][204]​​​​

Safety considerations for hypnotics

Prescribers should discuss safety considerations with patients when prescribing hypnotics.

Complex sleep-related behaviors

  • There have been several reports of this rare but potentially very serious adverse event. Reports include sleepwalking, sleep eating, sleep driving, turning on a stove, and even using a gun.[205]​ Such behavior has at times led to serious injury or death.

  • Benzodiazepine receptor agonists are contraindicated in patients with a history of drug-induced complex sleep-related behaviors.

  • Most of the incidents have occurred in patients receiving nonbenzodiazepine benzodiazepine receptor agonists, but such behaviors have occurred in association with all hypnotics, including dual orexin receptor antagonists.

Central nervous system (CNS) depressant effects

  • All hypnotics are considered to be CNS depressants. All patients receiving hypnotics should be vigorously warned regarding the potential for hypnotics to increase the risk of falls and accidents, especially when ambulating in the middle of the night, or to cause driving impairment the next day. Such adverse events are mostly dose-proportional and can be potentially mitigated by lower dosing.

  • Coadministration with other CNS depressants, including alcohol and sedating medications such as opioids, antihistamines, sedating antidepressants, antipsychotics, and anticonvulsants, should be avoided.

Sleep paralysis, cataplexy, and excessive daytime sleepiness (EDS)

  • All hypnotics decrease performance in a dose-proportional fashion. All hypnotic agents have been reported to induce excessive somnolence during the day, as well as very serious sleep paralysis and cataplexy, which can also occur during active daytime hours. Dual orexin receptor antagonists are contraindicated in patients with a history of narcolepsy. It should be noted that dual orexin receptor antagonists have much longer half-lives than do the nonbenzodiazepine benzodiazepine receptor agonists, so appreciable blood levels of these agents are likely present for days in patients after a single dose. Daytime somnolence, fatigue, motor and driving impairment, and daytime motor impairment has been demonstrated for dual orexin receptor antagonists at higher doses. One meta-analysis reporting treatment-emergent adverse events for dual orexin receptor antagonists demonstrated a relative risk of 2.15 for EDS and 3.40 for sleep paralysis compared with placebo.[206]

Hypnagogic or hypnopompic hallucinations

  • Hypnagogic (occurring while falling asleep) and hypnopompic (occurring when awakening) hallucinations have been reported for hypnotics and may be connected to or independent of the occurrence of cataplexy and sleep paralysis events.

Worsening of depression, suicidality, and impulsivity

  • Hypnotic agents can worsen depression and suicidal or homicidal thoughts, and increase impulsivity, placing patients at greater risk for acting out disturbed thoughts.[207]

Misuse or abuse

  • Misuse is the use of a medication for other than its intended purpose (e.g., taking zolpidem for a daytime nap). Abuse refers to the use of a substance for recreational purposes.

  • Both dual orexin receptor antagonists and nonbenzodiazepine benzodiazepine receptor agonists are classified as controlled substances, indicating that those agents carry some liability for abuse, though at a low level. The liability for hypnotic misuse appears to occur primarily when these agents are prescribed to patients with comorbid substance use disorder.

Dependence, tolerance, withdrawal, and rebound

  • Dependence, either physical, psychological, or both, can occur with any hypnotic. The capacity to induce tolerance, withdrawal, or rebound symptoms subsequent to abrupt discontinuation appears to be associated with the physical properties of the particular agent.

  • Nonbenzodiazepine benzodiazepine receptor agonists, being similar to benzodiazepines pharmacologically, possess the capacity for tolerance, rebound, and withdrawal, though at doses prescribed for insomnia the incidence appears low and to occur only for a few nights post discontinuation.[208]​ Ramelteon and zaleplon likely have little or no propensity to produce such adverse effects, but their utility is limited. Dual orexin receptor antagonists appear unlikely to exhibit withdrawal or rebound based on phase 3 studies. One controlled study addressing tolerance and zolpidem demonstrated that dose escalation occurred for subjects taking placebo, greater than that for zolpidem, a result potentially supporting the concept that untreated insomnia can confer a greater risk for patient inappropriate medication use than does the hypnotic itself.[209]

Respiratory suppression

  • As CNS depressants, all hypnotics can confer an increased risk for respiratory suppression, especially in those with comorbid respiratory compromise, such as obstructive sleep apnea (OSA) and COPD.

  • Ramelteon likely has the lowest liability for this effect. Doxepin and dual orexin receptor antagonists in controlled studies have shown little to no effect in mild or moderate OSA or COPD. There are no data to support the safety of any agents in severe OSA or COPD. The evidence for increased risk with recommended doses of nonbenzodiazepine benzodiazepine receptor agonists in mild to moderate OSA is unclear.

  • Adequate treatment of any comorbid respiratory illness should be pursued when considering prescribing hypnotics.

Duration of hypnotic treatment

The safety of long-term hypnotic use has not been established. For this reason, some guidelines recommend limiting treatment with hypnotics to 4-5 weeks, whereas others do not restrict treatment length.[106][130]​​​​ The Food and Drug Administration (FDA) has approved all hypnotics since 2004 without limitation on the duration of treatment. Some controlled studies indicate that longer-term treatment with zolpidem and eszopiclone is safe and efficacious.[210][211]​​​​​ Insomnia is likely to recur after stopping treatment, and untreated insomnia is associated with numerous risks to physical and mental health.[212][213]​​​​

A shared risk:benefit determination must be assessed for each individual that includes, as an important factor, patient preference in order to determine whether a patient should continue the hypnotic for the longer term. In general, we would suggest continued treatment with an evidence-based recommended hypnotic as described herein rather than leaving a patient with untreated recurrent illness without options. Even if patients are unwilling or unable to avail themselves of behavioral treatments, or have not responded to behavioral treatments, the next in line recommended approach remains treatment with a hypnotic. If hypnotic-related treatment adverse events are occurring such as daytime impairment, dose reduction or transitioning to another hypnotic that might minimize the occurrence of that particular adverse event are appropriate options to offer a patient. Specialist consultation (sleep medicine, psychiatrist, or insomnia specialist) and a collaborative care approach can assist with making such decisions and managing patients taking hypnotics over the longer term. Provision of CBT-I treatment has also been shown to assist patients with hypnotic medication discontinuation and usage.[214]

If symptoms of insomnia recur following tapering down of the hypnotic (note that 1-2 days' worsening post discontinuation may represent rebound and will resolve) and the insomnia has not responded to behavioral treatments such as CBT-I, reinstitution of the previous hypnotic that was well tolerated should be considered. Intermittent dosing strategies for the long-term pharmacologic treatment of insomnia can be considered.[215]

Use of this content is subject to our disclaimer