Kimberly A. Hardin, MD, MS, FAASM

Nonpharmacologic Interventions

Before using sedative/hypnotic agents, address sleep hygiene and other factors that disrupt sleep during a hospitalization such as those listed in Table 3.

Pharmacologic (Sedative/Hypnotic) Interventions

Pharmacologic therapy may be necessary to treat disordered sleep. The ideal sleep aid would reduce sleep latency or time to fall asleep, increase total sleep time (TST), not cause next‐day sedation, improve daytime functioning, and minimize the development of tolerance. Unfortunately, no single agent meets all these independent criteria. In the past 10 years, newer benzodiazepines (BzRAs) with shorter half‐lives have been shown to be efficacious in reducing sleep latency, but the problem of sleep maintenance without next‐day sedation persists.1 To choose an appropriate sleep agent, evaluate the drug's efficacy, mechanism of action, and side‐effect profile. Then, match these characteristics with the patient's clinical condition(s). In patients with comorbid sleep and psychiatric problems, consider using a sedating psychotropic at bedtime to promote sleep.

Non‐Food and Drug AdministrationApproved (Off‐Label) Sleep Aids: Psychotropic Medications

Limited data exist on the efficacy of non‐Food and Drug Administration (FDA)approved medications for insomnia,2 such as antidepressants and atypical antipsychotics (AAPs), and antihistamines; examples of which are listed in Table 4. The administration of antihistamines, barbiturates, chloral hydrate, and alternative/herbal therapies has been discouraged, because the benefits rarely outweigh the risks associated with their use. Currently, trazodone is the most commonly prescribed antidepressant for the treatment of insomnia, despite the relative lack of data regarding its use for insomnia.3 Prescription data suggest that trazodoneat hypnotic doses, which are lower than the full antidepressant doseis more commonly prescribed for insomnia rather than for its FDA‐approved use for depression.4 In general, sleep specialists refrain from recommending sedating antidepressants for primary insomnia due to insufficient data regarding efficacy and safety. In addition, trazodone has been associated with arrhythmias in patients with preexisting cardiac conduction system disease. Curry et al.3 speculated that trazodone is popular among prescribers because, unlike most BzRAs, trazodone does not have a recommended limited duration of use and is perceived as being safer than BzRAs. Walsh et al.5 conducted a randomized double‐blind, placebo‐controlled trial (n = 589) that compared the hypnotic efficacy and other sleep‐associated variables of trazodone (50 mg) and zolpidem (10 mg). During the first week of treatment, the subjects on trazodone or zolpidem decreased their time to fall asleep, or sleep latency, by 22% and 35%, respectively, compared to placebo. Sleep latency was significantly shorter on zolpidem (57.75 2.7 minutes) than for trazodone (57.7 + 4.0 minutes). By the second week, subjects on zolpidem continued to have a reduction in the time to fall asleep, but there was no significant difference between subjects on trazodone and placebo.5 Trazodone may be an acceptable short‐term alternative to BzRAs for patients with hypercapnia or hypoxemia, and in those with a history of drug abuse or dependence. At doses of 150 to 450 mg, trazodone may be an appropriate medication in patients with major depressive disorder and problems with sleep maintenance.6 Tolerance to trazodone's sedating property tends to develop after 2 weeks of treatment, however, so other treatments may need to be considered if sleep problems persist. The available data address relatively short‐term use of trazodone, so questions of safety and efficacy for chronic insomnia remain unanswered.

Mirtazapine (Remeron), which promotes both sleep and appetite, may be particularly helpful for patients with cancer, acquired immunodeficiency syndrome (AIDS), and other conditions in which the triad of poor sleep, anorexia, and depression are common. Mirtazapine is a noradrenergic and specific serotonergic agent that causes inverse, dose‐dependent sedation (doses 15 mg are less sedating).7 To target sleeplessness, start with a dose between 7.5 and 15 mg. If ineffective at this dose, it is unlikely that increasing the dose will be of benefit for sleep. A small randomized, double‐blind, placebo‐controlled trial found that low‐dose mirtazapine reduced the apnea‐hypopnea index (API) by half in newly‐diagnosed subjects with OSA (n = 12).8 The results were promising in terms of the use of mixed‐profile serotonergic drugs in treating OSA. However, as pointed out by the researchers, mirtazapine's tendency to cause weight gain, is problematic in this patient population.

Although sedating, tricyclic antidepressants (TCAs) should not be used to promote sleep in hospitalized patients. TCAs increase the risk of cardiac conduction abnormalities, decrease seizure threshold, and have significant anticholinergic and anti‐alpha‐adrenergic effects. In dementia patients, the anticholinergic effect of TCAs may precipitate delirium.

AAPs should not be used routinely as first‐line agents for insomnia, except in patients who are in the midst of acute manic or psychotic episodes.9 With chronic use of AAPs, the risks of hyperglycemia, hyperlipidemia, and weight gain outweigh the potential sleep benefits of these agents. AAPs, especially risperidone, may cause extrapyramidal syndrome (EPS). Risperidone, ziprasidone and quetiapine have been associated with prolonged QTc interval, but the relatively low doses of AAPs that are used purely for sedative purposes makes this risk relatively low. If a patient has a history of Parkinsonism or other EPS, risperidone should generally be avoided. If a patient treated with risperidone develops EPS, another AAP should be considered. A reasonable precaution is to obtain a pretreatment 12‐lead electrocardiogram. If the QTc is greater than 450 msec, consider using olanzapine rather than ziprasidone, risperidone, or quetiapine. Sedating AAPs include risperidone (Risperdal), olanzapine (Zyprexa), and quetiapine (Seroquel), with the latter 2 being especially sedating. Quetiapine may also cause orthostatic hypotension. The recent practice of using AAPs for delirium has not been reported to be associated with significant safety risks, probably because delirium treatment is typically of short duration under a period of close clinical observation. These agents should not be used indefinitely for insomnia without close monitoring of metabolic, psychiatric, and neurologic status. However, recent data suggest that the risk of serious adverse effects of AAPs may outweigh the potential benefits for the treatment of aggression or agitation in patients with Alzheimer's disease.10

A meta‐analysis of randomized placebo‐controlled trials of AAP use among dementia patients showed that overall, the use of AAP drugs for periods of less than 8 to 12 weeks was associated with a small increased risk for death compared with placebo.11 Data indicated that most patients' behaviors improved substantially during the first 1 to 4 weeks of treatment. In a double‐blind, placebo‐controlled trial, 421 patients with Alzheimer's disease and psychosis, aggression or agitation were randomly assigned to receive olanzapine (mean dose, 5.5 mg per day), quetiapine (mean dose, 56.5 mg per day), risperidone (mean dose, 1.0 mg per day), or placebo. Improvement was observed in 32% of patients assigned to olanzapine, 26% of patients assigned to quetiapine, 29% of patients assigned to risperidone, and 21% of patients assigned to placebo. A lower, but significant, proportion of the patients (24%, 16%, 18%, and 5%, respectively) discontinued these medications due to intolerable side effects. Thus, if minimal improvement is observed even after 8 weeks of treatment, prescribers should consider discontinuing the AAP. The management of agitation in dementia, particularly in the elderly, calls for an integrative and creative psychopharmacological approach, including the use of antidepressants, nonbenzodiazepine anxiolytics such as buspirone, and mood stabilizers such as divalproex sodium (Depakote) before exposing patients to the risks of AAPs.

Antihistamines are the most commonly used over‐the‐counter agents for chronic insomnia.1 Diphenhydramine (Benadryl) has been shown to be better than placebo to treat insomnia,12 but data is lacking to definitively endorse its use to promote sleep.13 Diphenhydramine is also limited by the development of tolerance within a few days of daily use. The anticholinergic action of antihistamines may lead to orthostatic hypotension, urinary retention, and may induce delirium in vulnerable patients. Therefore, diphenhydramine should be avoided in hospitalized patients.

Recent data suggest that hydroxyzine, an antihistamine, may be an appropriate sleep aid for patients with hepatic encephalopathy in whom BzRAs are contraindicated.14 Subjective improvement in sleep was observed in 40% of hydroxyzine‐treated patients with hepatic encephalopathy compared to placebo.

Chloral hydrate is one of the Western world's oldest known sedative‐hypnotics and was commonly used as a sleep aid through the 1970s.15 Chloral hydrate was eventually supplanted by BzRAs,16 and fell out of favor as a sleep aid due to its relatively high tolerance rate, drug‐drug interaction profile, and the high risk of death in an overdose. Doses of 500 to 1000 mg sufficed to promote sleep in most of the hospitalized subjects. More recent data regarding its use for treating insomnia are not available, but chloral hydrate may be an alternative short‐term treatment for insomnia in selected hospitalized patients. Because of its high‐risk profile, chloral hydrate would be used as a last‐resort medication, preferably with input from critical care and/or sleep medicine specialists.

FDA‐Approved Sleep Aids

As shown in Table 5, the FDA has approved 3 classes of medications for the treatment of insomnia: benzodiazepine gamma‐aminobutyric acid (GABA)_A receptor agonists (BzRAs), nonbenzodiazepine GABA_A receptor agonists (non‐BzRAs), and melatonin‐receptor agonists.17 BzRAs include estazolam (ProSom), flurazepam (Dalmane), quazepam (Doral), temazepam (Restoril), and triazolam (Halcion). Though BzRAs decrease sleep latency, increase TST, and decrease slow wave or deep sleep, they also have adverse side effects such as daytime sedation, anterograde amnesia, cognitive impairment, motor incoordination, dependence, tolerance, and rebound insomnia.18 Because of these side effects, BzRAs should be limited to generally healthy, young (ie, <45 years old) patients who are expected to have brief hospital stays.

Efficacy and safety studies have generally been limited to healthy, younger individuals without a history of primary sleep disorder. Potential adverse effects of BzRAs may become even more pronounced in hospitalized medical patients due to older age, acute illness, cointeraction drugs, and multidrug regimens. Although BzRAs are FDA‐approved for the treatment of insomnia, flurazepam and quazepam should generally be avoided in hospitalized patients. These agents' long half‐lives increase the risk of drug‐drug interactions and adverse events such as respiratory depression, cognitive decline, and delirium in acutely ill patients. For similar reasons, other long‐acting BzRAs such as clonazepam (Klonopin) and diazepam (Valium) should also not be used to treat insomnia in hospitalized patients. An exception to this is a patient with RLS, in which clonazepam is an approved treatment. However, now that ropinirole HCl (Requip) is FDA‐approved for RLS, BzARs may be able to be avoided. Lorazepam (Ativan), due to its relatively short half‐life and its anxiolytic property, is frequently used to treat insomnia in hospitalized medical patients.18 Start with the lowest dose possible (eg, 0.5 mg) as a one‐time‐only order, or on a as needed basis for 3 days. Alprazolam (Xanax), a potent, fast‐acting BzRA with a relatively short half‐life, has developed a reputation as being notoriously addictive, and experts feel alprazolam has similar potential for withdrawal and rebound.19, 20

The use of BzRAs should be minimized in all patients, and avoided in the elderly or those with a particularly high risk for delirium (eg, traumatic brain injury, stroke, multiple new medications). All BzRAs should be avoided in patients with a prior history of sedative‐hypnotic and/or alcohol dependence unless medically indicated, such as in alcohol withdrawal. Refrain from ordering nightly scheduled BzRAs without a specific time limit to ensure that sedative‐hypnotic use is closely monitored.

For the past 2 decades, physicians have been advised against using long‐acting BzRAs in the elderly (>65 years old) due to the increased risks of hip fractures, falls, motor vehicle accidents, daytime sedation, and adverse cognitive events such as delirium.2124 A large 5‐year prospective study in Quebec found that the risk of injury varied by the BzRA, and was independent of half‐life.25 Importantly, the risk of injury was dose‐dependent: the higher the dose of oxazepam, flurazepam, or chlordiazepoxide, the higher the risk of injury in the elderly.

Non‐BzRAs seem to have a superior side‐effect profile when compared to BzRAs, but should also be used with caution in the elderly. Non‐BzRAs include eszopiclone (Lunesta), zaleplon (Sonata), zolpidem (Ambien), and zolpidem extended‐release. The number of comparison studies is limited, but the available data reveal that: (1) zolpidem (Ambien) may be better than temazepam (Restoril) in terms of sleep latency and quality; and (2) zaleplon (Sonata) may lead to a shorter sleep latency than zolpidem (Ambien), but the latter is associated with longer sleep duration.26 Non‐BzRAs have less next‐day sedation, psychomotor dysfunction, tolerance/withdrawal, and rapid‐eye‐movement (REM) sleep rebound; and lower abuse potential than BzRAs.27

The most commonly prescribed hypnotic, zolpidem has a short half‐life, and seems to reduce sleep latency with minimal residual side effects when compared to BzRAs. The results of a recent multicenter, randomized, double‐blind, placebo‐controlled trial indicated that zolpidem extended‐release may be efficacious for up to 6 months in outpatients with chronic insomnia.28

The sole melatonin‐receptor agonist, ramelteon (Rozerem), also reduces time to fall asleep without next‐day psychomotor and memory effects.29 Ramelteon is believed to target receptors melatonin 1 and 2 receptors located in the brain's suprachiasmatic nucleus to stabilize circadian rhythms and stabilize the sleep‐wake cycle.30

Nonpharmacologic Interventions

Before using sedative/hypnotic agents, address sleep hygiene and other factors that disrupt sleep during a hospitalization such as those listed in Table 3.

Pharmacologic (Sedative/Hypnotic) Interventions

Pharmacologic therapy may be necessary to treat disordered sleep. The ideal sleep aid would reduce sleep latency or time to fall asleep, increase total sleep time (TST), not cause next‐day sedation, improve daytime functioning, and minimize the development of tolerance. Unfortunately, no single agent meets all these independent criteria. In the past 10 years, newer benzodiazepines (BzRAs) with shorter half‐lives have been shown to be efficacious in reducing sleep latency, but the problem of sleep maintenance without next‐day sedation persists.1 To choose an appropriate sleep agent, evaluate the drug's efficacy, mechanism of action, and side‐effect profile. Then, match these characteristics with the patient's clinical condition(s). In patients with comorbid sleep and psychiatric problems, consider using a sedating psychotropic at bedtime to promote sleep.

Non‐Food and Drug AdministrationApproved (Off‐Label) Sleep Aids: Psychotropic Medications

Limited data exist on the efficacy of non‐Food and Drug Administration (FDA)approved medications for insomnia,2 such as antidepressants and atypical antipsychotics (AAPs), and antihistamines; examples of which are listed in Table 4. The administration of antihistamines, barbiturates, chloral hydrate, and alternative/herbal therapies has been discouraged, because the benefits rarely outweigh the risks associated with their use. Currently, trazodone is the most commonly prescribed antidepressant for the treatment of insomnia, despite the relative lack of data regarding its use for insomnia.3 Prescription data suggest that trazodoneat hypnotic doses, which are lower than the full antidepressant doseis more commonly prescribed for insomnia rather than for its FDA‐approved use for depression.4 In general, sleep specialists refrain from recommending sedating antidepressants for primary insomnia due to insufficient data regarding efficacy and safety. In addition, trazodone has been associated with arrhythmias in patients with preexisting cardiac conduction system disease. Curry et al.3 speculated that trazodone is popular among prescribers because, unlike most BzRAs, trazodone does not have a recommended limited duration of use and is perceived as being safer than BzRAs. Walsh et al.5 conducted a randomized double‐blind, placebo‐controlled trial (n = 589) that compared the hypnotic efficacy and other sleep‐associated variables of trazodone (50 mg) and zolpidem (10 mg). During the first week of treatment, the subjects on trazodone or zolpidem decreased their time to fall asleep, or sleep latency, by 22% and 35%, respectively, compared to placebo. Sleep latency was significantly shorter on zolpidem (57.75 2.7 minutes) than for trazodone (57.7 + 4.0 minutes). By the second week, subjects on zolpidem continued to have a reduction in the time to fall asleep, but there was no significant difference between subjects on trazodone and placebo.5 Trazodone may be an acceptable short‐term alternative to BzRAs for patients with hypercapnia or hypoxemia, and in those with a history of drug abuse or dependence. At doses of 150 to 450 mg, trazodone may be an appropriate medication in patients with major depressive disorder and problems with sleep maintenance.6 Tolerance to trazodone's sedating property tends to develop after 2 weeks of treatment, however, so other treatments may need to be considered if sleep problems persist. The available data address relatively short‐term use of trazodone, so questions of safety and efficacy for chronic insomnia remain unanswered.

Mirtazapine (Remeron), which promotes both sleep and appetite, may be particularly helpful for patients with cancer, acquired immunodeficiency syndrome (AIDS), and other conditions in which the triad of poor sleep, anorexia, and depression are common. Mirtazapine is a noradrenergic and specific serotonergic agent that causes inverse, dose‐dependent sedation (doses 15 mg are less sedating).7 To target sleeplessness, start with a dose between 7.5 and 15 mg. If ineffective at this dose, it is unlikely that increasing the dose will be of benefit for sleep. A small randomized, double‐blind, placebo‐controlled trial found that low‐dose mirtazapine reduced the apnea‐hypopnea index (API) by half in newly‐diagnosed subjects with OSA (n = 12).8 The results were promising in terms of the use of mixed‐profile serotonergic drugs in treating OSA. However, as pointed out by the researchers, mirtazapine's tendency to cause weight gain, is problematic in this patient population.

Although sedating, tricyclic antidepressants (TCAs) should not be used to promote sleep in hospitalized patients. TCAs increase the risk of cardiac conduction abnormalities, decrease seizure threshold, and have significant anticholinergic and anti‐alpha‐adrenergic effects. In dementia patients, the anticholinergic effect of TCAs may precipitate delirium.

AAPs should not be used routinely as first‐line agents for insomnia, except in patients who are in the midst of acute manic or psychotic episodes.9 With chronic use of AAPs, the risks of hyperglycemia, hyperlipidemia, and weight gain outweigh the potential sleep benefits of these agents. AAPs, especially risperidone, may cause extrapyramidal syndrome (EPS). Risperidone, ziprasidone and quetiapine have been associated with prolonged QTc interval, but the relatively low doses of AAPs that are used purely for sedative purposes makes this risk relatively low. If a patient has a history of Parkinsonism or other EPS, risperidone should generally be avoided. If a patient treated with risperidone develops EPS, another AAP should be considered. A reasonable precaution is to obtain a pretreatment 12‐lead electrocardiogram. If the QTc is greater than 450 msec, consider using olanzapine rather than ziprasidone, risperidone, or quetiapine. Sedating AAPs include risperidone (Risperdal), olanzapine (Zyprexa), and quetiapine (Seroquel), with the latter 2 being especially sedating. Quetiapine may also cause orthostatic hypotension. The recent practice of using AAPs for delirium has not been reported to be associated with significant safety risks, probably because delirium treatment is typically of short duration under a period of close clinical observation. These agents should not be used indefinitely for insomnia without close monitoring of metabolic, psychiatric, and neurologic status. However, recent data suggest that the risk of serious adverse effects of AAPs may outweigh the potential benefits for the treatment of aggression or agitation in patients with Alzheimer's disease.10

A meta‐analysis of randomized placebo‐controlled trials of AAP use among dementia patients showed that overall, the use of AAP drugs for periods of less than 8 to 12 weeks was associated with a small increased risk for death compared with placebo.11 Data indicated that most patients' behaviors improved substantially during the first 1 to 4 weeks of treatment. In a double‐blind, placebo‐controlled trial, 421 patients with Alzheimer's disease and psychosis, aggression or agitation were randomly assigned to receive olanzapine (mean dose, 5.5 mg per day), quetiapine (mean dose, 56.5 mg per day), risperidone (mean dose, 1.0 mg per day), or placebo. Improvement was observed in 32% of patients assigned to olanzapine, 26% of patients assigned to quetiapine, 29% of patients assigned to risperidone, and 21% of patients assigned to placebo. A lower, but significant, proportion of the patients (24%, 16%, 18%, and 5%, respectively) discontinued these medications due to intolerable side effects. Thus, if minimal improvement is observed even after 8 weeks of treatment, prescribers should consider discontinuing the AAP. The management of agitation in dementia, particularly in the elderly, calls for an integrative and creative psychopharmacological approach, including the use of antidepressants, nonbenzodiazepine anxiolytics such as buspirone, and mood stabilizers such as divalproex sodium (Depakote) before exposing patients to the risks of AAPs.

Antihistamines are the most commonly used over‐the‐counter agents for chronic insomnia.1 Diphenhydramine (Benadryl) has been shown to be better than placebo to treat insomnia,12 but data is lacking to definitively endorse its use to promote sleep.13 Diphenhydramine is also limited by the development of tolerance within a few days of daily use. The anticholinergic action of antihistamines may lead to orthostatic hypotension, urinary retention, and may induce delirium in vulnerable patients. Therefore, diphenhydramine should be avoided in hospitalized patients.

Recent data suggest that hydroxyzine, an antihistamine, may be an appropriate sleep aid for patients with hepatic encephalopathy in whom BzRAs are contraindicated.14 Subjective improvement in sleep was observed in 40% of hydroxyzine‐treated patients with hepatic encephalopathy compared to placebo.

Chloral hydrate is one of the Western world's oldest known sedative‐hypnotics and was commonly used as a sleep aid through the 1970s.15 Chloral hydrate was eventually supplanted by BzRAs,16 and fell out of favor as a sleep aid due to its relatively high tolerance rate, drug‐drug interaction profile, and the high risk of death in an overdose. Doses of 500 to 1000 mg sufficed to promote sleep in most of the hospitalized subjects. More recent data regarding its use for treating insomnia are not available, but chloral hydrate may be an alternative short‐term treatment for insomnia in selected hospitalized patients. Because of its high‐risk profile, chloral hydrate would be used as a last‐resort medication, preferably with input from critical care and/or sleep medicine specialists.

FDA‐Approved Sleep Aids

As shown in Table 5, the FDA has approved 3 classes of medications for the treatment of insomnia: benzodiazepine gamma‐aminobutyric acid (GABA)_A receptor agonists (BzRAs), nonbenzodiazepine GABA_A receptor agonists (non‐BzRAs), and melatonin‐receptor agonists.17 BzRAs include estazolam (ProSom), flurazepam (Dalmane), quazepam (Doral), temazepam (Restoril), and triazolam (Halcion). Though BzRAs decrease sleep latency, increase TST, and decrease slow wave or deep sleep, they also have adverse side effects such as daytime sedation, anterograde amnesia, cognitive impairment, motor incoordination, dependence, tolerance, and rebound insomnia.18 Because of these side effects, BzRAs should be limited to generally healthy, young (ie, <45 years old) patients who are expected to have brief hospital stays.

Efficacy and safety studies have generally been limited to healthy, younger individuals without a history of primary sleep disorder. Potential adverse effects of BzRAs may become even more pronounced in hospitalized medical patients due to older age, acute illness, cointeraction drugs, and multidrug regimens. Although BzRAs are FDA‐approved for the treatment of insomnia, flurazepam and quazepam should generally be avoided in hospitalized patients. These agents' long half‐lives increase the risk of drug‐drug interactions and adverse events such as respiratory depression, cognitive decline, and delirium in acutely ill patients. For similar reasons, other long‐acting BzRAs such as clonazepam (Klonopin) and diazepam (Valium) should also not be used to treat insomnia in hospitalized patients. An exception to this is a patient with RLS, in which clonazepam is an approved treatment. However, now that ropinirole HCl (Requip) is FDA‐approved for RLS, BzARs may be able to be avoided. Lorazepam (Ativan), due to its relatively short half‐life and its anxiolytic property, is frequently used to treat insomnia in hospitalized medical patients.18 Start with the lowest dose possible (eg, 0.5 mg) as a one‐time‐only order, or on a as needed basis for 3 days. Alprazolam (Xanax), a potent, fast‐acting BzRA with a relatively short half‐life, has developed a reputation as being notoriously addictive, and experts feel alprazolam has similar potential for withdrawal and rebound.19, 20

The use of BzRAs should be minimized in all patients, and avoided in the elderly or those with a particularly high risk for delirium (eg, traumatic brain injury, stroke, multiple new medications). All BzRAs should be avoided in patients with a prior history of sedative‐hypnotic and/or alcohol dependence unless medically indicated, such as in alcohol withdrawal. Refrain from ordering nightly scheduled BzRAs without a specific time limit to ensure that sedative‐hypnotic use is closely monitored.

For the past 2 decades, physicians have been advised against using long‐acting BzRAs in the elderly (>65 years old) due to the increased risks of hip fractures, falls, motor vehicle accidents, daytime sedation, and adverse cognitive events such as delirium.2124 A large 5‐year prospective study in Quebec found that the risk of injury varied by the BzRA, and was independent of half‐life.25 Importantly, the risk of injury was dose‐dependent: the higher the dose of oxazepam, flurazepam, or chlordiazepoxide, the higher the risk of injury in the elderly.

Non‐BzRAs seem to have a superior side‐effect profile when compared to BzRAs, but should also be used with caution in the elderly. Non‐BzRAs include eszopiclone (Lunesta), zaleplon (Sonata), zolpidem (Ambien), and zolpidem extended‐release. The number of comparison studies is limited, but the available data reveal that: (1) zolpidem (Ambien) may be better than temazepam (Restoril) in terms of sleep latency and quality; and (2) zaleplon (Sonata) may lead to a shorter sleep latency than zolpidem (Ambien), but the latter is associated with longer sleep duration.26 Non‐BzRAs have less next‐day sedation, psychomotor dysfunction, tolerance/withdrawal, and rapid‐eye‐movement (REM) sleep rebound; and lower abuse potential than BzRAs.27

The most commonly prescribed hypnotic, zolpidem has a short half‐life, and seems to reduce sleep latency with minimal residual side effects when compared to BzRAs. The results of a recent multicenter, randomized, double‐blind, placebo‐controlled trial indicated that zolpidem extended‐release may be efficacious for up to 6 months in outpatients with chronic insomnia.28

The sole melatonin‐receptor agonist, ramelteon (Rozerem), also reduces time to fall asleep without next‐day psychomotor and memory effects.29 Ramelteon is believed to target receptors melatonin 1 and 2 receptors located in the brain's suprachiasmatic nucleus to stabilize circadian rhythms and stabilize the sleep‐wake cycle.30

Nonpharmacologic Interventions

Before using sedative/hypnotic agents, address sleep hygiene and other factors that disrupt sleep during a hospitalization such as those listed in Table 3.

Pharmacologic (Sedative/Hypnotic) Interventions

Pharmacologic therapy may be necessary to treat disordered sleep. The ideal sleep aid would reduce sleep latency or time to fall asleep, increase total sleep time (TST), not cause next‐day sedation, improve daytime functioning, and minimize the development of tolerance. Unfortunately, no single agent meets all these independent criteria. In the past 10 years, newer benzodiazepines (BzRAs) with shorter half‐lives have been shown to be efficacious in reducing sleep latency, but the problem of sleep maintenance without next‐day sedation persists.1 To choose an appropriate sleep agent, evaluate the drug's efficacy, mechanism of action, and side‐effect profile. Then, match these characteristics with the patient's clinical condition(s). In patients with comorbid sleep and psychiatric problems, consider using a sedating psychotropic at bedtime to promote sleep.

Non‐Food and Drug AdministrationApproved (Off‐Label) Sleep Aids: Psychotropic Medications

Limited data exist on the efficacy of non‐Food and Drug Administration (FDA)approved medications for insomnia,2 such as antidepressants and atypical antipsychotics (AAPs), and antihistamines; examples of which are listed in Table 4. The administration of antihistamines, barbiturates, chloral hydrate, and alternative/herbal therapies has been discouraged, because the benefits rarely outweigh the risks associated with their use. Currently, trazodone is the most commonly prescribed antidepressant for the treatment of insomnia, despite the relative lack of data regarding its use for insomnia.3 Prescription data suggest that trazodoneat hypnotic doses, which are lower than the full antidepressant doseis more commonly prescribed for insomnia rather than for its FDA‐approved use for depression.4 In general, sleep specialists refrain from recommending sedating antidepressants for primary insomnia due to insufficient data regarding efficacy and safety. In addition, trazodone has been associated with arrhythmias in patients with preexisting cardiac conduction system disease. Curry et al.3 speculated that trazodone is popular among prescribers because, unlike most BzRAs, trazodone does not have a recommended limited duration of use and is perceived as being safer than BzRAs. Walsh et al.5 conducted a randomized double‐blind, placebo‐controlled trial (n = 589) that compared the hypnotic efficacy and other sleep‐associated variables of trazodone (50 mg) and zolpidem (10 mg). During the first week of treatment, the subjects on trazodone or zolpidem decreased their time to fall asleep, or sleep latency, by 22% and 35%, respectively, compared to placebo. Sleep latency was significantly shorter on zolpidem (57.75 2.7 minutes) than for trazodone (57.7 + 4.0 minutes). By the second week, subjects on zolpidem continued to have a reduction in the time to fall asleep, but there was no significant difference between subjects on trazodone and placebo.5 Trazodone may be an acceptable short‐term alternative to BzRAs for patients with hypercapnia or hypoxemia, and in those with a history of drug abuse or dependence. At doses of 150 to 450 mg, trazodone may be an appropriate medication in patients with major depressive disorder and problems with sleep maintenance.6 Tolerance to trazodone's sedating property tends to develop after 2 weeks of treatment, however, so other treatments may need to be considered if sleep problems persist. The available data address relatively short‐term use of trazodone, so questions of safety and efficacy for chronic insomnia remain unanswered.

Mirtazapine (Remeron), which promotes both sleep and appetite, may be particularly helpful for patients with cancer, acquired immunodeficiency syndrome (AIDS), and other conditions in which the triad of poor sleep, anorexia, and depression are common. Mirtazapine is a noradrenergic and specific serotonergic agent that causes inverse, dose‐dependent sedation (doses 15 mg are less sedating).7 To target sleeplessness, start with a dose between 7.5 and 15 mg. If ineffective at this dose, it is unlikely that increasing the dose will be of benefit for sleep. A small randomized, double‐blind, placebo‐controlled trial found that low‐dose mirtazapine reduced the apnea‐hypopnea index (API) by half in newly‐diagnosed subjects with OSA (n = 12).8 The results were promising in terms of the use of mixed‐profile serotonergic drugs in treating OSA. However, as pointed out by the researchers, mirtazapine's tendency to cause weight gain, is problematic in this patient population.

Although sedating, tricyclic antidepressants (TCAs) should not be used to promote sleep in hospitalized patients. TCAs increase the risk of cardiac conduction abnormalities, decrease seizure threshold, and have significant anticholinergic and anti‐alpha‐adrenergic effects. In dementia patients, the anticholinergic effect of TCAs may precipitate delirium.

AAPs should not be used routinely as first‐line agents for insomnia, except in patients who are in the midst of acute manic or psychotic episodes.9 With chronic use of AAPs, the risks of hyperglycemia, hyperlipidemia, and weight gain outweigh the potential sleep benefits of these agents. AAPs, especially risperidone, may cause extrapyramidal syndrome (EPS). Risperidone, ziprasidone and quetiapine have been associated with prolonged QTc interval, but the relatively low doses of AAPs that are used purely for sedative purposes makes this risk relatively low. If a patient has a history of Parkinsonism or other EPS, risperidone should generally be avoided. If a patient treated with risperidone develops EPS, another AAP should be considered. A reasonable precaution is to obtain a pretreatment 12‐lead electrocardiogram. If the QTc is greater than 450 msec, consider using olanzapine rather than ziprasidone, risperidone, or quetiapine. Sedating AAPs include risperidone (Risperdal), olanzapine (Zyprexa), and quetiapine (Seroquel), with the latter 2 being especially sedating. Quetiapine may also cause orthostatic hypotension. The recent practice of using AAPs for delirium has not been reported to be associated with significant safety risks, probably because delirium treatment is typically of short duration under a period of close clinical observation. These agents should not be used indefinitely for insomnia without close monitoring of metabolic, psychiatric, and neurologic status. However, recent data suggest that the risk of serious adverse effects of AAPs may outweigh the potential benefits for the treatment of aggression or agitation in patients with Alzheimer's disease.10

A meta‐analysis of randomized placebo‐controlled trials of AAP use among dementia patients showed that overall, the use of AAP drugs for periods of less than 8 to 12 weeks was associated with a small increased risk for death compared with placebo.11 Data indicated that most patients' behaviors improved substantially during the first 1 to 4 weeks of treatment. In a double‐blind, placebo‐controlled trial, 421 patients with Alzheimer's disease and psychosis, aggression or agitation were randomly assigned to receive olanzapine (mean dose, 5.5 mg per day), quetiapine (mean dose, 56.5 mg per day), risperidone (mean dose, 1.0 mg per day), or placebo. Improvement was observed in 32% of patients assigned to olanzapine, 26% of patients assigned to quetiapine, 29% of patients assigned to risperidone, and 21% of patients assigned to placebo. A lower, but significant, proportion of the patients (24%, 16%, 18%, and 5%, respectively) discontinued these medications due to intolerable side effects. Thus, if minimal improvement is observed even after 8 weeks of treatment, prescribers should consider discontinuing the AAP. The management of agitation in dementia, particularly in the elderly, calls for an integrative and creative psychopharmacological approach, including the use of antidepressants, nonbenzodiazepine anxiolytics such as buspirone, and mood stabilizers such as divalproex sodium (Depakote) before exposing patients to the risks of AAPs.

Antihistamines are the most commonly used over‐the‐counter agents for chronic insomnia.1 Diphenhydramine (Benadryl) has been shown to be better than placebo to treat insomnia,12 but data is lacking to definitively endorse its use to promote sleep.13 Diphenhydramine is also limited by the development of tolerance within a few days of daily use. The anticholinergic action of antihistamines may lead to orthostatic hypotension, urinary retention, and may induce delirium in vulnerable patients. Therefore, diphenhydramine should be avoided in hospitalized patients.

Recent data suggest that hydroxyzine, an antihistamine, may be an appropriate sleep aid for patients with hepatic encephalopathy in whom BzRAs are contraindicated.14 Subjective improvement in sleep was observed in 40% of hydroxyzine‐treated patients with hepatic encephalopathy compared to placebo.

Chloral hydrate is one of the Western world's oldest known sedative‐hypnotics and was commonly used as a sleep aid through the 1970s.15 Chloral hydrate was eventually supplanted by BzRAs,16 and fell out of favor as a sleep aid due to its relatively high tolerance rate, drug‐drug interaction profile, and the high risk of death in an overdose. Doses of 500 to 1000 mg sufficed to promote sleep in most of the hospitalized subjects. More recent data regarding its use for treating insomnia are not available, but chloral hydrate may be an alternative short‐term treatment for insomnia in selected hospitalized patients. Because of its high‐risk profile, chloral hydrate would be used as a last‐resort medication, preferably with input from critical care and/or sleep medicine specialists.

FDA‐Approved Sleep Aids

As shown in Table 5, the FDA has approved 3 classes of medications for the treatment of insomnia: benzodiazepine gamma‐aminobutyric acid (GABA)_A receptor agonists (BzRAs), nonbenzodiazepine GABA_A receptor agonists (non‐BzRAs), and melatonin‐receptor agonists.17 BzRAs include estazolam (ProSom), flurazepam (Dalmane), quazepam (Doral), temazepam (Restoril), and triazolam (Halcion). Though BzRAs decrease sleep latency, increase TST, and decrease slow wave or deep sleep, they also have adverse side effects such as daytime sedation, anterograde amnesia, cognitive impairment, motor incoordination, dependence, tolerance, and rebound insomnia.18 Because of these side effects, BzRAs should be limited to generally healthy, young (ie, <45 years old) patients who are expected to have brief hospital stays.

Efficacy and safety studies have generally been limited to healthy, younger individuals without a history of primary sleep disorder. Potential adverse effects of BzRAs may become even more pronounced in hospitalized medical patients due to older age, acute illness, cointeraction drugs, and multidrug regimens. Although BzRAs are FDA‐approved for the treatment of insomnia, flurazepam and quazepam should generally be avoided in hospitalized patients. These agents' long half‐lives increase the risk of drug‐drug interactions and adverse events such as respiratory depression, cognitive decline, and delirium in acutely ill patients. For similar reasons, other long‐acting BzRAs such as clonazepam (Klonopin) and diazepam (Valium) should also not be used to treat insomnia in hospitalized patients. An exception to this is a patient with RLS, in which clonazepam is an approved treatment. However, now that ropinirole HCl (Requip) is FDA‐approved for RLS, BzARs may be able to be avoided. Lorazepam (Ativan), due to its relatively short half‐life and its anxiolytic property, is frequently used to treat insomnia in hospitalized medical patients.18 Start with the lowest dose possible (eg, 0.5 mg) as a one‐time‐only order, or on a as needed basis for 3 days. Alprazolam (Xanax), a potent, fast‐acting BzRA with a relatively short half‐life, has developed a reputation as being notoriously addictive, and experts feel alprazolam has similar potential for withdrawal and rebound.19, 20

The use of BzRAs should be minimized in all patients, and avoided in the elderly or those with a particularly high risk for delirium (eg, traumatic brain injury, stroke, multiple new medications). All BzRAs should be avoided in patients with a prior history of sedative‐hypnotic and/or alcohol dependence unless medically indicated, such as in alcohol withdrawal. Refrain from ordering nightly scheduled BzRAs without a specific time limit to ensure that sedative‐hypnotic use is closely monitored.

For the past 2 decades, physicians have been advised against using long‐acting BzRAs in the elderly (>65 years old) due to the increased risks of hip fractures, falls, motor vehicle accidents, daytime sedation, and adverse cognitive events such as delirium.2124 A large 5‐year prospective study in Quebec found that the risk of injury varied by the BzRA, and was independent of half‐life.25 Importantly, the risk of injury was dose‐dependent: the higher the dose of oxazepam, flurazepam, or chlordiazepoxide, the higher the risk of injury in the elderly.

Non‐BzRAs seem to have a superior side‐effect profile when compared to BzRAs, but should also be used with caution in the elderly. Non‐BzRAs include eszopiclone (Lunesta), zaleplon (Sonata), zolpidem (Ambien), and zolpidem extended‐release. The number of comparison studies is limited, but the available data reveal that: (1) zolpidem (Ambien) may be better than temazepam (Restoril) in terms of sleep latency and quality; and (2) zaleplon (Sonata) may lead to a shorter sleep latency than zolpidem (Ambien), but the latter is associated with longer sleep duration.26 Non‐BzRAs have less next‐day sedation, psychomotor dysfunction, tolerance/withdrawal, and rapid‐eye‐movement (REM) sleep rebound; and lower abuse potential than BzRAs.27

The most commonly prescribed hypnotic, zolpidem has a short half‐life, and seems to reduce sleep latency with minimal residual side effects when compared to BzRAs. The results of a recent multicenter, randomized, double‐blind, placebo‐controlled trial indicated that zolpidem extended‐release may be efficacious for up to 6 months in outpatients with chronic insomnia.28

The sole melatonin‐receptor agonist, ramelteon (Rozerem), also reduces time to fall asleep without next‐day psychomotor and memory effects.29 Ramelteon is believed to target receptors melatonin 1 and 2 receptors located in the brain's suprachiasmatic nucleus to stabilize circadian rhythms and stabilize the sleep‐wake cycle.30

General Medical Disorders

Primary sleep disorders, such as obstructive sleep apnea (OSA) and numerous other medical illnesses, can directly impair sleep physiology, leading to a cyclical interaction (Figure 2). Other conditions that disrupt sleep include congestive heart failure (CHF), diabetes mellitus, chronic obstructive pulmonary disease (COPD), gastroesophageal reflux, cardiovascular disease, thyroid disorders, renal disease, and severe liver disease.26 Table 2 lists selected medical and neurological conditions, their associated sleep‐related problems, and suggestions on how to ameliorate these problems.

Figure 2

Affecting approximately 24% of men and 9% of women in the United States, OSA is the most common primary sleep disorder,27, 28 and causes significant mental and physical morbidity. Risk factors for OSA include obesity, hypothyroidism‐induced muscle weakness, and structural abnormalities in the oropharynx region such as acromegaly, micrognathia, or retrognathia. OSA is characterized by episodes of complete or partial pharyngeal obstruction during sleep that cause snoring, apneic episodes, choking, dyspnea, and restlessness.28 These episodes are associated with intermittent nocturnal sympathetic activation leading to nocturnal awakenings and cortical arousals, all of which lead to daytime symptoms of fatigue, sleepiness, and cognitive impairment (Figure 2). In addition, chronic sympathetic activation causes numerous derangements in the vascular endothelium and platelet activation.29, 30 Sleep‐disordered breathing has been independently associated with cardiovascular diseases such as hypertension, CHF, ischemic heart disease, atrial fibrillation, and cerebrovascular disease.31, 32

OSA is also associated with sleep‐related gastroesophageal reflux, which is characterized by pain and nocturnal cough, and can induce nocturnal asthma attacks and laryngospasm.33 Green et al.29 found that OSA patients treated with continuous positive airway pressure (CPAP) had a 48% improvement in nocturnal reflux symptoms. Although the pathophysiology connecting OSA to the renal system is unknown, OSA has been found in up to 60% of patients with end‐stage renal disease and chronic renal failure.34

Patients with pulmonary disorders can be profoundly affected by the normal physiologic changes during sleep, particularly in REM sleep. During REM sleep, all respiratory muscles except the diaphragm become paralyzed. Thus, episodes of marked oxygen desaturation can occur in patients who rely on their accessory muscles for respiration. COPD patients have decreased TST, SWS, and REM sleep. Shortness of breath, nocturnal cough, and wheezing worsen sleep.35 The resulting fatigue and sleep deprivation negatively impact the work of breathing and impair gas exchange. Airflow obstruction tends to worsen in the early morning hours in patients with COPD and asthma, and may be related to the effect of REM on the accessory muscles for respiration. Although used to target CO₂ retention, investigations using bilevel positive airway pressure ventilators (BiPAP) for improving sleep in COPD patients have been limited. Noninvasive positive pressure ventilation (NPPV) appears to acutely improve SE and TST in patients with hypercapnic COPD without significantly improving gas exchange. Other sleep parameters such as sleep architecture and the number of arousals during the night, remain unchanged during NPPV.36

CPAP has several side effects that could worsen sleep, which may explain its poor adherence rate among ambulatory patients.37 Side effects include nasal bridge discomfort, nasal congestion, swallowing air, dry nose, dry or red eyes, noise, ear pain, and rhinitis.38 During hospitalization, efforts should be made to improve patient comfort by resizing ill‐fitting masks, adding heated humidification or nasal steroids to alleviate nasal congestion, or adding a chin strap to reduce air leak and ingestion of air.

Endocrine disorders have also been associated with sleep disruption. Studies suggest that patients with diabetes mellitus have decreased TST and impaired sleep quality due to nocturia and neuropathic pain.39 Inadequate sleep may also affect glucose control. Inadequate quality or quantity of sleep has been shown to be a risk factor for developing Type 2 diabetes mellitus in large prospective studies.40 Sleep duration and quality were significant predictors of increased levels of glycosylated hemoglobin (HbA_1c) in patients with Type 2 diabetes mellitus. Thyroid diseases often coexist with diabetes mellitus. Both hypo‐ and hyperthyroidism have been associated with sleep disruption. Hypothyroidism is associated with daytime somnolence and fatigue. Patients with hypothyroidism tend to have reduced SWS. Hyperthyroid patients often complain of insomnia, which has been attributed to a hypermetabolic state.

Approximately 50% of patients with chronic end‐stage renal disease (ESRD) have insomnia and other sleep disorders.41 Patients often complain of restless leg syndrome (RLS), periodic limb movement disorder (PLMD), bone pain, nausea, and pruritus. The etiology of sleep disorders appears to be related to metabolic derangements associated with ESRD or from coexisting diabetes mellitus.

RLS and PLMD are distinct problems that affect sleep differently. RLS is characterized by an unpleasant crampy, creeping or crawling sensation in the lower extremities that is relieved by movement of the legs.42 RLS symptoms typically occur soon after going to bed, and therefore tend to disrupt sleep onset. The requisite bed rest during hospitalization can worsen RLS, further exacerbating sleep problems.43 Since RLS may partially be caused by disrupted iron metabolism, serum ferritin levels should be evaluated.44 Other conditions associated with RLS include pregnancy, rheumatoid arthritis, fibromyalgia, multiple sclerosis, ESRD, and Parkinson's disease. The differential diagnosis for RLS and PLMD includes neuroleptic‐induced akathisia, peripheral neuropathy, and positional or nocturnal leg cramps. PLMD occurs in about 80% of those with RLS, and is characterized by involuntary limb movements that occur every 20 to 40 seconds during NREM sleep. Unaware of these movements, patients often experience frequent arousals throughout the night, and complain of daytime somnolence and fatigue.42

A pilot study of 35 patients with minimal hepatic encephalopathy found that nearly 50% complained of sleep difficulties.45 Hypothesizing that a dysregulation of histaminergic neurotransmission in cirrhosis alters the sleep‐wake cycle, Spahr et al.46 found that 40% of their patients reported subjective improvement in sleep when administered 25 mg of hydroxyzine, compared to none who received placebo.

Neurologic Disorders

Since the brain and its various neurotransmitter systems are critical in regulating sleep and wakefulness, patients with neurologic disorders have an increased risk of developing sleep disorders. Patients with dementia, other neurodegenerative disorders, epilepsy, and traumatic brain injury (TBI) have a higher prevalence of sleep disturbance and sleep disorders.47 Poststroke patients can develop insomnia or hypersomnia, a reduction in sleep latency, increased sleep, or excessive daytime sleepiness, and are at higher risk for OSA during the first several months after a stroke.48 Specific neurologic lesions may lead to uncommon problems such as inversion of the sleep‐wake cycle, parasomnias, and hallucinatory dream‐like states.

Both Parkinson's disease and Alzheimer's disease are associated with multiple sleep disturbances, which tend to worsen with disease progression.14 Common problems include increased sleep fragmentation and wakefulness, with increases of stage 1 sleep and reductions of SWS and REM. Patients with neurodegenerative disorders also have an increased risk of REM sleep behavior disorder, or RBD.49 RBD is characterized by vivid and unusual dreams, and physically vigorous sleep behaviors that may result in ecchymoses, lacerations, and fractures.50 Fifty percent of patients with TBI reported insomnia symptoms.51 Disorders in initiating and maintaining sleep were the most common complaints among hospitalized patients with TBI. Some patients with TBI may develop circadian rhythm disturbances.52

Pain

A majority of patients with chronic pain, 50% to 70%, complain of impaired sleep.53 Sleep disruption is so common in fibromyalgia (75%) that it is considered to be a key diagnostic symptom.54 In a study investigating the affect of pain on sleep in burn patients, pain was associated with increased intermittent awakenings and prolonged periods of wake time during the night.55 The following day, these patients had poorer pain tolerance and greater pain intensity. Pain causes sleep fragmentation by increasing cortical arousals. Recent evidence suggests that sleep deprivation can increase pain sensitivity by inhibiting opioid protein synthesis or reducing opioid receptor affinity.56

Psychiatric Disorders

Sleep problems are so common in psychiatric conditions that the Diagnostic and Statistical Manual of Mental Disorders (DMS‐IV‐TR) includes sleep disturbance as a diagnostic criterion for a manic episode, and for various depressive, anxiety, and substance abuse disorders.57 The presence of sleep disturbance in hospitalized patients may suggest the presence of an underlying psychiatric disorder that would otherwise go unrecognized. In a survey of 200 general medical patients in a Brazilian hospital, Rocha et al.58 found that 112 (56.5%) complained of insomnia, and 100 (50%) met criteria for at least 1 psychiatric disorder. However, only 3 out of the total number of 200 surveyed (1.5%) were identified as having psychiatric diagnoses in the medical record, and sleep history was not noted in the clinical evaluation. An episode of major depressive disorder was the most common psychiatric diagnosis (35%). In this study, hospitalized patients with insomnia had a 3.6 times higher risk of having major depressive disorder than inpatients without insomnia.

Insomnia has a profound effect on mental health by worsening health‐related quality of life. In a study of outpatients at family medicine, internal medicine, endocrinology, cardiology, and psychiatry clinics in 3 U.S. cities (n = 3,445), insomnia worsened health‐related quality of life nearly as much as CHF or major depressive disorder did.59 Another survey of outpatients found that those with chronic insomnia were nearly 40 times more likely to have major depression and 6 times more likely to have an anxiety disorder compared to those without insomnia.60 Longitudinal studies have found that prior insomnia was associated with 2‐ to 5‐fold increase in the odds of mood and anxiety disorders and suicide.61, 62 Examining prodromes and precursors to mental disorders, Eaton et al.63 found that 47% of those with onset of depression at the 1‐year follow‐up had sleep problems at baseline.

An estimated 65% of patients with major depression have difficulty falling asleep, frequent awakenings, or early morning awakenings.64 Three patterns of sleep architecture abnormalities have been observed in patients with major depression: 1) sleep continuity disturbances characterized by prolonged sleep‐onset, increased wake time during sleep, increased early morning wake time, and decreased TST; 2) decreased proportion and length of SWS; and 3) REM sleep abnormalities such as reduced time to REM sleep, prolonged first REM sleep episode, and increased REM sleep percentage.65 Sleep during a manic episode has been less studied than in depression, but the data suggest that abnormal sleep in mania includes disrupted sleep continuity, shortened REM latency, and increased REM density (REM eye movement activity/total REM sleep time).65

Substance use disorders are also associated with sleep problems. In a survey by Brower et al.66 of patients who were undergoing alcohol rehabilitation, 61% (n = 172) had symptoms of insomnia such as increased sleep latency during the 6 months prior to entering treatment. Approximately 45% of these patients reported using alcohol for the purpose of initiating sleep. Alcohol and illicit substance intoxication and withdrawal are known to be associated with disrupted sleep. However, sleep disturbances may persist long after withdrawal symptoms have abated. Drummond et al. found that some patients continued to have alcohol‐associated sleep problems even after 27 months of abstinence.67 Evidence also suggests that untreated insomnia and other sleep problems may increase the risk of developing substance abuse problems due to self‐medicating with alcohol and other substances to help with sleep.68

Drugs that Affect Sleep

Numerous drugs can alter sleep quantity and quality. Sedatives and opioids may initially help with sleep onset, but impair sleep architecture. Medications used to treat medical and psychiatric illnesses also disrupt sleep (Table 3). The most common agents that impair sleep include antiepileptic drugs, selective serotonin reuptake inhibitors, monoamine oxidase inhibitors, tricyclic antidepressants, antihypertensives, antihistamines, and corticosteroids.

Lipophilic beta antagonists such as propranolol and timolol can increase total wake time, decrease REM sleep, and increase the incidence of nightmares and insomnia.69 Anabolic steroids and beta‐agonist bronchodilator therapy can cause severe anxiety, sleeplessness, and even psychosis. Vasopressor agents such as dopamine can cause cortical activation, leading to increased arousal and reduced SWS.

Hospital Environment

Environmental noise and patient care activities often interfere with sleep in the hospital. They account for about 30% of patient awakenings in ICU patients.70 Noise levels in the ICU have average sound peaks of 150 to 200 dB, and evening peaks >80 dB between midnight and 6 _AM.71 By comparison, the front row seats at a rock concert have sound levels of 110 dB. The high noise level in hospitals has long been implicated as a sleep disruptor,72 but studies in the past decade have found that patient care activities probably contribute more to awakenings than does environmental noise.73 An analysis of critical care nursing routines found that activities such as taking vital signs and giving baths occurred a mean 42.6 times a night per patient.74 Tamburri et al.74 found that patients experienced 2 to 3 hours without interruption on only 6% of the 147 nights studied. Routine daily baths were provided on 55 of the 147 study nights between 2 _AM and 5 _AM, which is unlikely to be an opportune time for most patients.

General Medical Disorders

Primary sleep disorders, such as obstructive sleep apnea (OSA) and numerous other medical illnesses, can directly impair sleep physiology, leading to a cyclical interaction (Figure 2). Other conditions that disrupt sleep include congestive heart failure (CHF), diabetes mellitus, chronic obstructive pulmonary disease (COPD), gastroesophageal reflux, cardiovascular disease, thyroid disorders, renal disease, and severe liver disease.26 Table 2 lists selected medical and neurological conditions, their associated sleep‐related problems, and suggestions on how to ameliorate these problems.

Figure 2

Affecting approximately 24% of men and 9% of women in the United States, OSA is the most common primary sleep disorder,27, 28 and causes significant mental and physical morbidity. Risk factors for OSA include obesity, hypothyroidism‐induced muscle weakness, and structural abnormalities in the oropharynx region such as acromegaly, micrognathia, or retrognathia. OSA is characterized by episodes of complete or partial pharyngeal obstruction during sleep that cause snoring, apneic episodes, choking, dyspnea, and restlessness.28 These episodes are associated with intermittent nocturnal sympathetic activation leading to nocturnal awakenings and cortical arousals, all of which lead to daytime symptoms of fatigue, sleepiness, and cognitive impairment (Figure 2). In addition, chronic sympathetic activation causes numerous derangements in the vascular endothelium and platelet activation.29, 30 Sleep‐disordered breathing has been independently associated with cardiovascular diseases such as hypertension, CHF, ischemic heart disease, atrial fibrillation, and cerebrovascular disease.31, 32

OSA is also associated with sleep‐related gastroesophageal reflux, which is characterized by pain and nocturnal cough, and can induce nocturnal asthma attacks and laryngospasm.33 Green et al.29 found that OSA patients treated with continuous positive airway pressure (CPAP) had a 48% improvement in nocturnal reflux symptoms. Although the pathophysiology connecting OSA to the renal system is unknown, OSA has been found in up to 60% of patients with end‐stage renal disease and chronic renal failure.34

Patients with pulmonary disorders can be profoundly affected by the normal physiologic changes during sleep, particularly in REM sleep. During REM sleep, all respiratory muscles except the diaphragm become paralyzed. Thus, episodes of marked oxygen desaturation can occur in patients who rely on their accessory muscles for respiration. COPD patients have decreased TST, SWS, and REM sleep. Shortness of breath, nocturnal cough, and wheezing worsen sleep.35 The resulting fatigue and sleep deprivation negatively impact the work of breathing and impair gas exchange. Airflow obstruction tends to worsen in the early morning hours in patients with COPD and asthma, and may be related to the effect of REM on the accessory muscles for respiration. Although used to target CO₂ retention, investigations using bilevel positive airway pressure ventilators (BiPAP) for improving sleep in COPD patients have been limited. Noninvasive positive pressure ventilation (NPPV) appears to acutely improve SE and TST in patients with hypercapnic COPD without significantly improving gas exchange. Other sleep parameters such as sleep architecture and the number of arousals during the night, remain unchanged during NPPV.36

CPAP has several side effects that could worsen sleep, which may explain its poor adherence rate among ambulatory patients.37 Side effects include nasal bridge discomfort, nasal congestion, swallowing air, dry nose, dry or red eyes, noise, ear pain, and rhinitis.38 During hospitalization, efforts should be made to improve patient comfort by resizing ill‐fitting masks, adding heated humidification or nasal steroids to alleviate nasal congestion, or adding a chin strap to reduce air leak and ingestion of air.

Endocrine disorders have also been associated with sleep disruption. Studies suggest that patients with diabetes mellitus have decreased TST and impaired sleep quality due to nocturia and neuropathic pain.39 Inadequate sleep may also affect glucose control. Inadequate quality or quantity of sleep has been shown to be a risk factor for developing Type 2 diabetes mellitus in large prospective studies.40 Sleep duration and quality were significant predictors of increased levels of glycosylated hemoglobin (HbA_1c) in patients with Type 2 diabetes mellitus. Thyroid diseases often coexist with diabetes mellitus. Both hypo‐ and hyperthyroidism have been associated with sleep disruption. Hypothyroidism is associated with daytime somnolence and fatigue. Patients with hypothyroidism tend to have reduced SWS. Hyperthyroid patients often complain of insomnia, which has been attributed to a hypermetabolic state.

Approximately 50% of patients with chronic end‐stage renal disease (ESRD) have insomnia and other sleep disorders.41 Patients often complain of restless leg syndrome (RLS), periodic limb movement disorder (PLMD), bone pain, nausea, and pruritus. The etiology of sleep disorders appears to be related to metabolic derangements associated with ESRD or from coexisting diabetes mellitus.

RLS and PLMD are distinct problems that affect sleep differently. RLS is characterized by an unpleasant crampy, creeping or crawling sensation in the lower extremities that is relieved by movement of the legs.42 RLS symptoms typically occur soon after going to bed, and therefore tend to disrupt sleep onset. The requisite bed rest during hospitalization can worsen RLS, further exacerbating sleep problems.43 Since RLS may partially be caused by disrupted iron metabolism, serum ferritin levels should be evaluated.44 Other conditions associated with RLS include pregnancy, rheumatoid arthritis, fibromyalgia, multiple sclerosis, ESRD, and Parkinson's disease. The differential diagnosis for RLS and PLMD includes neuroleptic‐induced akathisia, peripheral neuropathy, and positional or nocturnal leg cramps. PLMD occurs in about 80% of those with RLS, and is characterized by involuntary limb movements that occur every 20 to 40 seconds during NREM sleep. Unaware of these movements, patients often experience frequent arousals throughout the night, and complain of daytime somnolence and fatigue.42

A pilot study of 35 patients with minimal hepatic encephalopathy found that nearly 50% complained of sleep difficulties.45 Hypothesizing that a dysregulation of histaminergic neurotransmission in cirrhosis alters the sleep‐wake cycle, Spahr et al.46 found that 40% of their patients reported subjective improvement in sleep when administered 25 mg of hydroxyzine, compared to none who received placebo.

Neurologic Disorders

Since the brain and its various neurotransmitter systems are critical in regulating sleep and wakefulness, patients with neurologic disorders have an increased risk of developing sleep disorders. Patients with dementia, other neurodegenerative disorders, epilepsy, and traumatic brain injury (TBI) have a higher prevalence of sleep disturbance and sleep disorders.47 Poststroke patients can develop insomnia or hypersomnia, a reduction in sleep latency, increased sleep, or excessive daytime sleepiness, and are at higher risk for OSA during the first several months after a stroke.48 Specific neurologic lesions may lead to uncommon problems such as inversion of the sleep‐wake cycle, parasomnias, and hallucinatory dream‐like states.

Both Parkinson's disease and Alzheimer's disease are associated with multiple sleep disturbances, which tend to worsen with disease progression.14 Common problems include increased sleep fragmentation and wakefulness, with increases of stage 1 sleep and reductions of SWS and REM. Patients with neurodegenerative disorders also have an increased risk of REM sleep behavior disorder, or RBD.49 RBD is characterized by vivid and unusual dreams, and physically vigorous sleep behaviors that may result in ecchymoses, lacerations, and fractures.50 Fifty percent of patients with TBI reported insomnia symptoms.51 Disorders in initiating and maintaining sleep were the most common complaints among hospitalized patients with TBI. Some patients with TBI may develop circadian rhythm disturbances.52

Pain

A majority of patients with chronic pain, 50% to 70%, complain of impaired sleep.53 Sleep disruption is so common in fibromyalgia (75%) that it is considered to be a key diagnostic symptom.54 In a study investigating the affect of pain on sleep in burn patients, pain was associated with increased intermittent awakenings and prolonged periods of wake time during the night.55 The following day, these patients had poorer pain tolerance and greater pain intensity. Pain causes sleep fragmentation by increasing cortical arousals. Recent evidence suggests that sleep deprivation can increase pain sensitivity by inhibiting opioid protein synthesis or reducing opioid receptor affinity.56

Psychiatric Disorders

Sleep problems are so common in psychiatric conditions that the Diagnostic and Statistical Manual of Mental Disorders (DMS‐IV‐TR) includes sleep disturbance as a diagnostic criterion for a manic episode, and for various depressive, anxiety, and substance abuse disorders.57 The presence of sleep disturbance in hospitalized patients may suggest the presence of an underlying psychiatric disorder that would otherwise go unrecognized. In a survey of 200 general medical patients in a Brazilian hospital, Rocha et al.58 found that 112 (56.5%) complained of insomnia, and 100 (50%) met criteria for at least 1 psychiatric disorder. However, only 3 out of the total number of 200 surveyed (1.5%) were identified as having psychiatric diagnoses in the medical record, and sleep history was not noted in the clinical evaluation. An episode of major depressive disorder was the most common psychiatric diagnosis (35%). In this study, hospitalized patients with insomnia had a 3.6 times higher risk of having major depressive disorder than inpatients without insomnia.

Insomnia has a profound effect on mental health by worsening health‐related quality of life. In a study of outpatients at family medicine, internal medicine, endocrinology, cardiology, and psychiatry clinics in 3 U.S. cities (n = 3,445), insomnia worsened health‐related quality of life nearly as much as CHF or major depressive disorder did.59 Another survey of outpatients found that those with chronic insomnia were nearly 40 times more likely to have major depression and 6 times more likely to have an anxiety disorder compared to those without insomnia.60 Longitudinal studies have found that prior insomnia was associated with 2‐ to 5‐fold increase in the odds of mood and anxiety disorders and suicide.61, 62 Examining prodromes and precursors to mental disorders, Eaton et al.63 found that 47% of those with onset of depression at the 1‐year follow‐up had sleep problems at baseline.

An estimated 65% of patients with major depression have difficulty falling asleep, frequent awakenings, or early morning awakenings.64 Three patterns of sleep architecture abnormalities have been observed in patients with major depression: 1) sleep continuity disturbances characterized by prolonged sleep‐onset, increased wake time during sleep, increased early morning wake time, and decreased TST; 2) decreased proportion and length of SWS; and 3) REM sleep abnormalities such as reduced time to REM sleep, prolonged first REM sleep episode, and increased REM sleep percentage.65 Sleep during a manic episode has been less studied than in depression, but the data suggest that abnormal sleep in mania includes disrupted sleep continuity, shortened REM latency, and increased REM density (REM eye movement activity/total REM sleep time).65

Substance use disorders are also associated with sleep problems. In a survey by Brower et al.66 of patients who were undergoing alcohol rehabilitation, 61% (n = 172) had symptoms of insomnia such as increased sleep latency during the 6 months prior to entering treatment. Approximately 45% of these patients reported using alcohol for the purpose of initiating sleep. Alcohol and illicit substance intoxication and withdrawal are known to be associated with disrupted sleep. However, sleep disturbances may persist long after withdrawal symptoms have abated. Drummond et al. found that some patients continued to have alcohol‐associated sleep problems even after 27 months of abstinence.67 Evidence also suggests that untreated insomnia and other sleep problems may increase the risk of developing substance abuse problems due to self‐medicating with alcohol and other substances to help with sleep.68

Drugs that Affect Sleep

Numerous drugs can alter sleep quantity and quality. Sedatives and opioids may initially help with sleep onset, but impair sleep architecture. Medications used to treat medical and psychiatric illnesses also disrupt sleep (Table 3). The most common agents that impair sleep include antiepileptic drugs, selective serotonin reuptake inhibitors, monoamine oxidase inhibitors, tricyclic antidepressants, antihypertensives, antihistamines, and corticosteroids.

Lipophilic beta antagonists such as propranolol and timolol can increase total wake time, decrease REM sleep, and increase the incidence of nightmares and insomnia.69 Anabolic steroids and beta‐agonist bronchodilator therapy can cause severe anxiety, sleeplessness, and even psychosis. Vasopressor agents such as dopamine can cause cortical activation, leading to increased arousal and reduced SWS.

Hospital Environment

Environmental noise and patient care activities often interfere with sleep in the hospital. They account for about 30% of patient awakenings in ICU patients.70 Noise levels in the ICU have average sound peaks of 150 to 200 dB, and evening peaks >80 dB between midnight and 6 _AM.71 By comparison, the front row seats at a rock concert have sound levels of 110 dB. The high noise level in hospitals has long been implicated as a sleep disruptor,72 but studies in the past decade have found that patient care activities probably contribute more to awakenings than does environmental noise.73 An analysis of critical care nursing routines found that activities such as taking vital signs and giving baths occurred a mean 42.6 times a night per patient.74 Tamburri et al.74 found that patients experienced 2 to 3 hours without interruption on only 6% of the 147 nights studied. Routine daily baths were provided on 55 of the 147 study nights between 2 _AM and 5 _AM, which is unlikely to be an opportune time for most patients.

General Medical Disorders

Primary sleep disorders, such as obstructive sleep apnea (OSA) and numerous other medical illnesses, can directly impair sleep physiology, leading to a cyclical interaction (Figure 2). Other conditions that disrupt sleep include congestive heart failure (CHF), diabetes mellitus, chronic obstructive pulmonary disease (COPD), gastroesophageal reflux, cardiovascular disease, thyroid disorders, renal disease, and severe liver disease.26 Table 2 lists selected medical and neurological conditions, their associated sleep‐related problems, and suggestions on how to ameliorate these problems.

Figure 2

Affecting approximately 24% of men and 9% of women in the United States, OSA is the most common primary sleep disorder,27, 28 and causes significant mental and physical morbidity. Risk factors for OSA include obesity, hypothyroidism‐induced muscle weakness, and structural abnormalities in the oropharynx region such as acromegaly, micrognathia, or retrognathia. OSA is characterized by episodes of complete or partial pharyngeal obstruction during sleep that cause snoring, apneic episodes, choking, dyspnea, and restlessness.28 These episodes are associated with intermittent nocturnal sympathetic activation leading to nocturnal awakenings and cortical arousals, all of which lead to daytime symptoms of fatigue, sleepiness, and cognitive impairment (Figure 2). In addition, chronic sympathetic activation causes numerous derangements in the vascular endothelium and platelet activation.29, 30 Sleep‐disordered breathing has been independently associated with cardiovascular diseases such as hypertension, CHF, ischemic heart disease, atrial fibrillation, and cerebrovascular disease.31, 32

OSA is also associated with sleep‐related gastroesophageal reflux, which is characterized by pain and nocturnal cough, and can induce nocturnal asthma attacks and laryngospasm.33 Green et al.29 found that OSA patients treated with continuous positive airway pressure (CPAP) had a 48% improvement in nocturnal reflux symptoms. Although the pathophysiology connecting OSA to the renal system is unknown, OSA has been found in up to 60% of patients with end‐stage renal disease and chronic renal failure.34

Patients with pulmonary disorders can be profoundly affected by the normal physiologic changes during sleep, particularly in REM sleep. During REM sleep, all respiratory muscles except the diaphragm become paralyzed. Thus, episodes of marked oxygen desaturation can occur in patients who rely on their accessory muscles for respiration. COPD patients have decreased TST, SWS, and REM sleep. Shortness of breath, nocturnal cough, and wheezing worsen sleep.35 The resulting fatigue and sleep deprivation negatively impact the work of breathing and impair gas exchange. Airflow obstruction tends to worsen in the early morning hours in patients with COPD and asthma, and may be related to the effect of REM on the accessory muscles for respiration. Although used to target CO₂ retention, investigations using bilevel positive airway pressure ventilators (BiPAP) for improving sleep in COPD patients have been limited. Noninvasive positive pressure ventilation (NPPV) appears to acutely improve SE and TST in patients with hypercapnic COPD without significantly improving gas exchange. Other sleep parameters such as sleep architecture and the number of arousals during the night, remain unchanged during NPPV.36

CPAP has several side effects that could worsen sleep, which may explain its poor adherence rate among ambulatory patients.37 Side effects include nasal bridge discomfort, nasal congestion, swallowing air, dry nose, dry or red eyes, noise, ear pain, and rhinitis.38 During hospitalization, efforts should be made to improve patient comfort by resizing ill‐fitting masks, adding heated humidification or nasal steroids to alleviate nasal congestion, or adding a chin strap to reduce air leak and ingestion of air.

Endocrine disorders have also been associated with sleep disruption. Studies suggest that patients with diabetes mellitus have decreased TST and impaired sleep quality due to nocturia and neuropathic pain.39 Inadequate sleep may also affect glucose control. Inadequate quality or quantity of sleep has been shown to be a risk factor for developing Type 2 diabetes mellitus in large prospective studies.40 Sleep duration and quality were significant predictors of increased levels of glycosylated hemoglobin (HbA_1c) in patients with Type 2 diabetes mellitus. Thyroid diseases often coexist with diabetes mellitus. Both hypo‐ and hyperthyroidism have been associated with sleep disruption. Hypothyroidism is associated with daytime somnolence and fatigue. Patients with hypothyroidism tend to have reduced SWS. Hyperthyroid patients often complain of insomnia, which has been attributed to a hypermetabolic state.

Approximately 50% of patients with chronic end‐stage renal disease (ESRD) have insomnia and other sleep disorders.41 Patients often complain of restless leg syndrome (RLS), periodic limb movement disorder (PLMD), bone pain, nausea, and pruritus. The etiology of sleep disorders appears to be related to metabolic derangements associated with ESRD or from coexisting diabetes mellitus.

RLS and PLMD are distinct problems that affect sleep differently. RLS is characterized by an unpleasant crampy, creeping or crawling sensation in the lower extremities that is relieved by movement of the legs.42 RLS symptoms typically occur soon after going to bed, and therefore tend to disrupt sleep onset. The requisite bed rest during hospitalization can worsen RLS, further exacerbating sleep problems.43 Since RLS may partially be caused by disrupted iron metabolism, serum ferritin levels should be evaluated.44 Other conditions associated with RLS include pregnancy, rheumatoid arthritis, fibromyalgia, multiple sclerosis, ESRD, and Parkinson's disease. The differential diagnosis for RLS and PLMD includes neuroleptic‐induced akathisia, peripheral neuropathy, and positional or nocturnal leg cramps. PLMD occurs in about 80% of those with RLS, and is characterized by involuntary limb movements that occur every 20 to 40 seconds during NREM sleep. Unaware of these movements, patients often experience frequent arousals throughout the night, and complain of daytime somnolence and fatigue.42

A pilot study of 35 patients with minimal hepatic encephalopathy found that nearly 50% complained of sleep difficulties.45 Hypothesizing that a dysregulation of histaminergic neurotransmission in cirrhosis alters the sleep‐wake cycle, Spahr et al.46 found that 40% of their patients reported subjective improvement in sleep when administered 25 mg of hydroxyzine, compared to none who received placebo.

Neurologic Disorders

Since the brain and its various neurotransmitter systems are critical in regulating sleep and wakefulness, patients with neurologic disorders have an increased risk of developing sleep disorders. Patients with dementia, other neurodegenerative disorders, epilepsy, and traumatic brain injury (TBI) have a higher prevalence of sleep disturbance and sleep disorders.47 Poststroke patients can develop insomnia or hypersomnia, a reduction in sleep latency, increased sleep, or excessive daytime sleepiness, and are at higher risk for OSA during the first several months after a stroke.48 Specific neurologic lesions may lead to uncommon problems such as inversion of the sleep‐wake cycle, parasomnias, and hallucinatory dream‐like states.

Both Parkinson's disease and Alzheimer's disease are associated with multiple sleep disturbances, which tend to worsen with disease progression.14 Common problems include increased sleep fragmentation and wakefulness, with increases of stage 1 sleep and reductions of SWS and REM. Patients with neurodegenerative disorders also have an increased risk of REM sleep behavior disorder, or RBD.49 RBD is characterized by vivid and unusual dreams, and physically vigorous sleep behaviors that may result in ecchymoses, lacerations, and fractures.50 Fifty percent of patients with TBI reported insomnia symptoms.51 Disorders in initiating and maintaining sleep were the most common complaints among hospitalized patients with TBI. Some patients with TBI may develop circadian rhythm disturbances.52

Pain

A majority of patients with chronic pain, 50% to 70%, complain of impaired sleep.53 Sleep disruption is so common in fibromyalgia (75%) that it is considered to be a key diagnostic symptom.54 In a study investigating the affect of pain on sleep in burn patients, pain was associated with increased intermittent awakenings and prolonged periods of wake time during the night.55 The following day, these patients had poorer pain tolerance and greater pain intensity. Pain causes sleep fragmentation by increasing cortical arousals. Recent evidence suggests that sleep deprivation can increase pain sensitivity by inhibiting opioid protein synthesis or reducing opioid receptor affinity.56

Psychiatric Disorders

Sleep problems are so common in psychiatric conditions that the Diagnostic and Statistical Manual of Mental Disorders (DMS‐IV‐TR) includes sleep disturbance as a diagnostic criterion for a manic episode, and for various depressive, anxiety, and substance abuse disorders.57 The presence of sleep disturbance in hospitalized patients may suggest the presence of an underlying psychiatric disorder that would otherwise go unrecognized. In a survey of 200 general medical patients in a Brazilian hospital, Rocha et al.58 found that 112 (56.5%) complained of insomnia, and 100 (50%) met criteria for at least 1 psychiatric disorder. However, only 3 out of the total number of 200 surveyed (1.5%) were identified as having psychiatric diagnoses in the medical record, and sleep history was not noted in the clinical evaluation. An episode of major depressive disorder was the most common psychiatric diagnosis (35%). In this study, hospitalized patients with insomnia had a 3.6 times higher risk of having major depressive disorder than inpatients without insomnia.

Insomnia has a profound effect on mental health by worsening health‐related quality of life. In a study of outpatients at family medicine, internal medicine, endocrinology, cardiology, and psychiatry clinics in 3 U.S. cities (n = 3,445), insomnia worsened health‐related quality of life nearly as much as CHF or major depressive disorder did.59 Another survey of outpatients found that those with chronic insomnia were nearly 40 times more likely to have major depression and 6 times more likely to have an anxiety disorder compared to those without insomnia.60 Longitudinal studies have found that prior insomnia was associated with 2‐ to 5‐fold increase in the odds of mood and anxiety disorders and suicide.61, 62 Examining prodromes and precursors to mental disorders, Eaton et al.63 found that 47% of those with onset of depression at the 1‐year follow‐up had sleep problems at baseline.

An estimated 65% of patients with major depression have difficulty falling asleep, frequent awakenings, or early morning awakenings.64 Three patterns of sleep architecture abnormalities have been observed in patients with major depression: 1) sleep continuity disturbances characterized by prolonged sleep‐onset, increased wake time during sleep, increased early morning wake time, and decreased TST; 2) decreased proportion and length of SWS; and 3) REM sleep abnormalities such as reduced time to REM sleep, prolonged first REM sleep episode, and increased REM sleep percentage.65 Sleep during a manic episode has been less studied than in depression, but the data suggest that abnormal sleep in mania includes disrupted sleep continuity, shortened REM latency, and increased REM density (REM eye movement activity/total REM sleep time).65

Substance use disorders are also associated with sleep problems. In a survey by Brower et al.66 of patients who were undergoing alcohol rehabilitation, 61% (n = 172) had symptoms of insomnia such as increased sleep latency during the 6 months prior to entering treatment. Approximately 45% of these patients reported using alcohol for the purpose of initiating sleep. Alcohol and illicit substance intoxication and withdrawal are known to be associated with disrupted sleep. However, sleep disturbances may persist long after withdrawal symptoms have abated. Drummond et al. found that some patients continued to have alcohol‐associated sleep problems even after 27 months of abstinence.67 Evidence also suggests that untreated insomnia and other sleep problems may increase the risk of developing substance abuse problems due to self‐medicating with alcohol and other substances to help with sleep.68

Drugs that Affect Sleep

Numerous drugs can alter sleep quantity and quality. Sedatives and opioids may initially help with sleep onset, but impair sleep architecture. Medications used to treat medical and psychiatric illnesses also disrupt sleep (Table 3). The most common agents that impair sleep include antiepileptic drugs, selective serotonin reuptake inhibitors, monoamine oxidase inhibitors, tricyclic antidepressants, antihypertensives, antihistamines, and corticosteroids.

Lipophilic beta antagonists such as propranolol and timolol can increase total wake time, decrease REM sleep, and increase the incidence of nightmares and insomnia.69 Anabolic steroids and beta‐agonist bronchodilator therapy can cause severe anxiety, sleeplessness, and even psychosis. Vasopressor agents such as dopamine can cause cortical activation, leading to increased arousal and reduced SWS.

Hospital Environment

Environmental noise and patient care activities often interfere with sleep in the hospital. They account for about 30% of patient awakenings in ICU patients.70 Noise levels in the ICU have average sound peaks of 150 to 200 dB, and evening peaks >80 dB between midnight and 6 _AM.71 By comparison, the front row seats at a rock concert have sound levels of 110 dB. The high noise level in hospitals has long been implicated as a sleep disruptor,72 but studies in the past decade have found that patient care activities probably contribute more to awakenings than does environmental noise.73 An analysis of critical care nursing routines found that activities such as taking vital signs and giving baths occurred a mean 42.6 times a night per patient.74 Tamburri et al.74 found that patients experienced 2 to 3 hours without interruption on only 6% of the 147 nights studied. Routine daily baths were provided on 55 of the 147 study nights between 2 _AM and 5 _AM, which is unlikely to be an opportune time for most patients.