Overview

Sleep disturbances occur in about 10% to 15% of the general population [1] and are often associated with situational stress, illness, aging, and drug treatment.[2] It is estimated that one-third to one-half of people with cancer experience sleep disturbance.[3,4] Physical illness, pain, hospitalization, drugs and other treatments for cancer, and the psychological impact of a malignant disease may disrupt the sleeping patterns of persons with cancer.[5] Poor sleep adversely affects daytime mood and performance. In the general population, persistent insomnia has been associated with a higher risk of developing clinical anxiety or depression.[6] Sleep disturbances and, ultimately, sleep-wake cycle reversals can be early signs of a developing delirium. (Refer to the PDQ summary on Cognitive Disorders and Delirium for more information.) Adequate sleep may increase the cancer patient's pain tolerance.

Sleep consists of two phases: rapid eye movement (REM) sleep and non-REM (NREM) sleep.[7] REM sleep, also known as dream sleep, is the active or paradoxic phase of sleep in which the brain is active. NREM sleep is the quiet or restful phase of sleep. NREM, also referred to as slow wave sleep, is divided into four stages of progressively deepening sleep based on electroencephalogram findings.

The stages of sleep occur in a repeated pattern or cycle of NREM followed by REM, with each cycle lasting approximately 90 minutes. The sleep cycle is repeated four to six times during a 7- to 8-hour sleep period.[7] The sleep-wake cycle is dictated by an inherent biological clock or circadian rhythm. Disruptions in individual sleep patterns can disrupt the circadian rhythm and impair the sleep cycle.[8]

Five major categories of sleep disorders have been defined by the Sleep Disorders Classification Committee of the American Academy of Sleep Medicine:[9]

In this summary, unless otherwise stated, evidence and practice issues as they relate to adults are discussed. The evidence and application to practice related to children may differ significantly from information related to adults. When specific information about the care of children is available, it is summarized under its own heading.

References:

Sleep Disturbance in Cancer Patients

Cancer patients are at great risk for developing insomnia and disorders of the sleep-wake cycle. Insomnia is the most common sleep disturbance in this population and is most often secondary to physical and/or psychological factors related to cancer and/or cancer treatment.[1,2,3,4,5] Anxiety and depression, common psychological responses to the diagnosis of cancer, cancer treatment, and hospitalization, are highly correlated with insomnia.[6,7]

Sleep disturbances may be exacerbated by paraneoplastic syndromes associated with steroid production and by symptoms associated with tumor invasion, such as draining lesions, gastrointestinal (GI) and genitourinary (GU) alterations, pain, fever, cough, dyspnea, pruritus, and fatigue. Medications—including vitamins, corticosteroids, neuroleptics for nausea and vomiting, and sympathomimetics for the treatment of dyspnea—as well as other treatment factors can negatively impact sleep patterns.

Side effects of treatment that may affect the sleep-wake cycle include the following:[8]

• Pain.
• Anxiety.
• Night sweats/hot flashes (refer to the PDQ summary onFever, Sweats, and Hot Flashesfor more information).
• GI disturbances (e.g., incontinence, diarrhea, constipation, or nausea).
• GU disturbances (e.g., incontinence, retention, or GU irritation).
• Respiratory disturbances.
• Fatigue.

Sustained use of the following medications commonly used in the treatment of cancer can cause insomnia:

• Sedatives and hypnotics (e.g., glutethimide, benzodiazepines, pentobarbital, chloral hydrate, secobarbital sodium, and amobarbital sodium).
• Cancer chemotherapeutic agents (especially antimetabolites).
• Anticonvulsants (e.g., phenytoin).
• Adrenocorticotropin.
• Oral contraceptives.
• Monoamine oxidase inhibitors.
• Methyldopa.
• Propranolol.
• Atenolol.
• Alcohol.
• Thyroid preparations.

In addition, withdrawal from the following substances may cause insomnia:

• CNS depressants (e.g., barbiturates, opioids, glutethimide, chloral hydrate, methaqualone, ethchlorvynol, alcohol, and over-the-counter and prescription antihistamine sedatives).
• Benzodiazepines.
• Major tranquilizers.
• Tricyclic and monamine oxidase inhibitor antidepressants.
• Illicit drugs (e.g., marijuana, cocaine, phencyclidine, and opioids).

Hypnotics can interfere with rapid eye movement (REM) sleep, resulting in increased irritability, apathy, and diminished mental alertness. Abrupt withdrawal of hypnotics and sedatives may lead to symptoms such as nervousness, jitteriness, seizures, and REM rebound. REM rebound has been defined as a marked increase in REM sleep with increased frequency and intensity of dreaming, including nightmares.[9] The increased physiologic arousal that occurs during REM rebound may be dangerous for patients with peptic ulcers or a history of cardiovascular problems. Newer medications for insomnia have reduced adverse effects.[10]

The sleep of hospitalized patients is likely to be frequently interrupted by treatment schedules, hospital routines, and roommates, which singularly or collectively alter the sleep-wake cycle. Other factors influencing sleep-wake cycles in the hospital setting include patient age, comfort, pain, and anxiety; and environmental noise and temperature.[11]

Consequences of sleep disturbances can influence outcomes of therapeutic and supportive care measures.[12] The patient with mild to moderate sleep disturbances may experience irritability and inability to concentrate, which may in turn affect the patient's compliance with treatment protocols, ability to make decisions, and relationships with significant others. Depression and anxiety can also be caused by sleep disturbances. Supportive care measures are directed toward promoting quality of life and adequate rest.

References:

Assessment

Assessment is the initial step in management strategies. Assessment data should include documentation of predisposing factors, sleep patterns, emotional status, exercise and activity levels, diet, symptoms, medications, and caregiver routines.[1] The sections below outline recommendations for a sleep history and physical examination. Data can be retrieved from multiple sources: the patient's subjective report of sleep difficulty, objective observations of behavioral and physiologic manifestations of sleep disturbances, and reports from the patient's significant others regarding the patient's quality of sleep.[2] Use of the Insomnia Severity Index is suggested to screen for insomnia in clinical settings.[3,4]

The diagnosis of insomnia is primarily based on a careful, detailed medical and psychiatric history. The American Academy of Sleep Medicine has produced guidelines for the use of polysomnography as an objective tool in evaluating insomnia. The routine polysomnogram includes the monitoring of electroencephalography, electro-oculography, electromyography, effort of breathing and air flow, oxygen saturation, electrocardiography, and body position. Polysomnography is the major diagnostic tool in sleep disorders and is indicated in the evaluation of suspected sleep-related breathing disorders and periodic limb movement disorder, and when the cause of insomnia is uncertain or when behavioral or pharmacologic therapy is unsuccessful.[5][Level of evidence: IV]

Risk Factors for Sleep Disorders

• Disease factors, including paraneoplastic syndromes with increased steroid production; and symptoms associated with tumor invasion (e.g., obstruction, pain, fever, shortness of breath, pruritus, and fatigue).
• Treatment factors, including symptoms related to surgery (e.g., pain, frequent monitoring, and use of opioids); chemotherapy (e.g., exogenous corticosteroids); and symptoms related to chemotherapy.
• Medications such as opioids, sedatives/hypnotics, steroids, caffeine/nicotine, some antidepressants, and dietary supplements, including some vitamins, diet pills, and other products promoting weight loss and appetite suppression.
• Environmental factors.
• Physical and/or psychological stressors.
• Depression (refer to the PDQ summary onDepressionfor more information).
• Anxiety (refer to theAnxiety Disorders: Description and Etiology section in the PDQ summary onAdjustment to Cancer: Anxiety and Distressfor more information).
• Delirium (refer to the PDQ summary onCognitive Disorders and Deliriumfor more information).
• Daytime seizures, snoring, and headaches.

Characterization of Sleep

• Usual patterns of sleep, including usual bedtime, routine before retiring (e.g., food, bath, and medications), length of time before onset of sleep, and duration of sleep (awaking episodes during night, ability to resume sleep, and usual time of awakening).
• Characteristics of disturbed sleep (changes following diagnosis, treatment, and/or hospitalization).
• Perception of significant others as to quantity and quality of patient's sleep.
• Family history of sleep disorders.

References:

Management

Management of sleep disturbances should focus on treatment of symptoms related to the cancer and its treatment, and identification and management of environmental and psychological factors. Treatment of the malignancy may resolve the sleep disturbance. When sleep disturbances are caused by symptoms of cancer or treatment, measures that control or alleviate symptoms are often the key to resolving sleep disturbances. Management of sleep disturbances combines nonpharmacologic and pharmacologic approaches individualized for the patient.

Nonpharmacologic Management of Sleep Disturbances

The environment can be modified to decrease sleep disruption. Minimizing noise, dimming or turning off lights, adjusting room temperature, and consolidating patient care tasks to reduce the number of interruptions can increase the amount of uninterrupted sleep.[1][Level of evidence: IV]

Other actions or interventions that may promote rest include the following:[2,3]

• Keeping the patient's skin clean and dry.
• Giving back rubs and/or massaging areas of the body to bring comfort to the patient (e.g., bony prominences, head and scalp, shoulders, hands, and feet).
• Keeping bedding and/or surfaces of support devices (chairs and pillows) clean, dry, and wrinkle-free.
• Ensuring adequate bedcovers for warmth.
• Regulating fluid intake to avoid frequent awakening for elimination.
• Encouraging bowel and bladder elimination before sleep.
• Promoting optimal bowel function (increased fluids, dietary fiber, and use of stool softeners and laxatives).
• Using a condom catheter for nocturnal incontinence.
• Providing a high-protein snack 2 hours before bedtime (e.g., milk, turkey, or other foods high in tryptophan).
• Avoiding beverages with caffeine and other stimulants, including dietary supplements that promote metabolism changes and appetite suppression.
• Encouraging the patient to dress in loose, soft clothing.
• Facilitating comfort through repositioning and support with pillows as needed.
• Encouraging exercise or activity no less than 2 hours before bedtime.
• Encouraging the patient to keep regular bedtime and awakening hours.
• Minimizing and coordinating necessary bedside contacts for inpatients.

Psychological interventions are directed toward facilitating the patient's coping processes through education, support, and reassurance. As the patient learns to cope with the stresses of illness, hospitalization, and treatment, sleep may improve.[4][Level of evidence: IV] Communication, verbalization of concerns, and openness between the patient, family, and health care team should be encouraged. Relaxation exercises and self-hypnosis performed at bedtime can help promote calm and sleep. Cognitive-behavioral interventions that diminish the distress associated with early insomnia and change the goal from "need to sleep" to "just relax" can diminish anxiety and promote sleep.[5]

Cognitive behavioral therapy (CBT) delivered by psychologists has shown promise for the treatment of insomnia in patients with cancer.[6][Level of evidence: I] A randomized controlled study investigated the effectiveness of a protocol-driven cognitive behavioral intervention for insomnia delivered by oncology nurses.[7][Level of evidence: I] This group intervention consisted of standard CBT components such as stimulus control and sleep restriction. Participants included patients with heterogeneous cancers randomly assigned to receive the intervention (n = 100) or treatment as usual (n = 50). Primary outcomes were sleep diary measures at baseline, posttreatment, and at 6-month follow-up. CBT was associated with significant and sustained improvements in several sleep aspects. These improvements were seen for both subjective (sleep diary) and objective (actigraphy) assessments. Additionally, CBT patients showed significant improvements in fatigue, anxiety, and depressive symptoms and reported improved quality of life relative to patients receiving treatment as usual.[7][Level of evidence: I]

Many people who experience insomnia have been found to practice poor sleep hygiene (such as smoking and drinking alcohol just before bedtime), which can exacerbate or perpetuate insomnia.[8][Level of evidence: III] Therefore, a complete assessment of sleep hygiene (i.e., time in bed; napping during the day; intake of caffeine, alcohol, or foods that are heavy, spicy, or sugary; exercise; and sleep environment) and use of behavioral management strategies (i.e., fixed bedtime; smoking, dietary, and alcohol restrictions 4–6 hours before bedtime; and increased exercise) may prove effective in reducing sleep disturbance.

Pharmacologic Management of Sleep Disturbances

When sleep disturbances are not resolved with other supportive care measures, the use of sleep medications on a short-term or intermittent basis may be helpful. Prolonged use of sleep medications for persistent insomnia, however, can impair natural sleep patterns (i.e., rapid eye movement [REM] deprivation) and alter physiologic functions. Prolonged use (>1–2 weeks) of these medications may result in tolerance, psychological and physical dependence, drug intoxication, and drug hangover.[1][Level of evidence: IV][9]

A newer agent, zolpidem, has reportedly not been associated with tolerance, dependence, sleep cycle alterations, or rebound insomnia. Zolpidem tartrate (Ambien) is administered in doses of 5 mg to 10 mg, 30 minutes before bedtime. This medication has not been widely used or studied in cancer patients.

Benzodiazepines have been widely used in the management of sleep disturbances. Used as an adjunct to other treatment for short periods of time, these agents are safe and effective in producing natural sleep because they are less disruptive of REM sleep than are other hypnotic agents. Benzodiazepines have an antianxiety effect in low doses and a hypnotic effect in high doses. Commonly used sleep aids are not well studied in cancer patients. A randomized, double-blind, placebo-controlled trial of triazolam was carried out in a major cancer center in women undergoing initial breast cancer surgery. The drug was superior to placebo with regard to improved sleep and restfulness. The remaining literature is sparse with regard to empirical studies and randomized controlled trials of sleep aids and is mostly anecdotal.[10][Level of evidence: I]

Benzodiazepines differ from each other in duration of action and pharmacokinetics. Liver disease has less of an effect on the metabolism of lorazepam, oxazepam, and temazepam than on the metabolism of other benzodiazepines. Whereas long-acting agents may produce daytime hangover, short-acting agents are more often associated with dependence, rebound insomnia, early morning insomnia, daytime anxiety, and serious withdrawal effects such as seizures.[4][Level of evidence: IV] The following general characterizations can be made:

• Intermediate- and short-acting benzodiazepines are characterized by half-lives of 4 to 24 hours.
• Short-acting benzodiazepines are characterized by the following:
  • Few active metabolites.
  • Rarely, accumulation with multiple doses.
  • Minimal effect on drug clearance by age and liver disease.
• Long-acting benzodiazepines are characterized by the following:
  • Half-lives longer than 24 hours.
  • Pharmacologically active metabolites.
  • Accumulation with multiple dosages.
  • Impaired clearance in older patients and those with liver disease.

Nonbenzodiazepine sleep aids include antidepressants, antihistamines, and antipsychotics. Antihistamines have been popular drugs for the management of sleep disturbances among cancer patients. The anticholinergic properties of antihistamines relieve nausea and vomiting as well as insomnia. These agents must be used with caution because daytime sedation and delirium can occur, especially in older patients. Tricyclic antidepressants such as amitriptyline or doxepin (Sinequan) may be effective in patients who are not depressed as well as those who are depressed. When given at bedtime, these sedating agents can eliminate the need for an additional hypnotic. Low doses of tricyclic antidepressants can be effective sleep agents and may be the treatment of choice for insomnia in patients who have neuropathic pain and appetite loss (e.g., doxepin 50–100 mg at bedtime; amitriptyline 25–100 mg at bedtime). In low doses, trazodone (50–150 mg) can promote sleep and is often combined with other antidepressants (e.g., fluoxetine 20 mg in the morning) in depressed patients with insomnia. A unique antidepressant, mirtazapine (Remeron), has been used clinically to treat depression and also induces sleep, stimulates appetite, and can decrease nausea in low bedtime doses. The hypnotic effects of marijuana (tetrahydrocannabinol [THC]) are similar to the effects of conventional hypnotics in reducing REM sleep; however, side effects experienced before sleep induction and hangover make the use of THC less acceptable than benzodiazepines.[11][Level of evidence: IV]

Low-potency neuroleptics are useful in promoting sleep in patients with insomnia associated with organic mental syndromes and delirium. (Refer to the PDQ summary on Cognitive Disorders and Delirium for more information.)

Barbiturates are generally not recommended for the management of sleep disturbances in cancer patients. Barbiturates have a number of adverse effects, including the development of tolerance, and they also have a narrow margin of safety.

Most hypnotics are effective initially but lose efficacy when used regularly, and they can become a primary cause of sleep disturbances.[12]

Medications Commonly Used to Promote Sleep

Melatonin, a hormone produced by the pineal gland during the hours of darkness, plays a major role in the sleep-wake cycle Although further study is indicated, melatonin may play an important role in the treatment of certain types of chronic sleep disorders.[13][Level of evidence: IV][14][Level of evidence: II] It is suggested that melatonin exerts a hypnotic effect through thermoregulatory mechanisms. By lowering the core body temperature, melatonin reduces arousal and increases sleep propensity. Melatonin is likely to be an effective hypnotic agent for sleep disruption associated with elevated temperature due to low circulating melatonin levels. The combined circadian and hypnotic effects of melatonin suggest a synergistic action in the treatment of sleep disorders related to the inappropriate timing of sleep and wakefulness. Adjuvant melatonin may also improve sleep disruption caused by drugs known to alter normal melatonin production (e.g., beta-blockers and benzodiazepines).[13][Level of evidence: IV]

Melatonin replacement has been shown to improve sleep in children with endocrine tumors that diminish the natural production of the hormone.[14][Level of evidence: II] This efficacy has not been shown beyond this particular study. Melatonin may affect the way tumor cells respond to chemotherapy and radiation therapy. Some studies in colon cancer and brain cancer suggest the effect of melatonin on chemotherapy and on radiation therapy may be beneficial.[15][Level of evidence: I] Not enough is known, however, to assure patients on these therapies that melatonin treatment for insomnia is safe. The use of melatonin to treat insomnia in cancer patients is under evaluation. Because the effect of melatonin on chemotherapy can vary, it is important for patients being treated with chemotherapy to consult with their health care professionals before using melatonin.

Changes in sleep-wake patterns are among the hallmarks of biologic aging.[16][Level of evidence: IV] Evidence suggests that circulating melatonin levels may be significantly lower in physically healthy older people and in insomniacs than in age-matched control subjects. In view of these findings, melatonin replacement therapy may be beneficial in the initiation and maintenance of sleep in elderly patients.[17][Level of evidence: II] Melatonin replacement, however, has not been studied in older people with cancer as a treatment for insomnia.

Current Clinical Trials

Check NCI's list of cancer clinical trials for U.S. supportive and palliative care trials about sleep disorders that are now accepting participants. The list of trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

Special Considerations

The Patient With Pain

Since enhanced pain control improves sleep, appropriate analgesics or nonpharmacologic pain management should be administered before introducing sleep medications. Tricyclic antidepressants can be particularly useful for the treatment of insomnia in patients with neuropathic pain and depression. Patients on high-dose opioids for pain may be at increased risk for the development of delirium and organic mental disorders. Such patients may benefit from the use of low-dose neuroleptics as sleep agents (e.g., haloperidol 0.5–1.0 mg).

The Older Patient

Older patients frequently have insomnia due to age-related changes in sleep. The sleep cycle in this population is characterized by lighter sleep, more frequent awakenings, and less total sleep time. Anxiety, depression, loss of social support, and a diagnosis of cancer are contributory factors in sleep disturbances in older patients.[1]

Sleep problems in older adults are so common that nearly half of all hypnotic prescriptions written are for persons older than 65 years. Although normal aging affects sleep, the clinician should evaluate the many factors that cause insomnia, such as medical illness, psychiatric illness, dementia, alcohol and/or polypharmacy, restless legs syndrome, periodic leg movements, and sleep apnea syndrome. Nonpharmacologic treatment of sleep disorders is the preferred initial management, with the use of medication when indicated and referral to a sleep disorder center when specialized care is necessary.[2]

Providing a regular schedule of meals, discouraging daytime naps, and encouraging physical activity may improve sleep. Hypnotic prescriptions for older patients must be adjusted for variations in metabolism, increased fat stores, and increased sensitivity. Dosages should be reduced by 30% to 50%. Problems associated with drug accumulation (especially flurazepam) must be weighed against the risks of more severe withdrawal or rebound effects associated with short-acting benzodiazepines. An alternate drug for older patients is chloral hydrate.[1]

Somnolence Syndrome in Children

Cranial irradiation and intrathecal methotrexate are used to prevent the development of central nervous system leukemia in children with acute lymphocytic leukemia. Somnolence syndrome (SS) is a complication of cranial irradiation occurring in 30% to 50% of patients who receive more than 18 Gy at daily dose fractions of 1.5 Gy to 2 Gy. The syndrome may appear 4 to 6 weeks posttherapy. SS is characterized by mild drowsiness to moderate lethargy and, occasionally, low-grade fever. The pathophysiology is unknown, but electroencephalogram and cerebral spinal fluid abnormalities are detectable in affected children. Although supportive care measures cannot prevent the occurrence of SS, acknowledgment of the existence of this problem may prevent or minimize anxieties for children and parents when symptoms of SS appear.

Sleep Apnea Following Mandibulectomy

Anterior mandibulectomy can result in the development of sleep apnea. All patients with head and neck tumors who have had extensive anterior oral cavity resection should be evaluated before decannulation of the tracheostomy tube. Subsequent flap and/or reconstruction of the lower jaw seems to prevent the development of sleep apnea. In contrast, facial sling suspension of the lower lip does not prevent the development of sleep apnea.[3] Assessment for symptoms and preparation for the appearance of symptoms in this population provide indications for interventions related to sleep apnea.

References:

Changes to This Summary (11 / 04 / 2011)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Overview

This section was extensively revised.

Sleep Disturbance in Cancer Patients

This section was extensively revised.

Assessment

Added American Academy of Sleep Medicine as reference 1 and Perlis et al. as reference 2. Added text to state that use of the Insomnia Severity Index is suggested to screen for insomnia in clinical settings (cited Bastien et al. as reference 3 and Savard et al. as reference 4).

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About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the pathophysiology and treatment of sleep disorders. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

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National Cancer Institute: PDQ® Sleep Disorders. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://cancer.gov/cancertopics/pdq/supportivecare/sleepdisorders/HealthProfessional. Accessed <MM/DD/YYYY>.

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Last Revised: 2011-11-04