SLEEP DISORDERS

Sleep Disturbances in Cancer Patients

Cancer patients are at great risk of developing insomnia and disorders of the sleep-wake cycle. Insomnia, the most common sleep disturbance in this population, is most often secondary to physical and/or psychological factors related to cancer and/or cancer treatment. Anxiety and depression—common psychological responses to the diagnosis of cancer, cancer treatment, and hospitalization—are highly correlated with insomnia. In addition, sleep disturbances may be part of cancer-related symptom clusters.

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.
Fatigue.

Sleep disturbance can also vary by diagnosis. In a study of patients with melanoma (n = 124), breast cancer (n = 124), and endometrial cancer (n = 82), symptom profiles differed by diagnosis. Four symptom profiles were identified: minimally symptomatic, insomnia-predominant, very sleepy with upper airway symptoms, and symptomatic with severe dysfunction.

Sustained use of the following can cause insomnia:

Sedatives and hypnotics (e.g., glutethimide, benzodiazepines, pentobarbital, chloral hydrate, secobarbital sodium, and amobarbital sodium).
Anticonvulsants (e.g., phenytoin).
Corticosteroids.
Oral contraceptives.
Monoamine oxidase inhibitors.
Methyldopa.
Propranolol.
Atenolol.
Alcohol.
Thyroid preparations.

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

Central nervous system 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.
REM rebound.

Assessment

Assessment is the initial step in managing sleep disturbances in people with cancer. Assessment data should include the following:

Documentation of predisposing factors.
Sleep patterns.
Emotional status.
Exercise and activity levels.
Diet.
Symptoms.
Medications.
Caregiver routines.

The sections below outline recommendations for a sleep history and physical examination. Data can be retrieved from multiple sources, such as:

The patient’s subjective report of sleep difficulty.
Objective observations of behavioral and physiological manifestations of sleep disturbances.
Reports from the patient's significant other regarding the patient's quality of sleep.

The Insomnia Severity Index, which has been validated in adult oncology populations, is recommended when screening for insomnia in clinical settings. In a 2021 study, the Insomnia Severity Index was validated in young adult (18–40 years of age) cancer survivors.

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 the following:

Electroencephalography.
Electro-oculography.
Electromyography.
Effort of breathing and air flow.
Oxygen saturation.
Electrocardiography.
Body position.

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. For more information, see Depression.
Anxiety. For more information, see the Anxiety Disorders: Description and Etiology section in Adjustment to Cancer: Anxiety and Distress.
Delirium.
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 (waking episodes during night, ability to resume sleep, and usual time of awakening).
Characteristics of disturbed sleep (changes after diagnosis, treatment, and/or hospitalization).
The significant other's perception of the patient's quantity and quality of sleep.
Family history of sleep disorders.

Nonpharmacological Management of Sleep Disturbances

Many people who experience insomnia have poor sleep hygiene (such as smoking and drinking excessive alcohol just before bedtime), which can exacerbate or perpetuate insomnia. 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; restrictions on smoking, diet, and excessive alcohol 4–6 hours before bedtime; and increased exercise) may prove effective in reducing sleep disturbances.

Sleep hygiene in an inpatient setting involves modifying the sleep environment 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.

Cognitive strategies include:

Restructuring negative thoughts, beliefs, and attitudes related to sleep.
Preventing excessive monitoring or worrying about getting enough sleep.

Behavioral strategies include:

Stimulus control.
Sleep restriction.

Both of these strategies seek to limit the time spent in bed that does not involve sleeping. Several large randomized trials and meta-analyses provide the evidence base for the efficacy of cognitive behavioral therapy (CBT) for insomnia (CBT-I).Most of these trials have been in populations of patients without cancer.

Components of CBT-I include the following:

Cognitive restructuring.
Behavioral strategies.
Relaxation training.
Basic sleep hygiene education.

Relaxation therapy can be used to achieve both behavioral and cognitive outcomes, particularly when it is combined with imagery. Educational objectives around sleep hygiene are also used to treat insomnia and include content on the following:

Sleeping and waking up at regular times.
Relaxing before bedtime.
Creating a dark, comfortable sleep environment.
Avoiding watching television or working in the bedroom.
Getting ample daylight during nonsleep hours.
Avoiding naps.
Limiting caffeine.
Getting regular exercise but no closer than 3 hours before bedtime.

Other actions or interventions that may promote rest in the hospital or extended-care setting include the following:

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 activity and being out of bed as much as possible during waking hours.
Encouraging the patient to keep regular bedtime and waking hours and avoid napping during the day.
Minimizing and coordinating necessary bedside contacts.

Pharmacological Management of Sleep-Wake Cycle Disturbances

When cancer survivors experience sleep-wake disturbances, cognitive behavioral intervention counseling should be the first consideration for management. Resources for education and training in CBT may not be readily available in many cancer centers; therefore, community resources need to be investigated. If CBT is not available or has not been successful, pharmacological management can be considered. In addition, when patients have comorbidities contributing to sleep-wake cycle disturbances (such as hot flashes, uncontrolled pain, anxiety, depression, or other mood disturbances), then pharmacological management will probably be necessary. While many pharmacological agents are approved for primary insomnia and many others are used off-label to manage sleep and related symptoms, most of the approved sleep aids have not been studied in cancer populations; therefore, the risk/benefit profiles of these drugs are not delineated in this setting.

Despite the lack of evidence in cancer populations, clinicians widely use pharmacological interventions. Therefore, the following discussion of pharmacological agents and recommendations for use is based on evidence from studies conducted in patients with primary insomnia and clinical experience.

Several classes of medications are used to treat sleep-wake cycle disturbances, including the following:

Nonbenzodiazepine benzodiazepine receptor agonists (e.g., zolpidem).
Benzodiazepines (e.g., lorazepam).
Melatonin receptor agonists (e.g., ramelteon).
Antihistamines (e.g., hydroxyzine).
Antidepressants (e.g., trazodone) and antipsychotics (e.g., quetiapine) that have sedative effects.

Drug characteristics to consider before a drug is chosen to treat an individual patient include the following:

Absorption.
Time to reach maximum concentration.
Elimination half-life.
Receptor activity.
Ability to cross the blood-brain barrier.
Dose and frequency.
Formulation (short-acting versus long-acting).

These pharmacokinetic principles are important to match the agent to the type of sleep disturbance (e.g., problems falling asleep versus problems staying asleep). There are also safety issues to be considered, such as potentials for tolerance, abuse, dependence, withdrawal (including risk of rebound insomnia), and drug-drug and drug-disease interactions. Medications for sleep-wake cycle disturbances should be used short term and/or as needed.

General considerations for the use of hypnotics

Medications used to induce sleep are intended for the short-term management of sleep disorders. The use of these medications for longer periods is poorly studied. They are usually combined with lifestyle changes that reinforce good sleep habits and negate the need for chronic hypnotic medications.

Most research studies of current and historic hypnotic medications rarely exceed a duration of 12 to 16 weeks. Additionally, no current hypnotic re-creates normal sleep architecture, and variations from normal periods of rapid eye movement (REM) sleep and non-REM sleep are common. It is important to taper hypnotic medications slowly, or the variations in normal sleep patterns can become even more pronounced, with the majority of time spent in REM sleep in a condition known as REM rebound

Nonbenzodiazepine benzodiazepine receptor agonists

All agents in this class are FDA approved for primary insomnia. These agents promote sleep by enhancing the effects of gamma-aminobutyric acid (GABA) at the GABA type A (GABAA) receptor. Unlike traditional benzodiazepines, these agents preferentially target specific GABAA receptor subtypes. Zolpidem and zaleplon bind predominantly to the alpha-1 subtype of GABAA, and eszopiclone preferentially targets the alpha-3 receptor subtype. This selective receptor subtype targeting has both advantages and disadvantages. These agents have mainly hypnotic/sedative effects and lack the anxiolytic, anticonvulsant, and myorelaxant effects seen with benzodiazepines. Conversely, because of the selective receptor subtype targeting, these agents have fewer effects on cognitive and psychomotor function and carry less risk of tolerance, dependence, and withdrawal (especially physical withdrawal) than benzodiazepines.

These agents may be preferred for use in patients with cancer when only hypnotic effects are desired and should be taken just before bedtime (or even in bed) because they enter the brain very quickly. Some of these agents (e.g., zaleplon) have a short elimination half-life. Because of their longer-lasting effects, zolpidem extended-release and eszopiclone are preferred in the treatment of difficulty staying asleep. However, these agents carry a higher risk of residual morning sedation and cognitive/motor impairments than do agents with shorter elimination half-lives (e.g., zaleplon and immediate-release zolpidem).

Benzodiazepines

Benzodiazepines target several GABAA receptor subtypes, including alpha-1, -2, -3, and -5, and work by enhancing GABA effects at these receptors. In addition to hypnotic/sedative effects, these agents also have anxiolytic, anticonvulsant, and myorelaxant effects. Benzodiazepines are preferred when other effects (such as antianxiety or muscle relaxation) are desirable with or without the hypnotic effects.

Benzodiazepines carry a much higher risk of tolerance, dependence, and withdrawal than nonbenzodiazepine receptor agonists. Benzodiazepine withdrawal has been associated with the risk of seizures, delirium tremens, autonomic instability, and death. These agents should be used with extreme caution and close monitoring in patients with histories of significant substance use because of potential tolerance and dependence issues. Benzodiazepines have also been associated with cognitive impairment and difficulties with motor coordination.

Generally, benzodiazepines with longer half-lives (e.g., clonazepam) are associated with a higher risk of residual morning sedation and cognitive/motor impairments. Agents with shorter elimination half-lives (e.g., lorazepam) are generally preferred for short-term anxiolytic effects and difficulties falling asleep and in older patients. Agents with longer half-lives (e.g., clonazepam) are preferred for the treatment of persistent anxiety and difficulties falling and staying asleep. All benzodiazepines are associated with risk of respiratory depression and should be used with caution in patients with preexisting respiratory disorders.

Melatonin receptor agonists: Ramelteon and tasimelteon

Ramelteon and tasimelteon work by binding to the melatonin receptor types MT1 and MT2. Ramelteon is useful only for the treatment of difficulties falling asleep and does not have any other effects, such as anxiolytic or myorelaxant effects. Tasimelteon is indicated for use in circadian sleep disorder. These agents do not treat difficulties staying asleep but also carry much less risk of cognitive/motor impairments and dependence.

Antihistamines

Diphenhydramine and hydroxyzine decrease arousal by blockading histamine receptors. Antihistamines are sold over the counter and are useful for treating difficulties in falling asleep only. There is limited evidence for the use of antihistamines to treat insomnia; these agents are used when traditional hypnotics or benzodiazepines are less suitable because of the risk of cross-dependence or other issues, such as vulnerability of a patient to addictions. The anticholinergic properties of antihistamines may also be beneficial in the treatment of nausea and vomiting. The sedative and anticholinergic properties of these agents increase the risk of delirium, especially in older patients.

Antidepressants

Sedating antidepressants are considered first-line agents when insomnia is comorbid with depression/anxiety symptomatology. These drugs include tricyclic antidepressants (e.g., amitriptyline) and second-generation antidepressants (e.g., mirtazapine). The sedating effects of tricyclic antidepressants are caused mainly by histamine receptor blockading and partially by blockading of 5-HT2 and muscarinic receptors. The sedating effects of mirtazapine are caused by its blocking of 5-HT2 and histamine receptors, while those of trazodone are caused by its blocking actions at the at histamine, 5-HT, and noradrenaline receptors.

Tricyclic antidepressants have a small therapeutic window and can be lethal in overdose, compared with second-generation antidepressants such as mirtazapine. Additionally, tricyclics carry other risks, such as weight gain, anticholinergic side effects, and cardiovascular side effects, and should be used under close supervision. These agents sometimes are used in low doses as adjuncts to other antidepressants to treat insomnia comorbid with depression/anxiety. This helps to avoid the side effects associated with higher doses while delivering the needed sedating effects. Tricyclics can also boost appetite and may be the treatment of choice for insomnia in patients with comorbid cachexia. Certain tricyclics (amitriptyline and nortriptyline) can also be beneficial in the treatment of pain syndromes (e.g., neuropathic pain) and headaches when these issues are comorbid with insomnia. Low doses of antidepressants (subtherapeutic for depression) are frequently used to treat insomnia without any comorbidities.

Mirtazapine has appetite-stimulating and antiemetic properties in addition to sedating effects. It is frequently used in insomniac patients with depression (therapeutic dose for depression, 15–45 mg) or without depression (subtherapeutic dose for depression, 7.5–15 mg) with comorbid nausea or loss of appetite. In low doses, trazodone (50–100 mg) can promote sleep and is often combined with other antidepressants (e.g., fluoxetine 20 mg in the morning) in depressed patients with insomnia.

Antipsychotics

Antipsychotics such as quetiapine have sedating effects caused mainly by the blockade of histamine receptors. However, these agents should be considered as a last resort and as a short-term treatment because of their serious side-effect profile. The use of antipsychotics has been associated with the following:

Weight gain.
Metabolic syndrome.
Diabetes.
Cardiovascular risks.
The risk of extrapyramidal side effects, including tardive dyskinesia.

Antipsychotics can be considered for treatment-refractory insomnia, especially with comorbid anxiety symptomatology.

Chloral derivative: Chloral hydrate

Chloral hydrate has sleep-promoting effects resulting from its effects on GABA systems. It is associated with risk of withdrawal symptoms similar to those of benzodiazepines and with rapid development of tolerance. Additionally, chloral hydrate carries the risk of gastric irritation and multiple drug interactions, and it is lethal in overdose. Like antipsychotics, chloral hydrate is usually considered only in cases of treatment-refractory insomnia because of its serious side-effect profile and the availability of safer alternatives.

Botanical/dietary supplements: Melatonin

Melatonin, a hormone produced by the pineal gland during the hours of darkness, plays a major role in the sleep-wake cycle and has been linked to the circadian rhythm. A review found that short-term use of melatonin appears to be safe; however, the studies were not conducted in the context of cancer therapy.Adjuvant melatonin may also improve sleep disruption caused by drugs known to alter normal melatonin production (e.g., beta-blockers and benzodiazepines). However, a meta-analysis of 25 studies exploring the efficacy and safety of melatonin in managing secondary sleep disorders or sleep disorders accompanying sleep restriction found that melatonin was not effective in these conditions.

Evidence suggests that circulating melatonin levels are 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 older patients. A slow-release formulation of melatonin is licensed in Europe and is approved as monotherapy for patients aged 55 years or older for the short-term treatment (up to 13 weeks) of primary insomnia characterized by poor-quality sleep. However, melatonin replacement as a treatment for insomnia has not been studied in older people with cancer. Ramelteon and tasimelteon work via the melatonin receptor system: ramelteon to support the initiation of sleep, and tasimelteon to correct circadian sleep disorder.

Melatonin may interact with certain chemotherapeutic regimens via the cytochrome P450 enzyme and other systems. It may augment the effects of some chemotherapeutic agents metabolized via the enzyme CYP1A2 and may exert inhibitory effects on P-glycoprotein–mediated doxorubicin efflux.

Clinical studies in individuals with renal, breast, colon, lung, and brain cancer suggest that melatonin exerts anticancer effects in conjunction with chemotherapy and radiation therapy; however, evidence remains inconclusive. All of the studies suggesting antitumor effects of melatonin have been conducted by the same group of investigators and were open label. Efforts by independent groups of investigators are under way to investigate these effects in carefully designed, randomized, blinded studies. In vitro and animal studies have demonstrated the anticancer effects of exogenous melatonin, and lower melatonin levels are associated with tumor growth. Human studies have yet to substantiate any causal or associative relationships.

Cannabis and cannabinoids

No studies have been conducted to specifically evaluate the effects of Cannabis inhalation or other Cannabis products in patients with primary or secondary sleep disturbances. Limited data from in vitro studies, animal studies, and small populations of healthy individuals or chronic Cannabis users are beginning to elucidate some of the relationships among various neurotransmitters, the sleep-wake cycle, and related effects of Cannabis pharmacology.

Cannabis-based medicines are under development as a treatment for chronic pain syndromes, including cancer-related pain. One such medication is nabiximols (Sativex), an oromucosal formulation (delta-9-tetrahydrocannabinol and cannabidiol mixed in a 1:1 ratio). Studies conducted with nabiximols, primarily focusing on pain syndromes, have shown improvement in subjective sleep quality when sleep was measured as a secondary outcome. Comorbidities such as pain are common reasons for sleep disturbances. Concerns have been raised about the abuse and dependence potential of nabiximols, especially in the subpopulation of patients with histories of Cannabis use. Nabiximols is approved in Canada for the treatment of central neuropathic pain in patients with multiple sclerosis. In the United States, it is only available for investigational use and is currently under investigation for the treatment of intractable cancer pain.