Nonpharmacologic Management of Sleep Disturbances
Inpatient nonpharmacologic management
Pharmacologic Management of Sleep-Wake Cycle Disturbances
Nonbenzodiazepine benzodiazepine receptor agonists (so-called Z-drugs)
Melatonin receptor agonist: Ramelteon
Chloral derivative: Chloral hydrate
Current Clinical Trials
Management of sleep disturbances should focus on treatment of problems with falling asleep, staying asleep, or early morning awakenings. Other areas to manage include symptoms from cancer and its treatment, and the identification and management of environmental and psychological factors. 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
Several large, randomized trials and meta-analyses provide the evidence base for the efficacy of cognitive behavioral therapy (CBT) for insomnia (CBT-I).[1-3] Almost all of these trials have been in populations of patients without cancer. Components of CBT-I include the following:
- Cognitive restructuring.
- Behavioral strategies.
- Basic sleep hygiene education.
Cognitive strategies include restructuring negative thoughts, beliefs, and attitudes related to sleep and preventing excessive monitoring or worrying about getting enough sleep. Behavioral strategies include stimulus control and sleep restriction. Both of these strategies seek to limit time spent in bed that does not involve sleeping.[1,4,5]
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.
Practice guidelines from the American Academy of Sleep Medicine clearly state that multicomponent therapy is recommended over single therapies. Because of insufficient evidence about its efficacy, sleep hygiene education should not be recommended as a single-modality management approach; other reviews state that sleep hygiene by itself is not effective.[2,6] Information about sleep hygiene, although not sufficient alone to combat sleep disturbances, should be included as a foundation of education related to sleep issues.
A four-arm study that evaluated zolpidem (Ambien) versus CBT versus zolpidem and CBT versus placebo reported a greater effect (P = .05) on sleep-onset latency for both groups involving CBT (change of 44%) versus the group receiving zolpidem alone (change of 29%). Another study evaluated CBT with temazepam alone versus a combination of CBT and temazepam versus placebo and found that all active treatments were significantly better than placebo and that there was a trend for the most improvement in the combined arm of CBT and temazepam. Both arms with CBT demonstrated greater reductions in time to sleep onset than did the pharmacotherapy-alone arm (64% combined arm, 55% CBT arm, and 47% temazepam arm). A meta-analysis examining pharmacologic and behavioral studies for persistent insomnia found that pharmacologic and behavioral treatments did not differ in magnitude of benefit except for latency to sleep onset, in which greater reductions were found with behavioral therapy.
There are limited data evaluating elements of CBT-I in cancer survivors, and most of the data that exist are about women with breast cancer. However, there have been at least four randomized, controlled trials of CBT-I in cancer survivors.[12-15] The intervention was typically delivered over 5 to 8 weekly, small-group, in-person sessions. Only one of these trials included patients with cancer diagnoses other than breast cancer, and results did not differ by cancer diagnosis. All studies showed improvements in numerous sleep parameters over time in the groups receiving CBT-I and demonstrated continued benefits 6 and 12 months later. Two of the four trials did not use active control arms.[12,14]
Both of the studies using active control arms were in breast cancer survivors. One study compared CBT-I with sleep education and hygiene in 72 women, while the other study used a healthy-eating education control group. In the study comparing CBT-I with sleep education and hygiene, both groups significantly improved over time, with some significant differences between groups favoring CBT-I for time to fall asleep, time awake after sleep, total sleep time, and overall sleep quality. For example, the group receiving CBT-I improved by 30 minutes in time to fall asleep, compared with 11 minutes in the sleep education and hygiene group.
In the study utilizing the healthy-eating education control, 219 women were randomly assigned to a behavioral therapy group consisting of stimulus control, general sleep hygiene (limiting naps, going to bed and rising at consistent times), and relaxation or to a healthy-eating education control group. The interventions were delivered by trained nurses in person, 2 days before the initiation of chemotherapy and before each chemotherapy treatment as well as 30 days after the last chemotherapy treatment. The nurses worked with women assigned to behavioral therapy to individualize and reinforce the behaviors. The Pittsburgh Sleep Quality Index (PSQI) was used to measure subjective sleep quality but was complemented by use of a sleep diary and wrist actigraph. Sleep quality significantly improved in the group receiving behavioral therapy, compared with the control group. These differences were also seen in data from the sleep diary and actigraph, with both showing significantly fewer awakenings in the behavioral therapy group. Sleep quality was significantly better at 90 days and 1 year in the behavioral therapy group, as measured by the PSQI but not the diary or actigraph.
In a small randomized trial of 20 postmenopausal women receiving hormonal treatment for breast cancer, sleep scores on the PSQI improved more with a home-based walking intervention than with usual care. Exercise is one of the elements of sleep hygiene.Inpatient nonpharmacologic management
CBT delivered by psychologists has shown promise for the treatment of insomnia in patients with cancer.[Level of evidence: I] A randomized controlled study investigated the effectiveness of a protocol-driven cognitive behavioral intervention for insomnia delivered by oncology nurses.[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, compared with patients receiving treatment as usual.[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.[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.
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.[Level of evidence: IV
- 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 the bed as much as possible during waking hours.
- Encouraging the patient to keep regular bedtime and awakening hours and avoid napping during the day.
- Minimizing and coordinating necessary bedside contacts.
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.[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.Pharmacologic Management of Sleep-Wake Cycle Disturbances
When cancer survivors experience sleep-wake disturbances, cognitive behavioral intervention counseling should be the first consideration for management. (Refer to the Nonpharmacologic Management of Sleep Disturbances section of this summary for more information.) It is acknowledged that resources for education and training in CBT may not be readily available in many cancer centers, and therefore community resources need to be investigated. In areas where CBT is not available or has been utilized but has not been successful, pharmacologic 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),[24,25] then pharmacologic management will probably be necessary. While many pharmacologic agents are approved for primary insomnia and many other agents 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, pharmacologic interventions are widely used by clinicians. Therefore, the following discussion of pharmacologic agents and recommendations for use is based on evidence from studies conducted in patients with primary insomnia and clinical experience.[4,26,27]
Several classes of medications are used to treat sleep-wake cycle disturbances:
- 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 that should be taken into account before a drug is chosen to treat an individual patient include the following:
- 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 for the matching of agents 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.
The table below lists the medication categories and specific medications, including doses, commonly used within those categories.Medications Commonly Used to Promote Sleep
|Nonbenzodiazepine benzodiazepine receptor agonist||zaleplon (Sonata)||5–20 mg||Useful for problems falling asleep only.|
|zolpidem tartrate (Ambien)||5–10 mg||Useful for problems falling asleep only.|
|zolpidem tartrate extended-release (Ambien CR)||6.25–12.5 mg||Biphasic release; useful for problems both falling asleep and staying asleep; do not crush or split tablets.|
|eszopiclone (Lunesta)||1–3 mg||Useful for problems both falling asleep and staying asleep; do not take with or right after meal.|
|Benzodiazepine||alprazolam (Xanax)||0.25–2 mg||Higher risk of withdrawal; side effects: lack of motor coordination, falls, and cognitive impairment.|
|lorazepam (Ativan)||0.5–4 mg||Side effects: lack of motor coordination, falls, and cognitive impairment.|
|clonazepam (Klonopin)||0.5–4 mg||Side effects: lack of motor coordination, falls, and cognitive impairment.|
|temazepam (Restoril)||15–30 mg||Side effects: lack of motor coordination, falls, and cognitive impairment.|
|Melatonin receptor agonist||ramelteon (Rozerem)||8 mg||Little negative effect on cognition, somnolence, motor coordination, or nausea; useful for problems falling asleep only.|
|Antihistamine||diphenhydramine (Benadryl)||25–100 mg||Useful for problems falling asleep only; good side-effect profile.|
|hydroxyzine (Vistaril, Atarax)||10–100 mg||Useful for problems falling asleep only; anticholinergic side effects.|
|Tricyclic antidepressant||doxepin (Sinequan)||10–25 mg||Lower doses used for treatment of primary insomnia when antidepressant effect not needed; risk of anticholinergic side effects and weight gain.|
|amitriptyline (Elavil)||10–15 mg||Lower doses used for treatment of primary insomnia when antidepressant effect not needed; risk of anticholinergic side effects and weight gain.|
|nortriptyline (Pamelor)||10–50 mg||Risk of anticholinergic side effects and weight gain.|
|Second-generation antidepressant||trazodone (Desyrel)||25–200 mg||Risk of orthostatic hypotension and falls.|
|mirtazapine (Remeron)||7.5–45 mg||If depression not a concern, 7.5–15 mg best for sleep, hot flashes, increased appetite, and less morning sedation. Be aware of fall risk.|
|Antipsychotic||quetiapine (Seroquel)||25–100 mg||Risk of weight gain, metabolic syndrome, abnormal/involuntary movements; possible cardiovascular effects (e.g., prolonged QT interval).|
|chlorpromazine (Thorazine)||10–50 mg||Risk of weight gain, metabolic syndrome, abnormal/involuntary movements; possible cardiovascular effects (e.g., hypotension).|
|Chloral derivative||chloral hydrate||0.5–1.0 g||Used mainly for sleep maintenance; risk of gastric irritation; risk of dependence and withdrawal; lethal in overdose.|
Nonbenzodiazepine benzodiazepine receptor agonists (so-called Z-drugs)
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 (e.g., lorazepam), the Z-drugs 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. The Z-drugs 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, psychomotor function and carry less risk of tolerance, dependence, and withdrawal (especially physical withdrawal) than do benzodiazepines.[4,26,27]
The Z-drugs are 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 difficulties in 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 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 relaxant effects) are desirable with or without the hypnotic effects.[4,26,27]
Benzodiazepines carry a much higher risk of tolerance, dependence, and withdrawal than do the Z-drugs. 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 with close monitoring in patients with histories of significant substance use because these patients are vulnerable to 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 elderly 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 agonist: Ramelteon
Ramelteon, the only agent in this class, works by binding to the melatonin receptors. This agent is useful only for the treatment of difficulties falling asleep and does not have any other effects such as anxiolytic or myorelaxant effects. Ramelteon does not treat difficulties staying asleep but also carries much less risk of cognitive/motor impairments and dependence issues.[26,27]Antihistamines
Diphenhydramine and hydroxyzine work by decreasing 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.[26,27]Antidepressants
Sedating antidepressants are considered first-line agents when insomnia is comorbid with depression/anxiety symptomatology. (Refer to the Pharmacologic Intervention section in the PDQ summary on Depression for more information.) 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.[4,26,27]
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 risk of weight gain, anticholinergic side effects, and cardiovascular side effects and should be used under close supervision. These agents sometimes are used in low doses (see table) as adjuncts to other antidepressants in the treatment of 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, a second-generation antidepressant, also 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 doses for depression, 7.5–15 mg) with comorbid nausea or loss of appetite. 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.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 weight gain, metabolic syndrome, diabetes, cardiovascular risks, and 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 is associated with rapid development of tolerance. Additionally, chloral hydrate carries the risk of gastric irritation and multiple drug-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, 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. Adjuvant melatonin may also improve sleep disruption caused by drugs known to alter normal melatonin production (e.g., beta-blockers and benzodiazepines).[Level of evidence: IV] Supplementation with melatonin (2–4 mg in the evening) has been shown to improve sleep in children with endocrine tumors that diminish the natural production of the hormone.[Level of evidence: II] 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 either of these conditions. The review found that short-term use of melatonin appears to be safe. However, these studies were not conducted in the context of cancer therapy.
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 elderly patients.[Level of evidence: II] 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.
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 renal, breast, colon, lung, and brain cancer suggest that melatonin exerts anticancer effects in conjunction with chemotherapy and radiation therapy; however, evidence remains inconclusive.[34,35] 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 between various neurotransmitters and the sleep-wake cycle and related effects of Cannabis pharmacology.[37,38]
Cannabis-based medicines are under development as a treatment for chronic pain syndromes, including cancer-related pain. One such medication under investigation 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.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
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