Nonpharmacologic Management of Sleep Disturbances
Pharmacologic Management of Sleep Disturbances

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.

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]

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] 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] Communication, verbalization of concerns, and openness between the patient, family, and health care team should be encouraged.

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.[6] 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.

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.[1,7]

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. To date, 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.[8]

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] 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 or THC) are similar to conventional hypnotics in reducing REM sleep; however, side effects experienced before sleep induction and hangover make the use of THC less acceptable than benzodiazepines.[9]

Low-potency neuroleptics (e.g., thioridazine 10–25 mg) 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.[10]

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.[11,12] 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).[11]

Melatonin replacement has been shown to improve sleep in children with endocrine tumors that diminish the natural production of the hormone.[12] 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.[13] 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.[14] 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.[15] Melatonin replacement, however, has not been studied in older people with cancer as a treatment for insomnia.

References

1. Savard J, Morin CM: Insomnia in the context of cancer: a review of a neglected problem. J Clin Oncol 19 (3): 895-908, 2001.  [PUBMED Abstract]
   
   
2. Page M: Sleep pattern disturbance. In: McNally JC, Stair JC, Somerville ET, eds.: Guidelines for Cancer Nursing Practice. Orlando, Fla: Grune and Stratton, Inc., 1985, pp 89-95. 
   
   
3. Kaempfer SH: Insomnia. In: Baird SB, ed.: Decision Making in Oncology Nursing. Philadelphia, Pa: B.C. Decker, Inc., 1988, pp 78-9. 
   
   
4. Berlin RM: Management of insomnia in hospitalized patients. Ann Intern Med 100 (3): 398-404, 1984.  [PUBMED Abstract]
   
   
5. Horowitz SA, Breitbart W: Relaxation and imagery for symptom control in cancer patients. In: Breitbart W, Holland JC, eds.: Psychiatric Aspects of Symptom Management in Cancer Patients. Washington, DC: American Psychiatric Press, 1993, pp 147-71. 
   
   
6. Jefferson CD, Drake CL, Scofield HM, et al.: Sleep hygiene practices in a population-based sample of insomniacs. Sleep 28 (5): 611-5, 2005.  [PUBMED Abstract]
   
   
7. Anderson P, Grant M: Comfort: Sleep. In: Johnson BL, Gross J, eds.: Handbook of Oncology Nursing. 3rd ed. Boston, Mass: Jones & Bartlett Publishers, 1998, pp 337-59. 
   
   
8. Jacobsen PB, Massie MJ, Kinne DW, et al.: Hypnotic efficacy and safety of triazolam administered during the postoperative period. Gen Hosp Psychiatry 16 (6): 419-25, 1994.  [PUBMED Abstract]
   
   
9. Hollister LE: Health aspects of cannabis. Pharmacol Rev 38 (1): 1-20, 1986.  [PUBMED Abstract]
   
   
10. Hayter J: Advances in sleep research: implications for nursing practice. In: Tierney AJ, ed.: Recent Advances in Nursing: Clinical Nursing Practice. Edinburgh, Scotland: Churchill Livingstone, 1986, pp 21-43. 
    
    
11. Dawson D, Encel N: Melatonin and sleep in humans. J Pineal Res 15 (1): 1-12, 1993.  [PUBMED Abstract]
    
    
12. Jan JE, Espezel H, Appleton RE: The treatment of sleep disorders with melatonin. Dev Med Child Neurol 36 (2): 97-107, 1994.  [PUBMED Abstract]
    
    
13. Lissoni P, Meregalli S, Nosetto L, et al.: Increased survival time in brain glioblastomas by a radioneuroendocrine strategy with radiotherapy plus melatonin compared to radiotherapy alone. Oncology 53 (1): 43-6, 1996 Jan-Feb.  [PUBMED Abstract]
    
    
14. Haimov I, Lavie L: Melatonin-a chronobiotic and soporific hormone. Arch Gerontol Geriatr 24 (2): 167-73, 1997. 
    
    
15. Haimov I, Lavie P, Laudon M, et al.: Melatonin replacement therapy of elderly insomniacs. Sleep 18 (7): 598-603, 1995.  [PUBMED Abstract]
    
    

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