It is estimated that nearly 45% of oncology patients experience sleep disturbances; this is nearly three times the estimate of its occurrence in the general population (National Cancer Institute, 2010). Sleep problems can be both physiological and psychological in nature, which can make the diagnosis and treatment of these disorders difficult. While the source of sleep disturbances can be complex, it is essential to identify and treat sleep disorders in cancer patients, as it can influence factors like the perception of physical symptoms, tolerance of treatment measures, and quality of life (Stepanski, Walker, Schwartzberg, Blakely, Ong, & Houts, 2008).
The American Academy of Sleep Medicine defines sleep disturbance as "difficulty initiating sleep, difficulty maintaining sleep, waking up too early, or sleep that is chronically non-restorative or poor in quality" (Berger, 2009, p. 166). In general, any real or perceived disruption in sleep pattern that results in altered daytime function, as defined by the patient, is considered a sleep disturbance (Berger). While there can be physiological and psychological sources of sleep pattern disruption, oncology patients are at an increased risk for physiologic disturbances, as the "cancer process may play a prominent role in disrupting sleep, circadian rhythms, and hypothalamic-pituitary-adrenal axis-regulated processes" (Berger, p. 165).
Identifying the potential cause of the sleep disturbance is necessary in order to determine the best means of treatment available. Symptoms of sleep disruption that are most commonly reported by patients in the oncology setting include: excessive fatigue, leg restlessness, insomnia, and excessive sleepiness (Parish, 2009). Physiologic sources of sleep disruption can include treatment side effects, tumor progression, thermoregulation disruption, and alteration in system function, such as the gastrointestinal and genitourinary systems (National Cancer Institute).
Stephen Stahl (2008) categorizes sleep pattern disruption into two categories, excessive nighttime arousal and deficient daytime arousal. There are two key neurotransmitters that regulate sleep-wake patterns: histamine and GABA (Stahl). Increased histamine production during the day controls the wake pattern, while increased GABA production at night allows for the regulation of sleep patterns (Stahl). The other primary influence on sleep-wake patterns is the hypothalamus, which is "the body's internal clock that is activated by melatonin, light, and activity to promote either sleep or wake" (Stahl, p. 822).
Sleep patterns become disrupted when neurotransmitter production is deficient. At night, too much histamine production and not enough GABA production can lead to insomnia, while during the day, too much GABA production and not enough histamine production can lead to excessive sleepiness (Stahl).
Sleep disturbances are defined as any alterations in sleep patterns that lead to a disruption in daytime function (Berger). It is essential to consider potential differential diagnoses for sleep pattern disruption even in cancer patients. Possible differential diagnoses include hyperthyroidism, gastroesophageal reflux disease or gastric ulcer, congestive heart failure, chronic obstructive pulmonary disease, bipolar affective disorder, and use of stimulants such as caffeine (Stahl).
Further investigation into the potential secondary physiologic sources of sleep disturbances is necessary. Secondary sources of sleep disruption are cancer related symptoms (i.e. pain), treatment related side effects (i.e. nausea, diarrhea), environmental and lifestyle factors, and emotional status and mood. Pain is one of the most common secondary sources of sleep disruption in cancer patients (Mills & Gracie, 2004). It is important to determine primary and secondary causes of sleep disturbances in order to determine the most effective means of treatment.
Pain is one of the primary sources of sleep disturbances in cancer patients (Mills, et al). The two principal sources of pain are disease progression and treatment side effects. Disease progression can lead to bone and nerve pain, while treatment-related side effects like mucositis and peripheral neuropathies can cause pain (Mills, et al). In addition, advancing disease can cause sleep disruption through presenting symptoms. For example, lung cancer can lead to respiratory problems like airway obstruction and dyspnea, while tumor progression in prostate cancer can produce genitourinary changes that lead to altered sleep-wake patterns secondary to symptoms like frequent urination (National Cancer Institute).
Treatment side effects can be caused by chemotherapy, radiation therapy, medication, hormonal therapy, and surgery. Radiation therapy often can lead to fatigue and interrupted sleep patterns, while chemotherapy agents, such as antimetabolites, can lead to insomnia (Mills, et al). Furthermore, side effects of chemotherapy, like diarrhea and nausea and vomiting, can be a source of sleep disturbances due to disrupted sleep cycles (National Cancer Institute). In a study conducted by Savard, et al (2009), women receiving anthracycline-based chemotherapy were assessed for sleep-wake pattern disturbances by evaluating their circadian rhythms. Sleep patterns were monitored prior to treatment onset and during three weeks of cycles 1 and 4 of chemotherapy. It was determined that initially sleep-wake patterns were disrupted, and progressively sleep-wake patterns worsened as the number of treatments received increased (Savard, et al).
Alterations in hormones can lead to poor sleep due to night sweats and hot flashes; sources of these alterations include surgery and hormonal therapies. Hysterectomy and oophorectomy are surgical procedures that can drastically alter hormone levels by inducing menopause (Mills, et al). Androgen deprivation therapy is a hormonal treatment that is used in prostate cancer and that can lead to hot flashes due to changes in testosterone levels (Yarbro, Frogge, & Goodman, 2005). Medications, such as corticosteroids, opioids, and thyroid replacement therapies, can also lead to sleep pattern disruptions (National Cancer Institute).
While physiologic sources are a primary cause of sleep disturbances, it is important to assess all factors that could be influencing sleep-wake patterns. Environmental factors, such as room temperature and noise, can significantly affect oncology patients, specifically in the hospital setting (National Cancer Institute). Other factors that can influence sleep are diet, exercise, sleep routines, and emotional state (National Cancer Institute).
In recent years, it has been identified that emotional status and mood play a significant role in the alteration of sleep patterns in patients with cancer (Stepanski, et al). Furthermore, there is a strong correlation between sleep disturbances, depression, and pain (Stepanski, et al). Pain and depression are associated with poor sleep, while decreased sleep can lead to worsening depression and pain (Palesh, Collie, Batiuchok, Tilston, Koopman, Perlis, et al, 2007). The relationship between increasing life stress, incidence of depression, and disrupted sleep has been determined and can have a significant effect on cancer patients' quality of life (Palesh, et al).
In a study conducted at the University of California San Diego, breast cancer patients undergoing chemotherapy were evaluated for the presence of a symptom cluster (that included sleep disturbances, fatigue, and depression) prior to starting treatment and after (Liu, Fiorentino, Natarajan, Parker, Mills, Sadler, et al, 2009). The Pittsburgh Sleep Quality Index was used to measure sleep disturbances, the Multidimensional Fatigue Symptom Inventory-Short Form was used to calculate fatigue, and the Center of Epidemiological Studies-Depression was used to determine the presence of depressive symptoms (Liu, et al). The study concluded that there was a considerable increase in the number of women who experienced symptoms during treatment than prior to starting chemotherapy (Liu, et al). Another significant finding was that women who had symptoms prior to treatment had clinically worse symptoms during treatment, which adversely affected their quality of life (Liu, et al). The study concluded that early identification and treatment of the sleep disturbance-fatigue-depression symptom cluster would lead to a decrease in the severity of symptoms and improve patients' overall quality of life (Liu, et al).
Another symptom cluster determined to have a significant impact on oncology patients' quality of life was the insomnia-fatigue-pain-depression symptom cluster, studied by Stepanski, et al. There was a direct correlation between depression and fatigue symptoms, while depression also influenced pain and sleep disturbances (Stepanski, et al). The study concluded that the treatment of depression could considerably improve pain and fatigue symptoms in this patient population and improve quality of life (Stepanski, et al).
Treatment of the primary source of sleep disturbances is essential, whether it be physiologic or psychological in nature. Due to the various causes of sleep pattern disruption, treatment measures include both pharmacologic and non-pharmacologic regimens. Pharmacologic management primarily focuses on the treatment of symptoms, while non-pharmacologic management focuses on lifestyle changes and psychosocial interventions (National Cancer Institute).
Pharmacologic management of sleep disturbances primarily promote the mechanisms of GABA or inhibit the mechanism of histamine (Stahl). GABA promoting drugs include zolpidem, eszopiclone, and benzodiazepines like temazepam and estazolam (Stahl). Histamine inhibiting drugs include the antidepressant trazodone and the antihistamine diphenhydramine (Stahl). Primary side effects of GABA promoting agents are amnesia, increased impulsivity, headache, increased appetite, and residual "hangover" effect in the morning (Stahl). Primary side effects of histamine reducing agents are memory problems, dry mouth, and blurred vision (Stahl).
Symptom management for sleep disturbances secondary to disease progression and treatment side effects is also essential. Symptoms that can be pharmacologically managed would include dyspnea, pain, nausea and vomiting, and hormone alterations. Opioids are used in the treatment of pain related to disease progression and the management of dyspnea. Pain related to nerve pathway involvement can be treated with Gabapentin. Gabapentin has also proven to be effective in the treatment of hot flashes in both men and women, as are selective serotonin reuptake inhibitors (SSRI's) and selective norepinephrine reuptake inhibitors (SNRI's) (Aleksun & Patterson, 2006). Antiemetics, such as Zofran, are used to decrease symptoms of nausea and vomiting associated with chemotherapy treatments (Yarbro, et al).
Pharmacologic treatment measures are also used in the management of depression and anxiety in oncology patients with sleep pattern alterations. Benzodiazepines are used as anxiolytics, and are also one of the primary treatment measures for insomnia (Hirst & Sloan, 2009). Antidepressants that have been proven to have secondary sleep benefits include second-generation antidepressants, like mirtazapine, and tricyclic antidepressants, like amitriptyline. Primary side effects of these agents include weight gain, dry mouth, and dizziness (Stahl).
Table of Commonly Used Pharmacologic Sleep Aids:
|Generic Name||Brand Name||Class of Drug||Most Common Side Effects||Usual Dose Range|
|clonazepam||Klonopin||Benzodiazepine/ anticonvulsant||Drowsiness, behavior disturbances||0.5 - 2 mg|
|lorazepam||Ativan||Benzodiazepine/ anti-anxiety||Drowsiness, disorientation, amnesia, sedation||0.5 - 1 mg|
|alprazolam||Xanax||Benzodiazepine/ anti-anxiety||Drowsiness, light headedness, depression, dry mouth||0.25 - 1 mg|
|temazepam||Restoril||Benzodiazepine/ hypnotic||Drowsiness, dizziness, lethargy||15 - 30 mg|
|estazolam||ProSom||Benzodiazepine/ hypnotic||Drowsiness, dizziness, lethargy||0.5 - 1 mg|
|triazolam||Halcion||Benzodiazepine/ hypnotic||Drowsiness, dizziness, headache||0.125 - 0.5 mg|
|zaleplon||Sonata||Hypnotic/ non-benzodiazepine||Headache||5 - 10 mg|
|zolpidem||Ambien||Hypnotic/ non- benzodiazepine||Headache||5 - 10 mg|
|eszopiclone||Lunesta||Sedative/ non- benzodiazepine||dizziness||1 - 3 mg|
|diphenhydramine||Benadryl||Antihistamine||memory problems, dry mouth, and blurred vision||25 - 50 mg|
Finally, melatonin can be used to regulate sleep-wake patterns (National Cancer Institute). Melatonin is available without a prescription and helps with the onset of sleep (Stahl). Its effect on temperature regulation is an additional benefit of using melatonin as a sleep aid (National Cancer Institute). In addition, kava-kava and valerian are herbal agents promoted as sleep aids. It is important to note that while these agents may be an effective treatment measure for sleep-wake pattern disruption, herbal products and nutritional supplements are not required to undergo the same rigorous testing as prescription medications in order to meet government standards. Their long-term impact, side effects and possible interactions with other drugs or medical conditions are often not known.
Non-pharmacologic management of sleep disturbances can vary from lifestyle modifications to psychosocial interventions. Improved sleep hygiene, or behaviors that affect sleep-wake cycle, can lead to improved sleep patterns. Areas of sleep hygiene that can promote sleep include: avoiding alcohol and cigarettes, decrease the use of caffeine and other stimulants, avoid napping, set a regular schedule for exercise and sleep, and improve dietary measures, such as decreasing the intake of high fat and spicy food (Mills, et al). Psychological management strategies aimed at improving coping mechanisms and communication of oncology patients has shown to have a positive effect on sleep (National Cancer Institute). Other effective psychosocial interventions include progressive muscle relaxation and cognitive behavioral therapy (Berger).
The aim of cognitive behavioral therapy (CBT) is to teach patients techniques to change actions or beliefs that lead to insomnia. These beliefs can include unrealistic sleep requirements, the role of sleep disturbance in daytime impairment, and the usual pattern of insomnia. A randomized controlled trial was conducted to determine the effectiveness of treating insomnia with cognitive behavior therapy interventions (Epstein & Dirksen, 2008). When the intervention group comprised of breast cancer survivors was compared to the control group, there was a noted improvement in symptoms of insomnia (Epstein, et al). CBT includes several techniques to reassociate bedtime and the bed / bedroom with sleep and reestablish a regular sleep-wake cycle. This can be accomplished by developing a pre-bedtime ritual, going to bed only when sleepy, and when unable to fall asleep (or go back to sleep) after 20 minutes, leaving the bedroom and return when sleepy. Other tips are listed here. Maintain a regular wakeup time and try not to nap. When necessary, limit naps to 30 minutes and not after 3 pm. Use the bed for sleep and sexual activities only. Do not watch television, eat, or read in the bed. Sleep restriction procedures require the time spent in bed to be limited to only the amount of time one is sleeping. Curtailing the time in bed causes mild sleep deprivation, which can then lead to more efficient sleep.
Lastly, relaxation therapy, which includes muscle relaxation, biofeedback, imagery training, hypnosis, and thought stopping, is helpful in treating insomnia. Professionals who specialize in instructing these techniques may be available at local cancer centers or support communities, but patients can accomplish some of these techniques on their own. Patients may find deep breathing, stretching, meditation or prayer to be relaxing. A warm bath, warm glass of milk or cup of chamomile tea at bedtime can help to induce a restful state. Alcohol should be avoided, as it may cause initial tiredness, but then leads to fragmented sleep.
As the primary cause(s) of sleep disturbances can vary widely, so do the treatment measures. It is important to do a complete assessment as to the source of sleep pattern disruption, which includes a comprehensive physiologic and psychological history, prior to determining a course of treatment. Both pharmacologic and non-pharmacologic treatment measures should be utilized when dealing with sleep disturbances in the oncology patient setting.
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