Sleep disturbances in cancer patients: Underrecognized and undertreated
ABSTRACTSleep-related complaints are extremely common in patients with cancer but often are not recognized, and even if they are, they are seldom treated. Recognizing insomnia in cancer patients is imperative, as appropriate treatment can improve quality of life.
KEY POINTS
- Sleep disturbances, primarily insomnia, profoundly affect all aspects of quality of life.
- Insomnia can be caused or worsened by a number of other conditions, such as pain, fatigue, depression, and anxiety, and these in turn can be worsened by insomnia.
- Cognitive-behavioral therapy is the treatment of choice for chronic insomnia. Underlying problems should be addressed.
- Drugs are often prescribed to help cancer patients sleep but should be used with caution, as there is limited information from clinical trials in this population.
Cancer-related fatigue and insomnia
Cancer-related fatigue is a distressing, persistent, subjective sense of tiredness or exhaustion that is related to cancer or cancer treatment, that is not proportional to recent activity and that interferes with usual functioning.25 It has been reported by up to 90% of cancer patients in some studies.26–28
Cancer-related fatigue worsens quality of life and is one of the most distressing and persistent symptoms experienced before, during, and after cancer treatment.29,30 Furthermore, it can lead to sleep disturbances and daytime somnolence and further aggravate insomnia.31,32 The two conditions are often reported as part of a cluster of interrelated symptoms that include pain, depression, and loss of concentration and other cognitive functions, suggesting that they may share a common etiology.33–35
Åhsberg et al36 examined different aspects of perceived cancer-related fatigue in patients undergoing radiotherapy and found correlations between lack of energy, sleepiness, and cancer-related fatigue.
Current understanding of the possible link between cancer-related fatigue and insomnia suggests that interventions targeting the insomnia and daytime sleepiness could decrease the fatigue as well.31
Pain and insomnia in cancer patients
Pain is reported by 60% to 90% of patients with advanced cancer,37,38 its intensity usually varying with the extent of disease. Too often, it is inadequately controlled.39 Furthermore, it is thought to contribute to insomnia.40
In a study of more than 1,600 cancer patients, nearly 60% reported insomnia in addition to pain.41 The severity of pain directly correlated with the probability of insomnia.
Conversely, research suggests that sleep disturbances, primarily insomnia, can increase cancer patients’ sensitivity to pain.42 One hypothesis is that adequate sleep is needed to promote processes relevant to recovery from pain, both physiologic (ie, tissue repair) and psychological (ie, transient cessation of the perception of pain signals).43
Paradoxically, opioids can worsen insomnia
Cancer pain is often treated with opioids, which, paradoxically, can cause or worsen insomnia.
Although opioids induce sleep, they also depress respiration, and at night, they can cause or worsen sleep-disordered breathing (obstructive or central sleep apnea or ataxic breathing), leading to episodes of hypoxia, arousals, and fragmented sleep.44 Moreover, opioids can lead to daytime sedation. Further, psychostimulants such as methylphenidate, given to counteract opioid-induced sedation, can cause anxiety and insomnia. Thus, the interaction between cancer-related pain, insomnia, and pain management leads to a vicious cycle. Understanding this process, we can try to break the cycle and help patients with cancer sleep better.
However, how best to treat sleep-disordered breathing in patients taking opioids long-term is not well established.
In general, the primary intervention is to reduce the opioid dose. Practitioners should continually assess the need for these drugs and consider referral to a drug-behavior treatment center to help with discontinuation of opioid use when deemed medically appropriate.45 Other strategies include positive airway pressure ventilation including continuous positive airway pressure, bilevel pressure devices with backup rate, or adaptive servoventilators. In some cases oxygen supplementation may be required.
Sleep-disordered breathing, when recognized and diagnosed, should be managed in partnership with a sleep specialist.
Depression and insomnia in cancer patients
By some estimates, up to half of cancer patients suffer from depression at some point in their illness.28 And not without reason: these patients face uncertainty about their life, and this often results in depression or anxiety.46
Many cancer patients with depression also have insomnia.28 Indeed, patients with persistent insomnia are at greater risk of developing psychological disorders such as depression and anxiety.47
In a survey of cancer patients, insomnia symptoms were more often attributed to thoughts or concerns about health, family, friends, the cancer diagnosis, and finances than to the actual physical effects of cancer.48
CANCER TREATMENT AND INSOMNIA
Many cancer patients experience sleep disturbances even before starting treatment.49 Liu et al50 showed that, in 76 women about to undergo chemotherapy for breast cancer, those who already had sleep disturbances, fatigue, and depression had more problems, and more severe problems, during chemotherapy.
Radiation therapy and chemotherapy have been reported to cause or precipitate insomnia (Table 2).8,13
Hormonal therapy and biological therapy can also cause or worsen preexisting insomnia.51,52 For example, androgen deprivation therapy for prostate cancer and hormonal therapy for breast cancer are often associated with sleep problems.49,50 Possible mechanisms of insomnia include hot flashes, night sweats, and anxiety caused by such treatments. Biological agents such as interferons, interleukins, and tumor necrosis factor (TNF) alpha, which are often used to treat malignant melanoma, can affect the sleep-wake cycle, leading to insomnia.53
Corticosteroids sharply raise serum cortisol levels, which can lead to insomnia. Cancer patients receiving dexamethasone to prevent radiation-induced emesis experienced more insomnia than patients who did not receive dexamethasone.54
IMMUNOLOGIC BASIS OF INSOMNIA IN CANCER PATIENTS
Cancer cells produce inflammatory cytokines such as interleukin 1 (IL-1), interleukin 6 (IL-6), and TNF alpha, and inflammation plays a role in tumor progression and possibly tumorigenesis.55
Specific cytokines also help regulate the sleep-wake cycle. Levels of IL-6 and TNF alpha peak during sleep, and daytime IL-6 levels are inversely related to the amount of nocturnal sleep.56 Vgontzas et al57 showed that although mean levels of 24-hour IL-6 and TNF alpha secretion were not significantly different in patients with insomnia vs healthy controls, chronic insomnia was associated with a shift in IL-6 and TNF alpha secretion from nighttime to daytime.57
Cancer and its treatment can affect secretion of the cytokines that play a role in the sleep-wake cycle. Thus, the sleep disturbances associated with cancer may also be related to the abnormalities in cytokine levels caused by either cancer or its treatment.
Mills et al58 found that inflammatory markers such as vascular endothelial growth factor and soluble intercellular adhesion molecule-1 were significantly elevated during chemotherapy in breast cancer patients, and the elevated vascular endothelial growth factor levels were associated with poorer sleep during treatment.
Further research is warranted to establish causality, to help us understand the mechanisms of insomnia and other cancer symptoms, and to develop new treatments for these complaints.
