A review of the treatment for insomnia in patients with cancers

Shuang Liu , Xiong-Zhi Wu *

1Tianjin Medical University, Tianjin, China. 2Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.

Keywords: Cancer, Sleep, Insomnia, Treatment

Introducion

There is a high proportion of insomnia in tumor patients. The tumors with high incidence are as follows: breast cancer (42% to 69%), gynecological tumors (33% to 68%), prostate cancer (25% to 39%) [1]. Insomnia is defined as difficulty falling asleep, multiple awakenings at night (defined as waking multiple times in the middle of the night, each waking time exceeds 30 minutes), early awakening (waking up 30 minutes earlier than scheduled), non-recovery sleep; difficulty in sleeping despite adequate time and sleep conditions; this sleep disorder is associated with damage or pain during the day; this sleep difficulty occurs at least 3 times a week, and it lasts for at least 1 month. These symptoms can affect daytime conditions, reduce the quality of life, promote cancer-related fatigue and depression, increase inflammatory response, reduce survival rates, and may even change the progression of tumors [2-5].

An observational study in different settings of palliative care found that 61% of cancer patients reported sleep disturbances. Hormonal therapy and the use of opioids and corticosteroids were positively correlated with sleep disorders [6]. A study of sleep quality in patients with advanced cancer pain using WHO's third-level opioids has proven that 78% of patients with advanced cancer receiving opioids have poor sleep quality [7].

Chemotherapy is often accompanied by a variety of side effects, including hair loss, nausea, cardiotoxicity, pain, neutropenia, depression, anxiety, cognitive impairment and fatigue. Among patients receiving chemotherapy, the number of patients reporting symptoms of insomnia and meeting the diagnostic criteria for insomnia is three times higher than the general population [3]. In an 18-month longitudinal study about Natural course of insomnia comorbid with cancer demonstrated that the insomnia rate of the general population is 6%-10%, and the insomnia rate of cancer patients is higher, which can reach 21% to 28%, and it is found that the incidence of insomnia among patients receiving chemotherapy can reach 35% to 43%. This statistic is higher than the above statistic, probably because of different standards for defining insomnia. Nevertheless, we can still see that the rate of insomnia in chemotherapy patients is significantly higher than in patients without chemotherapy.

Adverse effects of insomnia

In the general population, insomnia can impair cognitive and physiological functions and is closely related to a wide range of impaired daytime functions, including emotional, social, and physical functions. People with prolonged insomnia are more likely to have accidents during regular daytime activities than those without sleep disturbances [5].

Insomnia can lead to depression and anxiety, increasing the risk of depression. Depression and anxiety after cancer diagnosis also increase the probability of insomnia. Studies have shown that the pathological basis of insomnia is related to the excessive activation of the hypothalamus-pituitary-adrenal (HPA) axis and excessive secretion of cortisol [8]. Correspondingly, studies have shown that the typical corticotropin releasing hormone (CRH) system of patients with depression is activated, and the response to stress is too active, often accompanied by insomnia and loss of appetite [9]. Based on this, it can be inferred that insomnia and depression may have similar pathological mechanisms in terms of neuroendocrine. Reducing any one of the symptoms may relieve the other. Therefore, it is necessary to develop clinical treatment strategies for this common pathogenesis.

Persistent insomnia leads to deprivation of restorative sleep time, affects homeostasis regulation of the immune system, and increases the risk of tumor progression. A partial nocturnal sleep deprivation experimental study shows that sleep deprivation inhibits natural killer cell activity and cellular immunity [10]. Interleukin 6 (IL-6), as a pro-inflammatory factor, plays a key role in responding to infectious attacks and promoting the differentiation, maturation, and proliferation of T and B cells. Data shows that there are interactions with sleep conditions and circadian rhythm. The circulating concentration of IL-6 is lower during the day and higher at night [11]. When sleep deprivation occurs at night, the concentration of IL-6 decreases, resulting in impaired immune function, decreased resistance to pathogens, and an infection response, weakened immune surveillance of tumors, thereby inducing tumor progression. There is evidence that IL-6 can effectively activate the hypothalamic-pituitary-adrenal axis and stimulate adrenocortico-tropic hormone (ACTH) and cortisol secretion [12]. This is consistent with the above-mentioned, that CRH axis activation is consistent with the pathogenesis of insomnia and depression. At the same time, a study found that IL-6 has a hypnotic effect. Subjects reported fatigue, decreased activity, and inattention compared to responses to placebo after taking IL-6, which is also consistent with the above conclusion.

Treating or alleviating insomnia in cancer patients can help to promote recovery after diagnosis and treatment of tumors, improve the quality of life of patients after radiotherapy, chemotherapy, resection of primary tumor foci, hormone therapy, or even conservative treatment, prolong the quality of life and promote the survival of cancer patients. This article summarized the latest research progress and provides treatment ideas and methods for clinicians.

Pharmacological treatment

Drug therapy is still the most effective and commonly used intervention in the general population and among cancer patients, especially in patients with short-term acute insomnia [13]. For patients with chronic, long-term insomnia, the efficacy is often reduced and accompanied by a variety of side effects, such as drug tolerance, withdrawal effects, sedative effects, cognitive impairment, dizziness, drowsiness and so on. Commonly used drugs include benzodiazepines and non-benzodiazepines, the latter being better tolerated than the former [14]. Due to the longterm use of sleeping pills, it is often accompanied by a variety of adverse reactions, reducing the quality of life of cancer patients [15]. Therefore, a clinically meaningful recommendation is to use as few sleeping pills as possible in a short period of time, which can be used in combination with non-drug treatments to reduce the side effects of drugs.

Insomnia and depression often interact, and the use of antidepressants can help relieve insomnia. Some preliminary studies suggest that Mirtazapine and Trazodone have a certain therapeutic effect on insomnia in cancer patients with depression, but further research is needed [16-17].

In addition to the use of hypnotic sedatives and antidepressants, there is evidence that in the general population, the use of the melatonin receptor agonist, Ramelteon, can help alleviate insomnia based on the effects of melatonin-induced sleep, but the effect still needs more experimental research support in cancer patients [18].

Non-pharmacological treatment

Cognitive-behavioral therapy (CBT-I) is considered the gold standard for non-pharmacological treatment of chronic insomnia [19-22]. The goal of cognitive behavioral therapy is to adapt to those bad behaviors and ideas that have developed during insomnia, or contribute to the formation of insomnia, so as to achieve the purpose of effective intervention in insomnia [23]. Its effect is equivalent to or better than drug treatment [21].

CBT-I includes psychological and behavioral therapies, especially stimulation control therapies, sleep restriction therapies, relaxation training, cognitive therapies, and sleep hygiene education. Stimulation control therapy is to adjust all the factors that are not conducive to sleep around the patient, including limiting sound, light, daily activities and thinking activities that use high brains, and strictly distinguish between suitable and unsuitable sleeping environments. In this treatment, the stimulating activity on the bed is strictly limited, thereby increasing the connection between bed and sleep [23]. The goal of sleep restriction therapy is to match the time spent in bed with the actual average night's sleep time [24]. The patient determines the actual average nighttime sleep time by recording a sleep diary and then sets the patient's bedtime and a normal wake-up time. This time period depends on the actual average nighttime sleep time described above. The initial amount of time can be on the basis of the former add 30 minutes, but the total amount of time should not be less than 5 hours. When bedtime is strictly controlled, the actual average sleep time of the patient at night will tend to be stable, and so on, the bedtime of the patient can be gradually increased to ensure sufficient sleep time [23]. Limiting bedtime has proven to be an effective intervention for insomnia [25]. Relaxation training mainly includes progressive relaxation, image training, biofeedback, meditation, hypnosis, and auto-training, but the therapeutic effect of each method remains to be studied. The core of relaxation training treatment is to improve insomnia by improving muscle tension and cognitive arousal. But to achieve the desired effect, the key is to maintain a certain amount of training every day. Training just before bedtime often does not improve the effect of insomnia. Although this intervention has some effect on insomnia, it still cannot be used as an independent treatment for insomnia, and it is best to be combined with other treatments. Cognitive therapy is mainly to make patients realize how unhelpful and negative beliefs can increase the level of physical and mental arousal. These beliefs include overestimating the amount of sleep necessary each night and the effects of sleeping pills, underestimating the actual amount of sleep obtained, and the fear of stimulus-control therapies and sleep-limiting therapies. Improving these patients' perceptions can help improve insomnia. Sleep hygiene education emphasizes environmental factors, physiological factors, behaviors and habits that promote sleep, including reducing prolonged naps during the day, reducing the use of excitatory drugs, formulating regular wakesleep schedules, and maintaining a comfortable and comfortable sleeping environment.

Cognitive-behavioral therapy has similar effects to hypnotic drugs and can already be used as a first-line treatment for insomnia [26]. However, compared with hypnotics, this regimen has fewer adverse reactions to the body, and can maintain a longer-lasting therapeutic effect after stopping the treatment of this regimen [27-28].

A recent study showed that testing the effectiveness of Internet-provided insomnia cognitive behavioral therapy (iCBT-I) in breast cancer survivors with insomnia found that iCBT-I can significantly improve patients' insomnia severity and sleep quality, and at the same time reduce the symptoms of fatigue during the day, the effect can be maintained for at least six weeks [29]. However, the fact that CBT-I usually involves face-to-face interventions by in-person trainers on the spot limits the widespread use of this treatment. Especially in the actual cancer care environment, the lack of trained clinicians, the high cost of manpower and the distance between doctors and patients, and patient compliance with treatment options have limited the scope of CBT-I application [30-31]. Sometimes patients do not have easy access to CBT-I. In a survey by the National Cancer Institute, only 13% of cancer centers referred patients to CBT-I [32]. Even if doctors recommend this treatment plan to some patients, some patients still have resistance and stigma to the psychological treatment involved in CBT-I, especially when the psychological counseling in China has not been widely used. It is worth noting that iCBT-I retains the effect of CBT-I in treating insomnia, break through the obstacles mentioned earlier [33-34]. Evidence suggests that iCBT-I is not inferior to CBT-I in treating insomnia [35]. So our focus is on expanding access to CBT-I through telemedicine and online interventions [36].

Complementary medical treatment for insomnia

Tai Chi. Tai Chi is a gentle exercise that can reduce stress and relax the body and mind. As a combination of mindfulness meditation and exercise meditation, it is very popular among cancer patients and the general population. About 50% of breast cancer patients use Tai Chi every year to promote health [37]. Especially when the three major symptoms of insomnia, fatigue and depression are combined at the same time, Tai Chi can still play an active role widely and improve the quality of life of patients [38]. In a comparative trial of mindfulness-based stress reduction (MBSR) and cognitive behavioral therapy for cancer with insomnia, MBSR was not as good as CBT-1 in improving the severity of insomnia, but MBSR was not inferior to CBT-1 in subsequent follow-up [39].

Acupuncture treatment. In the insomniac population of non-cancer patients, acupuncture can improve subjective feelings and objective indicators of insomnia, and can also relieve pain and fatigue associated with cancer [40-42]. Among cancer patients' insomnia population, a randomized trial comparing CBT-I with acupuncture for insomnia showed that CBT-I can more effectively reduce the severity of insomnia immediately after treatment. It is more clinically significant that the two treatments reduced the severity of insomnia by at least 8 points in value, and the treatment effect was well maintained in the follow-up for 3 months [43].

Other mind-body treatments include hypnotherapy, Yoga, massage therapy and dietary supplements. Patients with breast cancer-related lymphedema were given physical and mental intervention and eight weeks of professional instruction. The results showed that people who practiced yoga showed significant improvements in physical functioning, emotional cognition and quality of life, as well as a significant reduction in cancer-related symptoms of insomnia, pain and fatigue [44].

Conclusion

Insomnia is a very common symptom in surviving cancer patients. In the above-mentioned methods of treating insomnia, the effectiveness varies from person to person, but it is generally recognized that for short-term and acute insomnia, drug treatment is more suitable; and for long-term, chronic insomnia, behavioral cognitive therapy is more effective, and can avoid the side effects brought by drugs.