Overview of fatigue in palliative care

INTRODUCTION — Fatigue is a common symptom in palliative care patients with serious and/or life-threatening illnesses. Fatigue has substantial adverse physical, psychosocial, and economic consequences for both patients and caregivers. However, due to its subjective nature and multidimensional causes, assessment and treatment of fatigue in the palliative settings can be complex.

This topic review will provide an overview of the clinical evaluation and treatment of fatigue in palliative care. A more extensive discussion of fatigue in patients with cancer and of the assessment and management of chronic fatigue syndrome (CFS), also known as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), is presented elsewhere. Most of the evidence presented in this topic relates to studies in cancer patients receiving palliative care. However, similar principles might apply to fatigue in patients with other end-stage conditions, although there are limited studies to better define the role of the described fatigue treatments in those patients. (See "Cancer-related fatigue: Prevalence, screening, and clinical assessment" and "Cancer-related fatigue: Treatment" and "Clinical features and diagnosis of myalgic encephalomyelitis/chronic fatigue syndrome" and "Treatment of myalgic encephalomyelitis/chronic fatigue syndrome".)

DEFINITION — Fatigue can be broadly defined as “a subjective state characterized by feelings of tiredness and a perception of decreased capacity for physical or mental work” [1]. The National Comprehensive Cancer Network defines cancer related fatigue as a “distressing, persistent, subjective sense of physical, emotional, and/or cognitive tiredness or exhaustion related to cancer or cancer treatment that is not proportional to activity and that interferes with usual functioning” [2]. The terms “asthenia” and “weakness” are often used in the same context. (See "Cancer-related fatigue: Prevalence, screening, and clinical assessment", section on 'Definition'.)

Fatigue should be distinguished from other common presentations in palliative care, including depression, delirium, drowsiness, demoralization, psychomotor retardation, and muscle weakness. Demoralization can be identified using a demoralization scale [3,4]. Psychomotor retardation involves a slowing down of thought and a reduction of physical movements, while muscle weakness describes a of lack of motor strength.

PREVALENCE — Fatigue is a common symptom in palliative care patients who have serious and/or life-threatening illnesses, although it may be underreported and undertreated [5-7]. The prevalence of fatigue in patients with cancer ranges from 48 to 75 percent and increases to 85 percent in patients with serious and/or life-threatening illnesses [8-10]. Fatigue is especially prevalent patients with end-stage heart failure or nonmalignant chronic lung disease, such as chronic obstructive pulmonary disease (COPD). (See "Palliative care for patients with advanced heart failure: Decision support and management of symptoms", section on 'Fatigue' and "Palliative care for adults with nonmalignant chronic lung disease", section on 'Other symptoms in chronic lung disease'.)

ETIOLOGY

Multiple causes likely — Among patients with serious and/or life-threatening illness, fatigue can be distinguished as acute (as caused by an acute illness, such as infection or cardiac decompensation) or chronic, as in most cancer-related causes. Possible contributors to fatigue in patients with advanced cancer are outlined in the table (table 1). Some of the common treatable causes of fatigue in cancer patients at the end of life include deconditioning, infection, dehydration, metabolic and endocrine disorders, and cancer-related symptoms such as pain, anorexia, insomnia, and psychological symptoms [3,4]. In palliative care patients, fatigue may have multiple causes including pain, dyspnea, anorexia, psychological symptoms, gastroparesis symptoms (such as upper abdominal discomfort, bloating, and abdominal distension), and constipation [11-14]. Other major contributors are anemia and medications. In patients at the end of life, fatigue is typically multifactorial, with additional contributions from psychological symptoms such as anxiety and depression, cachexia, physical inactivity, infection, and hypogonadism. Fatigue related to cancer treatment is discussed separately. (See "Cancer-related fatigue: Prevalence, screening, and clinical assessment", section on 'Main contributory factors'.)

Anemia — Anemia is a common cause of fatigue, especially in patients undergoing cancer treatment. However, in patients at the end of life, the importance of anemia as a contributor to fatigue is diminished [11,15]. This is discussed in detail elsewhere. (See "Cancer-related fatigue: Prevalence, screening, and clinical assessment", section on 'Anemia' and "Cancer-related fatigue: Treatment", section on 'Anemic patients'.)

Polypharmacy — Medications (side effects, cumulative effects of multiple drugs, and drug-drug interactions) are an important contributor to fatigue. As examples, coadministration of opioids with other sedating medications, or drug-drug interactions between classes of medications such as anticholinergics, antihistamines, anticonvulsants, neuroleptics, opioids, central antagonists, beta blockers, diuretics, antidepressants, muscle relaxants, and benzodiazepines, may contribute to drowsiness and fatigue. Statins were found to cause fatigue in a relatively healthy non-cancer population [16] and can be safely stopped without increasing mortality for those at the end of life, with an improvement in quality of life [17]. (See "Prevention and management of side effects in patients receiving opioids for chronic pain", section on 'Somnolence and mental clouding' and "Palliative care: The last hours and days of life", section on 'Eliminating non-essential medications' and "Deprescribing".)

Autonomic dysfunction — Autonomic dysfunction is a common complication of advanced cancer [18-20]. This syndrome includes fatigue, postural hypotension, occasional syncope, fixed heart rate, and gastroparesis.

Male hypogonadism — Hypogonadism affects at least two-thirds of males with advanced cancer. Low testosterone levels in males with cancer are associated with fatigue, anorexia, depression, and insomnia [21,22]. Chronic inflammation, cachexia, chemotherapy, and medications such as opioids, megestrol acetate, and glucocorticoids [23] can all contribute to hypogonadism.

Guidelines from the Endocrine Society recommend measuring testosterone levels in males requiring long-term opioid therapy [24]. (See "Prevention and management of side effects in patients receiving opioids for chronic pain", section on 'Neuroendocrine effects' and "Clinical features and diagnosis of male hypogonadism" and "Causes of secondary hypogonadism in males".)

Role of inflammatory cytokines — Cytokines, including those used therapeutically, have been associated with fatigue and have been studied primarily in patients with cancer [25-29]. Proinflammatory cytokines can act on mood, muscle mass, cognition, and metabolic status to induce fatigue [30,31]. The inflammatory cytokines may also induce disturbance in the hypothalamic pituitary axis, affecting the levels of corticotrophin-stimulating hormone and adrenocorticotropic hormone (ACTH). These hormones, in turn, may influence adrenocorticoid hormone secretion by the adrenals [31]. (See "Cancer-related fatigue: Prevalence, screening, and clinical assessment" and "Cancer-related fatigue: Prevalence, screening, and clinical assessment", section on 'Main contributory factors'.)

Inflammatory cytokines may have a role in the pathophysiology of fatigue, based upon several lines of evidence:

●Increased levels in non-oncologic conditions that are characterized by fatigue, such as chronic fatigue syndrome (CFS) [25,26]. (See "Clinical features and diagnosis of myalgic encephalomyelitis/chronic fatigue syndrome", section on 'Immune system differences'.)

●The occurrence of fatigue as a major side effect of therapeutic cytokines, including interleukins, tumor necrosis factor (TNF) alpha, and interferon [27-29].

●Upregulation of proinflammatory cytokines and their correlation with fatigue in cancer patients [32-35]. (See "Cancer-related fatigue: Prevalence, screening, and clinical assessment" and "Cancer-related fatigue: Prevalence, screening, and clinical assessment", section on 'Main contributory factors'.)

CLINICAL ASSESSMENT — Fatigue can be classified as acute (eg, due to an infection or cardiac decompensation), in which case treatment of the condition may successfully reverse fatigue, or as chronic, in which case a multidimensional approach is likely needed.

A comprehensive history and physical examination should be undertaken to ascertain the various organ systems affected by the underlying disease as well as the impact of fatigue on activities of daily living and quality of life. Potentially reversible or treatable contributory factors should be identified.

A review of all medications (both prescribed and over the counter, including complementary/alternative therapies) is important and may reveal potential side effects, cumulative effect of multiple drugs, or drug-drug interactions that may be contributing to fatigue. If a medication is identified as being a potential contributor to fatigue, altering the dose or dosing interval may improve fatigue, or deprescribing may be more appropriate.

In all patients, assessment of the current disease status, type of treatment, and response to treatment are important components of the initial evaluation. Factors potentially related to fatigue should be assessed, including disease-specific treatments, anemia, uncontrolled pain, emotional distress, sleep disturbance, poor nutrition, electrolyte disturbances, and other comorbidities. Laboratory or radiologic evaluations may be needed. A suggested initial workup for patients with cancer-related fatigue is provided in the table (table 2). A more in-depth discussion of clinical assessment of fatigue in patients with cancer is provided elsewhere. (See "Cancer-related fatigue: Prevalence, screening, and clinical assessment", section on 'Clinical assessment'.)

Fatigue can be quantified by using the “0 to 10” visual analog scale and instruments, such as the Brief Fatigue Inventory, which measure not only intensity of fatigue but also functional impact, yet are not useful in determining the cause (table 3). Use of the simple revised Edmonton Symptom Assessment Scale (table 4) [36] or other multidimensional tools can provide a more comprehensive assessment of fatigue (table 5) [37].

MANAGEMENT — Optimal management of fatigue involves aggressive treatment of reversible causes, if any are identified during the initial assessment. If a cause is not reversible or apparent, symptomatic treatment is appropriate.

The treatment of fatigue may necessitate involvement of an interdisciplinary team approach with participation by the clinician, nurse, psychiatric counselor, social worker, chaplain, physical therapist, or occupational therapist.

Multimodal interventions — Symptomatic treatment should be considered in all cases in which fatigue is not effectively managed by treatment of reversible causes. Patients may benefit from a combination of pharmacologic and nonpharmacologic interventions such as cognitive-behavioral therapy, increased physical activity, and pharmacologic therapy aimed at countering inflammation, changes in body composition, or brain function. In these cases, therapy must be individualized.

It is important to address fatigue as a subjective symptom and not as a physical syndrome; treatment should not focus solely on strategies to increase function/physical function. Lastly, patients suffer considerable distress if there is a gap between the patient’s expectation for improved physical function through intervention and the reality of actual decline in function over time; ultimately, many patients who are terminally ill will become bedridden. Measures that help adjust a patient’s expectation may include changing the focus from physical functioning to other enjoyable, non-physical activities [38].

Treatment of anemia

●Identify and treat underlying causes – Optimal management of symptomatic anemia requires an accurate diagnosis to identify potentially remediable causes (eg, ongoing blood loss, hemolysis, or deficiency of iron, folic acid, or vitamin B12).

●Transfusion – If a potentially treatable cause of anemia cannot be identified, red blood cell (RBC) transfusion may be an option for some patients, after reviewing the risks and potential benefits with the patient and family. Although some hospice providers may think of transfusions as “aggressive care,” patients and families or other loved ones generally do not [39].

Practice regarding RBC transfusion for treatment of fatigue in palliative care is not standardized. The decision to transfuse is multifactorial and must consider the anticipated benefits, risks, patient wishes, blood bank inventories, and alternatives to transfusion [40]. RBC transfusions may improve fatigue due to anemia in some patients, but the effect is short-lived [41-43]. In a systematic review of 12 observational before/after studies including 653 participants with advanced cancer who received RBC transfusions for treatment of fatigue or breathlessness, subjective symptom improvement was reported in 31 to 70 percent of patients [42]. Most studies reported an early response that waned by day 14. One-quarter to one-third of transfused patients died within two weeks of receiving transfusion.

The experience with RBC transfusion in this setting was described in a multicenter prospective study involving 140 patients who received RBC transfusions in various palliative care settings (inpatient hospice/palliative care units, consultative services, and ambulatory clinics) [43]. Most patients in the study (>95 percent) had advanced malignancy. The most common primary reasons for transfusion were fatigue (59 percent of patients), breathlessness (21 percent), and generalized weakness (9 percent). Approximately one-half of patients had improvement in the primary symptom following transfusion. Mild transfusion reactions occurred in 12 percent of patients.

In making decisions regarding transfusion, clinicians should weigh the potential benefits against the known risks of transfusion, including blood-borne infection, acute transfusion reaction, transfusion-associated graft-versus-host disease, subtle immune modulation, and iron overload. (See "Hemolytic transfusion reactions" and "Immunologic transfusion reactions" and "Transfusion-associated circulatory overload (TACO)" and "Transfusion-transmitted bacterial infection" and "Approach to the patient with suspected iron overload", section on 'Transfusional iron overload'.)

●Erythropoiesis-stimulating agents – Treatment with erythropoiesis-stimulating agents can be beneficial in relieving fatigue and improving quality of life in patients with chronic anemia related to cancer chemotherapy and chronic kidney disease. However, use in patients not receiving chemotherapy is not likely to be beneficial and is potentially harmful. This subject is addressed in detail elsewhere. (See "Role of erythropoiesis-stimulating agents in the treatment of anemia in patients with cancer", section on 'Clinical use of ESAs in cancer patients'.)

Symptom management

Pharmacologic approaches — There are a limited number of pharmacologic agents that may have efficacy in the treatment of fatigue in palliative care populations; however, a 2016 systematic review concluded that no specific drug could be recommended for treatment of fatigue in palliative care patients due to the limited evidence [44].

Glucocorticoids — Glucocorticoids may be helpful for short-term treatment of fatigue in patients who are in the terminal phases of advanced cancer [45-53]. The role of systemic glucocorticoids for cancer-related fatigue is also discussed elsewhere. (See "Cancer-related fatigue: Treatment", section on 'Glucocorticoids'.)

Unfortunately, side effects limit the long-term use of glucocorticoids. The severity of most toxicities is dose dependent. Side effects observed in some patients include infection, oral thrush, insomnia, mood swings [54], myalgia, and elevation of blood glucose. Prolonged use (for more than a month) of dexamethasone may cause gastritis (especially with concurrent use of nonsteroidal antiinflammatory drugs [NSAIDS]), hiccups, edema, muscle weakness, easy bruising, dizziness, unusual hair growth, bone loss, visceral perforation, decreased wound healing, and cardiovascular disease, including atrial fibrillation in some patients. (See "Major adverse effects of systemic glucocorticoids".)

The use of glucocorticoids in the management of fatigue in terminally ill patients with diseases other than cancer is considered investigational due to the lack of well controlled studies. For this reason, we do not routinely use these agents for treatment of fatigue in palliative care patients without cancer. Glucocorticoids are most likely to be useful for conditions where there is strong inflammatory component.

Megestrol acetate — Megestrol has been found to have benefit in patients with advanced cancer symptoms including anorexia-cachexia, and fatigue. In trials conducted among patients with advanced cancer and anorexia, megestrol acetate improved fatigue in addition to beneficial changes in appetite and overall wellbeing when compared with placebo [55]. However, treatment with megestrol is complicated by considerable risks, including edema, thromboembolic phenomena, and increased mortality. In a meta-analysis of 10 trials involving 1106 patients with anorexia-cachexia syndrome related to cancer, acquired immunodeficiency syndrome (AIDS), or another underlying pathology, megestrol improved appetite and weight compared with placebo (33 percent of megestrol-treated patients had improved weight compared with 25 percent in the placebo group; relative risk [RR] 1.51, 95% CI 1.08-2.11) [56]. However, mortality was higher in the megestrol group (15 versus 10 percent; RR 1.42, 95% CI 1.04-1.94) and treatment was associated with increased rates of thromboembolic events (19 versus 10 percent; RR 1.84, 95% CI 1.07-3.18) and edema (14 versus 10 percent; RR 1.36, 95% CI 1.07-1.72). Therefore, in clinical practice, megestrol acetate should be considered only in select advanced cancer patient populations with persistent cancer-related fatigue and rapid weight loss due to cachexia, with careful monitoring for side effects. (See "Management of cancer anorexia/cachexia", section on 'Progesterone analogs'.)

Psychostimulants — Both fatigue and depression in patients receiving palliative care can be treated with the psychostimulants such as dextroamphetamine, methylphenidate, pemoline (not available in the United States), bupropion [57,58], or modafinil. Psychostimulants act rapidly and are generally well tolerated and safe. However, they should be used with caution in patients with heart disease or delirium.

All of the available data addressing the role of psychostimulants in management of fatigue patients with serious and/or life-threatening illness are in patients with cancer, in whom the benefit has been best shown for methylphenidate, modafinil, and bupropion for treatment of severe fatigue; the benefit is less certain in patients with mild to moderate fatigue. (See "Cancer-related fatigue: Treatment" and "Cancer-related fatigue: Treatment", section on 'Psychostimulants and other wakefulness agents'.)

The use of psychostimulants in the management of fatigue in terminally ill patients with diseases other than cancer is considered investigational. However, a trial of psychostimulants such as methylphenidate, modafinil, or bupropion is reasonable for patients without cancer with severe fatigue who do not respond to or have a contraindication to other established therapies such as exercise or cognitive-behavioral therapy [59-63].

Testosterone for hypogonadal males — Hypogonadism affects two-thirds of males with advanced cancer; low testosterone levels in males with cancer are associated with fatigue, anorexia, depression, and insomnia. (See 'Male hypogonadism' above.)

Testosterone replacement improves quality of life and diminishes fatigue for hypogonadal males with non-cancer conditions; however, guidelines specifically recommend against testosterone supplementation in males with active breast or prostate cancer given concerns for acceleration of disease growth [24]. Relative contraindications, such as an undiagnosed prostate nodule or an elevated serum prostate-specific antigen (PSA) level, may be reconsidered on an individual basis depending on the overall prognosis [23]. A more in-depth discussion about contraindications to testosterone replacement therapy and an overview of monitoring during therapy are provided elsewhere. (See "Testosterone treatment of male hypogonadism", section on 'Contraindications to use' and "Testosterone treatment of male hypogonadism", section on 'Monitoring'.)

The use of testosterone in males with hypogonadism and cancer related fatigue is discussed elsewhere. (See "Cancer-related fatigue: Treatment", section on 'Testosterone for hypogonadal men'.)

Complementary medicines — For patients who have moderate to severe fatigue who are undergoing active anticancer therapy, American ginseng may be reasonable as long as the patient is not receiving drugs that may interact unfavorably with ginseng, such as anticoagulants. On the other hand, benefit is less clear for Asian ginseng (Panax ginseng) [64,65]. Ginseng for cancer-related fatigue is discussed elsewhere. (See "Cancer-related fatigue: Treatment", section on 'Ginseng and guarana'.)

Nonpharmacologic approaches

Exercise — Physical activity is important to maintain a sense of wellbeing and to enhance quality of life [66]. Most palliative care patients experience multiple symptoms, such as fatigue, pain, dyspnea, and nausea, that may all contribute to reduced physical activity, or even inactivity, and thereby reduced physical functioning. Exercise rehabilitation during or after curative or life-prolonging treatment is considered an effective means of restoring physical and psychological function [67,68].

The benefits of exercise in terms of improving physical performance have been shown in many trials conducted in patients with advanced cancer, although benefit in terms of fatigue has been more difficult to show. As an example, in a large randomized control study of 231 patients with incurable cancer and a life expectancy of three months to two years, physical exercise (60 minutes twice a week for eight weeks) provided significant improvement in physical performance as assessed by a hand grip strength test and the shuttle walk test, whereas fatigue, the predefined primary endpoint, was not significantly reduced [69]. (See "Cancer-related fatigue: Treatment", section on 'Exercise'.)

Additional randomized controlled trials are required in palliative care settings to assess the overall efficacy of exercise [70]. However, moderate exercise is a reasonable recommendation, if patients are able to tolerate it.

Yoga — Yoga may have benefit in patients with cancer-related fatigue and is discussed elsewhere. (See "Cancer-related fatigue: Treatment", section on 'Yoga'.)

Qigong/tai chi — Qigong is a traditional Chinese exercise therapy commonly used for the treatment of cancer-related fatigue. This is discussed elsewhere. (See "Cancer-related fatigue: Treatment", section on 'Tai chi/qigong'.)

Sleep hygiene — In patients with advanced cancer or other life-limiting disease states, it is common to have multiple symptoms occurring simultaneously; hence, it is difficult to determine that sleep disturbance is the sole causative mechanism for fatigue, or if fatigue is contributing to sleep disturbance. Sleep disturbance may be influenced by numerous factors including daytime naps, pain, depression, anxiety, medication, sleep interruption because of sleep apnea, nocturia or hot flashes, and evening food and/or beverage intake.

Few studies have evaluated sleep interventions to manage fatigue in advanced cancer and other life-limiting illnesses; the results are conflicting. Cognitive-behavioral therapy and stress reduction may help. Other suggestions for improving sleep patterns include taking a warm bath or drinking a glass of warm milk prior to bedtime, avoiding caffeinated beverages following dinner, emptying the bladder just before going to bed, and scheduling naps earlier in the day (table 6). Some patients require medications to help them sleep. (See "Insomnia in palliative care".)

Behavioral and psychosocial interventions — Cognitive-behavioral and psychosocial interventions (including mindfulness-based stress reduction) have been found to be an effective modality for the treatment of cancer-related fatigue and are discussed in detail elsewhere. (See "Cancer-related fatigue: Treatment", section on 'Cognitive-behavioral interventions'.)

Acupuncture — Acupuncture may have benefit in cancer-related fatigue and is discussed elsewhere. (See "Cancer-related fatigue: Treatment", section on 'Acupuncture'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Palliative care".)

SUMMARY AND RECOMMENDATIONS

●Significance – Fatigue (asthenia, weakness) is a common symptom in palliative care that affects the quality of life. Fatigue should be distinguished from other common presentations in palliative care, including depression, delirium, drowsiness, demoralization, psychomotor retardation, and muscle weakness. (See 'Definition' above and 'Prevalence' above.)

●Causes – In palliative care patients, acute fatigue may be due to a potentially reversible medical condition (eg, cardiac decompensation, infection), while chronic fatigue is more likely to have multiple contributing causes (table 7) (see 'Etiology' above). Anemia is a particularly important contributor in patients undergoing cancer treatment but is a less common contributor to fatigue in patients nearing the end of life. (See 'Multiple causes likely' above and 'Anemia' above.)

●Measurement – The intensity of fatigue can be assessed using the “0 to 10” visual analog scale or instruments, such as the Brief Fatigue Inventory, which measure not only intensity but also functional impact (table 3). (See 'Clinical assessment' above.)

●Assessment – A comprehensive history and physical examination is indicated to identify potentially reversible etiologies. (table 7). A review of all medications, both prescription and over the counter, is particularly important to identify side effects and potential drug-drug interactions that may be contributing to fatigue. Simply altering the dose or dosing interval may substantially improve fatigue. (See 'Polypharmacy' above and 'Clinical assessment' above.)

●Management of anemia

•Identify and treat underlying causes – Optimal management of symptomatic anemia requires an accurate diagnosis to identify potentially remediable causes (eg, ongoing blood loss, hemolysis, or deficiency of iron, folic acid, or vitamin B12). (See "Treatment of iron deficiency anemia in adults" and "Diagnostic approach to anemia in adults" and "Causes of anemia in patients with cancer".)

•Transfusion – If a potentially treatable cause of anemia cannot be identified, red blood cell (RBC) transfusion may be an option after weighing the anticipated benefits, risks, patient wishes, blood bank inventories, and alternatives to transfusion. RBC transfusions may improve fatigue due to anemia in some patients, but the effect is short-lived. (See 'Treatment of anemia' above.)

•Erythropoiesis-stimulating agents – Erythropoiesis-stimulating agents may be beneficial in relieving fatigue in patients with chronic anemia related to cancer chemotherapy or chronic kidney disease. However, use in other populations is not likely to be beneficial and is potentially harmful. This subject is addressed in detail elsewhere. (See "Role of erythropoiesis-stimulating agents in the treatment of anemia in patients with cancer", section on 'Clinical use of ESAs in cancer patients'.)

●Symptomatic management – If a specific cause of fatigue cannot be identified, our suggested approach to symptomatic management is as follows:

•We provide information on coping strategies that conserve energy (table 8 and table 9) and information on good sleep hygiene (table 6).

•Megestrol acetate has modest benefits on appetite and weight, but it has considerable side effects and may increase mortality. Use of this agent is generally limited to select advanced cancer patient populations with persistent cancer-related cachexia. This is discussed separately. (See "Management of cancer anorexia/cachexia", section on 'Progesterone analogs'.)

•For patients with opioid-related sedation and those with severe fatigue who do not respond to or cannot participate in exercise or cognitive-behavioral interventions, we suggest a trial of pharmacotherapy with methylphenidate, modafinil, armodafinil, or bupropion (Grade 2C). However, the role of psychostimulants is not well defined, particularly for patients with serious and/or life-threatening illnesses other than cancer. Thus, some patients may reasonably choose to forego pharmacotherapy and focus instead on nonpharmacologic approaches. (See 'Psychostimulants' above and "Cancer-related fatigue: Treatment", section on 'Psychostimulants and other wakefulness agents'.)

•Complementary medicine and nonpharmacologic approaches are available and may include ginseng, exercise, yoga, and cognitive-behavioral therapy, including mindfulness-based stress reduction [71,72]. (See 'Complementary medicines' above.)