Top Ten Tips Palliative Care Clinicians Should Know About Diagnosing, Categorizing, and Addressing Fatigue

Abstract

Fatigue is a multifactorial symptom that is commonly faced by patients with cancer, chronic disease, and other serious illnesses. Fatigue causes suffering across biopsychosocial domains and affects patients and their loved ones. In this article, a consortium of professionals across cancer care, physical therapy, exercise, pharmacy, psychiatry, and palliative medicine offers tips and insights on evaluating, categorizing, and addressing fatigue in the setting of serious illness. The comprehensive approach to managing fatigue underscores the importance of collaborative efforts characteristic of interdisciplinary palliative care. Prioritizing screening, diagnosing, and treating fatigue is crucial for enhancing patients’ and families’ overall quality of life.

Introduction

Fatigue is a common, complex, and impactful symptom of serious illness for many patients. Though almost nearly universal among people living with cancer, fatigue is also common in other serious illnesses including congestive heart failure, chronic obstructive pulmonary disease, cirrhosis, and end-stage renal disease.^1,2

Fatigue is significant both to individuals with serious illness and their caregivers and has been strongly associated with depression and poorer quality of life for patients with chronic illness.³ The negative effects of fatigue can also include impacts such as loss of productivity at work owing to medical disability, occupational hazards, deaths from medication errors, suicidal ideation, and accounts for over 100,000 motor vehicle accidents annually.^4–6

Fatigue poses significant challenges for clinicians to assess and manage owing to its overlap with many serious illnesses, their treatment, and the long-term effects these illnesses have on patients. In fact, while there is general acceptance of the idea that fatigue is multidimensional, negatively impactful on patient quality of life, and deserving of assessment and treatment, there is generally a lack of unanimity in the definition of fatigue.^7,8 The exact definitions, etiologies, and treatment strategies for fatigue aren’t always clear, either, posing challenges for palliative care (PC) clinicians.

Tip 1: Fatigue Should Be Considered “a Fever of Unknown Origin,” with a Large Differential, and Is Often Accompanied by Other Symptoms

Nearly all fatigue is multifactorial. Although it is often ascribed to medical conditions, such as cancer, hypothyroidism, multiple sclerosis, or fibromyalgia, fatigue usually has other contributing factors including psychiatric and physical symptoms such as poor sleep, depression, cognitive impairment, and pain.⁴ In PC, it is rare for fatigue to occur because of a single, predominant, treatable factor, such as hypothyroidism after neck irradiation for head and neck cancer.⁹ Instead, fatigue is usually associated with multiple contributing factors.¹⁰ Common concurrent symptoms of distress that require screening include the psychiatric symptoms of depression, anxiety, and insomnia, and physical symptoms of pain, nausea/vomiting, shortness of breath, and deconditioning.^10,11 Moreover, addressing associated physical symptoms has been shown to improve overall fatigue in patients with advanced cancer with a small but significant effect size that is comparable with methylphenidate (effect size 0.35, p = 0.005 at two months).¹²

In addition to concomitant symptoms, there are often other comorbidities such as anemia, nutritional deficits, hypothyroidism, and other factors such as medication side effects that should be considered depending on the clinical situation. Given that fatigue is usually because of multiple factors and treating those factors can significantly improve the patient’s quality of life, we recommend an approach like that, summarized in Figure 1. This approach is similar to that recommended by the National Comprehensive Cancer Network (NCCN) as well as the American Society of Clinical Oncology (ASCO) in conjunction with the Society for Integrative Oncology (SIO) in their guidelines for cancer-related fatigue.^10,18

FIG. 1.

Top ten tips references.^13–17

Tip 2: Don’t Assess Fatigue Without Also Assessing a Person’s Sleep Quality and Habits

It is crucial to consider the role of sleep when people present with fatigue. Sleep disturbances are common among people with serious illness, frequently resulting in fatigue and excessive daytime somnolence. These sleep disturbances include insomnia, obstructive sleep apnea, restless leg syndrome, Rapid Eye Movement (REM) sleep behavior disorder, and circadian rhythm disorders. A systematic review revealed the mean overall prevalence of insomnia to be nearly 50% in PC patients and the prevalence of sleep disturbances (and/or sleep disorders) to be up to 95% in cancer patients.^19,20 Predictors for sleep disturbances include sociodemographic factors, like age, and clinical characteristics, such as functional status, symptom burden, mood disorder symptoms, and treatment-related side effects.¹⁹

Though prevalent and important, evaluating clinicians may overlook and inadequately assess sleep disorders. One study revealed that almost no PC clinicians used validated patient-reported outcome measures for sleep, and only 40% reported they had access to sleep specialist services for patients.²¹ When people with serious illness present with fatigue, it is essential to conduct a detailed sleep history that includes sleep efficacy, latency, total time in bed, nighttime awakenings, and naps. This complete history may uncover sleep disturbances and identify areas for intervention. We also recommend implementing a low threshold to refer patients for a sleep study as sleep apnea is prevalent, underdiagnosed, and treatable.^19,20

Meta-analyses support the efficacy of behavioral, cognitive, and pharmacologic interventions for insomnia.²² Behavioral modifications for sleep should be the primary approach whenever feasible. Nonpharmacologic interventions include cognitive behavioral therapy for insomnia, sleep hygiene education, and environmental modifications. Clinicians can encourage appropriate sleep hygiene, including minimizing screen time, avoiding late afternoon or evening caffeine, utilizing mindfulness practices and daytime exercise, and avoiding overnight disruptions to promote restful sleep (see Tip 6). In the hospital setting, these practices might include consolidating overnight care (e.g., medications, tests, vital signs, and blood draws). Conversely, during the day, it is optimal to encourage exposure to natural light to regulate the patient’s circadian rhythm. Hypnotic medications may also be effective but must be carefully monitored for adverse effects and consideration of the patient’s overall health status. By incorporating comprehensive assessment and treatment of sleep habits and behaviors into the care plan for patients with serious illness, PC clinicians can address fatigue more effectively, improve quality of life, and promote overall well-being in their patients.

Tip 3: Use Validated Scales to Regularly Assess Fatigue Among People with Cancer

PC clinicians should regularly screen for fatigue in patients with cancer. Screening for fatigue should be conducted at least annually and as clinically indicated, in addition to screening at diagnosis and at the end of treatment.^10,23 Providers should initiate discussions about fatigue, as patients may face barriers to reporting symptoms. For instance, patients may assume that fatigue is not treatable or is an inevitable part of serious illness.²⁴ Providers can begin by asking patients to rate fatigue on a scale from 0 to 10 (0 indicating no fatigue and 10 indicating the worst fatigue imaginable).¹⁰ For people who endorse moderate to severe fatigue or a score >4, providers can use detailed scales to supplement a fatigue-focused history and physical assessment.²³

Many validated instruments exist to assess oncologic and nononcologic causes of fatigue. The instruments vary in length and the aspects of fatigue they measure, which may include physical, cognitive, and psychological dimensions. It can be challenging to find an instrument that measures beyond the physical aspects of fatigue yet remains brief enough to be useful in a clinical setting. A recent systematic review evaluated the psychometric properties of 19 cancer-related fatigue measures in PC, which included internal consistency, cross-cultural validity, hypotheses testing, and responsiveness.²⁵ Based on the quality methodological results, the authors recommended using one of the following four scales: (1) the Edmonton Symptom Assessment System (ESAS), (2) the Problems and Needs in PC Questionnaire, (3) the European Organization for Research and Treatment of Cancer Quality of Life 15-item Questionnaire for PC, or (4) the PC Quality of Life Instrument.^25–29 Among these scales, the ESAS can be utilized in busy clinical settings given its shorter length. The ESAS includes 10 numeric rating scales measuring pain, fatigue, nausea, depression, anxiety, drowsiness, shortness of breath, appetite, feeling of well-being, and sleep.³⁰ While longer tests may assist in identifying the many symptoms driving fatigue and its impact, providers must balance completeness with the practicality of administering a longer tool in clinical or research settings.

Tip 4: Providing Education About Fatigue to Patients and Caregivers Can Reduce Distress and Normalize Symptoms

Fatigue can be very distressing for patients with serious illnesses and their caregivers. For patients, normalizing fatigue as a common symptom in advanced disease can reduce anxiety, decrease distress, and improve overall well-being.

Patients with serious illness and their caregivers may also experience significant distress or anxiety when faced with symptoms of fatigue as these symptoms can run in parallel or be misunderstood as depression, demoralization, hopelessness, as well as progression of disease.³¹ This uncertainty can lead to increased anxiety and a sense of helplessness.

Educational interventions for managing fatigue have been shown to moderately reduce distress and anxiety and improve global quality of life.³² Providing education around fatigue, including simply naming it as a common symptom in serious or advanced illness, can alleviate anxiety and provide reassurance to caregivers.³² In addition to normalizing, providers can explain different contributors to a patient’s fatigue and elicit patient and family concerns about the impact, meaning, and narrative attributed to that fatigue.

Tip 5: First Prescribe Regular Sessions of Moderate Physical Activity Which Can Enhance Energy Levels, Improve Sleep, and Reduce Fatigue

Fatigue can be a challenging barrier to overcome. Movement of any type is a good start to combat fatigue and regular aerobic exercise has several benefits for patients experiencing fatigue.^33–35 Evidence shows that aerobic exercise can help reduce fatigue in PC patients. Exercise is also a safe strategy to address depression and sleep disturbances with well-documented positive benefits on quality of life and aerobic fitness.^36–38

PC clinicians can make guided recommendations for physical activity as a first-line nonpharmacological strategy to help reduce fatigue. Prescribing exercise as the first-line treatment of fatigue is endorsed by both NCCN and ASCO-SIO guidelines.^10,18 In the inpatient setting, practicing standing up from the bed or chair or walking around the room or through the halls are some beneficial activities for ambulatory patients. If unable to get out of bed or ambulate, suggested activities include moving the extremities in bed, using the incentive spirometer, or sitting up with or without support. In the outpatient setting, regular aerobic exercise for 20–30 minutes, four times weekly with low impact activities such as walking, yoga, or water exercises, is recommended. Additionally, if able, light resistance activities using body weight, elastic bands, or light weights twice a week can positively impact strength, as well as fatigue. Encouraging moving “fast enough that you’re just the smallest bit short of breath” provides a challenge that will change along with improvements in aerobic fitness.

Throughout illness, there is a role for discussing concepts of balance and pacing to help avoid over- or underexertion. In the final stages of life, it is crucial to recognize that fatigue can serve as a protective mechanism. Therefore, it is essential for PC clinicians to identify when exercise and physical activity cease to be beneficial.³⁹

Tip 6: Behavioral Strategies such as Energy Prioritization and Sleep Hygiene Can Be Useful as Symptomatic Treatments for Fatigue

It is important to acknowledge that there isn’t a one-size-fits-all behavioral intervention that will help all patients experiencing fatigue. Encouraging people to try various interventions will not only help them to identify what works best for them, but will also help build rapport and demonstrate our commitment to helping the patient improve.

Energy prioritization is one behavioral strategy which can be useful for patients experiencing fatigue. Energy prioritization stems from the acknowledgment that energy may be a limited resource. Asking a patient to prioritize how that limited resource is used can provide them with some sense of control in an otherwise challenging time. Simple questions like “what is the most important thing you want to do?” and “when is the most consistent window of energy in your day?” can help a patient prioritize how and where they spend their energy. Though some items may not be achieved, the highest priority one(s) can be done with optimal timing of energy level.

As noted elsewhere, the value of sleep hygiene has been recognized over the past several decades. Though first defined in the late 1970s, it has expanded to an extensive list of dos and don’ts when preparing for sleep.⁴⁰ Basic sleep hygiene recommendations are outlined in Table 1 and include maintaining a consistent sleep schedule and avoiding electronic devices and bright lights before bed. The study of sleep hygiene itself has shown that what works for one does not necessarily work for all, and tailoring to the individual is needed.

Table 1.

Common Sleep Hygiene Recommendations to Improve Sleep Quality^a

Daytime		Nighttime
Sleep hygiene tips	Description	Sleep hygiene tips	Description
Stick to a sleep schedule	Go to sleep and wake up at the same time everyday	Only go to bed when tired!	Don’t force sleep; instead, go to bed when you are tired and ready for sleep
Write down worries	Find ways, such as writing down worries in a diary, to prevent taking stress to bed	Take time to “wind-down”	Create a wind-down routine to calm your mind before bed
Create a welcoming sleep environment	Your bedroom should be relaxing, clean, and cozy to allow your mind to switch off	Block out light and noise	Lights and noise interfere with sleep; a quiet and dark room is best!
Avoid stimulants and alcohol	Avoid caffeine four to six hours before bed; alcohol use is linked to poor sleep and should be avoided	Bed is sacred (for sleep and intimacy only)	Don’t do work, eat, or do other activities in bed—it should only be used for sleep and intimacy
Exercise (outside if possible!)	Exercise during the day makes it easier to sleep at night	No devices in bed	Unplug at night—the screen mimics sunlight and keeps you awake!

^a Adapted from Smith et al., Zlott et al., Mindset Health, 2020.⁴¹

Tip 7: After Exercise and Behavioral Interventions, Consider Nonprescription and Integrative Treatment Options with Minimal or Mild Side Effects such as Caffeine, Ginseng, Yoga, Acupuncture, and Reflexology

There are a number of nonprescription, integrative treatment options available which are generally considered safe and effective for the treatment of fatigue encountered in PC settings.^42–48 In situations where it is available (both logistically and financially), a trial of acupuncture has the potential to offer significant improvement for some. In general, acupuncture has fewer side effects than pharmacological interventions, though caution is needed in the setting of neutropenia (owing to risk of infection) and thrombocytopenia (owing to risk of bleeding).^45,46 Reflexology, a type of massage therapy focused on applying targeted pressure to a patient’s hands and feet has been shown in combination with sleep hygiene education to improve sleep and fatigue.^40,43 Other treatments, including aromatherapy (with lavender being the most common aroma used), yoga, and moxibustion (a type of therapy involving burning small herbs called mugwort leaves), also have data supporting their use as nonpharmacologic treatments of fatigue.^18,44

Regarding nonprescription pharmacological options, American ginseng has positive data. A randomized controlled trial comparing 2000 mg of oral American ginseng daily with placebo for treatment of cancer-related fatigue showed significant improvement at eight weeks.⁴⁷ In fact, a recent meta-analysis comparing the efficacy and safety of ginseng and methylphenidate for cancer-fatigue suggests that while both agents are effective, ginseng may be more effective and may have fewer side effects.⁴⁸ Ginseng should be avoided in hormone-sensitive cancers (breast and prostate) owing to its potential estrogenic activity.⁴⁹ In addition, ginseng should be taken with food, used with caution in patients with hypertension, and stopped prior to surgery (owing to its potential for blood thinning).⁴⁹

Caffeine may be considered as a treatment of fatigue in the PC setting, as some patients experience a short-term increase in energy in response to caffeine. Avoiding any caffeine after midday, however, can help to avoid insomnia.

Tip 8: Though Psychostimulants Are Pharmacological Options for Treating Fatigue, Evidence Backing Their Use Is Limited

Psychostimulants are drugs that increase alertness and motivation through their influence on excitatory neurotransmitters. Commonly used psychostimulants include methylphenidate, amphetamine, and modafinil/armodafinil. These medications increase the effect of excitatory neurotransmitters by increasing the quantity of dopamine and/or norepinephrine at the synaptic cleft.

Methylphenidate and modafinil have been used as therapeutic agents to combat fatigue in patients with serious illnesses for decades. Benefits include their relative safety, their short time to benefit, which is usually hours to days, and their potential to rapidly improve symptoms of depression among individuals with limited prognoses.^50–53 Almost all experimental data on the use of psychostimulants for serious illness-related fatigue are drawn from cancer patients. Just one study examines the impact of modafinil on fatigue in patients with primary biliary cirrhosis.⁵⁴

In the past two decades, a number of Phase III and/or large randomized clinical trials have failed to show efficacy of psychostimulants in improving fatigue among patients with serious illness.^55–64 Clinicians continue to utilize psychostimulants for serious-illness-related fatigue, however, because of smaller positive studies and certain meta-analyses that do suggest treatment effects from modafinil and methylphenidate.^65–68 Only very limited study of amphetamine derivatives has been conducted in patients with serious illnesses.⁶⁹

New national guidelines from ASCO-SIO advise against routinely prescribing psychostimulants or wakefulness agents to manage symptoms of fatigue.¹⁸ Prior to considering psychostimulants, we strongly suggest the first-line use of psychosocial interventions and addressing reversible contributors to fatigue.

Despite the advice to not routinely recommend psychostimulants for cancer-related fatigue, there may be circumstances in which PC clinicians may consider their use. PC clinicians may feel more comfortable trying these agents when the patient’s prognosis is limited or when the duration of anticipated use is short. Prior to initiating psychostimulants, it is important that PC clinicians evaluate thoroughly for contraindications to the use of psychostimulants. Contraindications may include uncontrolled anxiety, cognitive disturbances, or heart disease.

Should psychostimulants be initiated, PC clinicians generally start with low dose (2.5–5 mg) immediate-release methylphenidate twice daily (with modafinil as a second line and amphetamine formulations as a third line). Methylphenidate can be rapidly titrated (e.g., by 5 mg every 2–4 days) to effect. If an adequate therapeutic effect is not obtained even with dose escalation (up to 20 mg per day), we recommend deprescribing to prevent adverse effects and polypharmacy. For patients who would benefit from long-acting agents, there is a range of such options for both methylphenidate and amphetamine salts (e.g., methylphenidate long-acting and an 8-hour amphetamine formulation). Initiating these formulations would only be appropriate once a beneficial dose has been found using immediate-release formulations.

Tip 9: Medications such as Corticosteroids, Bupropion, and Solriamfetol Can Also Be Pharmacological Treatment Options, Though Caution Is Needed as Supporting Data Are Limited

In addition to nonprescription and psychostimulant approaches, medications like steroids, bupropion, and solriamfetol, which affect norepinephrine and dopamine reuptake, may be explored to address fatigue within PC settings.

Corticosteroids such as dexamethasone, prednisone, and methylprednisolone are effective in short-term cancer-related fatigue management in PC, resulting in improved quality of life.¹⁰ Of all pharmacologic agents, steroids have perhaps the largest evidence base supporting their use.¹⁸ However, their long-term efficacy is inadequately researched; steroids carry a notable risk of adverse effects, especially in older patients, including neuropsychiatric symptoms (such as delirium, mood disorders, and sleep disturbances), gastrointestinal disturbances, and increased risk of infection, among others.^70–72 ASCO-SIO guidelines recommend steroids as treatment for cancer-related fatigue, but there is not enough evidence to support their use in fatigue outside of the context of advanced cancer.¹⁸ Consequently, their usage is generally reserved for terminally ill patients, those with fatigue accompanied by anorexia, and individuals experiencing pain from brain or bone metastases.¹⁰

Bupropion is a norepinephrine-dopamine reuptake inhibitor (NDRI) that is FDA-approved for major depressive disorder, seasonal affective disorder, and nicotine addiction. Its primary mechanism involves increasing dopamine neurotransmission in the frontal cortex of the brain. A recent systematic review that included seven studies with a total of 584 patients demonstrated bupropion’s efficacy and safety in managing both cancer- and noncancer-related fatigue. Dosages ranged between 75 and 300 mg daily. However, these findings are inconclusive owing to heterogeneity among the studies.⁷³

Solriamfetol is another NDRI that is FDA-approved for the treatment of excessive sleepiness in narcolepsy or obstructive sleep apnea and is predominantly used with these indications. To date, no studies have explored the effect of this medication on fatigue in the PC population. Its use might also be limited by cost considerations.

Tip 10: Don’t Just Add More Medications; Reducing Polypharmacy and Stopping Certain Medications such as Gabapentinoids and Anticholinergics Can Improve Fatigue

Medications are commonly associated with fatigue. Commonly prescribed medications in the PC setting associated with fatigue are listed in Table 2.⁷⁴

Table 2.

Common Medications in Palliative Care Setting with Known Mechanisms Contributing to Fatigue^a

Medication class	Commonly prescribed medications in PCb
Opioids	Morphine, oxycodone, hydromorphone, oxymorphone, fentanyl, methadone, hydrocodone, codeine
Benzodiazepines	Lorazepam, diazepam, clonazepam, alprazolam, midazolam, temazepam
Barbiturates	Phenobarbital, pentobarbital
Gabapentinoids	Gabapentin, pregabalin
Beta blockers	Metoprolol, carvedilol, propranolol, atenolol
Anticholinergics	Scopolamine, oxybutynin, atropine, dicyclomine, benztropine
Skeletal muscle relaxants	Baclofen, cyclobenzaprine, methocarbamol, cyclobenzaprine
1st generation antihistamines	Diphenhydramine, chlorpheniramine, promethazine
Central alpha2 agonists	Clonidine, tizanidine
Anticonvulsants	Carbamazepine, valproic acid, phenytoin
Antidepressants	Amitriptyline, nortriptyline, desipramine, doxepin, imipramine, mirtazapine, trazodone
Antipsychoticsc	Olanzapine, quetiapine, chlorpromazine, risperidone, prochlorperazine, haloperidol

^a Adapted from Zlott et al., PM&R. 2010.⁷⁴

^b This is not an all-inclusive list.

^c Antipsychotics with anticholinergic properties are the worst offenders.

The assessment of pharmacologically-induced fatigue requires the differentiation between two closely related adverse effects of medications: fatigue and drowsiness.⁷⁵ There are two primary mechanisms of pharmacologically induced fatigue: central nervous system depression, also known as “central fatigue,” and decreasing oxygen-carrying capacity, referred to as “peripheral fatigue.”⁷⁴ Medications like opioids, benzodiazepines, and anticholinergics can cause “central fatigue” by directly affecting brain receptors. Combining drugs such as opioids and benzodiazepines can significantly enhance “central fatigue” owing to their combined sedative effects, which can exceed what would be expected from simply adding their individual effects together. Conversely, peripheral fatigue may be exacerbated by disease states such as anemia, which is commonly associated with medications like antineoplastic agents.

A comprehensive medication review is recommended to identify all medications potentially contributing to fatigue. Furthermore, it is important to consider the additive effect of prescribing multiple medications with mechanisms contributing to fatigue. If clinically indicated, adjusting medication regimens by titrating dosages or discontinuing medications before initiating new treatments can effectively reduce the risk of polypharmacy.⁷⁶ If possible, we also recommend collaborating with other disciplines to determine if alternative medication agents are available.

Discussion

Fatigue is a multifactorial symptom commonly faced by patients with serious illness, and the potential impact on patients and families is significant. This symptom poses challenges for clinicians owing to its numerous causes and lack of robust treatments. Fatigue management requires multidisciplinary collaboration between physicians, nutrition, physiotherapists, nurses, mental health providers, and other members of the interdisciplinary team. Early identification and multimodal treatment, partnering with patients and caregivers, are key. Treatment strategies ideally include holistically targeting sleep, assessing contributing factors, and weighing risks and benefits for each individual patient to select interventions that minimize harm while maximizing patient quality of life.

Funding Information

W.E.R. is partially funded by NIH/NCI Comprehensive Cancer Center Grant P30 CA008748.

Author Disclosure Statement

No competing financial interests exist.