What causes fatigue and how is it managed?

Fatigue: Causes and Management

Fatigue should be systematically screened at every clinical visit using a 0-10 numeric rating scale, with scores ≥4 triggering comprehensive evaluation for treatable causes including anemia, sleep disorders, depression, thyroid dysfunction, and nutritional deficiencies, followed by evidence-based interventions prioritizing exercise and cognitive behavioral therapy. 1

Initial Screening and Assessment

• Screen all patients for fatigue using a 0-10 visual analogue scale at every clinical encounter, with 0 representing no fatigue and 10 representing severe fatigue 1, 2
• Patients scoring 0-3 require only basic education and counseling, while those scoring 4-10 warrant thorough evaluation for reversible causes 1, 2
• Document the multidimensional character of fatigue including physical exhaustion, emotional depletion, and cognitive tiredness, as fatigue is a subjective sense of exhaustion not proportional to recent activity that interferes with usual functioning 1, 2
• Assess concurrent symptoms systematically, as fatigue rarely occurs in isolation and commonly clusters with pain, emotional distress, anemia, and sleep disturbances 1

Common Causes by Context

Disease-Related Fatigue

• Cancer-related fatigue affects 80% of patients receiving chemotherapy/radiotherapy and exceeds 75% prevalence in metastatic disease, persisting months to years after treatment ends 1
• Inflammatory rheumatic and musculoskeletal diseases cause severe fatigue in 50% of patients, described as overwhelming and draining of physical and mental energy 1
• Inflammatory bowel disease produces fatigue in over 80% of patients, persisting in half of those achieving clinical and endoscopic remission 1
• Depression is the most common cause of persistent fatigue in primary care, accounting for 18.5% of cases 3

Physiologic and Secondary Causes

• Sleep disorders and sleep-related breathing disorders are among the most common causes of persistent fatigue 3
• Anemia and other organic causes account for only 4.3% of fatigue cases in primary care 3
• Previously undiagnosed cancer is rare, representing only 0.6% of fatigue presentations 3
• Medications, thyroid dysfunction, nutritional deficiencies (iron, B12, folate, vitamin D), and electrolyte disturbances are important reversible causes 1, 4, 5

Comprehensive Evaluation for Moderate-to-Severe Fatigue (Score ≥4)

Essential Laboratory Testing

• Complete blood count with differential to evaluate for anemia 1, 2, 4
• Comprehensive metabolic panel to assess electrolyte disturbances and organ function 2, 4
• Thyroid function tests (TSH, free T4) to exclude hypothyroidism 1, 2, 4
• Iron studies, vitamin B12, folate, and vitamin D levels to identify nutritional deficiencies 4
• Consider inflammatory markers and creatine kinase if muscle pain is prominent 2

Clinical Assessment

• Evaluate for depression, anxiety, and psychological distress using validated screening tools 1, 5
• Assess sleep quality and screen for sleep disorders including insomnia and sleep apnea 1, 3
• Review all medications for fatigue-inducing side effects 1, 5
• Document impact on daily activities, work performance, and social relationships 1, 6, 5

Important caveat: Investigations beyond history, physical examination, and simple laboratory tests are needed only in the presence of additional symptoms or findings, as excessive testing leads to overdiagnosis 3

Evidence-Based Management Algorithm

Step 1: Treat Identified Reversible Causes (Category 1)

• Correct anemia with appropriate iron supplementation or erythropoietin as clinically indicated 1, 2, 4
• Initiate antidepressants (fluoxetine, paroxetine, or sertraline) if depression is present 1, 5
• Replenish nutritional deficiencies with oral or intramuscular supplementation (iron, B12, folate, vitamin D) 1, 4
• Treat thyroid dysfunction with levothyroxine if hypothyroidism is identified 7, 2
• Optimize pain management and address emotional distress, as these frequently cluster with fatigue 1, 7

Step 2: Implement Non-Pharmacologic Interventions (Highest Evidence)

Physical Activity (Category 1 - Strongest Evidence)

• Exercise is the most strongly evidence-based intervention for fatigue and should be initiated as tolerated 1, 7
• Prescribe a combination of moderate-intensity endurance exercises (walking, jogging, swimming) and resistance training with light weights 1, 7
• Start at low intensity and gradually increase based on tolerance, with sessions 3-5 times weekly 2, 4
• Consider gentle movement-based therapies such as tai chi, qigong, or yoga as alternatives 2

Critical warning: Exercise should be prescribed cautiously in patients with bone metastases, thrombocytopenia, anemia, fever, or active infection 1, 7. Exercise can be harmful in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) as it triggers postexertional malaise 6

Cognitive Behavioral Therapy (Category 1)

• Offer cognitive behavioral therapy (CBT) to patients with persistent moderate-to-severe fatigue, as it has strong evidence for reducing fatigue 1, 7
• CBT for insomnia is specifically recommended when sleep disturbance is identified 1, 7, 2
• Solution-focused therapy may reduce fatigue with benefits lasting up to 3 months post-therapy 1, 4
• Mindfulness-based stress reduction, psychoeducational therapies, and supportive-expressive therapies are evidence-based options 1, 7

Energy Conservation Strategies

• Teach patients to schedule activities during peak energy periods by maintaining a daily diary to identify when energy levels are highest 1, 7
• Prioritize essential activities and delegate or postpone nonessential tasks when experiencing moderate to severe fatigue 1, 7
• Implement labor-saving techniques such as using reachers, rolling carts, and wearing a bathrobe instead of toweling off after bathing 7
• Limit daytime naps to less than 1 hour to avoid disrupting nighttime sleep quality 1, 7

Sleep Optimization

• Establish consistent sleep and wake times, eliminate electronic devices before bedtime, and avoid caffeine and alcohol in the evening 7
• Screen for and aggressively treat sleep disorders as these are common contributors to fatigue 7
• Implement sleep hygiene through structured sleep-wake schedules 4

Nutritional Interventions

• Refer patients to nutritional consultation to address dietary deficiencies or alterations that may contribute to fatigue 1, 7
• Ensure adequate hydration and balanced energy expenditure 6, 5

Step 3: Consider Pharmacologic Interventions (After Non-Pharmacologic Approaches)

• Consider methylphenidate (psychostimulant) only after ruling out other treatable causes of fatigue, but use cautiously and only after treatment- and disease-specific morbidities have been characterized 1, 7
• Optimal dosing and schedule for psychostimulants in cancer patients have not been established 7
• Short-term hypnotics may be used for insomnia if indicated 1
• For inflammatory rheumatic diseases, consider immunomodulatory treatment initiation or change if clinically indicated 1

Important distinction: The 2024 EULAR guidelines emphasize that for inflammatory rheumatic diseases, tailored physical activity and psychoeducational interventions should be offered first, with immunomodulatory treatment changes considered when disease activity is present 1

Patient Education and Counseling

• Reassure patients that treatment-related fatigue does not indicate disease progression or treatment failure, as this fear is a primary reason for underreporting symptoms 7
• Educate patients before starting treatments that fatigue may occur and typically peaks early in treatment 7
• Instruct patients to maintain a daily fatigue diary using the 0-10 numeric rating scale to track fatigue levels 7
• Inform patients and families that management of fatigue is an integral part of total health care and that fatigue can persist following treatment 1

Monitoring and Reassessment

• Reassess fatigue levels at every visit using the same 0-10 numeric scale to track response and document improvement 1, 7, 2
• Re-evaluate laboratory parameters 3 months after initiating supplementation to confirm correction 4
• Monitor response to psychological interventions at 3-month intervals, recognizing that maintenance therapy may be needed to sustain benefits 4
• If fatigue remains unresolved despite treating contributing factors and implementing interventions, refer to supportive care specialists or interdisciplinary teams 1, 7

Special Considerations

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

• ME/CFS is diagnosed using 2015 National Academy of Medicine criteria, with postexertional malaise as the most important symptom 6
• Patients with ME/CFS should be educated about pacing activity not to exceed their limited energy capacity, as exercise can trigger postexertional malaise 6
• Treatment should prioritize comorbidities and symptoms based on severity, as ME/CFS has no proven cure 6

End-of-Life Fatigue

• Fatigue will likely increase substantially as disease progresses, occurring in the context of multiple symptoms 1
• Focus on energy conservation, meaningful interactions, and promoting patient dignity 1
• Consider referral to occupational therapy and rehabilitation services 1

Disability and Advocacy

• Health care professionals should advocate for patients who require disability benefits and educate insurers about persistent fatigue, as it is often difficult for patients to obtain or retain benefits despite biomedical literature documenting this entity 1