What is the best treatment approach for a patient with chronic fatigue syndrome?

Treatment of Chronic Fatigue Syndrome

Cognitive behavioral therapy (CBT) should be offered as the primary first-line treatment for chronic fatigue syndrome, as it demonstrates the strongest evidence for improving health function, quality of life, and physical functioning. 1

Initial Assessment and Diagnosis

Before initiating treatment, systematically exclude treatable conditions that mimic chronic fatigue syndrome:

• Rule out anemia, hypothyroidism, depression, anxiety disorders, sleep disorders, electrolyte disturbances, and chronic infections before attributing symptoms to CFS. 1, 2
• Confirm the diagnosis requires profound fatigue lasting ≥6 months with substantial reduction in pre-illness activities, accompanied by postexertional malaise, unrefreshing sleep, and either cognitive impairment or orthostatic intolerance. 2
• Conduct a psychosocial assessment including psychological trauma history and obtain a complete medical history. 2

First-Line Non-Pharmacological Treatment

Cognitive Behavioral Therapy (Primary Intervention)

Structured CBT should be initiated as the primary intervention, tailored to address thoughts, feelings, and behaviors related to fatigue. 1, 2 This approach shows moderate improvements in fatigue, distress, cognitive symptoms, and mental health functioning in multiple randomized controlled trials. 1

Critical caveat: CBT for CFS/ME must be delivered by appropriately trained therapists working in close collaboration with the patient, and successful rehabilitation does not indicate the illness is not real. 3

Activity Management and Pacing

• Promote a consistent pattern of activity, rest, and sleep, starting physical activity at low intensity and gradually increasing based on tolerance. 1, 2
• Avoid postexertional malaise by carefully titrating exercise to prevent symptom exacerbation. 1
• Graded exercise therapy remains controversial for ME/CFS and should be delivered cautiously with close patient collaboration, despite showing statistical benefits in some trials. 2, 4

Complementary Mind-Body Approaches

• Mindfulness-based stress reduction or mindfulness-based cognitive therapy can be offered, showing moderate effect sizes for enhancing quality of life. 1
• Yoga or tai chi demonstrate significant improvements in physical functioning, quality of life, pain, fatigue, sleep quality, and mood, with longer duration showing greater improvement. 1, 2
• Manual acupuncture can be considered as part of management, with evidence supporting improvements in quality of life up to 3 months post-treatment. 1, 2

Pharmacological Management (Limited Role)

For Pain Management Only

• Serotonin-norepinephrine reuptake inhibitors (SNRIs) such as duloxetine can be considered for pain, providing 30-50% pain relief and improvements in Patient Global Impression of Change scores. 1, 2
• Pregabalin can be considered for pain management with similar efficacy. 1, 2
• Bupropion may be considered for refractory fatigue with depressive features, although evidence is limited. 1, 2

Medications to Explicitly Avoid

Do not prescribe the following medications for CFS/ME, as harms outweigh benefits:

• Stimulants (methylphenidate, modafinil) should be avoided despite fatigue being a core symptom. 2, 4
• Corticosteroids have no demonstrated benefit. 2, 4
• Antivirals are not effective. 2, 4
• Antibiotics should not be used. 2, 4
• Long-term opioid medications (including hydrocodone) are strongly recommended against, as potential harms and burdens outweigh any theoretical benefits in this population. 2

Common pitfall: Do not prescribe hydrocodone based on patient reports of severe pain alone without attempting evidence-based alternatives (CBT, SNRIs, pregabalin) first. 2

Treatment Algorithm

1. Systematically exclude treatable conditions causing chronic fatigue (anemia, thyroid disease, depression, sleep disorders). 1, 2
2. Initiate structured CBT as primary intervention, with activity pacing and mindfulness-based therapy added as complementary approaches. 1
3. Introduce graded exercise, yoga, or tai chi based on patient tolerance and preference, with manual acupuncture considered as complementary. 1
4. For persistent pain, trial SNRI or pregabalin before considering other options. 1, 2
5. Assess fatigue severity at every visit using a 0-10 numeric rating scale. 1, 2
6. Modify management strategies based on response and changes in clinical status. 1, 2

Monitoring and Specialist Referral

• Regularly evaluate fatigue impact, coping strategies, and treatment response at each clinical visit. 1, 2
• Consider referral to mental health professionals, physical therapists, or integrative medicine specialists for comprehensive management when symptoms are unresolved. 1, 2

Important Distinction from Other Fatigue Syndromes

CFS/ME requires different management than cancer-related fatigue or long COVID fatigue. 4 For cancer-related fatigue, methylphenidate and corticosteroids may have limited roles, but these should be avoided in CFS/ME. 5, 4 The 2022 ESCMID guidelines note that evidence is insufficient to provide recommendations for managing fatigue in long COVID, and graded exercise therapy remains controversial for ME/CFS. 5