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- Singapore Med J
- v.63(11); 2022 Nov
- PMC9815175
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Singapore Med J. 2022 Nov; 63(11): 674–678.
Published online 2022 Nov 29. doi:10.4103/SINGAPOREMEDJ.SMJ-2021-118
PMCID: PMC9815175
PMID: 36573655
Daphne Chien Hui Ho, BMed, MD1 and Ruth Mingli Zheng, MMed, FCFP1,2
Author information Article notes Copyright and License information PMC Disclaimer
Opening Vignette
Mrs Lim, a 56-year-old housewife, comes into your consultation room for complaints of fatigue over the past 1 month. She reports unrefreshing sleep and has been drinking 3-4 cups of coffee and taking 1-hour afternoon naps to keep her going throughout the day. During the consultation, you find out that she has recently stopped working to care for her elderly mother-in-law who has been recently diagnosed with dementia.
WHAT IS FATIGUE?
Fatigue can be defined as a state of physical or mental exhaustion with difficulty or inability to initiate or maintain activity.[1] It can compromise on a person’s mental alertness, physical motor skills, judgement and decision-making. Simply put, fatigue has been generally been described by patients as feeling tired or exhausted.
HOW RELEVANT IS THIS TO MY PRACTICE?
Fatigue is a common symptom presenting in general practice, which can negatively affect patients’ work performance and family and social relationships. It often poses as a diagnostic challenge with a variety of differential diagnoses, due to its associations with biophysical, psychological and social problems. International surveys have shown that 1 in 4 family medicine patients present with fatigue, with fatigue being the main reason for encounter in 6.5% and a secondary reason in 19%.[2] It is also prevalent in the young adults and paediatric population, with 1 in 3 adolescents reporting fatigue at least four times a week.[3]
WHAT CAUSES SHOULD BE CONSIDERED?
Fatigue can be classified according to time frame (acute, subacute, chronic) or aetiology (physiologic, secondary). Acute fatigue lasts for one month or less, subacute fatigue lasts between one and six months, while chronic fatigue lasts more than six months.[4] Secondary fatigue is due to an underlying medical condition, while physiologic fatigue is caused by a lifestyle imbalance in routines of sleep, exercise, diet or other activity not attributed to an underlying medical condition and is alleviated by rest.[5]
There are a multitude of causes for fatigue [Box 1]. Murtagh describes a practical diagnostic approach by classifying the causes of fatigue into probability diagnoses, serious disorders not to be missed and pitfalls.[6] Probability diagnoses include anxiety/stress, depression, viral/post-viral infections and sleep-related disorders. Serious disorders to be considered include anaemia, malignancy, and infective causes such as HIV/AIDS, hepatitis B/C, bacterial infections. Common pitfalls that are often missed include depression, medication and substance use, pregnancy, thyroid disorders, diabetes mellitus and incipient cardiac failure.
Box 1
Causes of fatigue. (Adapted from Murtagh)[6]
| Secondary Causes | ||
|---|---|---|
| Organic | Neuromuscular | Autoimmune/rheumatologic |
| Cardiopulmonary | • Parkinson disease | • Polymyalgia rheumatica |
| • Congestive cardiac failure | • Myasthenia gravis | • Fibromyalgia |
| • Asthma | • Multiple sclerosis | • Systemic lupus erythematosus |
| • Chronic obstructive pulmonary disease | Infectious | • Rheumatoid arthritis |
| • Sleep-related disorders (e.g. sleep apnoea) | • HIV/AIDS | Others |
| Metabolic/endocrine | • Viral hepatitis | • Chronic fatigue syndrome |
| • Thyroid disorders (hyper and hypo) | • Tuberculosis | • Irritable bowel syndrome |
| • Diabetes mellitus | • Postinfectious fatigue syndrome | Non-organic |
| • Chronic kidney disease | (influenza, mononucleosis) | Psychiatric |
| • Chronic liver disease | • Bacterial infections | • Anxiety disorders |
| • Electrolyte abnormalities (hypokalaemia, | Haematologic/neoplastic | • Depression |
| hypomagnesaemia, hypercalcaemia) | • Anaemia | • Grief/bereavement |
| • Nutritional deficiency | • Occult malignancy | • Somatisation disorder |
| • Addison disease | Medication toxicity | • Substance use or addiction disorders |
| Physiologic Causes | ||
| Lifestyle factors | • Sedentary lifestyle | • Mental and emotional stress |
| • Shift work • Workaholic tendencies/’burnout’ | • Inappropriate diet • Sleep deprivation | • Exposure to irritants (e.g. carbon monoxide, lead fumes) |
| • Workaholic tendencies/’burnout’ | • Sleep deprivation | |
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Chronic fatigue syndrome (CFS) is a complex syndrome causing profound unexplained fatigue and is an illness of uncertain aetiology. It is estimated to affect 17 to 24 million people worldwide, approximately 1% of the population.[7] CFS is a debilitating condition that is associated with a poorer quality of life, with over half of CFS patients being unemployed.[7] The diagnostic criteria of CFS are outlined in Box 2 and requires careful exclusion of alternative diagnoses by clinical history, examination and investigations as appropriate.
Box 2
Criteria for the diagnosis of chronic fatigue syndrome. (Adapted from Murtagh)[6]
| Fatigue |
| Clinically evaluated, unexplained, persistent or relapsing fatigue persistent for 6 months or more, that: |
| • Is of new or definite onset |
| • Is not the result of ongoing exertion |
| • Is not substantially alleviated by rest |
| • Results in substantial reduction in previous levels of occupational, educational, social or personal activities |
| And |
| Other symptoms |
| Four or more of the following symptoms that are concurrent, persistent for 6 months or more, and which did not exist prior to the fatigue: |
| • Impaired short-term memory or concentration |
| • Sore throat |
| • Tender cervical or axillary lymph nodes |
| • Myalgia |
| • Multi-joint arthropathy without arthritis |
| • New pattern, type or severity of headaches |
| • Unrefreshing sleep |
| • Post-exertional malaise lasting >24 h |
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WHAT CAN I DO IN MY PRACTICE?
International studies have demonstrated a wide variation in rates of formal diagnoses of organic pathology (e.g. thyroid disease, anaemia), ranging from as low as 8.2% to 50% in patients presenting with fatigue.[8,9,10] This discrepancy in findings may possibly be due to different ways of classifying organic or somatic diagnoses. Thus, despite being associated with various medical and psychological causes, fatigue remains unexplained in majority of cases, with the final diagnosis being “tiredness”.
General approach
In local primary care settings where time may be limited, it is recommended to schedule repeated appointments to explore and manage patients’ symptoms, as well as patients’ ideas, concerns and expectations. The first visit should aim to elucidate the underlying cause of fatigue using a biopsychosocial approach. Initiating the consultation with open-ended questions would help to narrow down the most likely differential diagnoses. An assessment of severity can be done by evaluating how fatigue has impaired the patient’s function and quality of life. It is recommended to allocate more time in the initial follow-up appointment to discuss the outcome of the investigations, further narrow down the differentials with more history-taking, and work towards a shared action plan with the patient. Subsequently, shorter appointments can be arranged to target specific action areas, such as sleep hygiene, stress management and relaxation techniques, and structured problem-solving.
Initial evaluation
Clinical evaluation of fatigue should begin with identifying the common causes, red flags and masquerades. A comprehensive history, by no means exhaustive, may include clarification on patient’s ideas/concerns/expectations on fatigue, onset/duration/severity and impact on function, associated somatic and psychological symptoms, alcohol, drug and medication history [Box 3], sleep patterns and hygiene, and social history including occupation (e.g. shift work). Red flags, which may point towards serious underlying pathology, include constitutional symptoms (unintentional loss of weight, loss of appetite, fever), recent onset in a previously well older patient, unexplained lymphadenopathy and abnormal bleeding. Similarly, physical examination findings that raise suspicion of underlying somatic diseases include pallor (anaemia, malignancy), lymphadenopathy (malignancy), goitre (thyroid disorder), murmurs (endocarditis) and oedema (cardiac failure, liver disease).
Box 3
Medications and substances that can cause fatigue.
| Alcohol | Cocaine and other |
| Anti-depressants | stimulants |
| Antibiotics | Marijuana |
| Antihistamines (especially first | Muscle relaxants |
| generation) | Nicotine |
| Benzodiazepines | Opioids |
| Beta-blockers | Sedative hypnotics |
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Investigations
In the climate of litigation fears as well as a lack of local guidelines for the evaluation of fatigue, general practitioners are often tempted to order an array of investigations. Investigations commonly ordered in the evaluation of fatigue include full blood count, electrolyte panel, thyroid hormone panel, renal function test, liver function test, blood glucose, urinalysis, inflammatory markers, and urine pregnancy test in females of child-bearing age. However, studies have demonstrated that there is limited positive predictive value of blood tests, as fatigue is associated with a low pre-test probability of underlying organic pathology, with results affecting management in only 5% of patients.[11,12] Given the low yield of investigations in elucidating an underlying cause for fatigue and the implications of false-positive results, it is reasonable to adopt an approach of watchful waiting in the absence of red flags and symptoms that point towards underlying pathology. Once the decision has been made to investigate, judicious selection of tests should be employed.
Follow-up
Based on the history and examination findings, targeted first-line screening investigations as presented earlier (e.g. full blood count, electrolytes and renal function, blood glucose, thyroid function, inflammatory markers) can be considered. Secondary causes of fatigue that are detected should then be managed accordingly.
In the absence of pathology, a common misunderstanding is that if patients do not return, it indicates fatigue resolution. However, on the contrary, patients’ fatigue may still be present, but they may feel that nothing can be done due to a lack of understanding of their fatigue and lack of an identified cause.
Scheduling an early appointment for review of symptoms, rather than sporadic walk-in encounters is thus recommended to monitor patients’ response to management plans. In patients with an identified cause of fatigue, if management of the underlying condition does not lead to resolution or improvement, further re-evaluation for alternative causes would be warranted. During these visits, consider equipping patients with helpful information, including symptom management, setting stepwise realistic goals, and coming to a shared understanding and identification of triggers such as lifestyle, social and environmental factors. Patients should be observed and re-evaluated at these visits to assess if treatment is effective or if reassessment is required.
Management
Management of fatigue involves both non-pharmacological and pharmacological strategies.
Non-pharmacological
Exercise therapy and sleep hygiene advice [Box 4] have been shown to improve fatigue regardless of aetiology and should be recommended to all patients with fatigue.[13] Cognitive behavioural therapy has also shown good response in patients with CFS.[14] Management strategies in CFS include validating that CFS is a real illness, patient education and reassurance that CFS is usually self-limiting with most patients returning to normal health, and providing continued support and counselling.[6]
Box 4
Non-pharmacological interventions for fatigue.
| Sleep hygiene |
| • Maintaining a regular sleep-wake cycle and schedule |
| • Increasing exercise/physical activity levels in the day, but not in the evening or close to bedtime |
| • Avoid caffeine/alcohol/nicotine and excessive meal and liquid consumption in the evening |
| • Using the bedroom only for sleep and sex |
| • Minimise screen time, light and noise exposure before sleep |
| Exercise therapy |
| • Regular aerobic exercise of moderate intensity |
| • (e.g. 30 min of walking/jogging on most days of the week) |
| • Yoga, group therapy and stress management are shown to improve cancer-related fatigue[15] |
| Psychotherapy |
| • Cognitive behavioural therapy |
| • Psychoeducation |
| • Counselling and support groups |
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It should be standard practice to advise patients to maintain good sleep hygiene, keep a symptom and sleep diary for self-management, and to engage in physical activity that involves stretching and aerobic exercise like walking.
Basic cognitive behavioural therapy strategies that primary care physicians can employ in their practice are highlighted in Box 5. Local resources, including psychologists, are often available in most polyclinic settings, and can provide cognitive behavioural therapy, problem-solving therapy, relaxation skills training and mindfulness-based interventions. To empower patients in self-management, physicians can also recommend self-help resources such as the “Headspace” and “Calm” meditation applications, local websites like “mindline.sg”, “HealthHub” and the “Understanding Your Mental Health” section on the Institute of Mental Health website which often feature articles on mental wellness tips, and hotlines such as “Samaritans of Singapore” at 1800-221 4444 for 24-hour emotional support.
Box 5
Cognitive behavioural therapy strategies.
| What is cognitive behavioural therapy (CBT)? |
| CBT aims to help patients change their thoughts through cognitive therapy, emotions through dearousal strategies, and behaviours via structured problem solving. |
| Cognitive therapy |
| • Ask: “What are some of your dysfunctional or selfdefeating thoughts and perceptions?” |
| • Ask: “What evidence is there for these thoughts?” |
| • Say: “Now challenge your thinking and put these new skills into practice.” |
| De-arousal (deep breathing techniques) |
| • Sit or lie down in a comfortable position |
| • Place one hand on your belly and one hand on your chest |
| • Take in a deep breath through your nose for 3 sec as you feel your belly rise |
| • Breathe out slowly through pursed lips for another 3 sec, feeling your belly fall |
| • Repeat up to 4 times |
| Structured problem solving |
| • Define the problem |
| • Brainstorm a number of solutions |
| • Consider the advantages and disadvantages of each |
| • Choose the most practical solution |
| • Plan how to carry it out |
| • Perform it |
| • Review and reconsider solutions |
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Pharmacological
In patients whom depression is suspected in the absence of organic pathology, a six-week trial of selective serotonin reuptake inhibitors (SSRIs) (e.g. fluoxetine, sertraline) may be considered.[5] A common pitfall is over-reliance on hypnotic medications such as antihistamines (e.g. hydroxyzine) to help with sleep. Primary care physicians should educate patients that fatigue is a symptom that can be managed non-pharmacologically, with pharmacotherapy being prescribed only when non-pharmacological interventions are deemed ineffective.
WHEN SHOULD I REFER TO A SPECIALIST?
Primary care physicians should consider referral to a specialist if there are secondary organic causes of fatigue to be managed at the specialist level. Timely psychiatric referral should also be considered in patients with psychiatric conditions that cannot be managed in the primary care setting such as bipolar disorder, schizophrenia and substance use disorder. Failure of treatment of depression, anxiety or somatisation disorders at the primary care level should also prompt a referral to psychiatry. Referral to allied healthcare professionals, such as psychologists, should also be considered for patients who may benefit from specialised interventions (e.g. cognitive behavioural therapy, psychotherapy).
A multidisciplinary approach is recommended in managing chronic fatigue syndrome, to provide psychological support and focused treatment on comorbid symptoms such as insomnia, mood disorders, pain, memory and concentration difficulties.
TAKE HOME MESSAGES
Fatigue is a common non-specific symptom presenting in primary care, associated with a wide range of underlying aetiologies. These include acute and chronic medical conditions, psychiatric conditions, medication/substance use, and physiologic fatigue.
Initial evaluation should be focused on identifying and managing common and life-threatening secondary causes. Laboratory tests often have a low yield in leading to a formal clinical diagnosis in patients with fatigue. Thus, it is reasonable to utilise a practical approach of taking a comprehensive history and examination, consider watchful waiting in the absence of red flags, and judicious selection of tests once one has made the choice to investigate.
In the absence of organic causes, consider a six-week trial of SSRIs in patients with fatigue in whom depression is suspected.
Exercise therapy and sleep hygiene advice should be recommended to all patients with fatigue, regardless of aetiology. Cognitive behavioural therapy can also be considered to manage fatigue symptoms for conditions such as chronic fatigue syndrome.
Closing Vignette
A comprehensive history and examination reveals no significant red flags. Mrs Lim shares that her mood is stable and is coping well with support from her husband and friends. You discuss appropriate sleep hygiene practices, counsel on relaxation techniques and provide psychological support for caregiver stress. You advise her to return earlier if new symptoms or red flags arise. Mrs Lim agrees to the treatment plan and a review in two weeks’ time.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
SMC CATEGORY 3B CME PROGRAMME
Online Quiz: https://www.sma.org.sg/cme-programme
Deadline for submission: 6 pm, 20 January 2023
| Question | True | False |
|---|---|---|
| 1. Fatigue is defined as a state of physical or mental exhaustion with difficulty or inability to initiate or maintain activity. | ||
| 2. Fatigue is the main reason for encounter in less than 5% and the secondary reason in less than 10% in patients presenting to family medicine clinics. | ||
| 3. Fatigue is not a common presenting symptom in the paediatric and adolescent population. | ||
| 4. Diagnosis of fatigue can be challenging due to its association with a variety of differentials, biophysical, psychological and social problems. | ||
| 5. Acute fatigue can be defined with a duration of 2 weeks or less. | ||
| 6. Subacute fatigue lasts between 2 weeks and 6 months. | ||
| 7. Chronic fatigue lasts for more than 6 months. | ||
| 8. Chronic fatigue syndrome requires fulfilling the definition of persistent, unexplained, clinically evaluated fatigue for 6 months or more, as well as 4 or more somatic symptoms such as myalgia, arthropathy, unrefreshing sleep and tender lymph nodes. | ||
| 9. The evaluation of fatigue requires careful exclusion of secondary medical and psychiatric conditions as these are managed differently. | ||
| 10. Medication and drug history, sleep patterns, social history and associated somatic and psychological symptoms are key features in a comprehensive history for evaluation of fatigue. | ||
| 11. Red flags include unintentional loss of weight, fever, loss of appetite, recent onset in a previously well older patient, unexplained lymphadenopathy and abnormal bleeding. | ||
| 12. Evaluation of fatigue should always include investigations as laboratory investigations have a high yield in elucidating an underlying cause for fatigue. | ||
| 13. Majority of patients with fatigue end up with a formal diagnosis of organic pathology. | ||
| 14. Scheduling regular follow-up visits, rather than sporadic walk-in encounters, is recommended to monitor patients’ response to management plans. | ||
| 15. If there is no improvement or resolution of fatigue with current management strategies, re-evaluation is necessary for alternative causes. | ||
| 16. A 6-week course of selective serotonin reuptake inhibitors (SSRIs) can be trialed in patients whom depression is suspected. | ||
| 17. Encouraging good sleep hygiene and regular exercise are recommended non-pharmacological strategies to improve fatigue in all patients. | ||
| 18. Increasing physical activity at night and heavy dinner consumption will help to improve fatigue. | ||
| 19. Primary care physicians should have a lower threshold for referral to specialists/allied healthcare professionals if there are secondary causes of fatigue. | ||
| 20. Patients with chronic fatigue syndrome benefit from reassurance, validation, counselling and support. | ||
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