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Fatigue
Fatigue
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Fatigue
Other namesExhaustion, weariness, tiredness, lethargy, listlessness
Artistic representation of ME/CFS
SpecialtyPrimary care Edit this on Wikidata
TreatmentAvoid known stressors and unhealthy habits (drug use, excessive alcohol consumption, smoking), healthy diet, exercise regularly, medication, hydration, and vitamins

Fatigue is a state of being without energy for a prolonged period of time.[1][2] Fatigue is used in two contexts: in the medical sense, and in the sense of normal tiredness.

In the medical sense, fatigue is seen as a symptom, and is sometimes associated with medical conditions including autoimmune disease, organ failure, chronic pain conditions, mood disorders, heart disease, infectious diseases, and post-infectious-disease states.[3] However, fatigue is complex and in up to a third of primary care cases no medical or psychiatric diagnosis is found.[4][5][6]

In the sense of tiredness, fatigue often follows prolonged physical or mental activity. Physical fatigue results from muscle fatigue brought about by intense physical activity.[7][8][9] Mental fatigue results from prolonged periods of cognitive activity which impairs cognitive ability, can manifest as sleepiness, lethargy, or directed attention fatigue,[10] and can also impair physical performance.[11]

Definition

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Fatigue in a medical context is used to cover experiences of low energy that are not caused by normal life.[1][2]

A 2021 review proposed a definition for fatigue as a starting point for discussion: "A multi-dimensional phenomenon in which the biophysiological, cognitive, motivational and emotional state of the body is affected resulting in significant impairment of the individual's ability to function in their normal capacity".[12]

Another definition is that fatigue is "a significant subjective sensation of weariness, increasing sense of effort, mismatch between effort expended and actual performance, or exhaustion independent from medications, chronic pain, physical deconditioning, anaemia, respiratory dysfunction, depression, and sleep disorders".[13]

Terminology

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The use of the term fatigue in medical contexts may carry inaccurate connotations from the more general usage of the same word. More accurate terminology may also be needed for variants within the umbrella term of fatigue.[14]

Comparison with other terms

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Tiredness

[edit]

Tiredness which is a normal result of work, mental stress, anxiety, overstimulation and understimulation, jet lag, active recreation, boredom, or lack of sleep is not considered medical fatigue. This is the tiredness described in MeSH Descriptor Data.[15]

Exhaustion

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Exhaustion is a state of extreme tiredness.[16]

Sleepiness

[edit]

Sleepiness refers to a tendency to fall asleep, whereas fatigue refers to an overwhelming sense of tiredness, lack of energy, and a feeling of exhaustion. Sleepiness and fatigue often coexist as a consequence of sleep deprivation.[17] However sleepiness and fatigue may not correlate.[18] Fatigue is generally considered a longer-term condition than sleepiness (somnolence).[19]

Presentation

[edit]

Common features

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Distinguishing features of medical fatigue include

  • unpredictability,
  • variability in severity,
  • fatigue being relatively profound/overwhelming, and having extensive impact on daily living,
  • lack of improvement with rest,
  • where an underlying disease is present, the amount of fatigue is often not commensurate with the severity of the underlying disease.[12][20][21][22]

Differentiating features

[edit]

Differentiating characteristics of fatigue that may help identify the possible cause of fatigue include

  • Post-exertional malaise; a common feature of ME/CFS,[23] and experienced by a significant proportion of people with Long Covid,[24] but not a feature of other fatigues.
  • Increased by heat or cold; MS fatigue is in many cases affected in this way.[25][26]
  • Flare-ups and Remissions; Some fatigue diseases have flareups of a few weeks (lupus,[27][28] fibromyalgia[29]). Other fatigue diseases may have longer patterns of activity and remission, or no remissions at all (MS[30][31][32]).
  • Variability within a day; Some fatigues (rheumatoid arthritis (RA),[33] cancer-related fatigue[34]) seem to often be continual (24/7), whilst others (MS, Sjögren's, lupus, brain injury[35][36]) often vary in intensity at different times within a day.[33] A 2010 study found that Sjögren's patients reported fatigue after rising, an improvement in mid-morning, and worsening later in the day, whereas lupus (SLE) patients reported lower fatigue after rising followed by increasing fatigue through the day.[37] ME/CFS symptoms can be continual, or can fluctuate during the day, from day to day, and over longer periods.[32] Fibromyalgia fatigue can be continual or variable.[38]
  • The pace of onset may be a related differentiating factor; MS fatigue can have abrupt onset.[39]
  • Feeling of weight; some fatigues, including that caused by MS, create a sense of weight or gravity; "I feel like I have lead weights attached to my limbs ... or I am being pulled down by gravity."[40]

Some people may have multiple causes of fatigue.

Causes

[edit]

Fatigue is complex and can be driven and maintained by a potentially wide range of biopsychosocial factors.[41] Tiredness is a common medically unexplained symptom.[5] In up to a third of fatigue primary care cases, no medical or psychiatric diagnosis is found.[4][5][6]

Adverse life events

[edit]

Adverse life events have been associated with fatigue.[12]

Drug use

[edit]

A 2021 study in a Korean city found that alcohol consumption was the variable with the most correlation with overall fatigue.[42] A 2020 Norway study found that 69% of substance use disorder patients had severe fatigue symptoms, and particularly those with extensive use of benzodiazepines.[43] Causality, as opposed to correlation, were not proven in these studies.[citation needed]

Sleep disturbance

[edit]

Fatigue can often be traced to poor sleep habits.[44] Sleep deprivation and disruption is associated with subsequent fatigue.[45][46] Sleep disturbances due to disease may impact fatigue.[47][48] Caffeine and alcohol can disrupt sleep, causing fatigue.[49]

Medications

[edit]

Fatigue may be a side effect of certain medications (e.g., lithium salts, ciprofloxacin); beta blockers, which can induce exercise intolerance, medicines used to treat allergies or coughs,[44] and many cancer treatments, particularly chemotherapy and radiotherapy. Use of benzodiazepines has been found to correlate with higher fatigue.[43]

Association with diseases and illnesses

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Fatigue is often associated with diseases and conditions. Some major categories of conditions that often list fatigue as a symptom include physical diseases, substance use illness, mental illnesses, and other diseases and conditions.[citation needed]

Physical diseases

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Mental illnesses

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Other

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Primary vs. secondary

[edit]

In some areas, it has been proposed that fatigue be separated into

  • primary fatigue, caused directly by a disease process, and
  • ordinary or secondary fatigue, caused by a range of causes including exertion and also secondary impacts on a person of having a disease (such as disrupted sleep).[80][81][82][83][84][85]

The ICD-11 MG22 definition of fatigue[86] captures both types of fatigue; it includes fatigue that "occur[s] in the absence of... exertion... as a symptom of health conditions."[medical citation needed]

Obesity

[edit]

Obesity correlates with higher fatigue levels and incidence.[87][88][89]

Somatic symptom disorder

[edit]

In somatic symptom disorder[90] the patient is overfocused on a physical symptom, such as fatigue, that may or may not be explained by a medical condition.[91][92][93]

Scientifically unsupported causes

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The concept of adrenal fatigue is often raised in media but no scientific basis has been found for it.[94][95][96]

Mechanisms

[edit]

The mechanisms that cause fatigue are not well understood.[50] Several mechanisms may be in operation within a patient,[97] with the relative contribution of each mechanism differing over time.[12]

Proposed fatigue explanations due to permanent changes in the brain may have difficulty in explaining the "unpredictability" and "variability" (i.e. appearing intermittently during the day, and not on all days) of the fatigue associated with inflammatory rheumatic diseases and autoimmune diseases (such as multiple sclerosis).[12]

Inflammation

[edit]

Inflammation distorts neural chemistry, brain function and functional connectivity across a broad range of brain networks,[98] and has been linked to many types of fatigue.[50][99] Findings implicate neuroinflammation in the etiology of fatigue in autoimmune and related disorders.[12][50] Low-grade inflammation may cause an imbalance between energy availability and expenditure.[100]

Cytokines are small protein molecules that modulate immune responses and inflammation (as well as other functions) and may have causal roles in fatigue.[101][102] However a 2019 review was inconclusive as to whether cytokines play any definitive role in ME/CFS.[103]

Reduced brain connectivity

[edit]

Fatigue has been correlated with reductions in structural and functional connectivity in the brain.[104] This has included in post-stroke,[105] MS,[106] NMOSD and MOG,[13] and ME/CFS.[107] This was also found for fatigue after brain injury,[108] including a significant linear correlation between self-reported fatigue and brain functional connectivity.[109]

Areas of the brain for which there is evidence of relation to fatigue are the thalamus and middle frontal cortex,[109] fronto-parietal and cingulo-opercular,[108] and default mode network, salience network, and thalamocortical loop areas.[104][110]

A 2024 review found that structural connectivity changes may underlie fatigue in pwRRMS but that the overall results were inconclusive, possibly explained by heterogeneity and limited number of studies.[111]

A small 2023 study found that infratentorial lesion volume (cerebellar and brainstem) was a relatively good predictor of RRMS fatigue severity.[112]

Damage to brain white matter

[edit]

Studies have found MS fatigue correlates with damage to NAWM (normal appearing white matter) (which will not show on normal MRI but will show on DTI (diffusion tensor imaging)).[113][13][114][115][116][117] The correlation becomes unreliable in patients aged over 65 due to damage due to ageing.[118]

Heat shock proteins

[edit]

A small 2016 study found that primary Sjögren's syndrome patients with high fatigue, when compared with those with low fatigue, had significantly higher plasma concentrations of HSP90α, and a tendency to higher concentrations of HSP72.[119] A small 2020 study of Crohn's disease patients found that higher fatigue visual analogue scale (fVAS) scores correlated with higher HSP90α levels.[120] A related small 2012 trial investigating if application of an IL-1 receptor antagonist (anakinra) would reduce fatigue in primary Sjögren's syndrome patients was inconclusive.[121][122][123]

Measurement

[edit]

Fatigue is currently measured by many different self-measurement surveys.[124] Examples are the Fatigue Symptom Inventory (FSI)[125][126][127] and the Fatigue Severity Scale.[128][129][130] There is no consensus on best practice,[131] and the existing surveys do not capture the intermittent nature of some forms of fatigue.

Diagnosis

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Diagnosis guidance

[edit]

A 2023 guidance indicates the following[4]

  • in the primary care setting, a medical or psychiatric diagnosis is found in at least two-thirds of patients;
  • the most common diagnoses are viral illness, upper respiratory infection, iron-deficiency anaemia, acute bronchitis, adverse effects of a medical agent in the proper dose, and depression or other mental disorder, such as panic disorder, and somatisation disorder;
  • the origin of fatigue may be central, brain-derived, or peripheral, usually of a neuromuscular origin—it may be attributed to physical illness, psychological (e.g., psychiatric disorder), social (e.g., family problems), and physiological factors (e.g., old age), occupational illness (e.g., workplace stress);
  • when unexplained, clinically evaluated chronic fatigue can be separated into ME/CFS and idiopathic chronic fatigue.[4]

A 2016 German review found that

  • about 20% of people complaining of tiredness to a GP (general practitioner) suffered from a depressive disorder.
  • anaemia, malignancies and other serious somatic diseases were only very rarely found in fatigued primary care patients, with prevalence rates hardly differing from non-fatigued patients.
  • if fatigue occurred in primary care patients as an isolated symptom without additional abnormalities in the medical history and in the clinical examination, then extensive diagnostic testing rarely helped detect serious diseases. Such testing might also lead to false-positive tests.[132]

A 2014 Australian review recommended that a period of watchful waiting may be appropriate if there are no major warning signs.[133]

A 2009 study found that about 50% of people who had fatigue received a diagnosis that could explain the fatigue after a year with the condition. In those people who had a possible diagnosis, musculoskeletal (19.4%) and psychological problems (16.5%) were the most common. Definitive physical conditions were only found in 8.2% of cases.[134]

Classification

[edit]

By type

[edit]
Uni- or multi-dimensional
[edit]

Fatigue can be seen as a uni-dimensional phenomenon that influences different aspects of human life.[135][136] It can be multi-faceted and broadly defined, making understanding the causes of its manifestations especially difficult in conditions with diverse pathology including autoimmune diseases.[50]

A 2021 review considered that different "types/subsets" of fatigue may exist and that patients normally present with more than one such "type/subset". These different "types/subsets" of fatigue may be different dimensions of the same symptom, and the relative manifestations of each may depend on the relative contribution of different mechanisms. Inflammation may be the root causal mechanism in many cases.[12]

Physical
[edit]

Physical fatigue, or muscle fatigue, is the temporary physical inability of muscles to perform optimally. The onset of muscle fatigue during physical activity is gradual, and depends upon an individual's level of physical fitness – other factors include sleep deprivation and overall health.[137] Physical fatigue can be caused by a lack of energy in the muscle, by a decrease of the efficiency of the neuromuscular junction or by a reduction of the drive originating from the central nervous system, and can be reversed by rest.[138] The central component of fatigue is triggered by an increase of the level of serotonin in the central nervous system.[139] During motor activity, serotonin released in synapses that contact motor neurons promotes muscle contraction.[140] During high level of motor activity, the amount of serotonin released increases and a spillover occurs. Serotonin binds to extrasynaptic receptors located on the axonal initial segment of motor neurons with the result that nerve impulse initiation and thereby muscle contraction are inhibited.[141]

Muscle strength testing can be used to determine the presence of a neuromuscular disease, but cannot determine its cause. Additional testing, such as electromyography, can provide diagnostic information, but information gained from muscle strength testing alone is not enough to diagnose most neuromuscular disorders.[142]

Mental
[edit]

Mental fatigue is a temporary inability to maintain optimal cognitive performance. The onset of mental fatigue during any cognitive activity is gradual, and depends upon an individual's cognitive ability, and also upon other factors, such as sleep deprivation and overall health.

Mental fatigue has also been shown to decrease physical performance.[10] It can manifest as somnolence, lethargy, directed attention fatigue, or disengagement. Research also suggests that mental fatigue is closely linked to the concept of ego depletion, though the validity of the concept is disputed. For example, one pre-registered study of 686 participants found that after exerting mental effort, people are likely to disengage and become less interested in exerting further effort.[143]

Decreased attention can also be described as a more or less decreased level of consciousness.[144] In any case, this can be dangerous when performing tasks that require constant concentration, such as operating large vehicles. For instance, a person who is sufficiently somnolent may experience microsleep. However, objective cognitive testing can be used to differentiate the neurocognitive deficits of brain disease from those attributable to tiredness.[145][146][147]

The perception of mental fatigue is believed to be modulated by the brain's reticular activating system (RAS).[148][149][150][151][152]

Fatigue impacts a driver's reaction time, awareness of hazards around them and their attention. Drowsy drivers are three times more likely to be involved in a car crash, and being awake over 20 hours is the equivalent of driving with a blood-alcohol concentration level of 0.08%.[153]

Neurological fatigue
[edit]

People with multiple sclerosis experience a form of overwhelming tiredness that can occur at any time of the day, for any duration, and that does not necessarily recur in a recognizable pattern for any given patient, referred to as "neurological fatigue", and often as "multiple sclerosis fatigue" or "lassitude".[154][155][156] People with autoimmune diseases including inflammatory rheumatic diseases such as rheumatoid arthritis, psoriatic arthritis and primary Sjögren's syndrome, experience similar fatigue.[12][50] Attempts have been made to isolate causes of central nervous system fatigue.

By timescale

[edit]
Acute
[edit]

Acute fatigue is that which is temporary and self-limited. Acute fatigue is most often caused by an infection such as the common cold and can be cognized as one part of the sickness behavior response occurring when the immune system fights an infection.[157] Other common causes of acute fatigue include depression and chemical causes, such as dehydration, poisoning, low blood sugar, or mineral or vitamin deficiencies.

Prolonged
[edit]

Prolonged fatigue is a self-reported, persistent (constant) fatigue lasting at least one month.[158][159]

Chronic
[edit]

Chronic fatigue is a self-reported fatigue lasting at least 6 consecutive months. Chronic fatigue may be either persistent or relapsing.[160] Chronic fatigue is a symptom of many chronic illnesses and of idiopathic chronic fatigue.[161]

By effect

[edit]

Fatigue can have significant negative impacts on quality of life.[162] Profound and debilitating fatigue is the most common complaint reported among individuals with autoimmune disease, such as systemic lupus erythematosus, multiple sclerosis, type 1 diabetes, celiac disease, Myalgic Encephalomyelitis/chronic fatigue syndrome, and rheumatoid arthritis.[12] Fatigue has been described by sufferers as 'incomprehensible' due to its unpredictable occurrence, lack of relationship to physical effort and different character as compared to tiredness.[163]

WHO classification

[edit]

The World Health Organization's ICD-11 classification[164] includes a category MG22 Fatigue (typically fatigue following exertion but sometimes may occur in the absence of such exertion as a symptom of health conditions), and many other categories where fatigue is mentioned as a secondary result of other factors.[165] It does not include any fatigue-based psychiatric illness (unless it is accompanied by related psychiatric symptoms).[166][167]

DSM-5 lists 'fatigue or loss of energy nearly every day' as one factor in diagnosing depression.[168]

Treatment and management

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Management may include review of factors and methods as explained below.

Cessation of medications causing fatigue

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Taking of medications with side effects of contributing to fatigue may be ceased.[169] [44][170][better source needed][171]

Medications to treat fatigue

[edit]
See also: List of investigational fatigue drugs

The UK NICE recommends consideration of amantadine, modafinil, and selective serotonin reuptake inhibitors (SSRIs) for MS fatigue.[172] A PCORI review, however, found amantadine, methylphenidate, and modafinil no more effective than placebo in reducing fatigue, with side effects reported.[173] Psychostimulants such as methylphenidate, amphetamines, and modafinil have been used in the treatment of fatigue related to depression,[174][175][176][177] and medical illness such as chronic fatigue syndrome[178][179] and cancer.[175][180][181][182][183][184][185] They have also been used to counteract fatigue in sleep loss[186] and in aviation.[187]

Mental health tools

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CBT can be useful for fatigue,[188][189] including ME/CFS[190][191] but is not included in NICE guidelines for ME/CFS treatment.[192][193]

Other approaches

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Avoidance of body heat

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Fatigue in MS often correlates with relatively high endogenous body temperature.[194][25][195][196][197][198][199][200][201][202][203][excessive citations]

Improved sleep

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Improving sleep has been associated with reduced fatigue but only in small studies.[204][205][189]

Intermittent fasting

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A very small 2022 study found 40% reductions in fatigue categorisations after three months of 16:8 intermittent fasting.[206]

Vagus nerve stimulation

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A very small 2023 study of Sjogren's patients showed reductions in self-reported fatigue after 56 days of vagus nerve stimulation.[102]

Qigong and Tai Chi

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Qigong and Tai chi have been postulated as helpful to reduce fatigue, but the evidence is of low quality.[207][208][209]

Approaches to managing fatigue

[edit]

Some health systems help people manage their fatigue better through attitude changes and skills transference.[189][210][211][212][213][214]

Prevalence

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2023 guidance stated fatigue prevalence is between 4.3% and 21.9%. Prevalence is higher in women than men.[4][215]

A 2021 German study found that fatigue was the main or secondary reason for 10–20% of all consultations with a primary care physician.[216]

A large study based on the 2004 Health and Retirement Study (HRS), a biennial longitudinal survey of US adults aged 51 and above, with mean age 65, found that 33% of women and 29% of men self-reported fatigue.[217]

Fatigue represents a large health economic burden and unmet need to patients and to society.[12]

Possible purposes of fatigue

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Body resource management purposes

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Fatigue has been posited as a bio-psycho-physiological state reflecting the body's overall strategy in resource (energy) management. Fatigue may occur when the body wants to limit resource utilisation ("rationing") in order to use resources for healing (part of sickness behaviour)[120] or conserve energy for a particular current or future anticipated need, including a threat.[12]

Evolutionary purposes

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It has been posited that fatigue had evolutionary benefits in making more of the body's resources available for healing processes, such as immune responses, and in limiting disease spread by tending to reduce social interactions.[97]

See also

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References

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Further reading

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[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Fatigue

View on Grokipedia
from Grokipedia
Fatigue is a common symptom characterized by a persistent feeling of extreme or unusual tiredness, weariness, lack of energy or strength that interferes with daily activities and is typically not relieved by rest or sleep. It can manifest as physical exhaustion, mental fog, or emotional depletion, often accompanying various underlying conditions or lifestyle factors. Symptoms of fatigue extend beyond simple drowsiness and may include difficulty concentrating, or pain, low motivation, anxiety, depression, and a general sense of that impacts productivity and . In severe cases, such as chronic fatigue syndrome (also known as myalgic encephalomyelitis), the exhaustion can last for weeks or months, severely limiting physical and mental functioning. Fatigue differs from normal tiredness in its persistence and resistance to recovery through rest, often signaling an underlying issue that requires medical attention. The causes of fatigue are multifaceted and can stem from lifestyle factors, medical conditions, or psychological states. Common contributors include insufficient or poor-quality sleep, poor diet or nutrient deficiencies (such as iron, vitamin B12, or vitamin D deficiencies), dehydration, sedentary lifestyle or overexertion, excessive stress, anxiety or depression, and excessive consumption of caffeine or alcohol. Medical causes encompass infections (acute or chronic), anemia, thyroid disorders (such as hypothyroidism), diabetes, heart or lung diseases, obstructive sleep apnea, autoimmune conditions, hormonal imbalances, and side effects from medications or treatments such as . In some cases, fatigue may be an early symptom of serious conditions such as cancer. Mental health issues like depression and anxiety also frequently underlie fatigue, creating a cycle where exhaustion exacerbates emotional distress. Diagnosis involves a thorough medical evaluation, including a review of symptoms, lifestyle, and medical history, followed by physical exams and laboratory tests such as blood work to identify potential deficiencies or illnesses. Management typically focuses on addressing the root cause, with strategies including lifestyle modifications such as prioritizing 7–9 hours of quality sleep per night with consistent sleep schedules and good sleep hygiene, consuming a balanced nutrient-rich diet and staying hydrated, engaging in regular moderate exercise, managing stress through mindfulness, meditation, yoga, or therapy, and limiting excessive caffeine, alcohol, and other substances. In cases linked to chronic conditions, ongoing medical treatment and monitoring are essential to alleviate symptoms and improve overall well-being. Individuals experiencing prolonged fatigue lasting more than 2 weeks, or fatigue that is sudden, severe, or accompanied by other symptoms such as unexplained weight loss, chest pain, or shortness of breath, should consult a healthcare provider promptly to identify the underlying cause. Self-medication should be avoided in favor of professional medical evaluation and guidance.

Definition

Terminology

Fatigue is defined as a subjective of physical and/or mental exhaustion, characterized by a profound sense of tiredness and lack of energy that interferes with daily activities and is not substantially relieved by rest. This sensation impacts an individual's ability to perform physical tasks or maintain mental focus, often described as weariness or sluggishness that persists despite adequate or recovery periods. In medical contexts, fatigue is distinguished from normal drowsiness, as it encompasses a broader disruption to overall functioning rather than mere sleepiness. The term "fatigue" originates from the Latin fatigare, meaning "to tire" or "to weary," entering English in the via French fatigue to denote weariness from . In , its usage evolved in the amid concerns over occupational in industrializing societies, where it described the debilitating effects of prolonged labor on workers' and well-being. By the early , studies on industrial fatigue, such as those by the American Committee on Industrial Fatigue led by physiologist Frederic S. Lee, examined how repetitive factory work led to diminished performance and risks among laborers, influencing early ergonomic reforms. This historical focus transitioned into modern classifications by the (WHO), integrating fatigue into standardized diagnostic frameworks. Foundational terms in fatigue terminology include acute fatigue, which lasts less than one month and often resolves with rest or addressing triggers, and chronic fatigue, persisting for more than six months and potentially indicating underlying issues. According to the WHO's , 11th Revision (), fatigue is classified as a symptom rather than a standalone , coded under MG22 as a feeling of exhaustion or not attributable to a specific disorder. Self-reported surveys indicate that fatigue affects more than 20% of the general adult population, highlighting its commonality as a nonspecific in . Fatigue is characterized as a persistent and overwhelming lack of or that interferes with daily functioning and does not resolve with rest or , distinguishing it from tiredness, which is a transient state typically arising from or lack of and alleviated by short-term recovery. In contrast, sleepiness refers to a physiological drive or urge to fall asleep, often accompanied by drowsiness and impaired , stemming from or disruptions in mechanisms, whereas fatigue lacks this direct propensity for sleep and may coexist with normal duration. Exhaustion, while related, denotes a more acute and total depletion of physical or mental resources following intense or prolonged stress, often resolving once the is removed, unlike the chronic, relapsing nature of fatigue that persists independently of immediate triggers. For instance, in clinical contexts such as , criteria describe fatigue as a near-daily loss of that endures despite adequate , exemplified by patients reporting an inability to initiate or sustain activities even after prolonged , highlighting its resistance to typical restorative measures. Conceptually, fatigue is often multidimensional, encompassing physical, cognitive, and emotional dimensions as assessed by tools like the Multidimensional Fatigue Inventory (MFI-20), which evaluates subscales for general fatigue, physical fatigue, , reduced activity, and mental fatigue, in contrast to the more unidimensional quality of sleepiness focused primarily on and propensity to sleep. This multidimensionality underscores fatigue's broader impact on and performance beyond mere physiological sleep needs. Historically, such distinctions have been blurred in medical literature; for example, 1980s research on frequently conflated fatigue with (), leading to underrecognition of fatigue as a distinct symptom until later studies emphasized their differentiation in patient presentations.

Clinical Presentation

Common Symptoms

Fatigue is characterized by a persistent sense of physical and exhaustion that interferes with daily activities, often described by individuals as a profound lack of despite adequate rest. This core symptom manifests as reduced stamina, making even routine tasks feel overwhelmingly effortful, and is typically required to last more than two weeks for clinical consideration. Mental fog, or cognitive fatigue, accompanies these physical sensations, involving difficulties with concentration, , and , which can lead to motivational deficits where initiating or sustaining activities becomes challenging. Observable signs of fatigue include slowed reaction times and decreased , which can be quantified through laboratory assessments such as sustained attention tests, where participants exhibit longer response latencies and higher error rates under prolonged cognitive demands. These manifestations distinguish fatigue from sleepiness, which primarily involves an urge to sleep rather than a broader depletion of mental and physical resources. Variations in fatigue presentation depend on context; acute fatigue often follows intense physical exertion, such as post-exercise recovery where individuals report temporary and lasting hours to days, as noted in patient self-reports from clinics. In contrast, chronic fatigue disrupts daily life more insidiously, with persistent interference in work, social interactions, and , exemplified by accounts of individuals struggling to complete household chores or maintain due to unrelenting tiredness. Patient reports consistently highlight how these symptoms compound over time, leading to a cycle of avoidance and further .

Differentiating Features

One key differentiator of pathological fatigue, particularly in chronic forms such as (ME/CFS), is (PEM), characterized by a worsening of symptoms following minimal physical, mental, or emotional exertion that would not typically provoke such a response in healthy individuals. This feature is a core diagnostic criterion established by the 2015 Institute of Medicine (IOM) report, which identifies PEM as essential for distinguishing ME/CFS from other fatiguing conditions. Unlike normal tiredness, which resolves with rest, pathological fatigue often involves unrefreshing , where individuals awaken feeling as exhausted as before despite adequate sleep duration, contributing to persistent daily impairment. Specific signs further aid in recognition, including diurnal variation in symptoms, where energy levels may peak in the morning but decline markedly in the afternoons, alongside cognitive deficits such as lapses or impaired concentration that exceed those seen in simple exhaustion from overexertion. These cognitive impairments, often termed "brain fog," are more pronounced in pathological states and disrupt complex tasks without corresponding motor in many cases. In , fatigue typically lacks focal neurological deficits—such as unilateral , , or —unlike tiredness associated with acute , which presents with abrupt, localized impairments. Recent research underscores biological distinctions, with 2023 studies identifying associations between inflammatory markers and pathological fatigue compared to transient exhaustion, suggesting an underlying immune dysregulation. Clinicians should note red flags like unexplained accompanying fatigue, which may signal secondary causes requiring further evaluation, though these do not alter the core differentiating traits. While fatigue may overlap with common symptoms like generalized , its persistence and lack of relief from rest set it apart from everyday tiredness.

Causes

Lifestyle and Environmental Factors

Common lifestyle factors contributing to fatigue include insufficient or poor-quality sleep, poor diet or nutrient deficiencies, dehydration, lack of exercise or a sedentary lifestyle, and excessive stress. Lifestyle factors play a pivotal role in the development of fatigue, often stemming from daily habits that disrupt energy balance and recovery. Poor sleep hygiene, including inconsistent sleep schedules and stimulating activities before bedtime, is strongly linked to elevated levels of physical and mental fatigue, as evidenced by studies showing that individuals with suboptimal sleep quality report significantly higher trait fatigue scores. A sedentary lifestyle compounds this issue by promoting poor sleep quality and reducing overall energy levels; research indicates that prolonged sitting is associated with disrupted sleep patterns, leading to increased daytime fatigue. Similarly, excessive physical activity without sufficient recovery can also induce fatigue through overtraining syndrome, characterized by persistent tiredness, reduced performance, and systemic stress on the body. Overwork and extended working hours heighten fatigue risk by limiting recovery time, with occupational studies highlighting how excessive demands contribute to persistent exhaustion among workers. Chronic stress arising from adverse life events, such as job loss, further amplifies fatigue through sustained psychological strain. Comprehensive reviews demonstrate that activates neuroendocrine responses that manifest as debilitating tiredness, with affected individuals experiencing compounded effects on daily functioning. Inadequate nutrition, including poor diet or specific nutrient deficiencies, and hydration exacerbate these lifestyle influences; low iron intake can result in deficiency states that impair oxygen and reduce work capacity, directly contributing to fatigue symptoms. Deficiencies in vitamin D and vitamin B12 are also common, with low vitamin D levels associated with persistent fatigue and muscle weakness, and correction of deficiency shown to improve symptoms, while vitamin B12 deficiency leads to pronounced exhaustion through impaired energy metabolism and neurological function. Blood sugar fluctuations, such as reactive hypoglycemia following carbohydrate-heavy meals or irregular eating patterns, can precipitate sudden energy drops, particularly in the evening. Even mild disrupts metabolic processes, leading to sensations of and , as supported by physiological evidence linking fluid deficits to depletion. Environmental exposures also drive fatigue by imposing physiological burdens that drain resources. Heat exposure in occupational or ambient settings elevates core body temperature and sweat loss, resulting in and cognitive fatigue that impair performance and alertness. At high altitudes, reduced oxygen availability triggers acute mountain sickness, where fatigue emerges as a core symptom alongside and , affecting up to 50% of rapid ascenders above 2,500 meters. Noise pollution, particularly in industrial environments, induces stress responses that culminate in auditory and general fatigue, with studies showing elevated exhaustion levels among exposed workers due to disrupted concentration and heightened . Urban represents another key environmental contributor, with fine particulate matter and other pollutants correlating with heightened fatigue, especially in adolescents who report increased tiredness on days of poor air quality. Circadian misalignment, such as that experienced in or irregular work schedules, disrupts internal rhythms and promotes fatigue; normal circadian rhythms also feature a post-afternoon dip in wakefulness, which can lead to sudden evening energy drops exacerbated by accumulated daily stress, mental exhaustion, inactivity, or excessive caffeine intake. For instance, shift workers face up to 90% prevalence of regular workplace fatigue due to desynchronized sleep-wake cycles. These factors often intersect with sleep disturbances, underscoring the need to address them holistically to mitigate fatigue onset. Fatigue can arise from the consumption of various substances, which disrupt normal physiological processes and lead to symptoms of exhaustion. Alcohol, for instance, contributes to hangover-related fatigue primarily through and the accumulation of , a toxic that impairs and induces inflammatory responses in the body. This effect is particularly pronounced after , where imbalances exacerbate the sensation of tiredness. Similarly, caffeine withdrawal triggers fatigue via an adenosine rebound mechanism, where the buildup of —a that promotes —overwhelms the after abrupt cessation, leading to and reduced alertness. Recreational drugs such as opioids also induce fatigue through their sedative properties, binding to mu-opioid receptors in the to suppress and promote drowsiness as a core effect. This can persist even at therapeutic doses, contributing to chronic tiredness in users. In terms of medications, antidepressants like selective serotonin reuptake inhibitors (SSRIs) are associated with fatigue in approximately 20-30% of patients, often due to their impact on serotonin signaling and subsequent alterations in sleep architecture. Beta-blockers, used for cardiovascular conditions, frequently cause fatigue by blocking beta-adrenergic receptors, which reduces and oxygen delivery to muscles, resulting in perceived exhaustion during . Other antihypertensive medications, including diuretics (such as thiazides), angiotensin-converting enzyme (ACE) inhibitors, and angiotensin II receptor blockers (ARBs), can also contribute to fatigue, particularly in older adults, through side effects such as electrolyte imbalances (e.g., hypokalemia from diuretics), dehydration, or hypotension. Antihistamines, particularly first-generation types, induce fatigue through their blockade of H1 receptors in the , promoting and impairing . Chemotherapy agents are a notable example among cancer treatments, with fatigue reported in up to 80% of patients according to FDA-reviewed data, stemming from direct cytotoxic effects on healthy cells and resultant or mitochondrial dysfunction. Toxins further contribute to substance-related fatigue; leads to tiredness by binding to and reducing oxygen transport, mimicking hypoxic states that deplete energy reserves. Heavy metal exposure, such as to lead or mercury, induces chronic fatigue through and disruption of enzymatic functions in cellular energy production pathways. The dose-response relationship in substance use often amplifies fatigue over time; chronic exposure can lead to tolerance, where higher doses are needed to achieve the same effect, but paradoxically results in persistent fatigue due to adaptive changes in systems, as evidenced in studies on alcohol and opioids. This overlap with lifestyle factors, such as poor diet, may compound these effects but is secondary to the pharmacological mechanisms at play.

Disease-Associated Causes

Fatigue frequently manifests as a symptom of underlying medical conditions, categorized as primary when it represents the core feature of an idiopathic disorder like (ME/CFS), or secondary when it arises from treatable diseases such as infections or endocrine imbalances. Fatigue can also serve as an early or nonspecific symptom of serious conditions, including various cancers and autoimmune diseases. In ME/CFS, post-exertional malaise manifests as profound whole-body fatigue following minimal exertion, such as walking, with delayed symptom worsening. In primary fatigue syndromes, no identifiable cause is found after excluding other pathologies, whereas secondary fatigue often resolves with treatment of the root condition. This distinction guides clinical evaluation to prioritize reversible causes. Among physical diseases, , particularly , is a common culprit, affecting a substantial portion of women of reproductive age (approximately 30% globally as of 2019) and contributing to exertional fatigue due to reduced oxygen transport. similarly induces fatigue through slowed and energy production deficits, often presenting alongside weight gain and cold sensitivity, with symptoms worsening after physical activity. Cardiovascular conditions such as heart failure cause exertional fatigue by limiting cardiac output and oxygen delivery to tissues during activity. Respiratory disorders impair gas exchange, similarly exacerbating fatigue with walking or exertion due to inadequate oxygenation, including chronic lung diseases such as chronic obstructive pulmonary disease (COPD). Postural orthostatic tachycardia syndrome (POTS) triggers whole-body fatigue after standing or light activity through orthostatic intolerance, tachycardia, and reduced cerebral blood flow. Autonomic neuropathy disrupts regulatory functions, leading to post-exertional exhaustion. Metabolic disorders, including metabolic myopathies and diabetes mellitus, produce rapid fatigue during physical efforts like walking owing to defects in cellular energy production; diabetes mellitus commonly causes fatigue due to unstable blood glucose levels, impaired energy utilization, and associated dehydration from polyuria. In cancer, fatigue may stem from paraneoplastic syndromes, where tumor-secreted factors trigger systemic exhaustion independent of treatment effects. Mental health disorders also prominently feature fatigue, with up to 80% of individuals with reporting it as a core symptom that persists even after mood improvement. Anxiety disorders contribute similarly, exacerbating exhaustion through heightened and disrupted . In , fatigue is particularly notable during depressive phases following manic episodes, marked by profound energy crashes and reduced functionality. Post-viral syndromes represent another key category, exemplified by , where approximately 50% of cases involve lingering fatigue as a dominant symptom, as documented in recent NIH-funded analyses. Likewise, chronic infections from various pathogens can produce persistent fatigue through sustained immune activation and inflammatory processes. Autoimmune conditions like systemic lupus erythematosus likewise cause debilitating fatigue in the majority of patients, driven by chronic inflammation and immune dysregulation. Obesity amplifies fatigue risk, primarily through its association with , which fragments sleep and leads to daytime somnolence in affected individuals. Addressing obesity-related sleep disturbances can mitigate this secondary fatigue. Notably, "" has been debunked as a pseudoscientific lacking empirical support, with the emphasizing that true requires specific diagnostic testing rather than stress-based attributions. In cases overlapping with , fatigue may be amplified by psychological factors, though medical evaluation remains essential.

Pathophysiology

Inflammatory Mechanisms

Inflammatory mechanisms play a central in the of fatigue by mediating energy conservation responses during immune activation. Pro-inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), released during infections or inflammatory states, signal the to induce "," a conserved adaptive that prioritizes recovery by reducing physical activity and promoting rest to allocate resources toward immune defense. This process involves cytokines acting on regions to alter and perceived effort, thereby manifesting as profound fatigue. In chronic conditions, persistent elevation of these cytokines sustains this response, contributing to long-term fatigue beyond acute illness. Elevated levels of (CRP), a marker of , are consistently observed in patients with chronic fatigue syndrome (CFS), supporting the link between ongoing inflammation and fatigue persistence. A of studies comparing CFS patients to healthy controls found significantly higher CRP concentrations in the former, with a mean difference of 0.39 µg/mL, indicating low-grade inflammation as a key feature. Recent research has further connected to this inflammatory milieu; for instance, 2024 studies in (IBS) patients demonstrate that microbial imbalances promote leaky gut, leading to via translocation and subsequent upregulation. Heat shock proteins (HSPs), such as and HSP60, function as molecular chaperones in the , helping to refold damaged proteins and mitigate oxidative damage during physical exertion. In exertional fatigue, these proteins are upregulated in as an adaptive mechanism to counteract stress-induced proteotoxicity, though dysregulation in chronic states may amplify perceived exhaustion. exercise, for example, specifically increases HSP60 content in type I muscle fibers, reflecting a protective response that intersects with inflammatory pathways to influence fatigue onset. Neuroinflammation contributes to fatigue by allowing peripheral inflammatory signals to breach the blood-brain barrier (BBB), resulting in hypothalamic dysregulation that impairs . Cytokines and microbial products can permeate a compromised BBB, activating and in the to disrupt neuroendocrine signaling and promote a state of central fatigue. Evidence from animal models underscores this mechanism; administration in induces acute fatigue-like behaviors through inflammasome activation and IL-1β release, mimicking systemic inflammation's central effects without direct . These models reveal prolonged reductions in locomotor activity and wheel-running performance post-LPS, attributable to hypothalamic neuroinflammatory cascades. In post-viral syndromes such as , persistent neuroimmune activation sustains fatigue through mechanisms like microglial priming and ongoing release, contributing to central sensitization and energy metabolism disruption as of 2025.

Neurological Mechanisms

Neurological mechanisms of fatigue involve disruptions in structures and pathways that regulate energy allocation, motivation, and cognitive effort. (fMRI) studies have identified reduced connectivity in key networks, particularly between the and , which are critical for executive function and reward processing. A transdiagnostic of data revealed weakened activation and connectivity in these prefrontal-basal ganglia circuits across conditions featuring chronic fatigue, contributing to diminished motivation and sustained cognitive performance. Structural alterations in also play a prominent role, especially in demyelinating disorders like (MS), where fatigue is a hallmark symptom. Diffusion tensor imaging (DTI) demonstrates microstructural damage, including demyelination and axonal loss in normal-appearing white matter tracts connecting cortical and subcortical regions. These changes are associated with significant volume reductions in affected areas such as the and frontal-parietal pathways, correlating directly with fatigue severity in relapsing-remitting MS patients. Neurotransmitter imbalances further exacerbate these network impairments, with , noradrenergic, and serotonergic systems being particularly implicated, alongside adenosine accumulation. Low levels in the disrupt reward signaling, reducing the perceived value of effortful actions and promoting behavioral withdrawal. In intense exercise, shifts in dopamine and noradrenaline levels combined with adenosine buildup trigger central fatigue, manifesting as post-exercise mental fog with reduced motivation and cognitive sharpness as a protective mechanism against overexertion. Similarly, serotonergic dysfunction in the and limbic regions impairs integration of motivational inputs, as evidenced in chronic fatigue states where altered serotonin signaling weakens frontal-basal ganglia circuitry. Chronic overtraining further diminishes activity in prefrontal regions involved in decision-making and focus. The contributes to fatigue signaling by conveying peripheral cues to the brain, triggering conserved responses akin to in animal models. In , vagal afferents mediate cytokine-induced and reduced activity, reflecting an evolutionarily preserved mechanism to conserve during stress or illness. This pathway overlaps briefly with neuroinflammatory processes, where vagal signaling modulates central to amplify fatigue perception.

Assessment and Diagnosis

Measurement Methods

Fatigue measurement relies on both subjective self-report instruments and objective physiological assessments to quantify its severity, duration, and functional impact. Subjective methods, such as validated questionnaires, capture perceived fatigue across physical, mental, and motivational domains, while objective techniques provide behavioral or physiological correlates to complement self-reports. These tools are essential for clinical and research settings, enabling standardized evaluation despite fatigue's subjective nature. Among the most widely used questionnaires is the Fatigue Severity Scale (FSS), a 9-item self-report instrument developed in 1989 that assesses the impact of fatigue on daily functioning and motivation, with items rated on a 7-point (1 = strongly disagree, 7 = strongly agree). The overall score is calculated as the mean of the items, ranging from 1 to 7, where a cutoff score greater than 4 indicates clinically significant fatigue. The FSS has demonstrated high (Cronbach's alpha >0.90) and test-retest reliability in diverse populations, including those with and systemic . Another prominent tool is the Chalder Fatigue Scale (CFQ), originally a 14-item revised to an 11-item version in 1993, which measures physical and mental fatigue separately using a 4-point (better than usual to much worse than usual). Scores are summed for a total ranging from 0 to 33, with higher values reflecting greater fatigue severity; it has shown good validity in general and clinical populations, with subscale correlations supporting its multidimensional structure. The Multidimensional Fatigue Inventory (MFI-20), introduced in , is a 20-item scale evaluating five fatigue dimensions—general fatigue, physical fatigue, reduced activity, reduced , and mental fatigue—each with four items rated on a 5-point , yielding subscale scores from 4 to 20. Validation studies since its inception have confirmed its reliability ( 0.84–0.93) and factorial structure across healthy and patient groups, including cancer and chronic illness populations. Recent adaptations include digital implementations, such as integrations for real-time tracking in clinical trials as of 2022, enhancing and longitudinal monitoring. Objective measurements provide quantifiable data less prone to self-perception biases. , involving wrist-worn accelerometers, estimates fatigue through rest-activity cycles, sleep efficiency, and daily movement levels, with validation studies showing correlations between reduced activity counts and self-reported fatigue in cancer survivors and older adults. For instance, lower actigraphic activity during waking hours has been linked to higher fatigue scores, offering a non-invasive proxy for physical fatigue. Cognitive batteries, such as the (PVT), assess fatigue-induced impairments in sustained attention and reaction time, typically over 3–10 minutes where participants respond to visual stimuli. The PVT measures lapses (responses >500 ms) and mean reaction time, with increased lapses indicating vigilance decrements associated with sleep-related fatigue; it is highly sensitive to cumulative sleep loss and has been validated in laboratory and field studies for detecting mental fatigue. Despite their utility, these methods have limitations, including subjectivity in responses, which can introduce reporting biases influenced by mood or expectations. Cultural variations also affect fatigue expression and scale interpretation, with studies showing differences in symptom attribution and endorsement rates across ethnic groups, necessitating culturally adapted versions for equitable assessment.

Diagnostic Approaches

The diagnostic approach to fatigue commences with a detailed history-taking, focusing on the symptom's duration, acute or gradual onset, potential triggers such as recent infections or changes, medication use (including antihypertensive agents), and associated symptoms including disturbances, mood alterations, or exertional patterns. This step helps differentiate physiologic from pathologic causes and guides subsequent evaluation. A comprehensive , emphasizing cardiopulmonary function, neurologic status, and skin integrity, is essential to detect signs of underlying disease, such as or . Laboratory investigations form the cornerstone of ruling out treatable etiologies, beginning with a (CBC) to detect anemia or infection, (TSH) testing (with free T4 if indicated) to screen for , and a comprehensive metabolic panel (CMP) to evaluate electrolytes (e.g., potassium, sodium), kidney function (creatinine, BUN), glucose, and liver function. In older adults (such as a 75-year-old patient) or those taking hypertension medications (e.g., diuretics, ACE inhibitors, or ARBs), additional tests are frequently recommended to identify common causes of fatigue and low energy. These include vitamin B12 levels (and possibly folate) to check for deficiency, ferritin or iron studies to assess iron stores if anemia is suspected, and hemoglobin A1c to screen for diabetes or poor glycemic control. Hypertension medications should be reviewed for potential contributions to fatigue, such as electrolyte imbalances (e.g., hypokalemia from diuretics) or other side effects. Additional tests (e.g., BNP for heart failure) may be considered based on clinical findings. These tests are guided by history, physical examination, and medication review. These tests have a variable and generally low diagnostic yield in settings, with studies reporting identification of organic causes in 8% to 50% of cases, though results often affect management in only about 5%. Certain red flags necessitate expedited investigation to exclude life-threatening conditions. Patients should seek prompt medical attention if fatigue is sudden in onset, severe, persists for more than 2 weeks, or is accompanied by symptoms such as significant unintentional , persistent , unexplained fever, chest pain, or shortness of breath, which may signal malignancy, infection, cardiovascular or pulmonary disease, endocrine disorders, or other serious conditions, according to recommendations. Self-medication should be avoided, as it may mask symptoms and delay proper diagnosis and treatment; consultation with a healthcare provider for thorough evaluation is recommended. Presence of such features prompts immediate or specialist referral. In instances where exhaustive evaluation reveals no organic pathology, should be considered when patients present with one or more distressing somatic symptoms—such as persistent fatigue—accompanied by excessive, disproportionate thoughts about symptom seriousness, high anxiety regarding health, or excessive time and energy devoted to health concerns, lasting at least six months, per criteria. For persistent or chronic fatigue, particularly when lasting over six months, a multidisciplinary approach is advised, incorporating input from , , , and specialists to systematically exclude alternative diagnoses; this may include for sleep studies to evaluate or other disruptions. Such strategies align with National Institute for Health and Care Excellence (NICE) guidelines from 2021, which underwent a surveillance review in January 2025 that identified no new evidence requiring updates. Fatigue severity scales, such as the Fatigue Severity Scale, can provide an initial quantitative screening to quantify symptom impact during history-taking.

Classification Systems

Fatigue is classified using multiple frameworks that consider its underlying mechanisms, duration, and clinical impact, aiding in and management. These systems distinguish fatigue based on physiological origins, temporal patterns, and whether it arises from transient circumstances or underlying . One primary classification differentiates fatigue by type, rooted in . Central fatigue, mediated by the including the and , involves reduced neural drive to muscles due to factors like imbalances or motivational deficits. In contrast, peripheral fatigue occurs at the muscular level or , resulting from metabolic disturbances such as lactate accumulation or imbalances that impair . This distinction is crucial in and rehabilitation, where central fatigue predominates in prolonged endurance activities, while peripheral mechanisms are more evident in short, high-intensity efforts. Classifications by timescale categorize fatigue as acute or chronic to guide evaluation. Acute fatigue typically lasts less than one month and often resolves with rest or addressing precipitating factors, such as or acute illness. Chronic fatigue, defined as persistent or relapsing exhaustion lasting more than six months that substantially reduces activity levels, aligns with criteria like the 1994 Fukuda definition for chronic fatigue syndrome (CFS), requiring unexplained fatigue accompanied by at least four of eight specific symptoms. Subacute fatigue, spanning one to six months, serves as an intermediate category. Fatigue is also classified by its effects as situational or pathological. Situational fatigue, often transient and reversible, arises from identifiable external triggers like post-viral recovery or overexertion, without evidence of underlying disease. Pathological fatigue, conversely, signals an abnormal state, such as in chronic illnesses, and is codified in the World Health Organization's under MG22 (Fatigue), encompassing and tiredness not attributable to other conditions, with postviral fatigue syndrome specifically under 8E49. This framework emphasizes the fatigue's disproportionate impact on daily functioning. Recent 2025 updates to fatigue classifications, informed by post-pandemic research, incorporate subtypes for conditions like , recognizing persistent fatigue as a distinct class within postviral syndromes. The RECOVER-Adult initiative, for instance, updated its subtype model in 2024 to include five symptom clusters, with fatigue-dominant profiles highlighting multisystem involvement in infection-associated fatigue. These evolutions integrate fatigue as a pathological subtype, emphasizing its chronicity and overlap with .

Management and Treatment

Pharmacological Strategies

Pharmacological strategies for managing fatigue primarily involve stimulants and targeted agents that address underlying contributors to excessive tiredness, often tailored to specific etiologies such as (MS), cancer, post-viral syndromes, or conditions. These approaches aim to enhance alertness and energy levels, but evidence varies by condition and drug, with systematic reviews indicating modest overall benefits and the need for individualized assessment. Common side effects include , anxiety, and cardiovascular changes, necessitating careful monitoring. Stimulants like are commonly prescribed for excessive daytime fatigue, particularly in MS. , a wakefulness-promoting agent, is typically administered at doses of 100-200 mg daily, with some trials extending to 400 mg. Evidence from randomized controlled trials, including a 2024 Lancet study, demonstrates that reduces fatigue severity in MS patients, with improvements in and comparable efficacy to at 12 weeks. , another , has been evaluated for cancer-related fatigue, often at doses of 10-54 mg daily. While earlier meta-analyses suggested limited efficacy, recent 2024 trials confirm it provides no significant advantage over after 6 weeks, though it remains well-tolerated. Targeted therapies include for post-viral fatigue, such as in , dosed at 100-200 mg daily. A 2024 randomized reported substantial fatigue relief with amantadine over 2 weeks, highlighting its safety and tolerability in this context. For mental fatigue associated with depression, antidepressants like bupropion (a norepinephrine-dopamine ) at 150-300 mg daily show benefits, with studies indicating greater resolution of fatigue symptoms compared to selective serotonin reuptake inhibitors. In cancer patients, bupropion has demonstrated fatigue improvements over in 4-week trials. Efficacy across these agents is generally modest, with systematic reviews of chronic fatigue syndrome (CFS) treatments indicating limited evidence for stimulants; for example, showed no significant benefit over . is a common side effect of stimulants like and , often managed by dose adjustment. As a first-line , discontinuing medications that induce fatigue, such as beta-blockers, is recommended when clinically feasible, with gradual tapering to prevent rebound effects like increased . Taper protocols typically reduce doses by 25-50% weekly under medical supervision to minimize risks.

Non-Pharmacological Approaches

Non-pharmacological approaches are often the first-line strategy for managing fatigue, especially when arising from common lifestyle factors. These approaches address prevalent contributors to low energy and are supported by clinical guidelines emphasizing their role prior to or alongside other interventions. Key lifestyle modifications include:
  • Prioritizing 7-9 hours of quality sleep per night with consistent sleep-wake routines and good sleep hygiene practices, such as limiting caffeine, alcohol, screen exposure, and exercise before bedtime.
  • Consuming a balanced, nutrient-rich diet and maintaining adequate hydration to prevent nutrient deficiencies (e.g., iron, vitamin D, B12) and dehydration that can contribute to fatigue.
  • Engaging in regular moderate physical activity to enhance energy levels and overall function, while pacing activity in conditions prone to post-exertional malaise.
  • Managing stress, anxiety, or depression through mindfulness, meditation, yoga, or professional therapy.
  • Limiting excessive caffeine, alcohol, and other substances that can disrupt sleep and energy balance.
If fatigue persists, worsens, or is accompanied by other symptoms, consultation with a healthcare professional is recommended to evaluate potential underlying medical conditions, such as anemia, thyroid disorders, sleep apnea, infections, diabetes, or heart disease. For mental fatigue specifically, no single ultimate recovery method exists scientifically, owing to varying individual causes, complex brain recovery mechanisms, and evidence indicating that combinations of approaches are most effective. Cognitive behavioral therapy (CBT), often incorporating graded exposure techniques, serves as a key non-pharmacological intervention for managing fatigue, particularly in chronic fatigue syndrome (CFS). This approach helps patients establish stable routines, address unhelpful beliefs about symptoms, and gradually increase activity levels to mitigate fatigue severity. A 2025 meta-analysis of randomized controlled trials (RCTs) demonstrated that CBT significantly reduces fatigue across long-term conditions, with individual face-to-face delivery showing a large (Cohen's d = 2.91) in CFS patients. Recent RCTs, including those from 2022, report symptom reductions of 20-40% in fatigue scores following CBT protocols tailored for CFS. Exercise-based strategies, such as aerobic training and pacing techniques, offer evidence-based options to alleviate fatigue without exacerbating . Aerobic exercises like walking or cycling, performed for approximately 30 minutes per day at moderate intensity (70-80% of reserve), have been shown to reduce patient-reported fatigue in and CFS populations over 10 weeks of supervised sessions. Pacing involves balancing activity and rest to maintain energy levels, preventing symptom flares; meta-analyses confirm that interventions with 30-36 sessions of aerobic or combined exercise yield large reductions in perceived fatigue (standardized mean difference = 0.94). These methods prioritize gradual progression to build tolerance and improve overall function. Mind-body practices like and provide moderate benefits for fatigue management, supported by meta-analyses across various conditions. These exercises, typically involving 30-minute sessions three or more times weekly for at least nine weeks, enhance energy and through gentle movements and breathing techniques. A found superior to conventional therapy in reducing fatigue (standardized mean difference = -0.45), while shows a standardized mean of 0.46 for cancer-related fatigue, indicating consistent moderate improvements. Non-invasive (VNS) devices represent an emerging tool for fatigue relief, targeting modulation. Transcutaneous VNS, applied via ear or neck devices, has demonstrated significant reductions in fatigue measures after 56 days of use in inflammatory conditions, with immediate post-session improvements in and multitasking. Clinical trials in patients report enhanced daily function and lower fatigue ratings with active tVNS alongside standard care. Intermittent fasting protocols support metabolic reset in obesity-related fatigue by promoting adaptive cellular responses and reducing . Time-restricted eating (e.g., 16:8 regimen) over three months has been linked to decreased physical and mental fatigue in obese and non-obese adults, alongside improvements in . A 2022 RCT found that such enhances mood and regulation without increasing adverse events in individuals. Improved protocols address fatigue by optimizing rest quality and duration. Recommendations include maintaining consistent schedules (7-9 hours nightly), minimizing and screen exposure before bed, and creating a cool, dark environment, which collectively reduce daytime fatigue in shift workers and chronic conditions. from systematic reviews confirms that these practices, when combined with bright light exposure during shifts, enhance alertness and mitigate fatigue accumulation. For heat-sensitive fatigue, such as in (MS), avoidance strategies like cooling vests prevent symptom worsening. Lightweight cooling vests improve walking capacity and distance in heat-sensitive MS patients by lowering core temperature, with RCTs showing physiological benefits like reduced fatigue during activity. Meta-analyses of cooling interventions report enhanced physical function and emotional well-being, making them a practical adjunct for daily management. Management of fatigue should follow guidelines from organizations such as the CDC, which emphasize treating underlying causes and prioritizing non-pharmacological approaches, particularly for chronic fatigue syndrome.

Epidemiology

Prevalence and Distribution

Fatigue is a common symptom affecting a significant portion of the global adult population, with a pooled of general fatigue estimated at 20.4% (95% CI: 16.7–25.0%). This figure is derived from systematic reviews encompassing diverse international studies, highlighting fatigue as a widespread issue transcending specific health conditions. Chronic fatigue, defined as persisting for at least six months, shows a lower of around 10.1% in adults. Prevalence exhibits notable gender disparities, with women experiencing higher rates than men, often at a approaching 1.5:1 in cases of chronic or severe fatigue. For instance, in community-based surveys, fatigue rates reach 23.4% among women compared to 20.3% among men. These differences persist across age groups and are attributed to physiological and factors, though exact mechanisms vary by context. Distribution patterns reveal peaks in older age groups, where fatigue affects approximately 42.6% of individuals aged 65 and above, compared to lower rates in younger adults. This elevation in the elderly is observed in meta-analyses of community-dwelling populations, underscoring the role of age-related physiological changes in amplifying fatigue susceptibility. The has further shifted distribution, with post-infectious fatigue contributing to an estimated 10–20% increase in overall prevalence in heavily affected regions, driven by syndromes where fatigue persists in up to 46.6% of cases beyond acute infection. In general populations monitored longitudinally, severe fatigue rose to about one-third two years into the . Occupationally, fatigue is particularly pronounced in high-stress sectors such as healthcare, where reaches around 50–54% among workers, based on 2023–2024 surveys of nurses and physicians. These rates reflect the cumulative impact of , emotional demands, and exposure risks, with systematic reviews confirming elevated levels during and post-pandemic periods. Socioeconomic variations also influence distribution, with higher in low-income groups; for example, chronic fatigue syndrome-like illnesses are reported at 2% among those below the federal poverty level, nearly double the general rate. Lower education and income levels correlate with 1.5–2 times greater of severe fatigue, as evidenced in multinational cohort studies. associations, such as those with chronic conditions, can further elevate local rates but are secondary to these demographic patterns. Longitudinal data indicate upward trends in fatigue , linked to global aging populations—projected to double the over-65 demographic by 2050—and rising stress from and economic pressures. Studies tracking cohorts over decades show a 10–15% increase in fatigue reports among older adults, compounded by post-pandemic stressors, emphasizing the need for ongoing surveillance.

Risk Factors

Several demographic factors contribute to increased susceptibility to fatigue. Women are approximately two to three times more likely to experience chronic fatigue than men, potentially due to hormonal influences such as fluctuations affecting immune and inflammatory responses. Individuals over 50 years of age exhibit higher prevalence rates of (ME/CFS), with rates reaching 2.0–2.1% in those aged 50–69 compared to 0.7% in younger adults aged 18–39. Low (SES), particularly household incomes below 100% of the federal level, is associated with a twofold higher likelihood of ME/CFS compared to higher income groups. Genetic predispositions also play a role in fatigue vulnerability, particularly through polymorphisms in genes that modulate inflammatory pathways. Variants in the IL-6 gene have been linked to elevated fatigue levels across various populations, including cancer survivors and those with chronic conditions, by enhancing pro-inflammatory signaling. These polymorphisms can increase fatigue risk by altering production, with specific IL-6 variants showing associations in multiple studies of persistent fatigue. Modifiable lifestyle factors further elevate fatigue risk. Smoking is associated with more severe cognitive and sleep-related fatigue symptoms in individuals with ME/CFS, independent of other comorbidities. Obesity, defined by a BMI greater than 30, correlates with higher chronic fatigue prevalence, as persons with ME/CFS are over twice as likely to have —a condition often tied to excess adiposity—compared to controls ( 2.12). Recent 2025 research underscores genetic-environmental interactions in heightening vulnerability to fatigue in , where variants influencing immune regulation interact with post-viral environmental triggers to promote persistent symptoms akin to ME/CFS. These findings suggest that combined genetic susceptibility and exposure to inflammatory environments amplify fatigue risk in this context.

Biological and Evolutionary Roles

Adaptive Functions

Fatigue serves as an adaptive biological signal that evolved to protect organisms by promoting and behavioral adjustments in response to threats such as illness or . In evolutionary terms, it functions similarly to a "behavioral shutdown" observed in animals, where reduced activity minimizes risks like predation or further harm while allowing resources to be redirected toward recovery. This response enhances survival by preventing overexertion when the body is compromised, a mechanism conserved across to prioritize immediate preservation over long-term activities. Theoretical frameworks in posit that acts as a safeguard against catastrophic physiological , particularly following infections or injuries, by signaling the need for and thereby improving overall rates. For instance, post-infection reduces physical exertion, conserving metabolic resources for immune functions like fever production and clearance, as evidenced in studies of . Seminal work highlights how this adaptive prevents excessive energy expenditure during vulnerable periods, aligning with pressures that favor individuals who strategically to outlast threats. Cross-species evidence underscores fatigue's evolutionary roots, with commonly observed in sick , where proinflammatory cytokines induce reduced locomotion to allocate energy toward immunity rather than movement. In human contexts, models derived from lifestyles suggest fatigue reliably signals the necessity for amid environmental stressors, mirroring ancestral scenarios where conserving strength during depletion or was crucial for in foraging societies. These patterns indicate fatigue's role in signaling rest needs across vertebrates, from showing decreased activity to exhibiting sleep-like inactivity during illness. A key evolutionary trade-off involves balancing fatigue-induced rest with maintained alertness, as complete inactivity could heighten predation risks, while insufficient rest might exacerbate injury. This equilibrium is shaped by selective pressures favoring moderated responses, such as cytokine-mediated enforcement of lethargy without total immobility, ensuring survival in threat-laden environments.

Resource Management Theories

Resource management theories posit that fatigue serves as a regulatory mechanism to optimize the allocation of physiological resources, particularly energy, thereby preventing depletion or overload in critical systems. Central to this framework is the central governor model, proposed by Tim Noakes in the late 1990s, which describes fatigue as a brain-mediated process that limits physical exertion to safeguard overall homeostasis and avoid metabolic catastrophe. However, the model has faced criticism for being too encompassing and potentially unfalsifiable. According to this model, the brain acts as a "governor" by integrating afferent signals from peripheral tissues—such as muscle metabolites, core temperature, and blood glucose levels—to modulate motor unit recruitment and pace performance, ensuring that exercise or activity does not exceed safe physiological limits. This anticipatory control, rather than peripheral failure, induces the subjective sensation of fatigue, thereby conserving resources for essential functions. In operational terms, the prioritizes resource distribution toward vital processes during states of physiological stress. For instance, during , neural circuits reallocate energy substrates away from locomotor activity to support immune responses, such as production and clearance, thereby reducing for exertion to minimize further metabolic demand. This prioritization manifests as behavioral withdrawal or reduced exercise tolerance, reflecting an adaptive to maintain core amid competing demands. A related concept is , introduced by in , which quantifies the cumulative wear from on multiple systems, including the hypothalamic-pituitary-adrenal axis and immune network. High signals resource reallocation through fatigue, prompting conservation of energy to repair and restore balance, as sustained activation without recovery leads to dysregulation and heightened vulnerability to exhaustion. In this context, fatigue emerges as a protective cue, diverting limited resources from non-essential activities to mitigate the long-term costs of stress exposure. Empirical support for these theories includes observations of glucose-sparing mechanisms in fatigued states, where the body shifts toward lipid oxidation to preserve stores for and vital organ function, thereby extending under duress. Recent metabolic studies, utilizing 31P magnetic , have demonstrated altered ATP utilization in fatigued , with reduced resynthesis and shifted energy flux toward recovery processes, underscoring the 's role in modulating metabolic efficiency. These findings highlight how fatigue enforces resource thriftiness, aligning with evolutionary pressures for during scarcity.

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