[5][6][7] Fatigue (in the general usage sense of normal tiredness) often follows prolonged physical or mental activity.

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

[2][3] 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".

[13] 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".

[14] The use of the term "fatigue" in medical contexts may carry inaccurate connotations from the more general usage of the same word.

[15] 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.

[38] A 2020 Norway study found that 69% of substance use disorder patients had severe fatigue symptoms, and particularly those with extensive use of benzodiazepines.

[45] 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,[40] and many cancer treatments, particularly chemotherapy and radiotherapy.

[94] Cytokines are small protein molecules that modulate immune responses and inflammation (as well as other functions) and may have causal roles in fatigue.

[98][104] 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.

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

[114] 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.

[129][130] 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.

[131] 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.

[134] During high level of motor activity, the amount of serotonin released increases and a spillover occurs.

However, objective cognitive testing can be used to differentiate the neurocognitive deficits of brain disease from those attributable to tiredness.

[139][140][141] The perception of mental fatigue is believed to be modulated by the brain's reticular activating system (RAS).

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%.

[13] 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] [40][164][better source needed][165] The UK NICE recommends consideration of amantadine, modafinil, and selective serotonin reuptake inhibitors (SSRIs) for MS fatigue.

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

[5][210] A 2021 German study found that fatigue was the main or secondary reason for 10–20% of all consultations with a primary care physician.

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

[13] Fatigue has been posited as a bio-psycho-physiological state reflecting the body's overall strategy in resource (energy) management.

[13] 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.