Fatigue in chronic inflammation – a link to pain pathways | 2015 Oct | Full-text PMC article
This is a long, detailed, technical article about the link between fatigue, pain, and inflammation.
Fatigue is a frequent symptom in several inflammatory diseases, particularly in rheumatic diseases. Elements of disease activity and cognitive and behavior aspects have been reported as causes of fatigue in patients with rheumatoid arthritis.
Fatigue could be associated with activity of inflammatory rheumatism. Indeed, biologic agents targeting inflammatory cytokines are effective in fatigue.
Different pathways could be involved in fatigue and interact:
- the immune system with increased levels of pro-inflammatory cytokines (interleukin-1 and −6 and tumor necrosis factor alpha),
- dysregulation of the hypothalamic-pituitary-adrenal axis and
- neurological phenomena involving the central and autonomic nervous systems.
Fatigue is also associated with pain and depressive symptoms
A pro-inflammatory process could be involved in pain and behavioral symptoms. Inflammation could be a common link between fatigue, pain, and depression.
Fatigue is usually defined as a state of exhaustion and decreased strength accompanied by a feeling of weariness, sleepiness, and irritability, with a cognitive component.
A physiological fatigue state, occurring after strong physical effort, sends a signal to the body to bring it to rest to rescue the exhausted tissues (that is, the muscles).
Unlike normal fatigue, pathological fatigue does not improve with rest. This kind of fatigue is seen in most acute and chronic inflammatory diseases, including arthritis.
This review discusses the place of fatigue in various inflammatory diseases but also the possible link with inflammation, pain and depression.
We explain this relationship in terms of physiopathologic mechanisms and discuss how inflammation could have a role in the three other domains – fatigue, stress or depression, and pain.
Multidimensional and multicausal aspects of fatigue
High fatigue is most often associated with high pain, and fatigue and pain seem to be synchronous
several aspects can affect fatigue: illness-related characteristics (pain, inflammation, disease activity and joint damage), physical functioning (disability, health-related quality of life, sleep quality), cognitive and emotional impairment (anxiety and depression) and personal components (gender, age, social support, work and environment)
The multidimensional nature of fatigue was well described by Hewlett et al.  in their conceptual model of the interaction between fatigue and three components – disease process, cognitive and behavior aspects, and personal life issues – with a bidirectional path suggesting interrelationships among these components. In this model, pain was included in the disease process and could cause fatigue but could also interact with other factors such as the inflammatory process (responsible for pain, joint damage and disability), anemia and sleep disturbance
Fatigue and inflammation
Fatigue is common among individuals living with a chronic illness, particularly a disease with an overriding inflammatory process:
Link between fatigue and pain
In a cross-sectional study, VAS fatigue score was mainly correlated with VAS pain score; pain was most strongly associated with the five variables explaining fatigue
To examine the bidirectional effect of pain and fatigue, van Dartel et al.  conducted a prospective study of patients with established RA who received DMARDs and/or biologic agents; pain and fatigue were measured monthly for 1 year
Pain and fatigue levels fluctuated, and the change in fatigue level was positively associated with change in pain level during the same month.
Moreover, in a cohort of patients with fibromyalgia, usually considered a non-inflammatory disease, pain and fatigue scores were correlated (r = 0.45, P < 0.001) and, in the prospective analysis at 1 week, daily pain evaluation predicted increased fatigue level reported the next day (more than depression or daily sleep quality)
Fatigue and pain pathways: role of inflammation
Role of inflammation in fatigue
Inflammation could play an important role (Table 1).
fatigue could be due to inflammation-induced anemia by decreasing iron levels mediated by IL-6-induced hepcidin and thyroid insufficiency or decreased hypothalamic-pituitary-adrenal (HPA) axis activity and resistance to glucocorticoids
Systemic inflammation could affect these central mechanisms. Under some circumstances, such as chronic anxiety, posttraumatic stress, and local or general inflammation diseases, the HPA axis was deregulated and the persistent secretion of corticoids induced glucocorticoid resistance
Role of inflammation in pain
Pain has been investigated in animal models and humans. In animal models, pain could result from complex interactions between joint inflammation and altered pain processing:
a peripheral mechanism (for example, increased innervation of the synovium; increased dorsal root ganglia expression of substrance P, calcitonin gene-related peptide and neuropeptide Y; increased expression of tyrosine kinase receptor A for nerve growth factor and neuronal death) and central mechanism (for example, nociceptive pathway activity, increased sensitivity of spinal neurons via glian, and activation via interleukin (IL-1, IL-6 and TNF), opiod expression in ganglia, central sensitization).
Central pain processing was increased in RA patients, with a change in neuronal adaptive response and increased activity of the thalamus, secondary sensory cortex and limbic system, which could be modulated by emotional processing or low mood
Proinflammatory cytokines could have a direct action on pain via sensory neurons or an indirect action via inflammatory mediators such as prostaglandins
Role of inflammation in altered central nervous system activity
Because fatigue is also often associated with anxiety and depression in inflammatory rheumatism, it may be due in part to a neurological phenomenon
A review showed that blood levels of some inflammatory cytokines, such as mitogen-stimulated cytokines and adipokines, were higher with depression
A meta-analysis of 24 publications reporting on levels of cytokines in depressed patients found increased levels of TNF-α and IL-6 but not IL-1β, IL-4, IL-2, IL-8, IL-10 or IFN-γ
Moreover, antidepressive agents might inhibit the production of pro-inflammatory IL-6 and stimulate anti-inflammatory IL-4, IL-10 and IL-1RA
However, levels of the proinflammatory cytokines could also be altered by stressors or lifestyle factors associated with depression. Indeed, stress caused by major life events such as interpersonal loss or social rejection was associated with levels of pro-inflammatory IL-6 and TNF-α and also CRP, especially in depressed patients
Inflammation: a potential link between fatigue, depression and pain
Although fatigue, stress or depression, and pain have complex and various mechanisms of action, some inflammatory cytokines are found associated with these three domains, so inflammation may be their potential link.
The association between these symptoms has been documented in various medical conditions: classical inflammatory diseases such as rheumatic diseases, cancer or infections but also CFS, metabolic disorders or depression, which exhibit low-grade inflammation
We have emerging evidence of the role of microbiota in the pathogenesis of autoimmune disease, particularly in rheumatologic disease
Recently, Galland  proposed a schema in which the gut microbiome could affect CFS or fibromyalgia: the bacterial components could excessively stimulate the innate immune system and induce systemic and CNS inflammation by producing neurotoxic metabolites or could directly stimulate afferent neurons of the nervous system to send signals to the brain via the vagus nerve. Then, the gut microbiome could affect the HPA axis and be responsible for fatigue and pain in these diseases.
Fatigue and pain are two symptoms frequently present in acute or chronic high-grade inflammatory diseases such as infection, rheumatoid diseases or cancers but also low-grade inflammatory diseases such as CFS.
These symptoms are often associated with depression. In all these diseases, several markers of inflammation have been highlighted, and among various and complex mechanisms of action, inflammation could be one of the common links between fatigue and pain among various and complex mechanisms.
In rheumatic diseases, decreasing inflammation may improve fatigue and pain.
Peripheral inflammation localized at organs is associated with central neurological phenomena.
The inflammatory cytokines and cells interact with the CNS: peripheral inflammation can provoke fatigue and pain, and an altered neuroendocrine system could modulate inflammation.
Because of multiple aspects of fatigue among patients and multiple mechanisms of action that could be involved, a future perspective would be to identify some phenotypes of fatigue to better target this treatment.