Chronic Fatigue Syndrome and chronic pain conditions – vitally protective systems gone wrong

1 Fatigue – a sensation with protective value

Fatigue is a sensation of extreme tiredness, a signal to “slow down” or “rest”. It is a common symptom and in a general population, the severity of fatigue is distributed as a continuous variable [1]. We know that infections, physical activity and mental exertion are associated with fatigue through different pathways. During an acute inflammation process, immune cells secrete cytokines to activate further immune responses. Some of these pro inflammatory cytokines like IL-1β and IL-6 also induces sickness behavior which includes fatigue [2], [3]. However, the sensation of fatigue during illness is not directly related to levels of cytokines and there is no difference in the level of cytokines in adolescents with Chronic Fatigue Syndrome (CFS) and healthy controls [4], [5].

In sports medicine, researchers are becoming aware of how important the brain is for both physical achievement and the sensation of fatigue. During physical activity, the brain regulates the recruitment of skeleton muscle [6]. The consequence of sudden activation of all muscle-cells in a muscle simultaneously can be fractures, as seen in patients infected with the tetanus bacillus (also known as “Jaw Lock”), or patients receiving electro-convulsive shock therapy without muscle relaxants [7], [8]. During extreme physical exercises, the consequence of activating too many motor units could be an overload of the heart, and in the worst case even death. Interestingly, this regulation of the brain governing exercise tolerance is a part of an anticipatory response and happens before there are any abnormal reactions within the body [9].

We know that fatigue may be experienced after working for a relatively short period of time, while working long hours does not always lead to fatigue [10]. In fact, if the reward of working long hours is perceived as high, this does not lead to fatigue at all [11]. This intricate regulation of fatigue has been hypothesized to be due to the brain’s constant evaluation of rewards and energy costs of every action and possible action we take [12].

Approximately 18% of the adult population in Western countries suffers from a substantial fatigue that has lasted for more than 6 months, also known as Chronic Fatigue [1], [13], [14]. In adolescents, about 20% of girls and 6.5% of boys have been severely fatigued in the last month [15].

2 Chronic Fatigue Syndrome – CFS

If fatigue is unexplained, long lasting, disabling, and accompanied by musculoskeletal pain, orthostatic intolerance, cognitive problems, post exertional malaise and other symptoms, the patient may fulfill one of the case-definitions for CFS [16], [17], [18].

CFS has two age peaks in the incidence, the first during adolescence and the second from 30 to 39 years [19]. Female-to-male ratios vary from 2:1 to 5:1 across studies [19], [20], [21]. The prevalence of CFS in the general population is estimated to be 0.1 to 1.9%, depending on which case-definition is applied [20], [21], and it constitutes one of the most significant health problems among young people. Fatigue is highly correlated to poor quality of life.

Many of the symptoms patients with CFS experience have to do with allostasis, the body’s adaption to the environment [22], [23]. Pathophysiological findings like autonomic dysfunction, hypothalamic-pituitary-adrenal-axis dysregulation, cognitive dysfunction, and low grade systemic sterile inflammation can be explained by a sustained arousal [24].

We know that stressful events, such as infections or negative life events, can initiate CFS [25]. Interestingly, a recent study showed that anxious mood was the strongest predictor of chronic fatigue following acute Epstein-Barr virus infection [26]. Sustained arousal or allostatic overload is not only associated with CFS, but is also an important association with many chronic pain syndromes [27].

3 Pain – a sensation with protective value

Pain is another sensation with protective value. Pain is an uncomfortable and disturbing sensation, telling you that a part of your body is in danger of being damaged or has been damaged and that you need to do something about it. Pain is a highly motivating sensation, leading us to want to react. Throughout the body we have specific “pain” neurons and pain nociceptors that are activated by tissue damage and other nociceptive stimuli [28], [29]. These neurons activate ascending neurons in the spinal cord which transmit the information to different parts of the brain making us consciously aware of the pain [30]. If the pain stimulus is sufficient enough, efferent neurons are activated in the spinal cord leading to muscle contractions removing the affected area from the hurtful stimuli. This is also known as the withdrawal reflex, and this happens before we become consciously aware of the pain [31].

Pain is a lifesaver. Every year, there are children born without the ability to feel pain, and these children usually die young. Without the knowledge of situations causing tissue damage, these children are not capable of protecting their own bodies from harm, sustaining burns, fractures, infections without pain’s protecting warning signal [32], [33].

4 Nociceptive pain stimuli and conscious pain experience

However, there is not a dose-response relationship between nociception and conscious pain-experience/pain-perception, nor between tissue damage and pain [34]. In addition to making us feel pain, the brain can also inhibit the nociceptive ascending neuropathway through descending inhibitory neurons [35], [36], [37]. It is common to have a pain-free period directly after an injury [38]. And if we interpret the situation as life threatening, there is an even higher chance of extensive wounds not being painful since “escape” is more important [39]. In general, the context surrounding the painful experience can modulate pain perception [40]. Experimental studies in the laboratory have shown a significant pain relief of having a friend or loved one beside you during painful stimuli [41].

5 The regulation of pain perception is multifactorial [37]

In addition to the survival value of a nociceptive stimulus, the expectation of pain is important. In 1995 a builder jumped down on a 15 cm nail (Fig. 1), he was rushed to the emergency department in excruciating pain. As the smallest movement of the nail was painful he was sedated with fentanyl and midazolam. Under sedation, the nail was pulled out and his boot was removed revealing that the nail had penetrated between the toes and the foot was entirely uninjured [42]. This shows how pain may be independent of tissue damage and that the brain itself can anticipate and create pain. A study by Bayer and colleagues showed this in a laboratory setting where the participants experience of pain intensity correlated with the intensity showed on the sham stimulator they wore [43]. fMRI studies looking at physically induced pain and hypnotically induced pain show that the same areas of the brain are activated [44].

Fig. 1:

Picture of the nail penetrating the shoe of a 29 year old builder. Fisher et al. [42].

When evaluating pain in a patient it is important to be aware of the brain’s involvement in pain sensations. Requisitioning radiographic imaging is common in the evaluation process. However, the pathological findings can be hard to interpret. For instance, studies have shown that if a patient has clinical osteoarthrosis with knee pain, there is only a 15–70% chance of finding radiographic signs of osteoarthrosis. Conversely, if a patient has radiographic osteoarthrosis, there is only a 15–70% chance of the patient having a clinical osteoarthrosis with knee pain [45]. Additionally, spine images of healthy individuals without back pain will show pathological findings in over 50% of all 30 year olds and in over 95% of all 80 year olds [46].

For 19% of adult Europeans, their pain becomes chronic, seriously affecting the quality of their social and working lives [47]. In children and adolescents, chronic and recurrent pain not associated with a disease process is also common. The prevalence of headaches, abdominal pain, back pain, musculoskeletal pain, and multiple pains rages from 4 up to 83%, generally higher in girls and increasing with age [48].

6 From acute to chronic pain and chronic fatigue

There are at least two important features that affect to both fatigue and pain when they progress from acute to chronic. The first is that both sensations become amplified, i.e. less intense stimuli activate a heightened perception of fatigue or pain [49]. For pain perception this can, in many cases, develop into allodynia, i.e. normally not painful stimuli, such as touch, become painful sensations. Fatigue can develop into CFS where the slightest mental or physical exertion can lead to a severe sense of fatigue.

The second feature, especially for chronic pain, is decreased precision, i.e. the pain spreads from the original painful area. Pain in different parts of the body is also a common feature in CFS [50].

7 Similarities between chronic fatigue and chronic pain

The similarities between chronic pain syndromes and CFS are striking. In both CFS and Chronic Widespread Pain the pathophysiological findings of family environment, autonomic dysfunction, low grade systemic sterile inflammation, hypothalamo-pituitary-adrenal axis dysregulation, cognitive dysfunction, reduced emotional awareness, central sensitization, correlations to anxiety and depression are often present in both conditions [50], [51] Additionally, when looking at CFS and Chronic Widespread Pain in a general population, these two condition overlap to a substantial degree [52].

Both pain and fatigue are subjective feelings with protective value. They are by nature highly motivating making you want to react to protect your body. However, it is important to remember that pain and fatigue are outputs from processes in the brain that are interpreted as actual or potential tissue damage, but they do not always necessarily mean tissue damage.

In these conditions, our understanding of our bodies is important.

8 Understanding our body; the bio-psycho-social model

In the 17th century the great philosopher, mathematician, and scientist René Descartes was one of the originators of dualism. He thought that the body consisted of two separate substances; the material unthinking body and the immaterial thinking brain. He claimed that the body is governed by mechanical laws. However, the mind is not. Therefore, he thought that the mind and soul could live on even if the body died.

Descartes’ dualism was part of the groundwork for scientism. Descartes advocated a complete and exact natural science through the analytic method. In medicine, the biomedical method arose where human beings were viewed as biological organisms to be understood by examining their constituent parts. The biomedical method has been the base of the medical knowledge through the last 300 years [53]. However, the biomedical method leaves no room for the social, psychological, and behavioral dimensions of illness.

In 1977 Georg Engel presented the biopsychosocial model of understanding illness and health. In this model the body, the mind, and the environment are looked upon as factors that are tightly associated and significantly interrelated. With this we understand that our social environment influences and is integral with our psychological and biological processes and vice versa. Today, this is a well-established model for understanding disease and illness [53].

9 The anticipating/predicting brain

Earlier, researchers believed that the brain solely reflected afferent stimuli and reacted to them. However, during the past two decades neuroscientists argue that all mental events, emotions and otherwise, are generated as predictions or anticipations, not reactions [54], [55]. Afferent stimuli are guiding the brains predictions. If an afferent stimulus fits fairly well with what the brain predicts, the brain comprehends the anticipation as real life. The brain’s predictions are created by learning and experience, so the predictions are flexible throughout life [54].

This way of thinking can be hard to comprehend. However, examples based on visual stimuli can be helpful. Fig. 2 shows four pictures of a hollow mask in frontal and side views. The outside of the mask is convex and has a black hat (picture a and b), while the inside is concave with a white hat (pictures c and d). When looking at these pictures, there appear to be two convex faces, one face with a black hat and one face with a white hat [56]. Our brain has a strong prediction based on past experience, and refuses to interpret facial features as a concave structure. The fact that our vision is more than a reflection of the retina becomes apparent when we look at the anatomy and physiology of the visual cortex. The parts of the visual cortex receiving information directly from the eyes are in a relatively small part [57], [58].

Fig. 2:

Photographs of a rotated hollow mask: (A) and (B) (black hat) show the front and side truly convex view; (D) (white hat) shows the inside of the mask: it appears convex although it is truly hollow; (C) is curiously confusing as part of the hollow inside is seen as convex, combined with the truly convex face. This is even more striking with the actual rotating mask. Gregory [56].

How our perception is somewhat based on flexible predictions helps us to understand how symptoms may linger past their time, and also how these symptoms can disappear by with the help of cognitive interventions.

10 Treatment

When treating patients with CFS or chronic pain syndromes, a holistic approach is most beneficial [59]. For patients with CFS, the best documented treatment is Cognitive Behavior Therapy (CBT) [60]. A Dutch study showed that approximately 70% of all adolescents receiving internet-based CBT improved [61]. CBT has also shown effect in patients with chronic widespread pain, [62], [63] and even more so if it is combined with emotional awareness therapy [64].

Physical activity has many benefits for general health. It modulates illness experiences [65], [66], increase general well-being [66], [67], and impacts markedly on immune processes [68], [69]. Graded exercise therapy has been shown to have effect in CFS patients [60], and is an integrated part of some therapy protocols [70]. In chronic pain patients, physical activity is also important [71], [72].

Pathophysiological findings suggest that patients with chronic fatigue and chronic pain suffer from a sustained arousal, thus it is not surprising that therapies for stress relief like meditation or mindfulness have shown effect on both conditions [73], [74].

Patients with chronic pain and patients with chronic fatigue have sleep disturbances [75], [76]. And for some patients, interventions may be needed, either cognitive behavior therapy for insomnia or melatonin and light treatment for delayed circadian rhythm [77].

11 Conclusions and implications

All pain and fatigue are equally real experiences, caused by events and processes in both peripheral tissue and in the brain itself. Both pain and fatigue can linger and become chronic. Patients with CFS and patients with chronic pain syndromes present many of the same symptoms and have many of the same pathophysiological findings. Neither of these syndromes should be viewed in a vacuum. Their comorbidities like sleeping difficulties and psychiatric diagnoses must also be taken into account and treating them appropriately improves the outcome. By combining our knowledge about the predicting/anticipating brain and how we become consciously aware of fatigue and pain, we can, with a holistic approach, offer effective treatment. And as both CFS and chronic pain syndromes are strongly associated with poor quality of life, these treatments should have high priority in our health care system.