Chronic Pain and Fatigue: Multifaceted Association and Diagnostic Implications

Clinically, it is very important to increase knowledge about pain and fatigue, since they are the most frequent complaints of patients. When these symptoms are "persistent" or "unexplained" they are associated with poorer quality of life and higher costs of care than other patient groups. They also pose a diagnostic conundrum and have a significant impact on healthcare costs and indirect costs.

• Fibromyalgia is characterized by chronic pain and fatigue, which are described as functional symptoms.
   
• Myalgic encephalomyelitis /chronic fatigue syndrome (ME/CFS) is a complex chronic condition, characterized by symptoms that include fatigue and malaise that worsens after exertion, cognitive and immunological dysfunction, non-restorative sleep, pain, autonomic dysfunction, neuroendocrine symptoms and immunological.
   
• Chronic pain affects one third to one half of the UK population, where the estimated prevalence of fibromyalgia is 5%.
   
• In a population sample of middle-aged people, fatigue was present in 1 in 5 subjects.

Assigning a diagnosis of ME/CFS in the clinical setting often takes years, the authors note. Many doctors are uninformed or misinformed about the disease.

It is estimated that in the UK, between 84 and 91% of patients affected by ME/CFS are not diagnosed with fibromyalgia and ME/CFS, representing a significant burden on patients and society. The delay in diagnosis of both conditions is significant and there are significant difficulties regarding nosology and nomenclature.

The presence of shared symptoms has led to the question of whether fibromyalgia and ME/CFS are manifestations of the same spectrum of disorders, or whether they are separate clinical entities.

In a previous study, the authors found an overlap in diagnoses of both entities, almost 90%.

Physicians from various specialties receive referrals requesting advice on the treatment of patients with chronic pain and fatigue. Most referrals are made to rheumatology, but also to neurologists, endocrinologists, infectologists and even cardiologists or hematologists, depending on the associated symptoms and comorbidities, the doctor’s preferences and the availability of appointments.

The Royal College of Physicians guidance suggests that rheumatology clinics include 6-7 new patients, but the patient overload that these clinics support in the UK prevents them from meeting that recommendation. There are huge variations in patient referral practices in the UK and the author, using an example, shows what the consequences of each referral modality can be.

To do this, it shows the different paths that a patient with muscle and joint pain and fatigue can follow, once she is referred by her treating doctor. Some of the possibilities are the following: ( in the original you can read the clinical history and the full texts of the answers to the queries )

•  The patient, armed with a detailed medical history, makes an appointment at the rheumatology clinic. Before the consultation, she goes through a regional triage process of some kind and, for some reason, is sent to a specialized "early arthritis" clinic, overcrowded with patients (22 patients), with the patient in the example being one of the last in the appointment list. In this clinic, as in others, the protocol approach is used to assign a "score" to disease activity, mainly because this method dictates therapeutic options, particularly if biological drugs are used. The “early rheumatoid arthritis” specialist’s response to the family doctor was that the patient does not have rheumatoid arthritis. On the other hand, the patient complained of having endured a long wait before being seen.

• The patient is not treated by the requested consultant, but another doctor who was collaborating in the care of the patients intervenes. This doctor, a Senior Research Registrar, cared for the patient while writing his doctoral thesis on transgenic murine models of Takayasu arteritis. The response that this professional sends to the family doctor informs several differential diagnoses plus the possibility of lupus and a long list of complementary studies requested, consistent with all of her diagnoses.

•  Having recently abandoned the regional triage process , the Head of the Department refers the patient to a newly created polyclinic for complex patients. She is seen by a rheumatologist, accompanied by an experienced psychiatrist, both of whom are especially interested in fibromyalgia and related conditions. This rheumatologist proposed several differential diagnoses, including fibromyalgia, and requested the corresponding complementary studies.

After this example, the author asks: “What are the possible consequences for the patient of these 3 “approaches” to care?”

•  In the first case, the likely result is that the patient requests to be referred to another specialist. Thus, she is at risk of suffering the consequences of long-term opioid use, inactivity, unemployment, and deteriorating mental health.

•  In the second case, the quality and quantity of diagnoses proposed by the collaborating doctor, perhaps this doctor should consult a more expert superior. However, the authors rule it out, since, despite having proposed so many diagnoses, the doctor does not report having examined the patient. He also has not distinguished between "live" symptoms and "historical" symptoms , and many of his medical comments are unconvincing. Regarding her diagnosis of lupus, the authors consider that there is nothing in the patient that suggests such a diagnosis. On the other hand, the studies requested will generate a very high cost. Furthermore, they say, the patient remains at risk of losing her job and will continue in her ’sick role’ as she undergoes more and more studies.

•  The third approach is the one that the authors consider appropriate. The consultation will be shorter, especially because of the time saved by not requesting unnecessary studies . The appropriate history and examination have allowed us to arrive at the correct diagnosis. The multidisciplinary approach has allowed the patient’s physical and mental health needs to be assessed, there is a clear management plan for the future, and the patient has been kept well informed.

So, the authors ask:

“ What is the significance of an association between chronic pain, fatigue, hypermotility, and autonomic dysfunction? (the patient has a history of irritable bowel syndrome).

> Associated symptoms

In addition to pain and fatigue, there are a variety of other symptoms commonly found in fibromyalgia and ME/CFS, which have a considerable impact on quality of life and function. These symptoms are gastrointestinal, neurological and cardiovascular and, in certain cases, endocrinological or other rheumatological symptoms , which are considered functional in origin.

Some are increasingly thought to be related to aberrant pain processing (such as central sensitization or abnormalities of the Autonomous Somatosensory System).

> Hypermobility

Joint hypermobility is a common connective tissue variant, affecting up to 20% of the general population and, in symptomatic individuals, is associated with a wide variety of extra-articular manifestations.

Hypermobility is associated with pain, fatigue, and gastrointestinal disturbances that are often missed in clinical practice but may provide an important etiologic connection to fibromyalgia, ME/CFS, and multiple systemic symptoms such as those described above. A recent study indicates that symptomatic hypermobility may be present in almost 80% of fibromyalgia and ME/CFS patients, but previously, it has only been diagnosed in 1 in 4 cases.

Differences in the connective tissue matrix (e.g., collagen) throughout the body could explain the disparate symptoms, including bowel and bladder irritability, headache, and dysfunctional uterine bleeding. Connective tissue disruption also provides a putative linking mechanism for brain-body symptoms , whereby differences in connective tissue could lead to defective vasoconstriction and subsequently impairment of cardiovascular autonomic function.

Joint hypermotility is strongly associated with dysautonomia.

Some authors suggest that at least 50% of patients with hypermobility meet the diagnostic criteria for orthostatic tachycardia syndrome and up to 80% of all forms of orthostatic intolerance .

There is phenomenological overlap with panic and anxiety, and those with hypermobility are overrepresented in panic and anxiety populations by a factor of 7.

Small fiber neuropathy ( SNF) is due to a selective structural lesion that affects small-caliber sensory and/or autonomic axons. The clinical presentation is dominated by peripheral neuropathic pain , in particular, but also by postural hypotension and other symptoms of autonomic dysfunction.

There is a clear clinical overlap with fibromyalgia, in association with anxiety syndrome, hypermobility and autonomic dysfunction.

In some patients in particular, autonomic nervous system symptoms may predominate. The most "typical" picture is that of a "length-dependent" neuropathy , with symptoms beginning in the feet and progressing proximally, ultimately resulting in a "gloves and stockings" picture .

As in fibromyalgia, the pain may be chronic, but there may be a marked stimulus -dependent component (e.g., a patient may not be able to tolerate wearing stockings or socks, or may complain of pain associated with the pain). weight of a quilt).

In related conditions, increased temperature can cause ’attacks’ , but this type of presentation is more common in certain rare cases, such as channelopathies, erythromelalgia and extreme paroxysmal pain syndrome.

NFP may be associated with diabetes, HIV (and certain reverse transcriptase inhibitors), alcohol use, Sjogren’s syndrome, and lupus, among others. Amyloid polyneuropathy can present as an NFP. However, at least 50% of cases are idiopathic, but of this group, almost a third have variants of the SCN9A gene, which encodes the sodium channel Nav1.7, a voltage-gated ion channel that is selectively expressed in the sensory and autonomic neurons.

Nav1.7 variants cause increased excitability of sensory neurons and eventual degeneration of small fibers. NFP may also be associated with variants of the SCN10A gene (encoding the Nav1.8 channel), which enhances the excitability of dorsal root ganglion cells. There are 2 main reasons why the true incidence is unknown.

First, there are no internationally agreed diagnostic criteria for NFP and, more importantly, the diagnosis is not easy to make.

The complete clinical neurological examination by the primary care physician is usually normal , including large fiber sensory function (touch, vibration, proprioception). There may be sensory loss distal to heat and pain (prickling). In reality, accurate thermal sensitivity tests are rarely performed and, in inexperienced hands, are unlikely to be reliable. Conventional electrophysiological tests are also normal.

The gold standard for diagnosis is quantification of the density of intraepidermal nerve fibers in a skin biopsy sample and histochemical staining for an antigen called PGP 9.5 (a ubiquitin hydrolase) that is found in all nerve fibers. This is a highly specialized technique, only performed in specialized centers.

In summary, it is certainly possible that a significant number of patients with pain and fatigue may have NFP.

The presence of a truly "length-dependent" neuropathy should alert the clinician to this possibility, but the variation in the clinical presentation of the condition and the difficulty in establishing a firm diagnosis means that many patients are, in all likelihood, currently ’omitted’.

There is growing interest in the role of mast cells in chronic diseases.

There are several groups in the UK, US and other countries actively advocating for the importance of mast cell activation disorders . (TAM), in patients with chronic fatigue and autonomic dysfunction, particularly in the context of hypermobility (Ehlers–Danlos type). If this were possible, the authors say: What clinical importance would it have?

Mature, differentiated mast cells are found only within tissues, where they congregate around nerves and blood and lymphatic vessels.

2 main types of mast cells have been described.

1. One is found in the connective tissue of the skin and the peritoneal cavity; They contain tryptase in their granules and express IL-5 and IL-6.
    
2. The other group is mast cells that are found in the respiratory and intestinal mucosa, contain tryptase and kinase, and express IL-4.

Activated mast cells produce preformed and newly synthesized mediators. Within minutes of activation, preformed markers (histamine and proteases) produce a de novo synthesis of membrane-derived lipid mediators (prostaglandins and leukotrienes) and a range of pro- and anti-inflammatory cytokines and chemokines.

In the context of disease, mast cells are often recognized for their role in the immediate IgE-mediated allergic response, anaphylaxis, urticaria, angioedema, food and pesticide allergy, and asthma.

However, pathological activation has also been implicated in nonallergic disorders , such as headache syndromes, irritable bowel syndromes, non-celiac gluten enteropathy, autoimmune syndromes, and neuropsychiatric disorders, as well as rare "primary" mast cell disorders, such as systemic mastocytosis and monoclonal mast cell activation syndrome . There are agreed upon diagnostic criteria for systemic mastocytosis, but not for other types of TAM.

Immunohistochemical analysis identified a higher content of positive CM kinases in healthy skin of patients with signs suggestive of "true" connective tissue disorders. Researchers have described symptoms compatible with a non-IgE-mediated TAM in patients with joint hypermobility. The most common symptoms are naso-ocular, and a history of anaphylaxis or asthma.

In 2015, a possible new syndrome was suggested involving mast cell activation syndrome, postural orthostatic tachycardia disorder, and hypermobility.

In an early cohort study, screening of patients with postural orthostatic tachycardia and Ehlers-Danlos syndrome revealed that two-thirds suffered from symptoms consistent with mast cell activation syndrome. The association has recently been reviewed in depth by Kohn and Chang. So, the authors ask: How is MCAS diagnosed and managed?

The tests are based on the measurement of mast cell mediators. It is suggested that, ideally, serum tryptase and chromogranin A, plasma histamine, prostaglandin D2 and heparin, as well as histamine, N-methylhistamine and 11-β-PGF2α should be measured. Leukotriene E4 should be evaluated. These tests are not widely available, but some can be done through specialized centers.

If mast cell activation syndrome is suspected in the setting of hypermobility, postural orthostatic tachycardia, and/or other suggestive symptoms, a pragmatic approach is to initiate a therapeutic trial with a combination of H1 and H2 blockers withcromoglycate or a leukotriene receptor blocker.

As in NFP, doctors are limited by a lack of readily available tests, a lack of diagnostic criteria, or clear treatment protocols. However, it seems likely that TAMs will become increasingly recognized and that mast cell activation syndrome will become a “mainstream” diagnosis.

There is evidence that in fibromyalgia and ME/CFS there is an elevation of inflammatory markers and proteomic analysis indicates that upregulation of inflammation may play an important role in the etiology of fibromyalgia.

Preliminary results from a recent study by the authors on the autonomic and inflammatory mechanisms of pain and fatigue suggest a correlation between baseline inflammatory markers and pain and fatigue symptoms. However, they say, in ME/CFS, conventional inflammatory markers (e.g., CRP and erythrocyte sedimentation rate) are normal .

Nonsteroidal anti-inflammatory drugs are rarely beneficial in the long term, and the associated gastrointestinal side effects and increased cardiovascular risks diminish their use.

Corticosteroids are also not indicated and can be harmful ; They cause mood disturbance, osteoporosis, glucose intolerance and hypertension, as well as "steroid dependence" as a consequence of adrenal suppression.

Differences in interoceptive processing (related to the sensation of what is happening in the body) may be key in constituting the brain-body mechanisms underlying such conditions, including hypermobility.

• Recent work suggests that fatigue may be related to disruption of interoceptive mechanisms.
   
• Likewise, pain is also related to differences in interoception.

The discordance between these sensory signals, which represent bodily states, may be important in the generation of symptoms and their maintenance. These models have been extended to fatigue. Thus, interoceptive mismatch may be a factor in the generation and maintenance of symptoms in such conditions, and may provide possibilities for therapeutic goals.

The UK and much of the world are still battling the consequences of the "second wave" of SARS-CoV-2 infection.

In the UK, the severity of this is perhaps greater than anticipated, mainly due to the lack of a general will to effectively support public health measures in a timely manner, due to socio-political and commercial imperatives taking precedence over high-quality scientific . However, while doctors’ ability to manage acute cases associated with infection has greatly improved over the past 9 months, mortality remains high in vulnerable groups.

Currently, the problem is increasingly focused on the long-term consequences of the infection.

The chronic disease especially affects the respiratory tract (well described in the original cases of SARS many years ago, when it affected up to 30% of patients). Carfi et al. identified for the first time a similar problem with SARSCoV-2 infection in a large group of Italian patients who had the persistence of at least one symptom, in particular fatigue and dyspnea, in almost 90% of the patients who had recovered from the infection.

After review, the authors concluded that there is a possibility that the symptoms described are due to a number of different syndromes (e.g., post-ICU care syndrome, post-viral fatigue syndrome, and long-term COVID syndrome). . 

Some people may be suffering from more than one syndrome at the same time. A proportion of patients who present with health problems after COVID will be found to have evidence of residual "physical" damage , affecting the lungs or cardiovascular system. This does not appear to be the case for the majority of patients, but there is also no objective evidence of an ongoing "inflammatory" process or the development of autoimmunity or conventional "reactive" disease .

Non-cardiopulmonary symptoms closely accompany pain and fatigue, raising the possibility that, in the long term, and in the absence of evidence of residual tissue injury, COVID should be considered part of a CFS spectrum , and treated as such.

Acute SARS-CoV-2 infection is an exogenous "stressor" , which has precipitated the condition. Individual physiological and psychological responses to such stressors are highly variable.

Considering the concomitant psychosocial stressors related to economic uncertainties, work problems, and disruption of normal social and family processes and structures, both at the individual level and within a social context, it can be very difficult to develop appropriate coping strategies. , allowing complete recovery from the disease. Therefore, the authors express that we should not be surprised that the condition that has been labeled COVID appears to be increasingly common.

It is also true that in acute SARS-CoV-2 infection, a specific "virological" diagnosis is required, for multiple purposes. The condition is now relatively common and its prevalence continues to increase.

There is no such specific virological diagnosis. It is generally performed in the majority of patients with post-viral syndromes . There is currently ongoing research designed to address (among other things) whether there is objective evidence of chronic damage to the nervous system (central, peripheral, or autonomic) and whether there are specific genetic factors that may predispose an individual to chronic disease after of an acute infection.

Outpatient evaluation of a patient with fatigue and chronic pain can be challenging. This is particularly the case when the patient is polysymptomatic and has had many interactions with healthcare professionals.

One way is to use the “snapshot” approach and question the patient to identify a maximum of 3 “live” clinical problems (e.g., occurring in the previous 2 weeks), highlighting which is the most significant.

If the main problem is fatigue or pain, it can be very helpful to identify important additional symptoms: This would be the "plus one" approach , which should raise a specific subset of diagnostic possibilities, often limited in number, which will generate more direct information, and may motivate an initial research strategy, if appropriate.

The authors state that “all physicians are trained to identify warning symptoms , such as unexplained weight loss, which, particularly in older patients, may point to a diagnosis of malignancy, malabsorption, endocrine disease, or depression.” However, they add, “there are a number of conditions that are overlooked, although they are easily identifiable.”

The average time it takes to diagnose Behçet’s disease , for example, can be up to 7 years and there is often a delay in the diagnosis of Sjogren’s syndrome . Few doctors ask about intestinal dryness or inflammation. Nor about endometrosis or HIV, especially in older patients. What is rarely useful or informative in a patient-overloaded clinical environment is exhaustively interrogating details and chronologies of health conditions that occurred several years ago.

All too often, this can result in a "memory test" for the patient, trying to respond to the doctor seeking to corroborate dates and details in the patient’s notes or history. “This is a waste of time and can be frustrating for the patient and the doctor.” However, it may be useful before, or more frequently, after the interview, to consult reports, images or results of previous pathologies, to help substantiate or refute a presumptive diagnosis.

In patients with a long history and multiple medical interactions, it is important to avoid "medical transfer" and giving undue credit to diagnoses made by other doctors, years ago. First, the patient’s memory of the results of a previous consultation may be far from accurate, and second, the professional at that time may have made a mistake.

In this brief review, the authors have highlighted what they consider to be a true association between chronic pain and fatigue, hypermobility, anxiety and dysautonomia , and suggest that these associations may be pathophysiologically related.

“We feel that explicit recognition of this phenotype is potentially of great importance and, in particular, of clinical utility in planning care at the level of each individual patient.

Furthermore, “we would strongly support the development of effective multidisciplinary clinical services, for example, for long-term COVID patients, to meet the true clinical needs of these patients, addressing physical and mental health, avoiding unnecessary studies and maximizing the opportunity to make the clinical diagnosis of other associated conditions.