The 2nd International

Virtual Congress on

Controversies in Fibromyalgia

Even if physicians started to recognize fibromyalgia as a clinical entity decades ago¹, it endures to be a controversial disease, even regarding its nosological classification. Diagnostic complexity is increased by the fact that it is characterized by a complex polysymptomatology, which can continuously evolve during the course of the disease in each single patient ². Therefore, diagnostic and classification criteria are still developing.

The American College of Rheumatology criteria was the first to put some order in fibromyalgia diagnosis. In the 90s it was shortly been officially recognized as a discrete clinical entity; therefore, physicians needed to have a clear, exhaustive list of symptoms that could be present in these types of patients (ACR 2010 symptom severity scale³ is a clear example). Although comprehensive, these criteria were not very feasible in daily clinical practice. They started to be simplified in 2011 ⁴, shortening the list of associated symptoms, and afterwards in 2016 ⁵, emphasizing more the concept of “generalized pain”. Anyway, latest AAPT diagnostic criteria ⁶ tried to create a really feasible tool for physicians in order to facilitate fibromyalgia diagnosis. They divided the criteria in different dimensions. Dimension 1 includes core diagnostic criteria, which are three: (1) multisite pain defined as 6 or more pain sites from a total of 9 possible sites; (2) Moderate to severe sleep problems OR fatigue; (3) MSP plus fatigue or sleep problems must have been present for at least 3 months. Other dimensions can reinforce diagnostic conviction: common features, epidemiology, psychiatric comorbidities, functional consequences and risk factors can all be taken into account by the physicians and have all to be thoroughly investigated during the history taking.

Importantly, AAPT criteria emphasised the fact that the presence of other disorders does not exclude the existence of fibromyalgia as a comorbidity; in fact, many rheumatic diseases have a high prevalence in fibromyalgia population – the opposite also being true. However, there may be a significant reluctance to diagnose fibromyalgia by some physicians, because of a number of reasons ⁷: uncertainty about diagnosis, especially in the lack of specific biomarkers or pathognomonic signs, hesitancy in “labelling” a patient with a “stigmatizing” syndrome, and so on.

In contrast, in some cases other conditions can mimic fibromyalgia, mainly: rheumatic diseases of recent onset (polymyalgia rheumatica, rheumatoid arthritis, etc.), endocrine diseases (hypothyroidism, vitamin D deficiency), gastrointestinal diseases (celiac disease), infectious diseases (Lyme disease, hepatitis C) and the early stages of a malignancy such as metastatic cancer, leukemia and lymphoma .⁸ Specific laboratory tests and a thorough history taking should always be performed.

Finally, it is getting clearer that, even though diagnostic criteria are quite accurate in delineating the typical symptomatic profile of fibromyalgia patients, people suffering from fibromyalgia are actually divided into subpopulations on the basis of their main symptoms and of their symptoms progression ^9,10. In particular, it is important to separate those patients whose main complaint is pain from those patients who have a prominent mood disorder component of their disease (mainly anxiety and depression). The creation of these, still hypothetical, patient subgroups in daily clinical practice would be of extreme utility from a therapeutic perspective.

References

1. Bennett, R. M. Fibrositis: misnomer for a common rheumatic disorder. West. J. Med. 134, 405–413 (1981).
2. Walitt, B. et al. The longitudinal outcome of fibromyalgia: a study of 1555 patients. J. Rheumatol. 38, 2238–46 (2011).
3. Wolfe, F. et al. The American College of Rheumatology preliminary diagnostic criteria for fibromyalgia and measurement of symptom severity. Arthritis Care Res. 62, 600–610 (2010).
4. Wolfe, F. et al. Fibromyalgia criteria and severity scales for clinical and epidemiological studies: A modification of the ACR preliminary diagnostic criteria for fibromyalgia. J. Rheumatol. 38, 1113–1122 (2011).
5. Wolfe, F. et al. 2016 Revisions to the 2010/2011 fibromyalgia diagnostic criteria. Semin. Arthritis Rheum. 46, 319–329 (2016).
6. Arnold, L. M. et al. AAPT Diagnostic Criteria for Fibromyalgia. J. Pain 00, 1–18 (2018).
7. Häuser, W., Sarzi-Puttini, P. & Fitzcharles, M.-A. Fibromyalgia syndrome: under-, over- and misdiagnosis. Clin. Exp. Rheumatol. 37 Suppl 1, 90–97 (2019).
8. Häuser, W., Perrot, S., Sommer, C., Shir, Y. & Fitzcharles, M.-A. Diagnostic confounders of chronic widespread pain: not always fibromyalgia. Pain reports 2, e598 (2017).
9. Vincent, A. et al. OMERACT-based fibromyalgia symptom subgroups: an exploratory cluster analysis. Arthritis Res. Ther. 16, 463 (2014).
10. Bartley, E. J., Robinson, M. E. & Staud, R. Pain and Fatigue Variability Patterns Distinguish Subgroups of Fibromyalgia Patients. J. Pain 19, 372–381 (2018).

While increasing knowledge is accumulating regarding the pathogenesis and underlying neurological pathways of the fibromyalgia Syndrome (FMS) and other centralized pain disorders, this progress has yet to be associated with major breakthroughs in the therapeutic realm. Treating FMS remains a complex and all-too-often frustrating endeavor. While there is evidence indicating that some patients significantly improve, or even cease to fulfill diagnostic criteria of FMS, many patients continue to experience a chronic course with ups and downs and fail to achieve any dramatic improvement after starting treatment. Moreover, while the introduction of three FDA – approved medications, i.e. Pregabalin, Duloxetine and Milnacipran during the first decade of the century, appeared to usher in a new era in the pharmacological treatment of FMS, these three have not been followed by any additional drug – approvals and evidence has since shown that only a relatively small proportion of patients are significantly improved with these treatments as well. This reality has led to an increasing emphasis on the necessity of implementing a multidisciplinary approach, combining pharmacological with non – pharmacological tools and recruiting the participation of healthcare professionals from various areas, e.g. psychotherapists, physiotherapists etc. as recognized by current treatment guidelines such as the 2012 Canadian, (1) German (2)  and the EULAR 2016 guidelines (3). Exercise has been recognized as one of the most evidence-based modalities for treating FMS with the highest level of recommendation. Additional non-pharmacological interventions include cognitive behavioral treatment (CBT), movement meditative therapies, hydrotherapy etc.

Among pharmacological treatments, amitriptyline is still often used as first line therapy and has received a strong recommendation from some of the guidelines. Anticonvulsants, which mainly include Pregabalin and gabapentin, are still used with varying rates of success although their use is often limited by side effects. The Serotonin – Norepinephrine reuptake inhibitors (SNRIs), Duloxetine and Milnacipran, also receive mixed – recommendations by various guidelines and appear to have a role in specific patients. Cyclobenzaprine, a centrally acting muscle – relaxant, is recommended by the EULAR (weak for). Selective serotonin reuptake inhibitors (SSRI) are not recommended by EULAR but are recommended by German and Canadian guidelines. In real life, combining SSRIs with amitriptyline is often a practical option, since many patients may present already being treated with SSRI (for depression or anxiety) and adding amitriptyline may be easier than switching to a SNRI under such circumstances.

Strong opioids are generally not recommended for use in fibromyalgia and there are indications that their use may in fact be deleterious, due to exacerbating opioid – induced hyperalgesia. Tramadol, a weak opioid with additional 5-HT and norepinephrine reuptake inhibition activity, does show some efficacy in FMS and is recommended by EULAR and Canadian guidelines. Cannabinoids continue to receive a great deal of attention in the field of FMS, as well as chronic pain in general. There is both theoretical as well as multiple anecdotal indications supporting the use of cannabinoids in the treatment of FMS for both improving sleep as well as combating pain, although this form of treatment cannot be regarded as evidence – base at present and most guidelines remain guarded on the question. Moreover, there is currently no consensus regarding the question which cannabinoid or cannabinoids is optimal for FMS, i.e. THC, CBD, an “entourage” of cannabinoids etc. There is an obvious need for further research on this topic.

In view of the limited success rates of pharmacological interventions, there is growing interest in the prospect of achieving neuroplasticity and reducing central sensitization in FMS, through various techniques. Among the more established of these, one might mention Trans cranial magnetic stimulation (TMS) and Trans cranial direct current stimulation (tDCS), while more experimental approaches include the implementation of hyperbaric oxygen therapy (HBOT) and neuro-feedback. Interesting results have been achieved with these last two modalities and research is ongoing. At present however these modalities remain investigational in nature and are not included in current management guidelines.

1. Fitzcharles M-A, Ste-Marie PA, Goldenberg DL, Pereira JX, Abbey S, Choinière M, et al. 2012 Canadian guidelines for the diagnosis and management of fibromyalgia syndrome: executive summary. Pain Research and Management. 2013;18(3):119-26.
2. Sommer C, Häuser W, Alten R, Petzke F, Späth M, Tölle T, et al. Drug therapy of fibromyalgia syndrome. Systematic review, meta-analysis and guideline. 2012.
3. Macfarlane GJ, Kronisch C, Dean LE, Atzeni F, Häuser W, Fluß E, et al. EULAR revised recommendations for the management of fibromyalgia. Annals of the rheumatic diseases. 2017;76(2):318-28.

For years considered an unexplained disorder, with controversies about its definition, causes, management, and even its existence, fibromyalgia has evolved in recent years into an impressive field of research and progress; this evolution has been associated with better understanding of pathophysiology as well as increasing recognition and awareness regarding this highly prevalent syndrome among both health care professionals and society at large.

Diagnostic criteria have considerably changed during the last decade, attempting to integrate new clinical and pathophysiological insights, better define generalized pain, emphasized the presence of associated symptoms and recognize the validity of making a diagnosis of fibromyalgia as a potential comorbid entity, rather than defining the syndrome by exclusion. Last year, an international fibromyalgia working group on behalf of the American Pain Society published a new set of diagnostic criteria, incorporating the core symptoms of fibromyalgia, associated features, common medical and psychiatric comorbidities, psychosocial and functional consequences, as well as pathophysiology, enabling better diagnosis and classification of fibromyalgia among other chronic pain syndromes.

Research in the field of pathophysiology has expanded considerably, exploring the role of genetics, immune system, autonomic system, gut microbiome, inflammatory response, neurotransmitters, psychological factors and life events, leading to a better and more holistic comprehension of fibromyalgia.  Recognition of fibromyalgia as a comorbid disorder, especially along with other rheumatic diseases, with its implications on evaluation, disease activity scores, treatment and outcomes, is crucial to improve management of these diseases. On the other hand, specifically addressing psychiatric comorbidities with psychological therapies will also permit a decrease in the burden of somatic symptoms and physical distress.

New therapeutic options are also emerging, in order to mitigate the aberrant patterns of central pain processing demonstrated in fibromyalgia, alleviate symptoms and improve functioning. Neuromodulation by transcranial magnetic stimulation or neurofeedback are promising strategies, and further research will help in defining the optimal stimulation protocol and the most effective brain targets. Recent studies have shown symptomatic improvement in fibromyalgia patients treated by hyperbaric oxygen therapy (HBOT). Better understanding the effects of HBOT on brain activity and the mechanisms underlying such effects, as well as defining clinical/psychological settings responsive to this therapy, will help identify patients likely to improve with HBOT.

Finally yet importantly, despite considerable uncertainty regarding mechanisms of action and its exact role in the management of pain and non-pain symptoms in fibromyalgia, medical cannabis has become in the last years a focus of intense research and controversies, but also a source of hope for patients.

Understanding and treating fibromyalgia is still challenging, but the future definitely lies in an integrative approach, taking into account all we are still learning in terms of genetic background, psychosocial factors, comorbidities, neurotransmitter profile and neuroimaging pain  signature in order to define the optimal individualized patient  profile and in order to devise the necessary elaborate, unique, personalized treatment approach.

The list of physiopathological mechanisms attributed to what is now recognized under the name of fibromyalgia is more or less long as it is that of Complex Regional Pain Syndromes (CRPS). For both of them a possible direct participation of a lesion or a disease of the nervous system in their genesis has been recognized: CRPS Type II and for fibromyalgia the presence of a C-fiber neuropathy (small fiber polyneuropathy). This has been induced someone to hypnotize that fibromyalgia is a form of CRPS.

None of these pathological findings have been recognized as the distinctive landmark of the disease. Moreover, and possibly at the very bottom of the problem, there is the difficulty in assigning fibromyalgia to the field of neuropathic pain or in the opposite field of nociceptive pain in the absurd attempt to distinguish between what is the nervous system from what is not. It is worth of mention to cite what is the actual definition of nociceptive pain. The term is used to describe pain occurring with a normally functioning somatosensory nervous system to contrast with the abnormal function seen in neuropathic pain. However this definition do not clearly distinguish between acute and chronic pain and moreover what is defined as neurogenic inflammation. Neurogenic inflammation is the best example of overlapping mechanisms:  a pathological condition outside the nervous system sustained by the same nervous system that at a certain point changes its toning, becoming more reactive and sometime triggering a self -maintaining process. Indeed scientific literature is full of papers related to the strong possibility that many if not all types of pain have some common mechanisms and that we have to deal with the ability to the nervous system -but I must say, the human body- in some circumstances to react and to adapt to inner and outer stimuli of sufficient bio-psycho-social importance. In this context fibromyalgia in its full clinical feature is the end of this process.  This ability has been defined by biologists as plasticity: all cells are plastic from skin cells to more specialized cells like those of the nervous system, both sharing the same embryologic origin. Plasticity as all the biological dynamic systems can varies in term of hypo- or hyper-functioning. An interesting case is that of the modification in the thickness of some brain cortex areas after prolonged torture: firstly the somatosensory areas seem to overreact while later the same areas shrink.  This is paralleled in fibromyalgia where different cortical areas seem to be overactive while others are hypoactive producing an overall maladaptive situation. This term has been proposed by Clifford Woolf ³ as maladaptive plasticity and fibromyalgia may represents a peculiar case of maladaptive plasticity where hypo-and hyper-functioning areas are present in the brain.

Recently to try to fill the conceptual nonsense of non-nociceptive non-neuropathic chronic pains a new term has been coined: nocipastic pain to define all those pains that are neither nociceptive nor neuropathic, including fibromyalgia².  A part from the recognized inadequacy of the formulation of the definition¹, nocipastic pain may by applicable for some pathologies still in the taxonomy limbo. However it doesn’t seem to be applicable to fibromyalgia if we take into account the bio-psicho-social model to understand the natural history of the fibromyalgic patient where, in a quite relevant number of cases, the trigger toward the evolution toward fibromyalgia has to be found in some psycho-social causes and where no apparent biological alterations are present in the nervous system.

Bibliography

1. Aydede M, Shriver A. Recently introduced IASP definition of ’nociplastic pain’ needs better formulation. PAIN 2018;159:1176–77
2. Kosek E, Cohen M, Baron R, Gebhart GF, Mico JA, Rice ASC, Rief W, Sluka AK. Do we need a third mechanistic descriptor for chronic pain states? PAIN 2016;157:1382–86.
3. Woolf CJ, Salter MW: Neuronal plasticity: Increasing the gain in pain. Science 2000; 288:1765–8

Fibromyalgia is characterized by widespread pain accompanied by somatic symptoms such as fatigue and sleep disorders. The diagnostic criteria for fibromyalgia have undergone many changes over the years. The first criteria of the American college of rheumatology (ACR) emphasized the presence of tender points. These criteria were changed in 2010 with an emphasis on the presence of pain along with somatic symptoms and the negation of another joint disease explaining patients pain .In 2016, the criteria were revised removing the negative criterion for another rheumatic disease. This change is required in light of the fact that fibromyalgia is particularly prominent in patients with rheumatic diseases. In addition, it is of great importance to recognize fibromyalgia as a source of pain and to separate it from the inflammatory process in order to properly treat the patient and prevent unnecessary changes of treatment. Databases indicate greater switching of biologics among patients with inflammatory arthropathies and concomitant fibromyalgia.

It is estimated that fibromyalgia is present in about 20 to 30% of patients with rheumatic diseases. A north American database of approximately 6000 patients identified a 21 % prevalence of fibromyalgia in patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and osteoarthritis. Similar rates have been described in spondyloarthritis (SpA), including psoriatic arthritis (PsA) and other connective tissue diseases. It should be noted that, like in primary fibromyalgia, secondary fibromyalgia is more common in women.

Different studies have shown that the intensity of pain and disability is higher in patients with rheumatic disease such as RA and PsA and concomitant fibromyalgia.  This fact may a have a profound impact on the evaluation of disease activity in patients with inflammatory rheumatic diseases

The treatment of RA and SpA is based on the treat to target concept. In the last 2 decades, the treatment of these diseases has been revolutionized by the introduction of biologic agents. The treat to target strategy aims at reaching a state of remission or low disease activity. When evaluating RA, common measures of disease activity are Disease activity score-28 (DAS-28) or Simplified disease activity score (SDAI). Both measures include the number of swollen and tender joints out of 28, patient’s disease activity assessment and a measure of inflammation such as ESR or CRP. Assessment of the disease activity by the patient may be influenced by many factors such as the objective state of inflammation but also by the intensity of non- inflammatory pain, due to fibromyalgia. It has been unequivocally shown that the presence of fibromyalgia among RA and PsA patients significantly increases the various measures of disease activity. A patient with RA and fibromyalgia may demonstrate a lack of swollen joints along with multiple tender joints raising the levels of DAS to rates of moderate to high disease activity. The same has been shown in PsA where the difficulty is further increased by the presence of enthesitis which may be confounded by tender points.

In patients with inflammatory disease and concomitant fibromyalgia, it seems that any change in disease modifying drugs (DMARDS) should be based on more objective methods of evaluation such as ultrasound and not only rely on physical examination and patients reported outcomes.

In conclusion, fibromyalgia is common among patients with rheumatic diseases. Identifying the phenomenon is of great importance in order to prevent misinterpretation of disease activity measures leading to unnecessary treatment. Proper identification of fibromyalgia in rheumatic patients will lead to a better understanding of patient’s symptoms and appropriate treatment.

Disease severity assessment is an indispensable tool for every rheumatologist dealing with his or her patients. Indeed, it gives a snapshot of the current clinical situation of each patient, helping in the decision making about treatment, which could be more or less aggressive, depending on the disease severity scale; also, it allows to obtain a full picture of each patient’s clinical progression in time, permitting the creation of a strong and reliable system of follow-up. The disease severity assessment should be based on reliable, easy-to-perform standard measurements of meaningful clinical outcomes. A clear example in rheumatology can be represented by the DAS28 in rheumatoid arthritis. However, it is not possible to rely on a single symptom assessment in the case of fibromyalgia, as, for example, pain intensity, since it is a syndrome comprising too many clinical aspects. Therefore, various composite indeces were validated, encompassing the main features of this polysymptomatic disease, namely pain, fatigue, sleep alteration, neurocognitive disorders, anxiety and depression. The most widely used include the Fibromyalgia Impact Questionnaire (FIQ) and its revised version (FIQR), the Fibromyalgia Assessment Status (FAS), the Fibromyalgia Survey Criteria (FSC) and the Patient Health Questionnaire 15 (PHQ15). Notwithstanding, controversies are still open regarding the reliability and usefulness of these composite tests from an inter-individual perspective, i.e., consensual severity cut-off points have not been established yet, and this creates difficulties regarding not only therapeutic decision-making, but also invalidity recognition by healthcare authorities. Anyway, research is currently ongoing ¹.

Disease severity assessment tools are useful, but therapeutic targets should always be set in agreement with each individual patient, in a shared decision-making process. In general, the improvement of everyday function, rather than the improvement of specific symptoms, could be considered a feasible therapeutic goal. From this perspective, treatment should be strictly individualized, combining both pharmacological and non-pharmacological tools, based on each patient’s needs and symptomatology. In fact, the latest EULAR criteria ² established a “strong” recommendation only for exercise and fitness for fibromyalgia patients. In order to give general indications for physicians’ daily clinical practice, we can divide the treatment in 3 “pillars”: (1) Education and fitness; (2) Pharmacological treatment; (3) Psychotherapy. It is advisable to start each therapeutic plan with an element taken from each single pillar, in order to be effective in all symptomatologic domains.

New promising treatment tools are currently under investigation. From a pharmacological point of view, mirtazapine, an α2 adrenergic antagonist with serotonergic and noradrenergic effects, and milnacipran, a serotonin and norepinephrine reuptake inhibitor, were tested for their effectiveness in fibromyalgia, but results have so far been controversial ^3,4. Conversely, cannabis plant seems to be a promising tool to fight fibromyalgia chronic pain ^5,6, even though further studies are needed in order to assess the correct posology and THC/CBD ratio. On the other hand, nonpharmacological treatments that are being studied include the hyperbaric oxygen therapy ^7,8 and neurostimulation ⁹, which, interestingly, are both able to act on neuroplasticity, which is particularly important in a disease such as fibromyalgia.

References:

1. Salaffi, F., Di Carlo, M., Arcà, S. & Galeazzi, M. Categorisation of disease severity states in fibromyalgia: a first step to support decision-making in health care policy. Clin. Exp. Rheumatol. 36, 1074–1081 (2018).
2. Macfarlane, G. J. et al. EULAR revised recommendations for the management of fibromyalgia. Ann. Rheum. Dis. 76, 318–328 (2017).
3. Welsch, P., Bernardy, K., Derry, S., Moore, R. A. & Häuser, W. Mirtazapine for fibromyalgia in adults. Cochrane Database Syst. Rev. (2018) doi:10.1002/14651858.CD012708.pub2.
4. Pickering, G. et al. Milnacipran poorly modulates pain in patients suffering from fibromyalgia: a randomized double-blind controlled study. Drug Des. Devel. Ther. 12, 2485–2496 (2018).
5. Yassin, M., Oron, A. & Robinson, D. Effect of adding medical cannabis to analgesic treatment in patients with low back pain related to fibromyalgia: an observational cross-over single centre study. Clin. Exp. Rheumatol. 37 Suppl11, 13–20 (2019).
6. Habib, G. & Artul, S. Medical Cannabis for the Treatment of Fibromyalgia. J. Clin. Rheumatol. 24, 255–258 (2018).
7. Efrati, S. et al. Hyperbaric oxygen therapy can diminish fibromyalgia syndrome – Prospective clinical trial. PLoS One 10, (2015).
8. Atzeni, F. et al. Hyperbaric oxygen treatment of fibromyalgia: a prospective observational clinical study. Clin. Exp. Rheumatol. 37, 63–69 (2019).
9. Brighina, F. et al. Brain Modulation by Electric Currents in Fibromyalgia: A Structured Review on Non-invasive Approach With Transcranial Electrical Stimulation. Front. Hum. Neurosci. 11, 13–40 (2019).

Even though fibromyalgia is not considered by most researchers as an autoimmune or autoinflammatory disease, fibromyalgia is common in these patients, hence, the immune system involvement is plausible both as a trigger factor and /or as facilitating/preventing its manifestations and their strength. Furthermore,  viruses and other infectious agents seem to be able to induce fibromyalgia, even if a direct causal relationship is not well documented. An important role dealing with these associations might be played by innate immunity, cytokines/chemokines/ growth factors, microbiome, and by glial cells, which for example, express receptors for bacteria and viruses.

Pain in rheumatologic conditions cannot always be directly correlated with frank inflammation (e.g. synovitis) and treatment with potent biologic agents that control inflammation does not always control pain although besides synovial  pressure relief possible overlap between inflammatory pathways and pain pathways, as for example the role of the JAK system in both inflammation and chronic pain.

Fatigue is another prominent feature of these conditions, which again tends to respond only partially  to potent biologic agents.

Centralized pain syndromes are associated with changes within the central nervous system that amplify peripheral input and/or generate the perception of pain in the absence of a noxious stimulus. Examples of idiopathic functional disorders that are often categorized as centralized pain syndromes include fibromyalgia, chronic pelvic pain syndromes, and even migraines. Patients often suffer from widespread pain, associated with more than one specific syndrome, and report fatigue, mood and sleep disturbances, and poor quality of life. In general, abnormal regulation and output of the hypothalamic-pituitary-adrenal axis, the “primary” stress response system, was suggested to be associated with centralized pain disorders. Activation of this axis was suggested to result in downstream production of cortisol and a dampening of the immune response. We would like to challenge this dogma, and present evidence indicating that the immune response is not a response which is subsequent to  hypothalamic-pituitary-adrenal axis activation,  but rather evolves simultaneously, leading perhaps to sensitization of nearby nociceptive afferents and increased peripheral input via nociceptor activation. This in turn may lead to further  central sensitization, through long-term potentiation in the central nervous system.

A Minerbi, Institute for Pain Medicine, Rambam Health Campus, Haifa, Israel
M Fitzcharles, McGill University, Montreal Canada

Almost every patient with fibromyalgia (FM) asks the question whether diet may affect symptoms of FM. Furthermore, abdominal complaints consistent with irritable bowel syndrome are common in FM. The emerging understanding of the gut microbiome in both health and disease may hold pertinence for FM.

The human body exists in a complex and dynamic ecosystem with extensive microbial colonization of the gut and other tissues. This symbiosis influences health status and can be affected by environmental and genetic factors, and is a driver for metabolic and immune physiology, but alternately can play a role in pathology. The physiological effects of the gut-brain axis in both health and disease result in a bidirectional interplay between the gut (hormonal mechanisms and microbiome) and the nervous system. Neurological effects mediated via the autonomic nervous system as well as the hypothalamic pituitary adrenal axis are directed to intestinal functional effector cells, which in turn are under the influence of the gut microbiota. Gut bacteria, in turn, have been shown to affect the activity of central-nervous-system functions, with several putative mechanisms, including, but not limited to the secretion of short-chain fatty acids, bile acids, neurotransmitters and other biologically active metabolites. Perturbations of the microbiome have been associated with a wide variety of pathologies, including the metabolic syndrome, gut related disorders, mental health conditions, immunologically mediated diseases, and with increasing evidence for effect in pain conditions. Pathological states may occur when there are perturbations of the microbiome composition, leading to alteration in its metabolic function and its interactions with the host physiology.

Any assessment of the microbiome requires meticulous attention to factors known to influence composition, including diet, age, physical activity, medications and other factors. The composition of the microbiome is typically evaluated by DNA sequencing of either bacterial specific sequences, such as 16S rRNA or by metagenomic sequencing. The function of the microbiome can be inferred by transcriptomic, proteomic and metabolomic analyses. Machine learning algorithms are used to identify specific microbiome-related patterns that distinguish patients from healthy controls.

There are emerging reports that FM patients can be differentiated from controls by their specific gut-microbiome composition, with either over- or underabundance of some taxa [1]. Furthermore, there is report of association between abundance of some taxa and severity of symptoms in FM, including pain intensity, fatigue, sleep disturbance and cognitive symptoms, findings that are independent of dietary differences, comorbidities or disease independent variables. Some of these abundant bacterial taxa are involved in metabolic pathways with effect on FM symptoms that is biologically plausible. It is too early to attribute specific microbes as “bad” or “good” in the context of FM, but further study is needed to explore causal associations between the gut microbiome and FM.

This first step in assessing the microbiome in FM may hold promise for a better understanding of mechanisms operative in FM and other chronic pain conditions, provide hope for a possible biomarker to aid diagnosis and hold potential for therapeutic interventions. At this time, we must still offer patients pragmatic advice regarding good lifestyle practices with attention to a balanced diet, sufficient exercise, and stress reduction, but with the hope that further microbiome study may unlock some of the mysteries of FM and other chronic pain conditions.

1. Minerbi, A., et al., Altered microbiome composition in individuals with fibromyalgia. Pain, 2019. 160(11): p. 2589-2602.

Yehuda Shoenfeld MD, FRCP ,MaACR ,
Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel-Aviv, Israel

Chronic fatigue syndrome, fibromyalgia, macrophagic myofasciitis, postural orthostatic tachycardia syndrome, complex regional pain syndrome, post-human papillomavirus vaccine syndrome/human papilloma virus vaccination associated neuroimmunopathic syndrome and sick building syndrome have been noted to share several major clinical features. Three of these disorders are included in the concept of autoimmune/inflammatory syndrome induced by adjuvants (ASIA), which sheds light on their autoimmune pathogenesis. In this paper we summarize the evidence regarding the role of autoimmunity in the seven outlined syndromes with respect to their genetics, autoimmune co-morbidities, immune cell subtype alterations, detection of autoantibodies and presentation in animal models. Furthermore, a symptom cluster of fatigue, dysautonomia, sensory disturbance and cognitive impairment which is common for all the syndromes is identified. We suggest a new concept of autoimmune neurosensory dysautonomia with common denominator of autoantibodies directed against adrenergic and muscarinic acetylcholine receptors with coexistent small fiber neuropathy, which might probably take part in the emergence of these symptoms. Possible modalities of therapy targeting autoimmunity and their efficiency in these seven outlined syndromes are also reviewed. Understanding the suggested concept may assist in identifying the subgroups of patients who may mostly benefit from targeted immunomodulatory therapeutic modalities.

Of therapy targeting autoimmunity in the outlined disorders. ASIA autoimmune syndrome induced by adjuvants, CFS chronic fatigue syndrome, CRP C-reactive protein, CRPS complex regional pain syndrome, FM fibromyalgia, ESR erythrocyte sedimentation rate, HPV human papilloma virus, IVIG intravenous immunoglobulin, MMF macrophagic myofasciitis, ND no data, POTS postural orthostatic syndrome, SCIG subcutaneous immunoglobulin.

The title of this presentation seems to be tremendously negative toward the so called physical and complementary therapies for fibromyalgia. Indeed most of the physical therapies so far used showed some benefits to the patient. What we want to stress is not the  uselessness of all these treatments that have been used and whose results have published in  authoritative journals rather that  the  substantial  similarities of results in average not exceeding 30% of positive response. This puts the accent on some possible factors: 1)a substantial lack of aknowlwdge of the  physiological mechanisms  which are at the basis of the use of physical agents to control pain. For instance TENS wich is one of the most used electrical therapies is used   without a real acknowledgement of the different neural pathways  activated changing intensity duration and frequency of stimulation; 2)  some therapies are “unspecific”, namely they do not have a  defined target as it is for chemical compounds   we are increasingly using more selective and targeted drugs toward one or another mechanism to control pain. For instance some  therapies based on mechanical stimulation have more or less the same mechanisms and the studies so far present in literature vary greatly only in the site of stimulation and in the way changes in the nervous system are recorded. In literature, the comparison data between all these techniques are very few and with not perfectly comparable data, do not allow to define which are the best parameters, including the type of stimulus. 3) Another critical point is the empirism used in  the application of a physical therapy that is mainly  unspecifically application on the painful site. However this way of application do not take into account referred as well as the projected pains.

Another series of criticisms come from the aetiopathogenesis of fibromyalgia. Fibromyalgia  must be considered a broad label including forms of fibromyalgia where the  physical symptoms are the most relevant and where a targeted physical therapy may be suggested. At the other end of the same rope, the fibromyalgic clinical picture may be dominated by psychological or even psychiatric features. In this last case physical therapies may be just prescribed as possible adjuvants.

Very promising therapies such as the use of hyperbaric oxygen (HBOT) or the use of oxygen in a mixture with ozone (O2O3) have obtained some results by means of an activation a series of broad mechanisms such as the induction of free radicals scavengers and they may be prescribed in a more extensive number of patients. In these cases the critical point is that sometime what is not correct are the parameters measured to ascertain the efficacy of a given therapy.

In this broad range of clinical presentation the prescription of physical therapies should be driven by the clinical picture of the single patient and the decision to prescribe one therapy rather than another must be shared with the patient: heating may be extremely useful in some patients while in other heating may enhance pain, a transcranial stimulation may not be accepted by the patient. Also physical activity has to be chosen in relationship to the actual physical condition of the patient as a normal exercise can be perceived as a physical overload by another patient.

As above stated physical therapies must be used as they are substantially without side effects and may relief symptoms in a non irrelevant percentage of pain. However more attention must be put on the choice of the therapy and this choice is strongly driven by the clinical picture of the single patient.

Bibliography

Casale, R., F. Atzeni, and P. Sarzi-Puttini. “Neurophysiological background for physical therapies in fibromyalgia.” Reumatismo 2012: 238-249.

Casale, R., Boccia, G., Symeonidou, Z., Atzeni, F., Batticciotto, A., Salaffi, F., Sarzi-Puttini, P., Brustio, P.R. and A. Rainoldi. Neuromuscular efficiency in fibromyalgia is improved by hyperbaric oxygen therapy: looking inside muscles by means of surface electromyography. Clin Exp Rheumatol, 2019: 37 (116), 75-80.

Kati Thieme¹ Delia Hirche¹ Marc G. Mathys¹ Stephen Folgers²

¹Medical Psychology, Philipps University Marburg, Germany, Germany
²Department of Physical Therapy Education, Elon-University, USA

Background. Pain and cardiovascular interaction is an important component of the pain regulatory system. This interaction is influenced by baroreflex sensitivity (BRS). Baroreceptor activity through the dorsal medial tractus solitarius (dmNTS) influences somatosensory, cognitive, affective and behavioural components of the pain network.

Objectives. This study tested if 1) Systolic Extinction Training (SET) a combination of baroreceptor training (BRT) and Behavioural Therapy (OBT) would increase BRS, (2) BRS increases central inhibitory changes, and (3) if treatment reduces pain intensity and to what amount.

Methods. Forty-six FM patients and 30 healthy controls (HC) were investigated with a baroreceptor training (BRT) protocol consisting in two 8-minutes-trials where 3 different and randomized electrical stimuli (50%, 75% of individual pain tolerance, and non-painful stimuli) were administered immediately after systolic and diastolic peak of the cardiac cycle. Additionally to BRT, 20 patients were treated with aerobic exercise (AE) and 26 with OBT. Evoked potentials, theta-and alpha-band activity measured with EEG, blood pressure and BRS were measured during treatment sessions before, post, and 12 months after therapy.

Results. The affective (P260) and cognitive (P390) components of pain, but not the attention (N50) and sensory (N150) components, showed significantly greater response in FM vs HCs before therapy (p = 0.005). Post SET and in the 12 months follow-up, the EEG components reversed and showed higher theta band activity. SET eliminated pain in 82% (BRS increased 48%) at the 12-month follow-up and BRT+AE reduced pain by 50% in 14% (BRS increased by 11%) of patients.

Conclusion. Alternative methods in FM increase BRS and change sensory, affective, cognitive and behavioural components of pain network resulting in long-lasting pain remission.

The quest for biomarkers in chronic pain syndromes has been in the focus of the research in the pain neurosciences for years. It has generated intense debate about where we stand, whether we have finally identified pain biomarkers, or not (Mouraux and Iannetti 2018, Archibald et al., 2018). Moreover, not all pain researchers enthusiastically joined the search, regarding the patients’ experience as the most important criterium for diagnosis and treatment outcome. In the end, a “normalization” of what may be considered an aberrant response does not impact the patients’ life, if it is not accompanied by a change in perception.  Both the International Association of the Study of Pain (IASP), and a recent relevant consensus paper on the topic (Davis et al., 2017) have underlined that “pain is an unpleasant sensory and emotional experience”, and that, as such, the subjective component remains the gold standard. Nevertheless, imaging methods, broadly defined, may complement, especially in certain conditions, the subjective reports. Moreover, they can be used to attempt predictions about the clinical trajectory, in terms of development of chronic pain (e.g. post-surgical pain), or suitability of certain therapeutic approaches over others (e.g. cognitive behavioural therapy vs. pharmacological treatment) (Davis et al., 2017). To do so several criteria should be satisfied before an indicator can be considered a reliable biomarker. At present, none of the proposed biomarkers satisfies them all. Indeed, many of the measures await validation in terms of test-retest reliability, specific and/or validity (Davis et al., 2017). To overcome such limitations research is trying to progress in three trajectories. Researchers using fMRI are trying to validate, in healthy volunteers and chronic pain patients (including fibromyalgia patients, López-Solà et al., 2017) Multivariate Pattern Analysis approaches, which would serve as a “signature” for the identification of cortical spatial patterns of pain activation (Reddan and Wager 2018, Wager et al., 2013). This approach constitutes a methodological advance, also in terms of physiological plausibility, to the idea of the “pain matrix”. Nevertheless, it is prone to specificity problems, as  a signature for pain can be considered as such only if its presence is unique for pain (Iannetti and Hu 2016). What is more, it still lacks normative data that could be used across a wide range of scanners, patients characteristics, and analysis methods. Gamma Band Oscillations (GBOs) have also been proposed, both in healthy volunteers and in patients, as a biomarker for pain (Zhang et al., 2012, Hu and Iannetti 2019, Gross et al., 2007). The problems with GBOs consists in the absence of  test-retest reliability and limited explanatory value. Moreover GBOs are often prone to muscular artefacts (van den Broeke et al., 2017), and above all, not observed when scalp and not intracerebral recordings are used. Due to the positive report bias in research, this latter finding is often underestimated. Finally, a third line attempts to identify markers of central sensitization, rather than pain per se. Indeed, some authors consider central sensitization as a potential mechanism, common to several pain syndromes, underlying the transition to chronic pain (Arendt-Nielsen et al., 2018). Recent findings have shown that pupil dilation (van den Broeke et al., 2019) and Reflex Receptive Fields (RRF, Biurrun-Manresa et al. 2014) increase concomitantly with mechanical hypersensitivity (a hallmark of central sensitization). Of note, while RRF seem to constitute a valid and reliable marker for central sensitization, it has poor discriminative value between acute and chronic low back pain (Müller et al. 2016).

Archibald J, Warner FM, Ortiz O, Todd M, Jutzeler CR (2018). Recent advances in objectifying pain using neuroimaging techniques. JNeurophysiol 120(2):387-390

Arendt-Nielsen L, Morlion B, Perrot S, Dahan A, Dickenson A, Kress HG, Wells C, Bouhassira D, Mohr Drewes A (2018). Assessment and manifestation of central sensitisation across different chronic pain conditions. Eur J Pain 22(2):216-241

Biurrun Manresa JA, Finnerup NS, Johannesen IL, Biering-Sørensen F, Jensen TS, Arendt-Nielsen L, Andersen OK (2014). Central sensitization in spinal cord injured humans assessed by reflex receptive fields. Clin Neurophysiol 125(2):352-62

Davis KD, Flor H, Greely HT, Iannetti GD, Mackey S, Ploner M, Pustilnik A, Tracey I, Treede RD, Wager TD (2017). Brain imaging tests for chronic pain: medical, legal and ethical issues and recommendations. Nat Rev Neurol 13(10):624-638

Gross J, Schnitzler A, Timmermann L, Ploner M (2007). Gamma oscillations in human primary somatosensory cortex reflect pain perception. PLoS Biol 5(5):e133

Hu L, Iannetti GD (2016). Painful Issues in Pain Prediction Trends Neurosci. 39(4):212-220

Hu L, Iannetti GD (2019). Neural indicators of perceptual variability of pain across species. Proc Natl Acad Sci 116(5):1782-1791

López-Solà M, Woo CW, Pujol J, Deus J, Harrison BJ, Monfort J, Wager TD (2017). Towards a neurophysiological signature for fibromyalgia. PAIN 158(1):34-47

Mouraux A, Iannetti GD (2018). The search for pain biomarkers in the human brain. Brain 141(12):3290-3307

Müller M, Biurrun Manresa JA, Treichel F, Agten CA, Heini P, Andersen OK, Curatolo M, Jüni P (2016). Discriminative ability of reflex receptive fields to distinguish patients with acute and chronic low back pain. PAIN 157(12):2664-2671

Reddan MC, Wager TD (2018). Modeling Pain Using fMRI: From Regions to Biomarkers. Neurosci Bull 34(1):208-215

van den Broeke EN, de Vries B, Lambert J, Torta DM, Mouraux A (2017). Phase-locked and non-phase-locked EEG responses to pinprick stimulation before and after experimentally-induced secondary hyperalgesia. Clin Neurophysiol 128(8):1445-1456

van den Broeke EN, Hartgerink DM, Butler J, Lambert J, Mouraux A (2019). Central sensitization increases the pupil dilation elicited by mechanical pinprick stimulation. J Neurophysiol 121(5):1621-1632

Wager TD, Atlas LY, Lindquist MA, Roy M, Woo CW, Kross E (2013). An fMRI-based neurologic signature of physical pain. N Engl J Med 368(15):1388-97

Zhang ZG, Hu L, Hung YS, Mouraux A, Iannetti GD (2012). Gamma-band oscillations in the primary somatosensory cortex–a direct and obligatory correlate of subjective pain intensity. J Neurosci. 32(22):7429-38

Recent years have witnessed intense interest in the potential of cannabis and cannabinoids for effective pain management.  Cannabis-based medicines are being approved for pain management in an increasing number of countries worldwide, amidst some uncertainty and controversy on their role and appropriate use.   Cannabinoids are the biologically active constituents of the cannabis plant, or their biologically active synthetic analogues, having affinity for, and activity at, cannabinoid (CB) receptors.  Two CB receptors have been discovered and characterized: CB₁ and CB₂.    Furthermore, endogenous cannabinoids (endocannabinoids) are synthesized in most tissues and organs of humans and other animals and act at CB receptors to regulate numerous physiological and pathophysiological processes, including pain.    For example, endocannabinoids are a key component of the endogenous analgesic system, and mediate stress-induced analgesia.   Moreover, elevation of endocannabinoids within the somatosensory system or in discrete brain regions implicated in pain, modulates nociception.    There are now thousands of published studies demonstrating antinociceptive effects of phytocannabinoids (e.g. delta-9-tetrahydrocannabinol [THC]), synthetic CB₁ or CB­₂ receptor agonists, and drugs that elevate endocannabinoid levels in animal models of acute and chronic pain.   Sites of action include peripheral primary afferent neurons, the dorsal horn of the spinal cord and discrete brain regions implicated in pain processing.    Mechanisms of action include attenuation of nociceptive transmission, activation of descending pain modulatory pathways, anti-inflammatory effects, and neuroimmune modulation.   The complexity and multitude of targets within the endocannabinoid system presents an opportunity for rational design of novel analgesics with favourable side-effect profiles.    Relative to preclinical studies, there are far fewer clinical trials of cannabinoids or cannabis for chronic pain.    There is some limited evidence from clinical trials for efficacy in specific types of chronic pain (e.g. neuropathic pain, cancer pain), but further studies with larger sample sizes, of longer duration, with a broader range of drugs, formulations and routes of administration, and in other types of pain, would be very welcome.   Challenges to clinical trials with, and regulation of, cannabinoids/cannabis include their legal/illegal status in many countries, potential psychoactivity and implications for blinding studies, complexity of plant-based medicines, funding for large-scale trials, and attitudes and education of both doctors and patients.   A recent European Pain Federation (EFIC) Position Paper on the topic recommended that therapy with cannabis-based medicines should only be considered by experienced clinicians as part of a multidisciplinary treatment and preferably as adjunctive medication in properly selected and supervised patients if first and second line therapies have not provided sufficient efficacy or tolerability (Häuser et al., 2018; Starowicz and Finn, 2017; Woodhams et al., 2017). This Position Paper advised that the quantity and quality of evidence are such that cannabis-based medicines may be reasonably considered for chronic neuropathic pain and that for all other chronic pain conditions (cancer,non-neuropathic non-cancer pain), the use of cannabis-based medicines should be regarded as an individual therapeutic trial.

In summary, the endocannabinoid system plays a key role in regulating pain, and a large body of preclinical research supports the contention that cannabinoids and/or modulators of the endocannabinoid system are promising novel analgesic agents.   Further clinical research and trials are warranted, alongside continued preclinical elucidation of targets, mechanisms and candidate drugs.

References

Häuser W, Finn DP, Kalso E, Krcevski-Skvarc N, Kress HG, Morlion B, Perrot S, Schäfer M, Wells C, Brill S (2018).  European Pain Federation (EFIC) position paper on appropriate use of cannabis-based medicines and medical cannabis for chronic pain management.  Eur J Pain. 22(9):1547-1564. doi: 10.1002/ejp.1297.

Starowicz K, Finn DP (2017).  Cannabinoids and Pain: Sites and Mechanisms of Action.  Adv Pharmacol., 80:437-475. doi: 10.1016/bs.apha.2017.05.003.

Woodhams SG, Chapman V, Finn DP, Hohmann AG, Neugebauer V (2017).  The cannabinoid system and pain.  Neuropharmacology, 124:105-120.

¹Laura Bazzichi, ¹Arianna Consensi, ¹Camillo Giacomelli, ²Piercarlo Sarzi Puttini

¹U.O. of Rheumatology, Pisa A.O.U.P, Pisa, Italy

²U.O. of Rheumatology, L. Sacco University Hospital, Milan, Italy

Fibromyalgia is a syndrome characterized by widespread pain, fatigue, sleep disturbances and a constellation of dysfunctional symptoms, which lead to poor quality of life and negative consequences for patients’ family and work life. People affected by fibromyalgia have no specific changes in blood and instrumental tests and there is no specific therapy for the disease. Patients easily develop adverse effects to drug therapies, hardly withstand physical therapies and even psychological therapies are not always readily available and specific.

Fibromyalgia syndrome appears to be a chronic disturbance characterized by central sensitization, whose typical clinical manifestations are hyperalgesia and allodynia, also associated with chronic peripheral stimuli. Among the various etiopathogenetic hypotheses formulated for fibromyalgia, alterations of the endocannabinoid and opioid systems probably play an important role. Both of these systems are activated primarily in conditions of cellular stress and in response to pain; they are interactive and changes in one of the two systems induce negative or positive feedback mechanisms in the other. Indeed, there is growing evidence on the positive effects of Cannabis Sativa for fibromyalgia, with effects on chronic pain, sleep, rigidity, gastrointestinal disorders and general well-being depending on different concentrations of its active ingredients (tetrahydrocannabinol and cannabidiol) and on the way of administration. On the contrary, treatment with strong opioids in fibromyalgia has proven to be a failure in the majority of cases, because of not only ineffectiveness, but also many adverse events, as for example the hyperalgic syndrome. Therefore, the use of opioids antagonists such as naltrexone may be promising. If used at low doses (1 to 5 mg), naltrexone has a neuroprotective effect, since it acts as a glial modulator, inhibiting microglial activation. Furthermore, it elicits the so-called rebound effect of the opioids, since a transitory block of the opioid receptor increases opioid  endogenous production.

1)Sarzi-Puttini P et al :Medical cannabis and cannabinoids in rheumatology: where are we now?.Expert Rev   Clin Immunol. 2019 Oct; 15(10):1019-1032

2)Arnold LM et al. AAPT Diagnostic Criteria for Fibromyalgia.J Pain. 2019 Jun;20(6):611-628. Review.

3)Ngian GS et Al.The use of opioids in fibromyalgia. Int J Rheum Dis. 2011 Feb;14(1):6-11. Review.

4)Patten DK et Al: The Safety and Efficacy of Low-Dose Naltrexone in the Management of Chronic Pain and Inflammation in Multiple Sclerosis, Fibromyalgia, Crohn’s Disease, and Other Chronic Pain Disorders. Pharmacotherapy. 2018 Mar;38(3):382-389.

Howard Amital MD MHA

Department of Medicine ‘B’, Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, Ramat-Gan, Israel

During the last century, the history of cannabis has been rewritten several times; the once commonly used natural remedy had been criminalized, faded into oblivion, resurrected and undergone a recent interesting process of medicalization.

In several countries, Health ministries legislated paths for legal permits for the use of cannabis to many patients, primarily to patients suffering from continuous and troublesome pain.

Recent retrospective analyses had marked an impressive effect of cannabis extracts used either by smoking, inhalation or sublingually on many functional, mental and pain parameters. These interesting results are even more challenging given the borderline outcomes of the current medical agents that had been approved by the FDA and EMEA.  Of course the need for properly designed prospective studies are in need; it seems that such studies are pending and will contribute to the harnessing of cannabis for medical use.