Current Rheumatology Reviews - Volume 11, Issue 2, 2015

Central sensitization (CS), simply defined as an amplified response of the central nervous system to peripheral input, is a concept of great importance in clinical medicine. It has helped to explain aspects of the pathophysiology of common diseases, e.g. fibromyalgia syndrome (FMS), irritable bowel syndrome, vulvodynia, headaches, chronic pelvic pain and other overlapping conditions (collectively called central sensitivity syndromes, or CSS). It also applies to pain of complex regional pain syndrome, osteoarthritis (OA), rheumatoid arthritis (RA) and post-operative pain. The pathology-pain gap in CSS is readily explained by CS. Many FMS and other CSS patients have peripheral pathology, e.g. nociceptive areas in the muscles, arthritis, small fiber neuropathy and inflammation. Pro-inflammatory cytokines are elevated in some patients. Identification of CS in patients with structural pathology, e.g. OA and RA, has helped to explain why not all patients benefit from nonsteroidal anti-inflammatory drugs or joint replacement surgery, and require therapy directed at CS. Glial cells are important in pain processing. Remarkable advances have been achieved in neuroimaging, including visualization of grey matter and white matter, not only during provoked pain but also pain at rest. Based on CS mechanisms, targeted individual therapy may now be possible. Appropriate nosology is important particularly for effective patient care. Dichotomy of neurochemical-structural (“functional”) and structural (“organic”) pathology should be abandoned; many patients have both. Psychobiology is also biology. Patient-blaming terms like somatization, somatizer and catastrophizing should be avoided. For therapy, both pharmacological and non- pharmacological approaches are important, including recognition of subgroups and person/patient-centered care.

Fibromyalgia or fibromyalgia syndrome (FMS) is a complex chronic pain disorder of unknown causation frequently associated with debilitating fatigue, unrefreshing sleep, cognitive and affective symptoms. A fibromyalgia-type suffering was possibly described in the Book of Job. Analogous symptomatic conditions have been medically recognized since the early 1900s, when initially labeled as “fibrositis”. Since the early 1980s, FMS has evolved and differentiated after its characterization in a controlled study. Since then, research has focused on multiple aspects of this disorder, including characterization and management of symptoms, psychophysiology, neuroendocrine-immune pathophysiology, including central sensitization mechanisms. The complex and multifaceted nature of FMS lends itself better to a holistic (integrative medicine) or biopsychosocial approach than the more specific bioscientific pathways typical for a pathologically-defined disease. A person-centered approach to evaluation and care more effectively addresses and encompasses the biopsychosocial aspects of this disorder than traditional bioscientific clinical methods. This review outlines a holistic multi-modal, patientcentered approach to evaluation and care as a framework for primary clinic settings. Future directions in research, diagnosis, and management of fibromyalgia patients should incorporate revised person-centered and other qualitative models of care for critical comparison to current conventional concepts and clinical practice. The more comprehensive personcentered services need to be compared to the current standardized practice in terms of their cost-effective outcomes, patient satisfaction, physician gratification, and practical logistics of providing long-term follow up and management.

Central sensitivity syndromes (CSSs) represent a heterogeneous group of disorders (e.g., fibromyalgia [FM], irritable bowel syndrome [IBS], chronic headache, temporomandibular disorders [TMDs], pelvic pain syndromes) that share many common symptoms, with persistent pain being the most prominent feature. Although the etiology and pathophysiology of CSSs are currently incompletely understood, central sensitization has emerged as one of the significant mechanisms. Given that there are currently no known cures for CSSs, people living with these disorders must learn to cope with and manage their symptoms throughout their lives. Medical interventions alone have not proven to be sufficient for helping people with CSSs manage their symptoms. A biopsychosocial perspective that considers the ways that biological, psychological, and social factors work independently and jointly to affect a person’s experience is the most effective conceptualization and guide for effective treatment. In this article, we discuss several psychological and social features that may influence the experience of a person with CSS and their symptom management, regardless of their specific diagnosis. We highlight the longitudinal aspect of adjustment to illness, the distinction between psychosocial factors as causes of symptoms versus modifiers and perpetuators of symptoms, dispel the notion that all patients with the same diagnosis are a homogeneous group (the “patient-uniformity myth”), and acknowledge the importance of environmental and situational context on symptom management for individuals with any CSS.

The nervous system as well as the immune system use common signaling molecules for intra- and inter-system communications. Specifically, both entities produce a similar array of peptide and non-peptide transmitters that act on a common set of receptors present in the two systems. One important set of such signaling molecules are cytokines. The wide distribution of cytokine receptors throughout the body, including the immune and the nervous system allows direct communication between these two entities. In addition to cytokines the nervous system and immune system also communicate with each other using shared ligands such as neurotransmitters and neuroendocrine hormones, and their respective receptors. Some of the most important clinical interactions between these two systems are associated with the “sickness response” as well as pain and analgesia. This “sickness response” which has been frequently attributed to inflammatory cytokines, strongly resembles the core symptoms of fibromyalgia and other Central Sensitivity Syndromes (CSS). Therefore a large number of research studies have focused on the relationship between peripheral cytokines and CSS. However, a lack of consistent associations was observed between CSS symptoms and peripheral cytokines which seem to suggest that maybe cytokines abnormalities of the central nervous system contribute to the pathogenesis of these illnesses. Better knowledge of cytokine –nervous system interactions may ultimately benefit the development of interventions that improve CSS manifestations including the “sickness response” and chronic pain.

Central sensitivity syndromes (CSS) share features of similar multiple symptoms, virtually unknown mechanisms and lack of effective treatments. The CSS nomenclature was chosen over alternatives because it focused on a putative physiological mechanism of central sensitization common to disorders such as fibromyalgia, irritable bowel syndrome, vulvodynia and temporomandibular disorder. Increasing evidence from multiple biological systems suggests a further development. In this new model central sensitization is part of a ensemble that includes also the symptoms of widespread pain, fatigue, unrefreshing sleep and dyscognition. The main feature is an intrinsic program that produces this ensemble to guide behavior to restore normal function in conditions that threaten survival. The well known “illness response” is a classic example that is triggered in response to the specific threat of viral infection. The major leap for this model in the context of CSS is that the symptom complex is not a reactive result of pathology, but a purposeful feeling state enlisted to combat pathology. Once triggered, this state is produced by potential mechanisms that likely include contributions of the peripheral and central immune systems, as well as stress response systems such as the autonomic system and the hypothalamic–pituitary–adrenal (HPA) axis. These act in concert to alter behavior in a beneficial direction. This concept explains similar symptoms for many triggering conditions, the poorly understood pathology, and the resistance to treatment.

Fibromyalgia syndrome (FM), the most common central sensitivity syndrome (CSS) affecting over 5% of the population, is a disorder of chronic widespread pain accompanied by numerous other symptoms that causes significant functional impairment. The core FM symptom domains can be recalled using the FIBRO mnemonic and include Fatigue and Fog (cognitive dysfunction), Insomnia (difficulties with all aspects of sleep including initiation, maintenance and restorative), Blues (depression and anxiety), Rigidity (stiffness in muscles and joints) and Ow! (widespread pain and tenderness). While typically presenting in middle-aged women, FM can affect both sexes at any age. FM is a syndrome of abnormal central pain processing and increased central sensitivity caused by neurobiological changes that cause dysregulation of mechanisms that normally regulate pain sensation. There are currently three different methods for diagnosing FM; the 1990, 2010 and modified 2010 American College of Rheumatology (ACR) criteria. While disabling, FM symptoms can be managed with a regimen of pharmacologic and nonpharmacologic treatments. Medication types with benefit in treating FM include anticonvulsants, antidepressants, anti-inflammatories, muscle relaxers, tramadol, and stimulants. Beneficial nonpharmacologic therapies include aerobic and resistance exercise, stretching, cognitive behavioral therapy, and education. Effective management requires formulation of an individualized regimen since patients differ widely in symptoms and treatments they find beneficial. Such an individualized regimen should be based on a systematic assessment of problematic symptoms conducted at baseline and each follow-up with treatments modified over time. While challenging, FM symptoms can be effectively managed and patients can lead full, productive lives.

Women with chronic pelvic pain (CPP) often present without obvious cause on imaging studies, laboratory values or physical exam. Dysfunctional sensory processing in the central nervous system (CNS) may explain pain of unclear origin. Central sensitization (CS), a mechanism of centrally mediated pain, describes this abnormal processing of sensory information. Women with CPP often present with several seemingly unrelated symptoms. This can be explained by co-existing chronic pain syndromes occurring in the same patient. Central sensitization occurs in all of these pain syndromes, also described as dysfunctional pain syndromes, and thus may explain why several often occur in the same patient. Six of the most common pain disorders that co-exist in CPP include endometriosis, painful bladder syndrome/interstitial cysitis, vulvodynia, myofascial pain/ pelvic floor hypertonus, irritable bowel syndrome, and primary dysmenorrhea. Central pain generators, (pain originating from CS) and peripheral pain generators, (pain from local tissue damage), can both occur in each of these six conditions. These pain generators will be described. Chronic pain, specifically dysfunctional sensory processing, is recognized as a systemic disease process like diabetes to be managed as opposed to a local problem to be “fixed” or cured. A multi-disciplinary approach to assessment and treatment with a focus on improving emotional, physical and social functioning instead of focusing strictly on pain reduction is more effective in decreasing disability. This is best achieved by determining the patient’s needs and perspective through a patient-centered approach. Algorithms for such an approach to assessment and treatment are outlined.

Chemical intolerance (CI) is a term used to describe a condition in which the sufferer experiences a complex array of recurrent unspecific symptoms attributed to low-level chemical exposure that most people regard as unproblematic. Severe CI constitutes the distinguishing feature of multiple chemical sensitivity (MCS). The symptoms reported by CI subjects are manifold, involving symptoms from multiple organs systems. In severe cases of CI, the condition can cause considerable life-style limitations with severe social, occupational and economic consequences. As no diagnostic tools for CI are available, the presence of the condition can only be established in accordance to criteria definitions. Numerous modes of action have been suggested to explain CI, with the most commonly discussed theories involving the immune system, central nervous system, olfactory and respiratory systems as well as altered metabolic capacity, behavioral conditioning and emotional regulation. However, in spite of more than 50 years of research, there is still a great deal of uncertainties regarding the event(s) and underlying mechanism( s) behind symptom elicitation. As a result, patients are often misdiagnosed or offered health care solutions with limited or no effect, and they experience being met with mistrust and doubt by health care professionals, the social care system and by friends and relatives. Evidence-based treatment options are currently unavailable, however, a person-centered care model based on a multidisciplinary treatment approach and individualized care plans have shown promising results. With this in mind, further research studies and health care solutions should be based on a multifactorial and interdisciplinary approach