Inflammation and inflammatory cytokines in fibromyalgia, pain, depression, chronic fatigue

Articles on Inflammation & Fibromyalgia

The role of IL-8 in patients with fibromyalgia: a prospective longitudinal study of 6 months. Wang H. Buchner M. Moser MT. Daniel V. Schiltenwolf M. Clinical Journal of Pain. 25(1):1-4, 2009 OBJECTIVE: In this prospective longitudinal clinical study, we evaluated the role of proinflammatory cytokine IL-8 and its clinical relevance in patients with fibromyalgia (FM) who fulfilled clearly defined inclusion and exclusion criteria and underwent a 3-week inpatients multidisciplinary pain therapy. METHODS: IL-8 in sera was measured in 20 patients with FM and 80 healthy participants at 4 fixed time points: at the beginning of the study, at 10 days, 21 days, and 6 months, respectively. Pain intensity, back function, depression, nicotine/alcohol consumption, and medication were assessed in the patient group and correlated with IL-8 levels. RESULTS: Before and during the inpatient therapy, the serum level of IL-8 was significantly higher in patients with FM compared with controls (P<0.001), but did not correlated with pain intensity and medication. Already at T1 there was a significant reduction of IL-8 serum level (P=0.023) in patient group. Six months after multidisciplinary pain therapy, IL-8 serum level in FM patients was still significantly higher than controls (P=0.044) but reduced approximately to normal range and correlated significantly negatively with pain intensity (r=-0.782, P=0.001). Patients with FM had significantly less pain (P<0.001) and better back function (P<0.001) at day 2 than at day 0. In addition, in patients with FM, IL-8 serum level correlated with nicotine consumption (r=0.471, P=0.042). CONCLUSIONS: Our results suggest that IL-8 level contributes in patients with FM whose pain intensity and back function can be improved under influence of multidisciplinary pain therapy without need of an anti-IL-8 therapy.

Fibromyalgia: an update and immunological aspects. [Review] [60 refs] Paiva ES. da Costa ED. Scheinberg M. Current Pain & Headache Reports. 12(5):321-6, 2008 Fibromyalgia syndrome (FMS) is now understood as a chronic pain syndrome, and recent evidence indicates it is not a pure psychosomatic disorder. We review the current knowledge in FMS pain pathways, focusing on the central system sensitization phenomenon and the abnormalities in the inhibitory pain systems. Chronic headache is one of the most common symptoms in FMS, and better knowledge of their common pathophysiologic features can help us understand both conditions better. These features include the nerve growth factor actions and failure of the endocannabinoid system. In addition, we review new immunological aspects of FMS, both in their humoral (autoantibodies, antipolymer antibodies) and cytokine (interleukin-2) aspects.

Circulating cytokine levels compared to pain in patients with fibromyalgia -- a prospective longitudinal study over 6 months. Wang H. Moser M. Schiltenwolf M. Buchner M. Journal of Rheumatology. 35(7):1366-70, 2008. OBJECTIVE: This prospective study examined circulating cytokines in patients with fibromyalgia (FM) over 6 months rather than at only one timepoint, and investigated correlations between serum cytokine concentrations and pain intensity in FM patients receiving multidisciplinary pain therapy. METHODS: Serum concentrations of proinflammatory cytokines interleukin 6 (IL-6), IL-8, and tumor necrosis factor-alpha (TNF-alpha) and antiinflammatory cytokines IL-4 and IL-10 were measured (Bio-Plex system) in 20 FM patients and 80 healthy subjects on admission and 10, 21, and 180 days after initiation of treatment and correlated to pain intensity. RESULTS: On admission, serum levels of IL-8 (p < 0.001) and TNF-alpha (p < 0.001), but not IL-6, were elevated in patients with FM. No significant difference in IL-4 and IL-10 was found between FM patients and controls. High IL-8 levels remained consistent during the followup, but TNF-alpha was already reduced after 10 days and until 6 months after therapy. After 6 months' treatment with multidisciplinary pain therapy, IL-8 and TNF-alpha levels were significantly lower than at the beginning (p < 0.05 for IL-8, p < 0.001 for TNF-alpha). IL-8 but not TNF-alpha serum levels were correlated with pain intensity (r = -0.782, p = 0.001) in FM patients after 6 months' multidisciplinary pain therapy. CONCLUSION: Our results suggest that proinflammatory cytokines TNF-alpha and IL-8 are involved in FM, but they do not apparently provoke the pain of FM directly. Multidisciplinary pain therapy modified the cytokine profile in patients with FM during the observation period.

High plasma levels of MCP-1 and eotaxin provide evidence for an immunological basis of fibromyalgia. Zhang Z. Cherryholmes G. Mao A. Marek C. Longmate J. Kalos M. Amand RP. Shively JE. Experimental Biology & Medicine. 233(9):1171-80, 2008. Fibromyalgia (FMS), a predominantly female (85%) syndrome, affects an estimated 2% of the US population with skeletal muscle ache, fatigue, headache, and sleep disorder. The pathogenesis of FMS is unknown and there is no laboratory test for diagnosis. In this study, plasma levels of 25 cytokines and chemokines in 92 female patients with FMS and 69 family members were measured compared to 77 controls. Trans-endothelial migration of normal leukocytes in response to FMS plasma and the cytokine profile of human myoblasts were analyzed. High levels of MCP-1 (P<0.001) and eotaxin (P<0.01) were found in patients and family members compared to controls. Patients (56/92) treated with the single agent guaifenesin (>3 months) had higher levels of eotaxin than those not treated (P<0.01). Diluted plasma from patients increased the migration of normal eosinophils and monocytes, but not neutrophils, through an endothelial/Matrigel barrier only when mast cells are included in the lower wells (P<0.05). Furthermore, myoblasts can secrete MCP-1, eotaxin, and IP-10, while treatment with MCP-1 caused secretion of IL-1beta, eotaxin and IP-10. FMS is associated with inflammatory chemokines, that MCP-1 and eotaxin may contribute to the symptoms of FMS, and that similar cytokine profiles found in family members support the idea that FMS has a genetic component. Furthermore, the chemokine profile associated with FMS has direct effects on the migration of eosinophils and monocytes in the presence of mast cells, and skeletal muscle itself may secrete.

Glucocorticoid sensitivity in fibromyalgia patients: decreased expression of corticosteroid receptors and glucocorticoid-induced leucine zipper. Macedo JA. Hesse J. Turner JD. Meyer J. Hellhammer DH. Muller CP. Psychoneuroendocrinology. 33(6):799-809, 2008. In fibromyalgia (FM) patients, differences in glucocorticoid receptor (GR) affinity and disturbances associated with loss of hypothalamic-pituitary-adrenal (HPA) axis resiliency have been observed. Based on these studies, we investigated whether FM would be associated with abnormalities in glucocorticoid (GC) sensitivity. Salivary and blood samples were collected from 27 FM patients and 29 healthy controls. Total plasma cortisol and salivary free cortisol were quantified by ELISA and time-resolved fluorescence immunoassay, respectively. GR sensitivity to dexamethasone was evaluated through IL-6 inhibition in stimulated whole blood. The corticosteroid receptors, GR alpha and mineralocorticoid receptor, as well as the glucocorticoid-induced leucine zipper (GILZ) and the FK506 binding protein 5 mRNA expression were assessed in peripheral blood mononuclear cells (PBMCs) by real-time RT-PCR. Furthermore, the corticosteroid receptors were analysed for polymorphism. We observed lower basal plasma cortisol levels (borderline statistical significance) and a lower expression of corticosteroid receptors and GILZ in FM patients when compared to healthy controls. The MR rs5522 (I180V) minor allele was found more often in FM patients than in controls and this variant was recently associated with a mild loss of receptor function. The lower GR and MR expression and possibly the reduced MR function may be associated with an impaired function of the HPA axis in these patients which, compounded by lower anti-inflammatory mediators, may sustain some of symptoms that contribute to the clinical picture of the syndrome.

Treatment strategy in fibromyalgia syndrome: where are we now?. [Review] [144 refs] Sarzi-Puttini P. Buskila D. Carrabba M. Doria A. Atzeni F. Seminars in Arthritis & Rheumatism. 37(6):353-65, 2008 INTRODUCTION: The treatment of the fibromyalgia syndrome (FMS) is not standardized and often ineffective, and the course of disease progression is unpredictable. OBJECTIVES: To highlight the efficacy of the pharmacologic and nonpharmacologic treatments administered to FMS patients. METHODS: Medline search for articles published between 1983 and 2007, using the keywords fibromyalgia, pharmacologic and nonpharmacologic treatment, and multidisciplinary modalities. RESULTS: Randomized controlled trials (RCTs) indicate that FMS has been treated by a wide range of drugs including antidepressants, opioids, nonsteroidal anti-inflammatory drugs, sedatives, muscle relaxants, and antiepileptic agents. Although the syndrome is now more widely recognized and understood, its treatment remains challenging and some physicians believe that no effective treatment exists. Only a few drugs have been shown to have clear-cut benefits in RCTs. FMS sufferers benefit from exercise and a number of the tested programs have involved more than 1 type of exercise. Two other major approaches are psychophysiologically based therapy, such as electromyography biofeedback, and interventions based on cognitive-behavioral therapy. Twelve controlled clinical studies have provided evidence supporting the efficacy of treatments administered to people with FMS by multidisciplinary teams using multicomponent strategies. CONCLUSIONS: It is difficult to draw definite conclusions concerning the most appropriate approach to managing FMS because of the methodological limitations of the available studies and the fact that the heterogeneity and nonstandardized nature of their therapeutic programs make them difficult to compare. An individually tailored multidisciplinary pharmacologic, rehabilitative, and cognitive-behavioral approach currently seems to be the most effective.

Fibromyalgia: nosography and therapeutic perspectives. [Review] [90 refs] Coaccioli S. Varrassi G. Sabatini C. Marinangeli F. Giuliani M. Puxeddu A. Pain Practice. 8(3):190-201, 2008. Fibromyalgia (FM) is an important cause of morbidity and health expenditure. Severe widespread extra-articular chronic pain, along with nonrestorative sleep, dominates the clinical syndrome. The pathogenesis of FM remains unclear. While dysfunction in serotoninergic neurotransmission is believed to play an important role, several neurologic and immuno-endocrine mechanisms may also be relevant. A theory is advanced based on an inherited imbalance in neuro-vegetative systems resulting from increased sympathetic tone because of a metabolic deficiency in the serotoninergic system that, when exposed to a precipitating event, leads to the development of the clinical manifestations of FM. The importance of both nonpharmacological treatments and multimodal medication management is stressed.

The association between fibromyalgia and polymorphism of monoamine oxidase A and interleukin-4. Su SY. Chen JJ. Lai CC. Chen CM. Tsai FJ. Clinical Rheumatology. 26(1):12-6, 2007. Because fibromyalgia (FM) is often comorbid with anxiety, and monoamine oxidase A (MAOA) was reported to be associated with anxiety, we determine if there is MAOA gene polymorphism associated with FM patients. Moreover, interleukin 4 (IL-4) was found to be an important cytokine participating in the immunologic pathway of T-helper 2 (Th-2) cells, in this study, we search if the genetic polymorphism of IL-4 intron3 could be demonstrated in FM patients. The genotype of sixty-two FM patients was compared with that of control subjects. The polymorphism of IL-4 intron3 variable number of tandem repeats (VNTR) was demonstrated by performing the genomic polymerase chain reaction (PCR) and analyzing the length of PCR product. Furthermore, the MAOA 941 G to T polymorphism was also determined by PCR-RFLP (restriction fragment length polymorphism) analysis. The MAOA 941 position genotype polymorphism between FM and control subjects was found neither statistically different in male (p=0.60) or female (p=0.52), nor total allelic frequency (p=0.52). Similarly, the difference of IL-4 intron3 polymorphism between FM and control was neither existing in genotype (p=0.06), nor allele frequency (p=0.07). The result suggests either the genetic linkage between FM and anxiety or that between FM and immunologic diseases are weak. Accordingly, the MAOA 941 position and IL-4 intron3 polymorphisms are not susceptible markers to predict FM.

Cytokine patterns in fibromyalgia and their correlation with clinical manifestations. Bazzichi L. Rossi A. Massimetti G. Giannaccini G. Giuliano T. De Feo F. Ciapparelli A. Dell'Osso L. Bombardieri S. Clinical & Experimental Rheumatology. 25(2):225-30, 2007. OBJECTIVE: To examine the possible role of the soluble factor in fibromyalgia (FM) by studying the correlation of cytokine levels with the patients' clinical and psychiatric profile. METHODS: Eighty FM patients underwent clinical and psychiatric evaluations, and plasma levels of cytokines (IL-1, IL-6, IL-8, IL-10, TNF-alpha), aspecific markers of inflammation, rheumatoid factor (RF), anti-extractable nuclear antigen (ENA) antibodies, and anti-nuclear factor (FAN) were measured. RESULTS: Higher levels of IL-10, IL-8 and TNF-alpha were found in FM patients than in controls. Significant correlations between the biochemical parameters and clinical data were found. CONCLUSION: The higher levels of cytokines found in FM patients suggest the presence of an inflammatory response system (IRS) and highlight a parallel between the clinical symptoms and biochemical data. They support the hypothesis that cytokines may play a role in the clinical features of fibromyalgia. In addition, the similar cytokine patterns found in FM patients with different psychiatric profiles suggests that IRS impairment may play a specific role in the disease.

The biochemical origin of pain--proposing a new law of pain: the origin of all pain is inflammation and the inflammatory response. Part 1 of 3--a unifying law of pain. Omoigui S. Medical Hypotheses. 69(1):70-82, 2007. We are proposing a unifying theory or law of pain, which states: the origin of all pain is inflammation and the inflammatory response. The biochemical mediators of inflammation include cytokines, neuropeptides, growth factors and neurotransmitters. Irrespective of the type of pain whether it is acute or chronic pain, peripheral or central pain, nociceptive or neuropathic pain, the underlying origin is inflammation and the inflammatory response. Activation of pain receptors, transmission and modulation of pain signals, neuro plasticity and central sensitization are all one continuum of inflammation and the inflammatory response. Irrespective of the characteristic of the pain, whether it is sharp, dull, aching, burning, stabbing, numbing or tingling, all pain arise from inflammation and the inflammatory response. We are proposing a re-classification and treatment of pain syndromes based upon their inflammatory profile. Treatment of pain syndromes should be based on these principles: 1. Determination of the inflammatory profile of the pain syndrome; 2. Inhibition or suppression of production of the appropriate inflammatory mediators, e.g. with inflammatory mediator blockers or surgical intervention where appropriate; 3. Inhibition or suppression of neuronal afferent and efferent (motor) transmission, e.g. with anti-seizure drugs or local anesthetic blocks; 4. Modulation of neuronal transmission, e.g. with opioid medication. At the L.A. Pain Clinic, we have successfully treated a variety of pain syndromes by utilizing these principles. This theory of the biochemical origin of pain is compatible with, inclusive of, and unifies existing theories and knowledge of the mechanism of pain including the gate control theory, and theories of pre-emptive analgesia, windup and central sensitization.

Ardic F. Ozgen M. Aybek H. Rota S. Cubukcu D. Gokgoz A. Effects of balneotherapy on serum IL-1, PGE2 and LTB4 levels in fibromyalgia patients. Rheumatology International. 27(5):441-6, 2007. The purpose of this study was to investigate the clinical effects of balneotherapy in the treatment of Fibromyalgia Syndrome (FMS) and to determine if balneotherapy influences serum levels of inflammation markers, IL-1, PGE2 and LTB4. 24 primary fibromyalgia female patients diagnosed according to American College of Rheumatology criteria were included to the study. Their ages ranged between 33 and 55 years. FMS patients were randomly assigned in two groups as, group 1 (n = 12) and group 2 (n = 12). Group 1 received 20-min bathing, once in a day for five days per week. Patients participated in the study for 3 weeks (total of 15 sessions) in Denizli. Group 2 did not receive balneotherapy. FMS patients were evaluated by tenderness measurements (tender point count and algometry), Visual Analogue Scale, Beck's Depression Index, Fibromyalgia Impact Questionnaire. Ten healthy women recruited group three as the controls. Serum PGE2, LTB4 and IL1-alpha levels were measured in all three groups. The biochemical measurements and clinical assessments were performed before and at the end of general period of therapy. Statistically significant alterations in algometric score, Visual Analogue score, Beck's Depression Index and PGE2 levels (P < 0.001), numbers of tender points (P < 0.01) and Fibromyalgia Impact Questionnaire score (P < 0.05) were found after the balneotherapy between group 1 and 2. Mean PGE2 level of FMS patients were higher compared to healthy control group (P < 0.0001) and decreased after the treatment period, only in group 1 (P < 0.05). As in the group 2 and 3, detectable IL-1 and LTB4 measurements were insufficient, statistical analysis was performed, only in group 1. After balneotherapy IL-1 and LTB4 significantly decreased in group 1 (P < 0.05). In conclusion, balneotherapy is an effective choice of treatment in patients with FMS relieving the clinical symptoms, and possibly influencing the inflammatory mediators.

Kaufmann I. Eisner C. Richter P. Huge V. Beyer A. Chouker A. Schelling G. Thiel M. Lymphocyte subsets and the role of TH1/TH2 balance in stressed chronic pain patients. Neuroimmunomodulation. 14(5):272-80, 2007. BACKGROUND: The complex regional pain syndrome (CRPS) and fibromyalgia (FM) are chronic pain syndromes occurring in highly stressed individuals. Despite the known connection between the nervous system and immune cells, information on distribution of lymphocyte subsets under stress and pain conditions is limited. METHODS: We performed a comparative study in 15 patients with CRPS type I, 22 patients with FM and 37 age- and sex-matched healthy controls and investigated the influence of pain and stress on lymphocyte number, subpopulations and the Th1/Th2 cytokine ratio in T lymphocytes. RESULTS: Lymphocyte numbers did not differ between groups. Quantitative analyses of lymphocyte subpopulations showed a significant reduction of cytotoxic CD8+ lymphocytes in both CRPS (p < 0.01) and FM (p < 0.05) patients as compared with healthy controls. Additionally, CRPS patients were characterized by a lower percentage of IL-2-producing T cell subpopulations reflecting a diminished Th1 response in contrast to no changes in the Th2 cytokine profile. CONCLUSIONS: Future studies are warranted to answer whether such immunological changes play a pathogenetic role in CRPS and FM or merely reflect the consequences of a pain-induced neurohumoral stress response, and whether they contribute to immunosuppression in stressed chronic pain patients.

Macedo JA. Hesse J. Turner JD. Ammerlaan W. Gierens A. Hellhammer DH. Muller CP. Adhesion molecules and cytokine expression in fibromyalgia patients: increased L-selectin on monocytes and neutrophils. Journal of Neuroimmunology. 188(1-2):159-66, 2007. Several lines of evidence implicate the immune system in the pathophysiology of fibromyalgia (FM). We investigated the role of cytokines and adhesion molecules involved in immune cell trafficking and the influence of 1.5 mg of dexamethasone (DEX) per os on their expression. L-selectin was elevated on monocytes and neutrophils of FM patients. Differences in group response to DEX were observed for CD11b on NK cells, sICAM-1 and IL-2. This study shows a slight disturbance in the innate immune system of FM patients, and suggests an enhanced adhesion and recruitment of leukocytes to inflammatory sites.

Wallace DJ. Is there a role for cytokine based therapies in fibromyalgia. [Review] [68 refs] Current Pharmaceutical Design. 12(1):17-22, 2006. Cytokines are glycoproteins that serve as chemical messengers between cells. They assist in the regulation of cell growth and repair and also have immune modulating properties. Cytokines play a role in diverse clinical processes and phenomena such as fatigue, fever, sleep, pain, stress and aching. A review of the fibromyalgia literature and related studies suggest that IL-1, IL-6 and IL-8 are dysregulated in the syndrome. Therapies directed against these cytokines may be of potential importance in the management of fibromyalgia.

Ozgocmen S. Ozyurt H. Sogut S. Akyol O. Current concepts in the pathophysiology of fibromyalgia: the potential role of oxidative stress and nitric oxide. [Review] [144 refs] Rheumatology International. 26(7):585-97, 2006. Fibromyalgia (FM) is a common chronic pain syndrome with an unknown etiology. Recent years added new information to our understanding of FM pathophysiology. Researches on genetics, biogenic amines, neurotransmitters, hypothalamic-pituitary-adrenal axis hormones, oxidative stress, and mechanisms of pain modulation, central sensitization, and autonomic functions in FM revealed various abnormalities indicating that multiple factors and mechanisms are involved in the pathogenesis of FM. Oxidative stress and nitric oxide may play an important role in FM pathophysiology, however it is still not clear whether oxidative stress abnormalities documented in FM are the cause or the effect. This should encourage further researches evaluating the potential role of oxidative stress and nitric oxide in the pathophysiology of FM and the efficacy of antioxidant treatments (omega-3 and -6 fatty acids, vitamins and others) in double blind and placebo controlled trials. These future researches will enhance our understanding of the complex pathophysiology of this disorder.

Lorton D. Lubahn CL. Estus C. Millar BA. Carter JL. Wood CA. Bellinger DL. Bidirectional communication between the brain and the immune system: implications for physiological sleep and disorders with disrupted sleep. [Review] [189 refs] Neuroimmunomodulation. 13(5-6):357-74, 2006. This review describes mechanisms of immune-to-brain and brain-to-immune signaling involved in mediating physiological sleep and altered sleep with disease. The central nervous system (CNS) modulates immune function by signaling target cells of the immune system through autonomic and neuroendocrine pathways. Neurotransmitters and hormones produced and released by these pathways interact with immune cells to alter immune functions, including cytokine production. Cytokines produced by cells of the immune and nervous systems regulate sleep. Cytokines released by immune cells, particularly interleukin-1beta and tumor necrosis factor-alpha, signal neuroendocrine, autonomic, limbic and cortical areas of the CNS to affect neural activity and modify behaviors (including sleep), hormone release and autonomic function. In this manner, immune cells function as a sense organ, informing the CNS of peripheral events related to infection and injury. Equally important, homeostatic mechanisms, involving all levels of the neuroaxis, are needed, not only to turn off the immune response after a pathogen is cleared or tissue repair is completed, but also to restore and regulate natural diurnal fluctuations in cytokine production and sleep. The immune system's ability to affect behavior has important implications for understanding normal and pathological sleep. Sleep disorders are commonly associated with chronic inflammatory diseases and chronic age- or stress-related disorders. The best studied are rheumatoid arthritis, fibromyalgia and chronic fatigue syndromes. This article reviews our current understanding of neuroimmune interactions in normal sleep and sleep deprivation, and the influence of these interactions on selected disorders characterized by pathological sleep.

Bennett R. Fibromyalgia: present to future. [Review] [42 refs] Current Rheumatology Reports. 7(5):371-6, 2005. There has been a dramatic increase in our understanding of fibromyalgia throughout the past 14 years since the publication of the 1990 American College of Rheumatology classification criteria. Before 1990, and for most of the 20th century, fibromyalgia was considered to be predominantly a muscle disorder; now the critical abnormality is described as "central sensitization." However, central sensitization has to have an initial genesis and nociceptive stimuli from painful foci in muscle are increasingly recognized as being relevant to the development of fibromyalgia. Clinicians also recognize an association between the initiation of fibromyalgia and chronic psychologic stressors and inflammatory disorders. It has been more difficult to understand how two such apparently diverse events could affect central pain physiology. However, some clues are emerging from the role of diverse stimuli in activating glial cells and the role of disordered cytokine networks. Some predictions about future developments in fibromyalgia are ventured based on the current state of knowledge.

Russo EB. Clinical endocannabinoid deficiency (CECD): can this concept explain therapeutic benefits of cannabis in migraine, fibromyalgia, irritable bowel syndrome and other treatment-resistant conditions?. [Review] [120 refs] Neuroendocrinology Letters. 25(1-2):31-9, 2004. OBJECTIVES: This study examines the concept of clinical endocannabinoid deficiency (CECD), and the prospect that it could underlie the pathophysiology of migraine, fibromyalgia, irritable bowel syndrome, and other functional conditions alleviated by clinical cannabis. METHODS: Available literature was reviewed, and literature searches pursued via the National Library of Medicine database and other resources. RESULTS: Migraine has numerous relationships to endocannabinoid function. Anandamide (AEA) potentiates 5-HT1A and inhibits 5-HT2A receptors supporting therapeutic efficacy in acute and preventive migraine treatment. Cannabinoids also demonstrate dopamine-blocking and anti-inflammatory effects. AEA is tonically active in the periaqueductal gray matter, a migraine generator. THC modulates glutamatergic neurotransmission via NMDA receptors. Fibromyalgia is now conceived as a central sensitization state with secondary hyperalgesia. Cannabinoids have similarly demonstrated the ability to block spinal, peripheral and gastrointestinal mechanisms that promote pain in headache, fibromyalgia, IBS and related disorders. The past and potential clinical utility of cannabis-based medicines in their treatment is discussed, as are further suggestions for experimental investigation of CECD via CSF examination and neuro-imaging. CONCLUSION: Migraine, fibromyalgia, IBS and related conditions display common clinical, biochemical and pathophysiological patterns that suggest an underlying clinical endocannabinoid deficiency that may be suitably treated with cannabinoid medicines.

Thompson ME. Barkhuizen A. Fibromyalgia, hepatitis C infection, and the cytokine connection. [Review] [44 refs] Current Pain & Headache Reports. 7(5):342-7, 2003. Fibromyalgia and chronic hepatitis C infection share many clinical features including prominent somatic complaints such as musculoskeletal pain and fatigue. There is a growing body of evidence supporting a link between cytokines and somatic complaints. This review discusses alterations of cytokines in fibromyalgia, including increased serum levels of interleukin (IL)-2, IL-2 receptor, IL-8, IL-1 receptor antagonist; increased IL-1 and IL-6 produced by stimulated peripheral blood mononuclear cell in patients with FM for longer than 2 years; increased gp130, which is a neutrophil cytokine transducing protein; increased soluble IL-6 receptor and soluble IL-1 receptor antagonist only in patients with fibromyalgia who are depressed; and IL-1 beta, IL-6, and TNF-a by reverse transcriptase-polymerase chain reaction in skin biopsies of some patients with fibromyalgia. In addition, this review describes the mechanism by which alterations in cytokines in fibromyalgia and chronic hepatitis C infection can produce hyperalgesia and other neurally mediated symptoms through the presence of cytokine receptors on glial cells and opiate receptors on lymphocytes and the influence of cytokines on the hypothalamus-pituitary-adrenal axis such as IL-1, IL-6, and TNF-a activating and IL-2 and IFN-a down-regulating the HPA axis, respectively. The association between chronic hepatitis C infection and fibromyalgia is discussed, including a description of key cytokine changes in chronic hepatitis C infection. Future studies are encouraged to further characterize these immunologic alterations with potential pathophysiologic and therapeutic implications.

Gur A. Karakoc M. Erdogan S. Nas K. Cevik R. Sarac AJ. Regional cerebral blood flow and cytokines in young females with fibromyalgia. Clinical & Experimental Rheumatology. 20(6):753-60, 2002. OBJECTIVE: To determine whether there is any difference in regional cerebral blood flow (rCBF) and serum cytokine levels and association between clinical parameters and rCBF and serum cytokine levels in young females with fibromyalgia (FM). The other aim was to search whether the depression state has any effect on these two parameters. METHODS: Nineteen women with FM and 20 healthy women had 99mTc-HMPAO brain single-photon-emission computed tomography (SPECT) to evaluate rCBF. Serum interleukin (IL) levels (IL 1 beta, IL 2r, IL 6 and IL 8) were measured. Clinical and psychological evaluation was also carried out in FM patients and healthy controls. RESULTS: The patients with FM had significantly higher radioactivity uptake ratio in right and left caudate nucleus (p = 0.009, p = 0.001, respectively) than healthy controls. There was statistically significant decrease in the 99mTc-HMPAO uptake in the right superior parietal (p = 0.041), gyrus rectalis (p = 0.036) and pons (p = 0.023). FM patients had significantly higher serum IL 2r and IL 8 levels (p = 0.023, p = 0.011, respectively) than controls. Additionally, FM patients had significantly higher Fibromyalgia Impact Questionnaire (FIQ), Health Assessment Questionnaire (HAQ), and Hamilton Depression Rate scale (HDRS) scores (p = 0.000) than controls. Interestingly, the patients with mild depressive symptoms or without (i.e. HDRS-score < or = 16) had significantly higher serum IL 8 levels (p = 0.027) and increased radioactivity uptake ratio in the pons (P = 0.036) than the patients with more severe depressive symptoms (i.e. HDRS-score > 16). With regard to regional cerebral blood flow, significant correlations were detected between RSP and morning stiffness (r = 0.70, p < 0.01) and sleep disturbance (r = -0.53, p < 0.05), and between gyrus rectalis and FIQ score. There were significant correlations between LCN and IL-2 (P = 0.025), between RSP and morning stiffness (P = 0.006), sleep disturbance (P = 0.021) according to multiple regression analysis test. CONCLUSION: This study shows a significant increase in rCBF of caudate nuclei, a reduction in the pons, some cortical regions activity and a increase in IL 8, IL2r levels of young female patients with FM. These findings are more prominent in patients with low HDRS scores.

Schwarz MJ. Offenbaecher M. Neumeister A. Ewert T. Willeit M. Praschak-Rieder N. Zach J. Zacherl M. Lossau K. Weisser R. Stucki G. Ackenheil M. Evidence for an altered tryptophan metabolism in fibromyalgia. Neurobiology of Disease. 11(3):434-42, 2002. Fibromyalgia (FM) is a prevalent syndrome with chronic pain and a hypothesized underlying disturbance of the tryptophan (TRP) metabolism. We performed a tryptophan depletion (TD) test in 17 FM patients and 17 controls. TRP, 5-hydroxyindoleacetic acid (5-HIAA), kynurenine (KYN), and interleukin-6 (IL-6) were measured. Additionally pain perception was monitored in the FM patients. FM patients and controls exhibited a decrease of TRP and KYN during TD. 5-HIAA levels also decreased in all controls and in 11 FM patients, but showed a marked increase in 6 FM patients. IL-6 significantly increased during TD in the patients, but not in the controls. Pain perception was not affected in the FM patients. These data demonstrate an altered TRP metabolism in a subgroup of FM patients, where the TD seems to activate 5-HT metabolism. Our findings may have diagnostic as well as therapeutic implications in the field of fibromyalgia.

Mullington JM. Hinze-Selch D. Pollmacher T. Mediators of inflammation and their interaction with sleep: relevance for chronic fatigue syndrome and related conditions. [Review] [53 refs] Annals of the New York Academy of Sciences. 933:201-10, 2001. In humans, activation of the primary host defense system leads to increased or decreased NREM sleep quality, depending on the degree of early immune activation. Modest elevations of certain inflammatory cytokines are found during experimental sleep loss in humans and, in addition, relatively small elevations of cytokines are seen following commencement of pharmacological treatments with clozapine, a CNS active antipsychotic agent, known to have immunomodulatory properties. Cytokines such as TNF-alpha, its soluble receptors, and IL-6, present in the periphery and the CNS, comprise a link between peripheral immune stimulation and CNS-mediated behaviors and experiences such as sleep, sleepiness, and fatigue. The debilitating fatigue experienced in chronic fatigue syndrome and related diseases may also be related to altered cytokine profiles.

Hedenberg-Magnusson B. Ernberg M. Alstergren P. Kopp S. Pain mediation by prostaglandin E2 and leukotriene B4 in the human masseter muscle. Acta Odontologica Scandinavica. 59(6):348-55, 2001. The pathophysiology behind chronic pain from masticatory muscles is unclear. Our hypothesis was that this pain is of inflammatory origin and associated with release of inflammatory mediators. The aim of this study was therefore to investigate the presence of prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) in the masseter muscle and plasma and their relation to myalgia. Nineteen patients with fibromyalgia, 19 with local myalgia of the masseter muscle, and 11 healthy individuals were examined with regard to local muscular pain intensity at rest and pressure pain threshold. Inclusion criteria were masseter muscle pain for at least 3 months and masseter muscle tenderness on digital palpation. Samples were obtained from the masseter muscle by microdialysis, and the dialysates and venous blood samples were analyzed with regard to PGE2 and LTB4 concentration. Intramuscular levels were found in all groups, with significantly higher levels of LTB4 in the patients with fibromyalgia, in whom PGE2 was positively correlated to muscular pain. In the healthy individuals PGE2 was negatively correlated to pressure pain threshold. In both patient groups but not in the healthy individuals LTB4 increased during the consecutive samplings. PGE2 and LTB4 were detectable in the plasma of all groups. In conclusion, both PGE2 and LTB4 were found in the human masseter muscle. LTB4 levels are increased on needle trauma in patients with myalgia. PGE2 levels are related to muscular pain in patients with fibromyalgia. Masseter muscle pain therefore seems to be partly of peripheral inflammatory origin in fibromyalgia.

van West D. Maes M. Neuroendocrine and immune aspects of fibromyalgia. [Review] [92 refs] Biodrugs. 15(8):521-31, 2001. Fibromyalgia is a form of non-articular rheumatism characterised by long term (>3 months) and widespread musculoskeletal aching, stiffness and pressure hyperalgesia at characteristic soft tissue sites, called soft tissue tender points. The biophysiology of fibromyalgia, however, has remained elusive and the treatment remains mainly empirical. This article reviews the neuroendocrine-immune pathophysiology of fibromyalgia. There is no major evidence that fibromyalgia is accompanied by activation of the inflammatory response system, by immune activation or by an inflammatory process. There is some evidence that fibromyalgia is accompanied by some signs of immunosuppression, suggesting that immunomodifying drugs could have potential in the treatment of fibromyalgia. Recent trials with cytokines, such as interferon-alpha, have been undertaken in patients with fibromyalgia. Immunotherapy with these agents, however, may induce symptoms reminiscent of fibromyalgia and depression in a considerable number of patients. Lowered serum activity of prolyl endopeptidase (PEP), a cytosolic endopeptidase that cleaves peptide bonds on the carboxyl side of proline in proteins of relatively small molecular mass, may play a role in the biophysiology of fibromyalgia through diminished inactivation of algesic and depression-related peptides, e.g. substance P. Trials with PEP agonists could be worthwhile in fibromyalgia. The muscle energy depletion hypothesis of fibromyalgia is supported by findings that this condition is accompanied by lowered plasma levels of branched chain amino acids (BCAAs), i.e. valine, leucine and isoleucine. Since there is evidence that BCAA supplementation decreases muscle catabolism and has ergogenic values, a supplemental trial with BCAAs in fibromyalgia appears to be justified.

Elenkov IJ. Wilder RL. Chrousos GP. Vizi ES. The sympathetic nerve--an integrative interface between two supersystems: the brain and the immune system. [Review] [445 refs] Pharmacological Reviews. 52(4):595-638, 2000. The brain and the immune system are the two major adaptive systems of the body. During an immune response the brain and the immune system "talk to each other" and this process is essential for maintaining homeostasis. Two major pathway systems are involved in this cross-talk: the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS). This overview focuses on the role of SNS in neuroimmune interactions, an area that has received much less attention than the role of HPA axis. Evidence accumulated over the last 20 years suggests that norepinephrine (NE) fulfills the criteria for neurotransmitter/neuromodulator in lymphoid organs. Thus, primary and secondary lymphoid organs receive extensive sympathetic/noradrenergic innervation. Under stimulation, NE is released from the sympathetic nerve terminals in these organs, and the target immune cells express adrenoreceptors. Through stimulation of these receptors, locally released NE, or circulating catecholamines such as epinephrine, affect lymphocyte traffic, circulation, and proliferation, and modulate cytokine production and the functional activity of different lymphoid cells. Although there exists substantial sympathetic innervation in the bone marrow, and particularly in the thymus and mucosal tissues, our knowledge about the effect of the sympathetic neural input on hematopoiesis, thymocyte development, and mucosal immunity is extremely modest. In addition, recent evidence is discussed that NE and epinephrine, through stimulation of the beta(2)-adrenoreceptor-cAMP-protein kinase A pathway, inhibit the production of type 1/proinflammatory cytokines, such as interleukin (IL-12), tumor necrosis factor-alpha, and interferon-gamma by antigen-presenting cells and T helper (Th) 1 cells, whereas they stimulate the production of type 2/anti-inflammatory cytokines such as IL-10 and transforming growth factor-beta. Through this mechanism, systemically, endogenous catecholamines may cause a selective suppression of Th1 responses and cellular immunity, and a Th2 shift toward dominance of humoral immunity. On the other hand, in certain local responses, and under certain conditions, catecholamines may actually boost regional immune responses, through induction of IL-1, tumor necrosis factor-alpha, and primarily IL-8 production. Thus, the activation of SNS during an immune response might be aimed to localize the inflammatory response, through induction of neutrophil accumulation and stimulation of more specific humoral immune responses, although systemically it may suppress Th1 responses, and, thus protect the organism from the detrimental effects of proinflammatory cytokines and other products of activated macrophages. The above-mentioned immunomodulatory effects of catecholamines and the role of SNS are also discussed in the context of their clinical implication in certain infections, major injury and sepsis, autoimmunity, chronic pain and fatigue syndromes, and tumor growth. Finally, the pharmacological manipulation of the sympathetic-immune interface is reviewed with focus on new therapeutic strategies using selective alpha(2)- and beta(2)-adrenoreceptor agonists and antagonists and inhibitors of phosphodiesterase type IV in the treatment of experimental models of autoimmune diseases, fibromyalgia, and chronic fatigue syndrome.

Pay S. Calguneri M. Caliskaner Z. Dinc A. Apras S. Ertenli I. Kiraz S. Cobankara V. Evaluation of vascular injury with proinflammatory cytokines, thrombomodulin and fibronectin in patients with primary fibromyalgia. Nagoya Journal of Medical Science. 63(3-4):115-22, 2000. OBJECTIVE: Cold intolerance, cold induced peripheral vasospasm, Raynaud's phenomenon, livedo reticularis and immunoglobulin deposition in the skin are often encountered clinical and laboratory findings in patients with primary fibromyalgia (FM). These findings are suggestive of vascular injury. METHODS: Eighty patients (4 male, 76 female) with fulfilling primary FM criteria (FM (+) patient group), 60 patients (3 male, 57 female) with chronic musculoskeletal complaints but without FM (FM (-) patient control group) and 40 healthy volunteers (1 male, 39 female) without musculoskeletal complaints (healthy control group) were enrolled in this cross-sectional study. The study was carried out in two steps. In the first step, the clinical findings, routine laboratory tests, autoantibodies and radiological findings were investigated. The second step were consisted of the laboratory investigations of thrombomodulin and fibronectin as the mediators indicating vascular injury and proinflammatory cytokines in FM patients with Raynaud's phenomenon and/or livedo reticularis and in control groups. RESULTS: There were no differences between study and control groups with regard to laboratory, radiological and immunological (ANA, AntidsDNA, ENA, anticardiolipin IgG and IgM) results. No statistically significant differences were found in the levels of proinflammatory cytokines between FM (+) patient group and control groups (p > 0.05). Thrombomodulin was also shown statistically insignificant difference between FM (+) patient group and control groups (p > 0.05). However, fibronectin, another mediator of vascular injury, was higher in FM (+) patient group and the differences between FM (+) patients and each control groups were statistically significant (p < 0.0001). CONCLUSION: Our results were suggestive of the presence of a non-immunological vascular injury in FM patients with Raynaud's phenomenon and/or livedo reticularis.

Hader N. Rimon D. Kinarty A. Lahat N. Altered interleukin-2 secretion in patients with primary fibromyalgia syndrome. Arthritis & Rheumatism. 34(7):866-72, 1991. Interleukin-2 (IL-2) production was studied in T lymphocytes and isolated CD4+ T lymphocytes from 12 patients with primary fibromyalgia syndrome and 10 healthy volunteers. The dose and time kinetics of IL-2 production by concanavalin A-stimulated T cells and CD4+ T cells of fibromyalgia patients differed from findings in controls by 1) a need for a higher concentration of mitogen in order to achieve optimal IL-2 secretion, and 2) a delay in the peak time of optimal IL-2 secretion. Unlike normal IL-2 secretion, which was higher after removal of CD8+ T cells, the pattern and degree of IL-2 secretion by cells from fibromyalgia patients were not changed following removal of CD8+ T cells. Addition of calcium ionophore in assays using suboptimal concanavalin A concentrations did not correct the reduction in IL-2 secretion by fibromyalgia patient T cells, but addition of phorbol myristate acetate induced normal secretion of IL-2. These findings suggest that there is a defect in the IL-2 pathway, which is related to protein kinase C activation and does not involve impairment of Ca2+ elevation, in patients with fibromyalgia.

The biochemical origin of pain: the origin of all pain is inflammation and the inflammatory response. Part 2 of 3 - inflammatory profile of pain syndromes. Omoigui S. Medical Hypotheses. 69(6):1169-78, 2007. Every pain syndrome has an inflammatory profile consisting of the inflammatory mediators that are present in the pain syndrome. The inflammatory profile may have variations from one person to another and may have variations in the same person at different times. The key to treatment of Pain Syndromes is an understanding of their inflammatory profile. Pain syndromes may be treated medically or surgically. The goal should be inhibition or suppression of production of the inflammatory mediators and inhibition, suppression or modulation of neuronal afferent and efferent (motor) transmission. A successful outcome is one that results in less inflammation and thus less pain. We hereby briefly describe the inflammatory profile for several pain syndromes including arthritis, back pain, neck pain, fibromyalgia, interstitial cystitis, migraine, neuropathic pain, complex regional pain syndrome/reflex sympathetic dystrophy (CRPS/RSD), bursitis, shoulder pain and vulvodynia. These profiles are derived from basic science and clinical research performed in the past by numerous investigators and serve as a foundation to be built upon by other researchers and will be updated in the future by new technologies such as magnetic resonance spectroscopy. Our unifying theory or law of pain states: the origin of all pain is inflammation and the inflammatory response. The biochemical mediators of inflammation include cytokines, neuropeptides, growth factors and neurotransmitters. Irrespective of the type of pain whether it is acute or chronic pain, peripheral or central pain, nociceptive or neuropathic pain, the underlying origin is inflammation and the inflammatory response. Activation of pain receptors, transmission and modulation of pain signals, neuro plasticity and central sensitization are all one continuum of inflammation and the inflammatory response. Irrespective of the characteristic of the pain, whether it is sharp, dull, aching, burning, stabbing, numbing or tingling, all pain arise from inflammation and the inflammatory response. We are proposing a re-classification and treatment of pain syndromes based upon their inflammatory profile.

Psychophysical and neurochemical abnormalities of pain processing in fibromyalgia. [Review] [65 refs] Staud R. Spaeth M. Cns Spectrums. 13(3 Suppl 5):12-7, 2008. Fibromyalgia pain is frequent in the general population, but its pathogenesis is only partially understood. Patients with fibromyalgia lack consistent tissue abnormalities but display features of hyperalgesia (increased sensitivity to painful stimuli) and allodynia (lowered pain threshold). Many recent fibromyalgia studies have demonstrated central nervous system (CNS) pain processing abnormalities, including abnormal temporal summation of pain. In the CNS, persistent nociceptive input from peripheral tissues can lead to neuroplastic changes resulting in central sensitization and pain. This mechanism appears to represent a hallmark of fibromyalgia and many other chronic pain syndromes, including irritable bowel syndrome, temporomandibular disorder, migraine, and low back pain. Importantly, after central sensitization has been established, only minimal peripheral input is required for the maintenance of the chronic pain state. Additional factors, including pain-related negative affect and poor sleep have been shown to significantly contribute to clinical fibromyalgia pain. Better understanding of these mechanisms and their relationship to central sensitization and clinical pain will provide new approaches for the prevention and treatment of fibromyalgia and other chronic pain syndromes.

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