In addition to central hyperexcitability and impaired top–down modulation, chronic inflammation probably plays a role in the pathophysiology of fibromyalgia (FM). Indeed, on the basis of both animal experiments and human studies involving the analysis of cytokines and other inflammation-related proteins in different body fluids, neuroinflammatory mechanisms are considered to be central to the pathophysiology of many chronic pain conditions. However, concerning FM, previous human plasma/serum and/or cerebrospinal fluid (CSF) cytokine studies have looked only at a few predetermined cytokine candidates. Instead of analyzing only a few substances at a time, we used a new multiplex protein panel enabling simultaneous analysis of 92 inflammation-related proteins. Hence, we investigated the CSF and plasma inflammatory profiles of 40 FM patients compared with CSF from healthy controls (n=10) and plasma from blood donor controls (n=46). Using multivariate data analysis by projection, we found evidence of both neuroinflammation (as assessed in CSF) and chronic systemic inflammation (as assessed in plasma). Two groups of proteins (one for CSF and one for plasma) highly discriminating between patients and controls are presented. Notably, we found high levels of CSF chemokine CX3CL1 (also known as fractalkine). In addition, previous findings concerning IL-8 in FM were replicated, in both CSF and plasma. This is the first time that such an extensive inflammatory profile has been described for FM patients. Hence, FM seems to be characterized by objective biochemical alterations, and the lingering characterization of its mechanisms as essentially idiopathic or even psychogenic should be seen as definitively outdated.

Pain medicine lacks objective biomarkers to guide diagnosis and treatment. Combining two-dimensional gel proteomics with multivariate data analysis by projection, we exploratively analyzed the cerebrospinal fluid of eleven patients with severe peripheral neuropathic pain due to trauma and/or surgery refractory to conventional treatment and eleven healthy controls. Using orthogonal partial least squares discriminant analysis, we identified a panel of 36 proteins highly discriminating between the two groups. Due to a possible confounding effect of age, a new model with age as outcome variable was computed for patients (n=11), and four out of 36 protein spots were excluded due to a probable influence of age. Of the 32 remaining proteins, the following seven had the highest discriminatory power between the two groups: an isoform of angiotensinogen (upregulated in patients), two isoforms of alpha-1-antitrypsin (downregulated in patients), three isoforms of haptoglobin (upregulated in patients), and one isoform of pigment epithelium-derived factor (downregulated in patients). It has recently been hypothesized that the renin–angiotensin system may play a role in the pathophysiology of neuropathic pain, and a clinical trial of an angiotensin II receptor antagonist was recently published. It is noteworthy that when searching for neuropathic pain biomarkers with a purely explorative methodology, it was indeed a renin–angiotensin system protein that had the highest discriminatory power between patients and controls in the present study. The results from this hypothesis-generating pilot study have to be confirmed in larger, hypothesis-driven studies with age-matched controls, but the present study illustrates the fruitfulness of combining proteomics with multivariate data analysis in hypothesis-generating pain biomarker studies in humans.

LAY ABSTRACTPatients with fibromyalgia have treatment-resistant chronic pain. More research is needed in order to understand how and why fibromyalgia develops. Neurotrophins, such as nerve growth factor and brain-derived neurotrophic factor, are involved in peripheral and central nervous system development of pain and hyperalgesia, but few studies have examined circulating nerve growth factor and brain-derived neurotrophic factor in fibromyalgia or have investigated whether exercise interventions affect the levels of these peptides. This study compared blood levels of nerve growth factor and brain-derived neurotrophic factor in fibromyalgia with those in healthy controls, and investigated the effect of exercise on these levels. Brain-derived neurotrophic factor levels were higher and levels of nerve growth factor were lower in fibromyalgia, compared with healthy controls. Clinical improvements were achieved following the exercise intervention, but the levels of brain-derived neurotrophic factor and nerve growth factor were not normalized.Background: The pathophysiology of fibromyalgia includes central and peripheral factors. Neurotro phins, such as nerve growth factor and brainderived neurotrophic factor, are involved in peripheral and central nervous system development of pain and hy peralgesia. Few studies have examined circulating nerve growth factor and brainderived neurotrophic factor in fibromyalgia or have investigated whether exercise interventions affect the levels of these pep tides. Objectives: To compare plasma levels of nerve growth factor and brainderived neurotrophic factor in fibromyalgia and in healthy controls, to investiga te correlations between levels of nerve growth fac tor, brainderived neurotrophic factor, and cytokines and clinical variables, and to investigate the effect of exercise on these levels. Subjects and methods: A total of 75 women with fibromyalgia participated in blood tests at baseline and after the 15week intervention, and 25 healthy controls participated at baseline. Patients were ran domized to a 15week progressive resistance exer cise intervention or a relaxation intervention. Results: Brainderived neurotrophic factor level was significantly higher (p < 0.001) and nerve growth factor level was significantly lower (p < 0.001) in fi bromyalgia than in healthy controls. Neither resis tance exercise nor relaxation interventions affec ted the levels of brainderived neurotrophic factor or nerve growth factor. No significant correlations were found between brainderived neurotrophic fac tor or nerve growth factor plasma levels in fibromy algia and cytokine levels or clinical variables. Conclusion: Changes in circulating nerve growth factor and brainderived neurotrophic factor levels may affect nociception/pain in fibromyalgia. Clinical improvements were achieved following the exercise intervention, but the levels of brainderived neuro trophic factor and nerve growth factor were not nor malized.

According to animal models, neuroinflammation is a major feature of neuropathic pain. The present findings confirm that this hypothesis is of relevance to humans.

ObjectiveTo subgroup chronic pain patients using psychometric data and regress the variables most responsible for subgroup discrimination.DesignCross-sectional, registry-based study.Setting and subjectsChronic pain patients assessed at a multidisciplinary pain centre between 2008 and 2015.MethodsData from the Swedish quality registry for pain rehabilitation (SQRP) were retrieved and analysed by principal component analysis, hierarchical clustering analysis, and partial least squares–discriminant analysis.ResultsFour subgroups were identified. Group 1 was characterized by low “psychological strain”, the best relative situation concerning pain characteristics (intensity and spreading), the lowest frequency of fibromyalgia, as well as by a slightly older age. Group 2 was characterized by high “psychological strain” and by the most negative situation with respect to pain characteristics (intensity and spreading). Group 3 was characterized by high “social distress”, the longest pain durations, and a statistically higher frequency of females. The frequency of three neuropathic pain conditions was generally lower in this group. Group 4 was characterized by high psychological strain, low “social distress”, and high pain intensity.ConclusionsThe identification of these four clusters of chronic pain patients could be useful for the development of personalized rehabilitation programs. For example, the identification of a subgroup characterized mainly by high perceived “social distress” raises the question of how to best design interventions for such patients. Differentiating between clinically important subgroups and comparing how these subgroups respond to interventions is arguably an important area for further research.