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characterization of its mechanisms as essentially idiopathic or even psychogenic should be seen as definitively outdated.

Animal models suggest that chemokines are important mediators in the pathophysiology of neuropathic pain. Indeed, these substances have been called “gliotransmitters,” a term that illustrates the close interplay between glial cells and neurons in the context of neuroinflammation and pain. However, evidence in humans is scarce. The aim of the study was to determine a comprehensive cerebrospinal fluid (CSF) inflammatory profile of patients with neuropathic pain. Our hypothesis was that we would thereby find indications of a postulated on-going process of central neuroinflammation. Samples of CSF were collected from 2 cohorts of patients with neuropathic pain (n = 11 and n = 16, respectively) and healthy control subjects (n = 11). The samples were analyzed with a multiplex proximity extension assay in which 92 inflammation-related proteins were measured simultaneously (Proseek Multiplex Inflammation I; Olink Bioscience, Uppsala, Sweden). Univariate testing with control of false discovery rate, as well as orthogonal partial least squares discriminant analysis, were used for statistical analyses. Levels of chemokines CXCL6, CXCL10, CCL8, CCL11, CCL23 in CSF, as well as protein LAPTGF-beta-1, were significantly higher in both neuropathic pain cohorts compared with healthy controls, pointing to neuroinflammation in patients. These 6 proteins were also major results in a recent similar study in patients with fibromyalgia. The findings need to be confirmed in larger cohorts, and the question of causality remains to be settled. Because it has been suggested that prevalent comorbidities to chronic pain (eg, depression, anxiety, poor sleep, and tiredness) also are associated with neuroinflammation, it will be important to determine whether neuroinflammation is a common mediator.

To subgroup chronic pain patients using psychometric data and regress the variables most responsible for subgroup discrimination. Cross-sectional, registry-based study. Chronic pain patients assessed at a multidisciplinary pain centre between 2008 and 2015. Data 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. Four 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. The 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.

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.

This cross-sectional study investigates the plasma inflammatory profile of chronic widespread pain (CWP) patients compared to healthy controls (CON). Rather than analyzing a relatively few substances at a time, we used a new multiplex proximity extension assay (PEA) panel that enabled the simultaneous analysis of 92 inflammation-related proteins, mainly cytokines and chemokines. Seventeen women with CWP and 21 female CON participated and a venous blood sample was drawn from all subjects. Pain intensity and pain thresholds for pressure, heat, and cold were registered. A PEA panel (92 proteins) was used to analyze the blood samples. Multivariate data analysis by projection was used in the statistical analyses. Eleven proteins significantly differentiated the CON and CWP subjects (R2 = 0.58, Q2 = 0.37, analysis of variance of cross-validated predictive residuals P = 0.006). It was not possible to significantly regress pain thresholds within each group (CON or CWP). Positive significant correlations existed between several proteins and pain intensities in CWP, but the model reliability of the regression was poor. CWP was associated with systemic low-grade inflammation. Larger studies are needed to confirm the results and to investigate which alterations are condition-specific and which are common across chronic pain conditions. The presence of inflammation could promote the spreading of pain, a hallmark sign of CWP. As it has been suggested that prevalent comorbidities to pain (e.g., depression and anxiety, poor sleep, and tiredness) also are associated with inflammation, it will be important to determine whether inflammation may be a common mediator.

Background: Topical anaesthesia is important to optimize pain control during dental injection. Our aim was to describe a new simple method for topical anaesthesia of oral mucosa and to compare the effectiveness of ice and lidocaine 5% gel for topical anaesthesia of oral mucosa. Methods: A total of 40 patients aged 10.7–19.5 years were included. The side and method of application were both randomized. Heart rate was recorded, and discomfort and pain were evaluated with a visual analogue scale (VAS). A paired t-test was used to compare mean values, a chi² test was used to compare proportions, and a Pearson correlation test was used to examine correlations between variables. Results: When ice was used, buccal injection VAS pain was rated lower (p = 0.044), and VAS discomfort was rated higher (p = 0.001), in comparison to when lidocaine 5% gel was used. There was no significant difference in relative heart rate change between ice and lidocaine 5% gel at either needle stick or injection. Lidocaine 5% gel produced a relative heart rate reduction after palatal injection (0.99 ± 0.06) while buccal injection produced an increased relative heart rate (1.02 ± 0.08) (p = 0.010). Unpleasant taste was more frequently reported when lidocaine 5% gel was used (p = 0.025). An application time of 1 min was sufficient for both ice and lidocaine 5% gel to achieve pain reduction from needle stick in buccal mucosa. Conclusion: The cheap and readily available described method using ice for topical anaesthesia of oral mucosa before dental injection is an effective alternative to lidocaine 5% gel. Trial registration: The European Union Drug Regulating Authorities Clinical Trials Database EudraCT201300530531. Date of registration: February 10th, 2014.