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Background: Chronic postoperative pain after total knee replacement (TKR) is a major clinical problem. It is still unclear if specific inflammatory mediators are associated with long‐term postoperative pain complications. The current exploratory study aimed to (1) evaluate a multiplex of inflammatory mediators 5 years after TKR surgery in patients with different degrees of postoperative pain intensities and (2) study any association of the markers with clinical pain intensity, cognitive and functional outcomes. Methods: Plasma samples were collected 5 years after TKR surgery from 76 knee patients (43 females; 33 males) and analysed for 44 inflammatory markers. Pain (using visual analogue scale, VAS), the pain catastrophizing scale (PCS) and the Oxford knee score (OKS) were evaluated. Patients were categorized as high or low groups based on VAS, PCS and OKS scores. Associations between inflammatory markers, VAS, PCS and OKS were analysed and the marker expressions were compared between groups. Results: Pearson's correlations found 12 biomarkers associated with VAS (p < 0.05), 4 biomarkers with PCS and 3 biomarkers with OKS (p < 0.05). Four markers were altered in patients suffering from high compared to low chronic postoperative pain, three markers were altered in high compared to low catastrophizers and three markers were altered in patients with poor functional scores (p < 0.05). Conclusions: The present exploratory study suggests that low‐grade inflammation might be present in a subset of patients with high pain, high catastrophizing and low function 5 years after TKR. These exploratory results provide insights into some of the long‐term postoperative complications after TKR surgery. Significance Statement: This exploratory study evaluated a subset of inflammatory markers and the association to clinical pain intensity, knee function and pain catastrophizing in patients 5 years after total knee replacement surgery. Our results provide insights into the understanding of the underlying mechanisms that may drive the long experience of pain after TKR surgery. [ABSTRACT FROM AUTHOR]

Studies suggest that a range of pain mechanisms, such as poor quality of sleep, perceived stress, pain catastrophizing or pain sensitivity, are likely to enhance clinical pain. Animal studies suggest that these pain mechanisms can be modulated by increasing physical activity, but human data are needed to support this hypothesis. This exploratory study aimed to investigate the changes in pain mechanisms after a simple self-directed walking program of 8-weeks. Additionally, this exploratory study investigated the interaction between changes over time in assessments of poor quality of sleep, perceived stress, pain catastrophizing or pain sensitivity and how these changes interacted with each other. This prospective cohort study included 30 healthy subjects who were assessed at baseline and 4- and 8-weeks after initiating the walking program (30 min walking/day for 8 weeks). Self-report outcomes included: Pain Catastrophizing Scale (PCS), the Perceived Stress Scale (PSS) and Pittsburgh Sleep Quality Index. Pressure pain thresholds, temporal summation of pain and conditioned pain modulation (CPM) were assessed using cuff algometry. Twenty-four subjects completed all the visits (age: 42.2, SD: 14.9, 16 females). PCS and PSS significantly decreased at the 8-week's visit compared to baseline (p<0.05). No significant differences were seen for an improvement in quality of sleep (p=0.071) and pain sensitivity (p>0.075) when comparing the 8-week's visit to the baseline visit. Changes in pain mechanisms comparing baseline and 8-weeks data were calculated and regression analyses found that an improvement in PCS was associated with an improvement in CPM (R2=0.197, p=0.017) and that a higher adherence to the walking program was associated with a larger improvement in PCS (R2=0.216, p=0.013). The current exploratory study indicates that a simple self-directed walking program of 8-weeks can improve pain catastrophizing thoughts, perceived stress. Higher adherence to the walking program were associated with an improvement in pain catastrophizing and an improvement in pain catastrophizing was associated with an increase in conditioned pain modulation. [ABSTRACT FROM AUTHOR]

Background: A subset of osteoarthritis patients will experience chronic postoperative pain after total knee arthroplasty (TKA), but the source of pain is unclear. The aim of this exploratory study was to assess patients with and without postoperative pain after TKA using magnetic resonance imaging (MRI), quantitative sensory testing (QST), clinical assessment of pain and assessments of catastrophizing thoughts.Methods: Forty-six patients completed the 6-month postoperative assessment. MRI findings were scored according to the MRI Osteoarthritis Knee Score recommendation for Hoffa synovitis, effusion size and bone marrow lesions. QST included assessment of pressure pain thresholds (PPTs), temporal summation of pain (TSP) and conditioned pain modulation (CPM). Pain catastrophizing was assessed using the Pain Catastrophizing Scale (PCS). Clinical pain assessment was conducted using a visual analogue scale (VAS, 0-10 cm), and groups of moderate-to-severe (VAS > 3) and none-to-mild postoperative pain (VAS ≤ 3) were identified.Results: Patients with moderate-to-severe postoperative pain (N = 15) demonstrated higher grades of Hoffa synovitis (p < 0.001) and effusion size (p < 0.001), lower PPTs (p = 0.039), higher TSP (p = 0.001) and lower CPM (p = 0.014) when compared with patients with none-to-mild postoperative pain (N = 31). No significant difference was found in PCS scores between the two groups. Multiple linear regression models found synovitis (p = 0.036), effusion size (p = 0.003), TSP (p = 0.013) and PCS (p < 0.001) as independent parameters contributing to the postoperative pain intensity.Conclusion: These exploratory findings could indicate that chronic postoperative pain after TKA is a combination of joint-related synovitis and effusion, sensitization of central pain mechanisms and potentially pain catastrophizing thoughts, but larger studies are needed to confirm this.Significance: The end-stage treatment of knee osteoarthritis is total knee arthroplasty. Some patients experience chronic postoperative pain after total knee arthroplasty, but the mechanism for chronic postoperative pain is widely unknown. The current study indicates that higher levels postoperative of synovitis and effusion, higher temporal summation of pain and higher pain catastrophizing scores could be associated with higher chronic postoperative pain. [ABSTRACT FROM AUTHOR]

Background: MicroRNAs (miRNAs) can modulate several biological systems, including the pain system. This study aimed to evaluate the temporal expression of circulating miRNAs in the plasma of healthy volunteers as a marker for epigenetic changes before and after an acute, experimental, pain provocation by intramuscular hypertonic saline injection. Methods: Twenty volunteers were randomly allocated into two groups and received either hypertonic (pain) or isotonic (control) saline injection in the first dorsal interosseous muscle of their dominant hand. Pain intensity was continuously recorded for 20 minutes after injection on a VAS scale from 0 to 100 (0 indicates no pain and 100 the worst imaginable pain). Blood samples were taken at baseline, 30 minutes, 3 hours, and 24 hours post‐injection, and plasma was separated. MiRNA extracts were used for RNA sequencing with the Illumina NextSeq platform. MiRNA transcripts were compared between the pain and the no‐pain, control group at every time point. Significant differences were considered when folds were >2 and the False Discovery Rate was p < 0.05. Results: After 30 minutes, 4 miRNAs were significantly altered in the pain group compared to controls, which increased to 24 after 3 hours and to 42 after 24 hours from baseline (p < 0.0001). Two miRNAs were consistently upregulated throughout the experiment. Enrichment analysis showed significant miRNAs involved in brain perception of pain, brain signalling and response to stimuli. Conclusions: This exploratory study is the first to report on the temporal expression of circulating miRNAs after an acute, human experimental muscle pain model. Significance: This exploratory study evaluated the temporal profile of circulating miRNAs in the plasma of healthy subjects after acute experimental pain. Several miRNAs were altered in subjects at the times of follow‐up after the acute pain model when compared to controls. MiRNAs previously associated with pain processes were altered in the pain group. Our results, by showing the fast and prolonged modifications of miRNA elicited by the acute experimental pain model, add new perspectives to the topic of epigenetics and pain. [ABSTRACT FROM AUTHOR]

This article, published in the British Journal of Pain, explores the interaction between psychological factors and conditioned pain modulation (CPM) in patients with chronic spinal pain. The authors conducted a systematic review and meta-analysis of seven studies, finding that pain catastrophizing was associated with CPM, but anxiety, depression, and fear avoidance were not. However, the overall quality of the included studies was low, and more research is needed in this area. The authors suggest that future studies should focus on the interaction between pain sensitivity and psychological factors. [Extracted from the article]

Summary Sleep disturbances exacerbate chronic pain, increase psychological load, and increase inflammation. Delayed onset muscle soreness (DOMS) mimics aspects of chronic pain, predominantly affecting peripheral pain mechanisms, while experimental sleep provocations have been shown to impact central pain mechanisms. This study aimed to combine a DOMS model with total sleep deprivation (TSD) to create a novel model affecting both peripheral and central pain mechanisms. A total of 30 healthy participants attended two sessions (baseline and follow‐up) separated by 24 h of TSD and a home rating after 48 h. Assessments of interleukin 6 (IL‐6) levels, sleep quality, pain catastrophising, affect, and symptoms of depression and anxiety were included in the baseline and follow‐up sessions. Additionally, pressure pain and tolerance thresholds, temporal summation, and conditioned pain modulation (CPM) were assessed using cuff‐pressure algometry in the baseline and follow‐up sessions. DOMS was induced with eccentric calf raises during the baseline session followed by 24 h of TSD. At follow‐up pain tolerance (p = 0.012) was significantly reduced, and CPM (p = 0.036) was significantly impaired compared to baseline. Psychological changes included decreases in pain catastrophising (p = 0.027), positive affect (p < 0.001), negative affect (p = 0.003), and anxiety (p = 0.012). Explorative regression models predicted 58% and 68% of DOMS pain intensity after 24 and 48 h, respectively, based on baseline body mass index, pain thresholds, psychological measures, and IL‐6 (p < 0.01). Combining DOMS with 1 night of TSD induced pain hypersensitivity, impaired CPM, and altered psychological states. A combination of baseline inflammation, psychological measures, and pain sensitivity significantly predicted DOMS pain intensity after 24 and 48 h. [ABSTRACT FROM AUTHOR]

Background: Pain profiles (e.g. pro- and anti-nociceptive) can be developed using quantitative sensory testing (QST) but substantial variability exists. This study describes the variability in temporal summation of pain (TSP) and conditioned pain modulation (CPM) in chronic musculoskeletal pain patients, proposes cut-off values, and explores the association with clinical pain intensity., Methods: This is a secondary analysis in which TSP and CPM were assessed using cuff algometry in pain-free subjects (n = 69), and patients with chronic low back pain (cLBP, n = 267), osteoarthritis (n = 134), and fibromyalgia (n = 101). Using TSP and CPM from the pain-free subjects as a reference, four distinct pain profiles TSP (low/high) and CPM (low/high) were created, and differences in clinical pain between pain profiles were explored., Results: Individual data revealed large inter-person variability. High TSP and low CPM were found in fibromyalgia (p < 0.01) and osteoarthritis (p < 0.01) but not cLBP when compared to pain-free subjects. The proportion of patients classified into the distinct pain profiles was significantly different (p < 0.001) with the largest proportion in the high TSP and low CPM group in fibromyalgia (52.5%) and osteoarthritis (41.4%). Clinical pain was not significantly different comparing the pain profiles, and no significant correlations were observed between clinical pain and TSP or CPM., Conclusion: These results demonstrated substantial inter-person variability in TSP and CPM in patients with different chronic pain conditions and pain-free subjects. The proportion of patients with a pro-nociceptive profile appears larger in fibromyalgia and osteoarthritis, but we found no association to clinical pain., Significant Statement: This analysis shows that there is variability when assessing TSP and CPM in both pain-free subjects and patients with chronic pain. A cut-off for determining when a person is pain-sensitive is proposed, and data based on this cut-off approach suggest that significantly more patients with osteoarthritis and fibromyalgia are pain-sensitive (i.e. higher TSP and lower CPM) compared to pain-free subjects. This analysis does not find an association between pain sensitivity and clinical pain., (© 2024 The Author(s). European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation ‐ EFIC ®.)

Abstract: Chronic postoperative pain is present in approximately 20% of patients undergoing total knee arthroplasty. Studies indicate that pain mechanisms are associated with development and maintenance of chronic postoperative pain. The current study assessed pain sensitivity, inflammation, microRNAs, and psychological factors and combined these in a network to describe chronic postoperative pain. This study involved 75 patients with and without chronic postoperative pain after total knee arthroplasty. Clinical pain intensity, Oxford Knee Score, and pain catastrophizing were assessed as clinical parameters. Quantitative sensory testing was assessed to evaluate pain sensitivity and microRNAs, and inflammatory markers were likewise analyzed. Supervised multivariate data analysis with "Data Integration Analysis for Biomarker Discovery" using Latent cOmponents (DIABLO) was used to describe the chronic postoperative pain intensity. Two DIABLO models were constructed by dividing the patients into 3 groups or 2 defined by clinical pain intensities. Data Integration Analysis for Biomarker discovery using Latent cOmponents model explained chronic postoperative pain and identified factors involved in pain mechanistic networks among assessments included in the analysis. Developing models of 3 or 2 patient groups using the assessments and the networks could explain 81% and 69% of the variability in clinical postoperative pain intensity. The reduction of the number of parameters stabilized the models and reduced the explanatory value to 69% and 51%. This is the first study to use the DIABLO model for chronic postoperative pain and to demonstrate how different pain mechanisms form a pain mechanistic network. The complex model explained 81% of the variability of clinical pain intensity, whereas the less complex model explained 51% of the variability of clinical pain intensity., (Copyright © 2024 International Association for the Study of Pain.)

Abstract: Total knee arthroplasty (TKA) is the end-stage treatment of knee osteoarthritis (OA), and approximately 20% of patients experience chronic postoperative pain. Studies indicate that inflammatory biomarkers might be associated with pain in OA and potentially linked to the development of chronic postoperative pain after TKA. This study aimed to (1) evaluate preoperative serum levels of inflammatory biomarkers in patients with OA and healthy control subjects, (2) investigate preoperative differences of inflammatory biomarker profiles in subgroups of patients, and (3) compare subgroups of patients with and without postoperative pain 12 months after surgery. Serum samples from patients with OA scheduled for TKA (n = 127) and healthy participants (n = 39) were analyzed. Patients completed the Knee-injury-and-Osteoarthritis-Outcome-Score (KOOS) questionnaire and rated their clinical pain intensity using a visual analog scale (VAS) before and 12 months after TKA. Hierarchical cluster analysis and Orthogonal Partial Least Squares Discriminant Analysis were used to compare groups (patients vs control subjects) and to identify subgroups of patients in relation to postoperative outcomes. Difference in preoperative and postoperative VAS and KOOS scores were compared across subgroups. Twelve inflammatory markers were differentially expressed in patients when compared with control subjects. Cluster analysis identified 2 subgroups of patients with 23 proteins being significantly different ( P < 0.01). The 12-months postoperative VAS and KOOS scores were significantly different between subgroups of patients ( P < 0.05). This study identified differences in specific inflammatory biomarker profiles when comparing patients with OA and control subjects. Cluster analysis identified 2 subgroups of patients with OA, with one subgroup demonstrating comparatively worse 12-month postoperative pain intensity and function scores., (Copyright © 2023 International Association for the Study of Pain.)