Psychophysical changes after total sleep deprivation and experimental muscle pain.

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.

Intra-articular injection of gold micro-particles with hyaluronic acid for painful knee osteoarthritis.

BACKGROUND: Recently, in an open pilot study, we found up to two years, a potential pain-relieving effect of intra-articular gold micro-particles using the patient's synovial fluid for patients with knee osteoarthritis (KOA). During the study the excluded group of patients, due to multisite pain, co-morbidities, and other exclusion criteria., received intra-articular gold micro-particles using hyaluronic acid,. We aimed to identify if pre-treatment characteristics influence the global outcome two years after intra-articular treatment for painful KOA with gold microparticles using hyaluronic acid. METHODS: Using hyaluronic acid as the carrier, 136 patients with KOA received intraarticular injections with 20 mg gold microparticles (72.000 particles, 20-40 µm in diameter). In the analysis, we included the Global Rating of Change Scale, Pain Detect Questionnaire (PDQ), Body Mass Index (BMI), and Kellgren & Lawrence score at the inclusion, Western Ontario, and McMaster Universities Osteoarthritis Index (WOMAC) sub-scores for pain, stiffness, and function at inclusion and two years. RESULTS: On the Global Rating Change Scale, 69.1% of patients reported a positive effect, 28.7% no effect, and 2.2% worse. PDQ and the three WOMAC subscores all improved at two years of follow-up. PDQ ≥ 13 (P = 0.028), BMI (P = 0.022) and Kellgren & Lawrence grade 4 (P = 0.028) at inclusion reduced the effect with a minor odds ratio compared to the baseline effect of treatment (P = 0.025). WOMAC subscores at inclusion did not influence the outcome (P > 0.5). CONCLUSIONS: Severe osteoarthritis, obesity, and neuropathic pain, reduced the effect of intra-articular gold microparticles for knee OA. TRIAL REGISTRATION: The study followed the principles of the Declaration of Helsinki and was approved by the local ethics committee of the North Denmark Region by 27/07/2016 (N-20,160,045). The regional data protection agency approved the project by 06/07/2016 (2008-58-0028, ID 2016 - 116) and registered in ClinicalTrial.Gov by 04/01/2018 (NCT03389906).

CXCL13 predicts long-term radiographic status in early rheumatoid arthritis.

OBJECTIVES: Identification of RA patients at a high risk of joint destruction remains challenging. The C-X-C motif chemokine 13 (CXCL13) has previously been suggested as a marker of disease activity in RA. Here, we investigate the potential of plasma CXCL13 as a marker of long-term radiographic status and progression. METHODS: CXCL13 was measured in plasma from treatment-naïve RA patients (n = 158) with an 11-year follow-up. At baseline, clinical and biochemical DASs were obtained; among these CRP, ESR, DAS in 28 joints with CRP (DAS28CRP), number of swollen joints (SJC28) and radiographic status, evaluated by total Sharp score (TSS). Age- and gender-matched healthy controls (HCs) were included. RESULTS: CXCL13 was significantly increased at baseline and decreased during treatment; however, it was not reduced to the level in HCs. At baseline, CXCL13 was associated with both CRP and ESR, but not with other markers of disease activity. Baseline CXCL13 was correlated with both TSS and radiographic progression (ΔTSS) at 11 years. With an 89% probability, levels of CXCL13 above 85 pg/ml predicted the risk of a TSS of 5 or above, after 11 years of treatment. Compared with CRP, DAS28CRP, SJC28 and ACPA status, CXCL13 was superior in predicting 11-year joint destruction. CONCLUSION: In early RA, one single measurement of plasma CXCL13 at baseline is superior to currently used clinical and serological disease markers in the prediction of long-term radiographic status and progression.

Nasal vestibule squamous cell carcinoma: a population-based cohort study from DAHANCA.

BACKGROUND: Cancer of the nasal vestibule is a rare type of malignancy dominated by squamous cell carcinoma (SCC), and with poor survival. The treatment is either radiotherapy, surgery or a combination of both. Previous studies have shown a 5-year disease-specific survival of 74% and overall survival (OS) of 50%.Our objective was to describe the consecutive cohort of patients diagnosed with SCC of the nasal vestibule in Denmark from 2008 until 2018 and evaluate prognostic factors and treatment outcome using locoregional failure (LRF), disease-specific mortality (DSM), and OS as endpoints. METHODS: All patients diagnosed with SCC of the nasal vestibule from 2008 until 2018 were identified in the nationwide clinical database, DAHANCA and were followed for LRF and death (DSM and OS) until March 2021. OS was analysed using Kaplan-Meier estimator, and cumulative incidence of LRF and DSM were analysed using the Aalen-Johansen estimator. Analysis of prognostic factors was performed using Cox proportional hazard models. RESULTS: A total of 162 patients were identified. The median age was 71 years and 54% were male. Disease stage at the time of diagnosis were stage I (70%), II (17%), III (2%) and IV (11%). Curatively intended treatment was performed in 146 patients (90%), of which treatment failure occurred in 42 patients (29%). Most failures occurred at the primary tumour site (64%). Cancer Patient Pathways recommended time to treatment was fulfilled in 71% of patients. The 5-year OS and DSM in patients treated with curative intent were 65% and 11%, respectively. Stage was a significant independent prognostic factor. No difference in LRF, DSM or OS were shown between the applied treatments. CONCLUSIONS: Stage is the main independent prognostic factor, and failure most commonly appear at the primary tumour site.

The Modulatory Effect of Quantitative Sensory Testing in Shoulder Pain: A Systematic Review and Meta-Analysis.

BACKGROUND: The underlying mechanisms for shoulder pain (SP) are still widely unknown. Previous reviews have reported signs of altered pain processing in SP measured with quantitative sensory testing (QST). Evidence suggests that QST might hold predictive value for SP after an intervention, yet it is not known whether QST profiles can be modulated in response to different treatments. Therefore, this systematic review and meta-analysis aimed to assess whether QST parameters can be modified by interventions for patients with SP. METHODS: Three databases were searched to identify eligible studies. Eligible studies had a prospective design, with at least one QST variable as an outcome in conjunction with an intervention measured before and after the intervention. Studies that involved SP caused by spinal or brain injury and studies looking at combined chronic neck pain and SP were excluded. RESULTS: Nineteen studies investigating SP were eligible for inclusion in this review. Pressure pain threshold (PPT) was the most frequently used QST parameter to investigate local and widespread hyperalgesia. A meta-analysis was performed on data from 10 studies with a total of 16 interventions. Results demonstrated an overall acute effect (<24 hours after intervention) of interventions in favor of local decreased pain sensitivity and remote decreased pain sensitivity when PPTs before and after interventions were compared. CONCLUSIONS: This study demonstrates that interventions such as exercise and manual therapy can modulate PPTs acutely, both locally and remotely, in patients with SP. Further research investigating the acute and long-term modulatory ability of these interventions on other QST parameters is needed in patients with SP.

Is pain associated with premature mortality in patients with psoriatic arthritis? A nested case-control study using the DANBIO Register.

OBJECTIVES: It has been hypothesized that the presence of chronic pain causes excess mortality. Since chronic pain is prevalent among patients with PsA this potential association should be explored. We aimed to investigate whether higher cumulative pain intensity is associated with an excess mortality risk in patients with PsA. METHODS: A nested case-control study using data from the nationwide DANBIO Register (Danish Database for Biological Therapies in Rheumatology) Register and Danish healthcare registers. Cases were patients who died and corresponding to the date of death, matched on sex, year of birth and calendar period at the time of death with up to five controls. Exposure of interest was mean pain intensity reported during the time followed in routine rheumatology practice. Pain intensity was measured using a visual analogue scale from 0 to 100 and conditional logistic regression was used to calculate odds of mortality per 5 unit increase in pain while adjusting for confounders. RESULTS: The cohort consisted of 8019 patients. A total of 276 cases were identified and matched with 1187 controls. Higher mean pain intensity was associated with increased odds of mortality [odds ratio 1.06 (95% CI 1.02, 1.10)] in the crude model, but there was no association [odds ratio 0.99 (95% CI 0.95, 1.03)] when adjusting for additional confounders. Factors shown to increase the odds of mortality were recent glucocorticoid use, concomitant chronic obstructive pulmonary disease, diabetes mellitus, cancer and cardiovascular disease. CONCLUSION: These results indicate that experienced pain in itself is not associated with premature mortality in patients with PsA. However, recent glucocorticoid use and concurrent comorbidities were.

Sinonasal cancer in Denmark 2008-2015: a population-based phase-4 cohort study from DAHANCA.

BACKGROUND: Sinonasal cancer is considered a rare disease with poor survival. Its treatment has changed profoundly in recent years, primarily following the introduction of intensity-modulated radiation therapy (IMRT) and minimally invasive endoscopic surgery. Danish national guidelines on treatment of patients diagnosed with sinonasal carcinoma were introduced in 2007. The aim of this phase-4 study was to assess the effect of the implementation of guidelines by describing treatment outcomes in a consecutive nationwide cohort. METHODS: All patients diagnosed with sinonasal carcinoma in Denmark from 2008 to 2015 were identified in the nationwide clinical database, DAHANCA, and were followed until May 2020. Overall survival (OS) was analysed using Kaplan-Meier estimator. Cumulative incidence of locoregional failure (LRF) and disease-specific mortality (DSM) were analysed using the Aalen-Johansen estimator. Competing risks were death from other causes (DSM) and distant failure and death (LRF). Analysis of prognostic factors was performed using Cox proportional hazard analysis. Start of follow-up was time of diagnosis. The results are presented as estimates with 95% confidence intervals (95% CIs). RESULTS: A total of 331 patients were identified. Curatively intended treatment was performed in 264 patients (80%). Non-compliance with treatment guidelines was registered in 24 patients (9%). Non-compliance was associated with LRF (hazard ratio [HR], 2.0 [95% CI: 1.1-3.5]). Among patients qualified for curative treatment, failure occurred in 109 patients (41%), primarily at the primary tumour site (81%). Anatomical tumour site and disease stage were independent prognostic factors. The 5-year OS was 56% in patients treated with curative intent, and a combined treatment strategy showed reduced LRF (HR, 0.53 [95% CI: 0.30-0.92]) in a multivariate analysis. CONCLUSIONS: Guideline compliance and a combined treatment approach reduced the incidence of LRF and thereby increased OS. Our results confirm those of international studies. Treatment of sinonasal carcinoma remains a challenge that requires multidisciplinary team coordination.

Bedside clinical tests to assess sensitization in office workers with chronic neck pain.

OBJECTIVE: This study aimed to assess pain sensitization in individual office workers with chronic neck pain through simple bedside quantitative sensory tests (QST) and to associate the findings with pain intensity and pain catastrophizing. METHODS: One hundred-and-four office workers with chronic neck pain were assessed using pressure pain threshold (PPT) considering pain sensitive if PPTs were lower than 155 kPa in the upper trapezius and 245 kPa in the tibialis anterior. Pain sensitive to temporal summation of pain (TSP) was considered if there was a difference of two points in the visual analogue scale (VAS) comparing the first and last stimulus. Pain sensitive was considered to conditioned pain modulation (CPM) if the CPM-effect was less than -7.5%. Pain intensity and catastrophizing were measured using VAS and with the Pain Catastrophizing Scale. RESULTS: There was at least one pain sensitive QST finding in 66 office workers (63.5%). TSP findings were the most common (48.1%), followed by PPT's (31.7%) and CPM (20.2%). Based on the QST findings, office workers were divided based on the number of individual QST findings, and higher pain intensity and pain catastrophizing scores were found in office workers with one (N = 38, P < 0.05) or two (N = 28, P < 0.05) compared with office workers with no QST findings (N = 38). CONCLUSION: This study demonstrated that most office workers with chronic neck pain exhibit either widespread pressure hyperalgesia, facilitated TSP or impaired CPM, indicating pain sensitization within the central nervous system. This was associated with increased clinical pain and pain catastrophizing rumination scores.

The Combination of Preoperative Pain, Conditioned Pain Modulation, and Pain Catastrophizing Predicts Postoperative Pain 12 Months After Total Knee Arthroplasty.

OBJECTIVES: Approximately 20% of knee osteoarthritis patients undergoing total knee arthroplasty (TKA) report chronic postoperative pain. Studies suggest that preoperative variables such as impaired descending pain control, catastrophizing, function, and neuropathic pain-like symptoms may predict postoperative pain 12 months after TKA, but the combined prediction value of these factors has not been tested. The current prospective cohort study aimed to combine preoperative risk factors to investigate the predictive value for postoperative pain 12 months after TKA. DESIGN: Prospective cohort with follow-up 12 months after surgery. PATIENTS: A consecutive sample of 131 knee osteoarthritis patients undergoing TKA. METHODS: Pain intensity, Pain Catastrophizing Scale (PCS) scores, PainDETECT Questionnaire scores, conditioned pain modulation (CPM), and Oxford Knee Score (OKS) were obtained before and 12 months after TKA. RESULTS: TKA improved pain (P < 0.001), PCS scores (P < 0.001), PainDETECT Questionnaire scores (P < 0.001), and OKSs (P < 0.001). Preoperative pain correlated with preoperative PCS scores (r = 0.38, P  <  0.001), PainDETECT scores (r = 0.53, P  <  0.001), and OKSs (r = -0.25, P  =  0.001). Preoperative PainDETECT scores were associated with preoperative PCS scores (r = 0.53, P  <  0.001) and OKSs (r = -0.25, P  =  0.002). Higher postoperative pain was correlated with high preoperative pain (r = 0.424, P  <  0.001), PCS scores (r = 0.33, P  <  0.001), PainDETECT scores (r = 0.298, P  =  0.001), and lower CPM (r = -0.18, P  =  0.04). The combination of preoperative pain, PCS score, and CPM explained 20.5% of variance in follow-up pain. PCS scores had a significant effect on pain trajectory when accounting for patient variance (t  =  14.41, P  <  0.0005). CONCLUSION: The combination of high preoperative clinical pain intensity, high levels of pain catastrophizing thoughts, and impaired CPM may predict long-term postoperative pain 12 months after surgery.

Pressure pain thresholds in office workers with chronic neck pain: A systematic review and meta-analysis.

OBJECTIVES: The purpose of this study was to (a) compare pressure pain threshold (PPT) values between office workers with chronic neck pain and asymptomatic controls; (b) establish reference PPT values in chronic neck pain; and (c) evaluate associations between PPTs and pain intensity, and disability. METHODS: Seven English/Portuguese databases were searched for relevant literature. Studies investigating adult office workers (age >18 years) with chronic neck pain were included if PPTs were an outcome. The risk of bias was assessed using the Downs and Black checklist. Meta-analysis was conducted if a cluster contained at least two studies reporting the same PPTs. RESULTS: Ten high quality, two low quality, and one poor quality studies were included. The meta-analysis revealed decreased PPT values in the upper trapezius, extensor carpi ulnaris, and tibialis anterior in office workers with chronic neck pain when compared with healthy workers, without a statistical difference (p > 0.05). The PPT reference value in the upper trapezius was 263 kPa (95% confidence interval [CI] = 236.35 to 289.70), and 365 kPa (95% CI = 316.66 to 415.12) for the tibialis anterior in office workers with chronic neck pain. No correlations were found between the upper trapezius PPT and pain intensity and disability. CONCLUSION: This meta-analysis found that all the PPT measurements were not significantly reduced in office workers with chronic neck pain compared with healthy workers. These assumptions were based on a small sample of existing studies, and therefore further studies are necessary to quantify the differences in PPTs. Hypersensitivity PPT reference values are proposed for localized and extrasegmental sites in office workers with chronic neck pain.

Preoperative serum circulating microRNAs as potential biomarkers for chronic postoperative pain after total knee replacement.

BACKGROUND: Chronic postoperative pain affects approximately 20% of patients with knee osteoarthritis after total knee replacement. Circulating microRNAs can be found in serum and might act as biomarkers in a variety of diseases. The current study aimed to investigate the preoperative expression of circulating microRNAs as potential predictive biomarkers for the development of chronic postoperative pain in the year following total knee replacement. METHODS: Serum samples, collected preoperatively from 136 knee osteoarthritis patients, were analyzed for 21 circulatory microRNAs. Pain intensity was assessed using a visual analog scale before and one year after total knee replacement. Patients were divided into a low-pain relief group (pain relief percentage <30%) and a high-pain relief group (pain relief percentage >30%) based on their pain relief one year after total knee replacement, and differences in microRNAs expression were analyzed between the two groups. RESULTS: We found that three microRNAs were preoperatively dysregulated in serum in the low-pain relief group compared with the high-pain relief group. MicroRNAs hsa-miR-146a-5p, -145-5p, and -130 b-3p exhibited fold changes of 1.50, 1.55, and 1.61, respectively, between the groups (all P values < 0.05). Hsa-miR-146a-5p and preoperative pain intensity correlated positively with postoperative pain relief (respectively, R = 0.300, P = 0.006; R = 0.500, P < 0.001). DISCUSSION: This study showed that patients with a low postoperative pain relief present a dysregulation of circulating microRNAs. Altered circulatory microRNAs expression correlated with postoperative pain relief, indicating that microRNAs can serve as predictive biomarkers of pain outcome after surgery and hence may foster new strategies for preventing chronic postoperative pain after total knee replacement (TKR).

Chronic Postoperative Pain After Hysterectomy for Endometrial Cancer: A Metabolic Profiling Study.

INTRODUCTION: One out of seven women will develop a state of chronic postoperative pain following robot-assisted hysterectomy for endometrial cancer. Recently, metabolic studies have indicated that circulating lipids and lipoproteins could act as nociceptive modulators and thereby influence the induction and perpetuation of pain. The objectives of this explorative study were (1) to examine the preoperative serologic variations in concentrations of lipids, lipoproteins, and various low-molecular metabolites in patients with and without chronic postoperative pain after robot-assisted hysterectomy and (2) to explore if any of these serological biomarkers were predictive for development of chronic postoperative pain. MATERIALS AND METHODS: The study was designed as a nested case-control study within a cohort of women treated for endometrial cancer with robot-assisted laparoscopic hysterectomy. Twenty-six women with chronic postoperative pain were matched on age and body mass index with fifty-two controls without chronic postoperative pain, and metabolic profiling of preoperatively drawn blood samples from a biobank was performed by means of nuclear magnetic resonance spectroscopy. RESULTS: Nineteen metabolites, including cholesterol, cholesteryl ester, linoleic acid, phospholipids, lipids, and triglycerides had statistically significant higher concentrations in a subgroup of patients who would develop chronic postoperative pain on a later stage compared to the group of patients who would not develop chronic postoperative pain (p < 0.05). A sparse Partial Least Squares-Discriminant Analysis model explained 38.1% of the variance and had a predictive accuracy of 73.1%. CONCLUSIONS: This explorative study substantiates the hypothesis that certain lipids, lipoproteins, and fatty acids are associated with chronic postoperative pain.

Eccentric Training Changes the Pressure Pain and Stiffness Maps of the Upper Trapezius in Females with Chronic Neck-Shoulder Pain: A Preliminary Study.

OBJECTIVE: Between 50% and 67% of adults suffer from neck-shoulder pain, which may be associated with increased stiffness of neck muscles. We assessed pressure pain sensitivity and muscle stiffness maps of the upper trapezius in female computer users with and without chronic neck-shoulder pain and investigated the effects of eccentric training on females with neck-shoulder pain. DESIGN: Cross-sectional (part 1) and open-label (part 2) study. SETTING: University. SUBJECTS: Twenty females with neck-shoulder pain were compared with 20 controls (part 1). In part 2, neck-shoulder pain participants followed a five-week unilateral upper trapezius eccentric training program. METHODS: Topographical maps of pressure pain thresholds (pressure algometer) and muscle stiffness (myotonometer), using a 15-point grid covering myotendinous and muscle belly sites, and shoulder elevation force and range of elevation (dynamometer) were assessed at baseline and after training. RESULTS: There were no differences in pressure pain thresholds between sites (P = 0.243) or groups (P = 0.068), and there were significant differences in stiffness between myotendinous and muscle belly sites (P < 0.001) but not groups (P = 0.273). After training, pressure pain thresholds increased, stiffness decreased (P < 0.005), and shoulder elevation force and range of elevation improved (P < 0.001). CONCLUSIONS: The lack of differences in upper trapezius pressure pain sensitivity and stiffness between females with or without neck-shoulder pain confirms no clear etiology among computer users reporting neck-shoulder pain. A five-week eccentric training protocol showed positive effects on pressure pain sensitivity, stiffness, shoulder force, and range of motion.

Modulation of Exercise-Induced Hypoalgesia Following an Exercise Intervention in Healthy Subjects.

BACKGROUND: Exercise is recommended to promote and maintain health and as treatment for more than 25 diseases and pain conditions. Exercise-induced hypoalgesia (EIH), a measure of descending pain inhibitory control, has been found to be impaired in some chronic pain conditions, but it is currently unclear if EIH is modifiable. This study investigated whether a long-term exercise intervention could modulate EIH in healthy subjects. METHODS: In 38 healthy subjects, EIH was assessed as change in pressure pain threshold (PPT) after a three-minute isometric wall squat within the first week and after approximately seven weeks of military training (MT). Further, temporal summation of pain (TSP) and Knee injury and Osteoarthritis Outcome Score (KOOS) were assessed. Physical performance capacity was assessed using the Endurance 20-m shuttle run fitness test (20MSR). Hypoalgesic (EIH > 0.0 kPa) and hyperalgesic (EIH ≤ 0.0 kPa) subgroups were defined based on baseline EIH. Change in EIH following MT was used as the primary outcome. RESULTS: Increased EIH (P = 0.008), PPT (P < 0.003), and 20MSR (P < 0.001) were found following MT, with no changes in TSP and KOOS (P > 0.05). Subjects with a hyperalgesic EIH response at baseline (26% of the participants) presented significantly improved EIH following MT (P = 0.010). Finally, an association between 20MRS change and EIH change was found (r = 0.369, P = 0.023). CONCLUSIONS: MT increased EIH, especially in subjects who demonstrated a hyperalgesic response at baseline. Improvement in physical performance capacity was associated with an improvement in EIH, indicating that improvement in physical performance capacity may improve central pain mechanisms.

Manifestations of Pain Sensitization Across Different Painful Knee Disorders: A Systematic Review Including Meta-analysis and Metaregression.

OBJECTIVES: Previous reviews have reported that manifestations of pain sensitization may play an important role in the pain experienced by people with knee osteoarthritis. However, it is unknown if manifestations of pain sensitization are common features across other painful knee disorders or if sensitization requires targeted intervention. This review aims to synthesize the published research investigating manifestations of pain sensitization in painful knee disorders and to evaluate if the manifestations of pain sensitization change in response to treatment. METHODS: The systematic review protocol was registered with PROSPERO (CRD42015024211). We searched Medline, Embase, CINAHL, Web of Science, Sportsdiscus, and Cochrane Central for studies that investigated between-group differences (knee pain vs pain-free subjects) or the effect of treatment on manifestations of pain sensitization. Two reviewers independently assessed studies for inclusion and quality. Available data were synthesized via predetermined levels of evidence, meta-analysis, and metaregression where possible. RESULTS: Fifty-two studies investigating evidence related to pain sensitization distributed across four different painful knee disorders were identified. CONCLUSIONS: Our meta-analysis provides evidence of pain sensitization in people with knee osteoarthritis (strong evidence), people with patellofemoral pain (moderate evidence), and postmeniscectomy patients (very limited evidence). However, conflicting evidence exists in patellar tendinopathy. Metaregression indicates that pain is associated with pressure pain thresholds in knee osteoarthritis. In people with knee osteoarthritis and patellofemoral pain, several interventions were found to reduce manifestations of pain sensitization. This review highlights that pain sensitization may be amenable to treatment through exercise therapy, mobilization, and pharmacological and surgical intervention.

Impaired Conditioned Pain Modulation in Young Female Adults with Long-Standing Patellofemoral Pain: A Single Blinded Cross-Sectional Study.

OBJECTIVE: Patellofemoral pain (PFP) is common among young individuals. Female adolescents with PFP present typically with localized mechanical hyperalgesia around the knee, but the effect of central pain mechanisms are unknown. This study aimed to compare temporal summation of pain, conditioned pain modulation (CPM), and widespread hyperalgesia in young female adults with PFP and age-matched pain-free controls. DESIGN: Cross-sectional study. SETTING AND SUBJECTS: Twenty young female adults (19-21 years old) with long-standing PFP were compared with 20 pain-free controls from the same population-based cohort. METHODS: Cuff algometry was used to assess the pain detection threshold. Temporal summation of pain was assessed by recording the pain intensity on a visual analog scale during repeated cuff pressure stimulations at pain tolerance intensity on the lower leg. CPM was recorded as an increase in the cuff pain detection threshold in response to experimental conditioning pain imposed on the contralateral arm. Handheld pressure algometry was used to assess pressure pain thresholds (PPTs) on the knee, shin, and forearm. The examiner was blinded to the type of subject assessed. RESULTS: Compared with pain-free controls, young females with PFP showed no decrease in cuff pain thresholds (P < 0.40) or facilitated temporal summation (P < 0.15) but had a lower CPM response (P < 0.04) and lower PPTs (P < 0.005). CONCLUSIONS: Young female adults with long-standing PFP demonstrated impaired CPM. This is important because PFP, a peripheral pathology, might have important central components that need to be studied in order to understand its extent and therapeutic implications.

Interface Pressure Behavior During Painful Cuff Algometry.

OBJECTIVE: Cuff algometry is used for the psychophysical assessment of deep-tissue pain sensitivity. The cuff pressure homogeneity may affect the pain sensitivity assessment and potentially be improved by alternative cuff designs optimizing the pressure distribution. The aim of this study was to investigate the relationship between pain sensitivity, inflation pressure, and distribution of interface pressure between the skin and cuff during stimulation with a conventional air tourniquet and a novel tourniquet including a water tube interfacing the air cuff with the skin. METHODS: Air and water cuff stimulations were applied separately on the right lower leg of 12 subjects until the tolerance pain threshold. The inflation pressure was controlled and recorded by a computer-control program, while the interface pressure distribution was measured by a flexible pressure sensor mat located between the cuff and skin. RESULTS: The mean interface pressure across the entire stimulation surface was not significantly different from inflating pressure during air-cuff algometry. For the water cuff there was a significant reduction in the mean interface pressure compared with the inflating pressure at both the detection and tolerance pain levels (P < 0.002). The interface pressure distribution of the water cuff around the limb was significantly more homogeneous compared with the air cuff (P < 0.03). This homogeneity showed a significant correlation with pain sensitivity (P < 0.008). CONCLUSION: Cuff systems with a liquid medium optimize the homogeneity of the interface pressure distribution. However, the deviation of the interface pressure from the inflating pressure is crucial as it counteracts the effects of pressure homogeneity on pain sensitivity in water-cuff algometry.

Altered Central Sensitization and Pain Modulation in the CNS in Chronic Joint Pain.

Musculoskeletal pain disorders are the second largest contributor to global disability underlining the significance of effective treatments. However, treating chronic musculoskeletal pain, and chronic joint pain (osteoarthritis (OA)) in particular, is challenging as the underlying peripheral and central pain mechanisms are not fully understood, and safe and efficient analgesic drugs are not available. The pain associated with joint pain is highly individual, and features from radiological imaging have not demonstrated robust associations with the pain manifestations. In recent years, a variety of human quantitative pain assessment tools (quantitative sensory testing (QST)) have been developed providing new opportunities for profiling patients and reaching a greater understanding of the mechanisms involved in chronic joint pain. As joint pain is a complex interaction between many different pain mechanisms, available tools are important for patent profiling and providing the basic knowledge for development of new drugs and for developing pain management regimes.

Type X collagen levels are elevated in serum from human osteoarthritis patients and associated with biomarkers of cartilage degradation and inflammation.

BACKGROUND: Osteoarthritis (OA) is the most common degenerative joint disease, of which the pathogenesis is inadequately understood. Hypertrophy-like changes have been observed as part of the progression of OA. The aim of the study was to develop and characterize a novel biomarker of chondrocytes hypertrophy and investigate how this marker was associated with cartilage degradation and inflammation in patients with various degrees of OA. METHODS: A competitive ELISA, C-Col10, applying a well-characterized monoclonal antibody was developed as a biomarker of chondrocyte hypertrophy through measurement of type X collagen (ColX). The levels of C-Col10, C2M (matrix metalloproteinase-derived fragments of type II collagen) and hsCRP (high sensitive C-reactive protein) were quantified by ELISAs in serum of 271 OA patients stratified by Kellgren-Lawrence (KL) score 0-4. Associations between serum levels of the three biomarkers (log transformed) were analyzed by Pearson's correlation and differences in C-Col10 levels between patients with high and low levels of inflammation measured by hsCRP were analyzed by ANOVA. RESULTS: We developed a C-Col10 assay measuring the C-terminus of ColX. We found significantly higher levels of ColX in patients with KL score 2 compared to patients with no radiographic evidence of OA (KL0) (p = 0.04). Levels of ColX were significantly elevated in OA patients with above normal hsCRP levels (p < 0.0001), as well as significantly correlated with levels of C2M (r = 0.55, p < 0.0001), which suggested that chondrocyte hypertrophy was associated with inflammation and cartilage degradation. There was no correlation between C2M and hsCRP. Age and BMI adjustment didn't change the results. Immuno-staining revealed that ColX was predominately located around the hypertrophic chondrocytes and the clustered chondrocytes indicating that C-Col10 measures may be linked to cartilage hypertrophic changes. CONCLUSIONS: We developed a novel assay, C-Col10, for measurement of chondrocyte hypertrophy and found its levels significantly elevated in OA patients with KL score of 2, and also in OA patients with above normal hsCRP levels. Concentration of C-Col10 strongly correlated with levels of C2M, a marker of cartilage destruction. The data suggest that chondrocyte hypertrophy and subsequent collagen X fragmentation seem to be increased in a subset of patients with inflammatory OA.

Inflammatory biomarkers in patients with painful knee osteoarthritis: exploring the potential link to chronic postoperative pain after total knee arthroplasty-a secondary analysis.

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.