Quantitative sensory testing, psychological factors, and quality of life as predictors of current and future pain in patients with knee osteoarthritis.

ABSTRACT: Substantial interindividual variability characterizes osteoarthritis (OA) pain. Previous findings identify quantitative sensory testing (QST), psychological factors, and health-related quality of life as contributors to OA pain and predictors of treatment outcomes. This exploratory study aimed to explain baseline OA pain intensity and predict OA pain after administration of a nonsteroidal anti-inflammatory drug in combination with paracetamol for 3 weeks. The Knee Injury and Osteoarthritis Outcome Score (KOOS) pain score was used to estimate OA pain presentation. One hundred one patients were assessed at baseline and follow-up using QST (pressure pain thresholds and temporal summation of pain [TSP]), symptoms of depression and anxiety, pain catastrophizing scales (PCSs), and health-related quality of life. Linear regression with backward selection identified that PCS significantly explained 34.2% of the variability in baseline KOOS pain, with nonsignificant contributions from TSP. Pain catastrophizing score and TSP predicted 29.3% of follow-up KOOS pain, with nonsignificant contributions from symptoms of anxiety. When assessed separately, PCS was the strongest predictor (32.2% of baseline and 24.1% of follow-up pain), but QST, symptoms of anxiety and depression, PCS, and quality of life also explained some variability in baseline and follow-up knee OA pain. Further analyses revealed that only TSP and PCS were not mediated by any other included variables, highlighting their role as unique contributors to OA pain presentation. This study emphasizes the importance of embracing a multimodal approach to OA pain and highlights PCS and TSP as major contributors to the baseline OA pain experience and the OA pain experience after OA treatment.

A potential link between inflammatory profiles, clinical pain, pain catastrophizing and long-term outcomes after total knee arthroplasty surgery.

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.

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.

The potential effect of walking on quantitative sensory testing, pain catastrophizing, and perceived stress: an exploratory study.

OBJECTIVES: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

The temporal expression of circulating microRNAs after acute experimental pain in humans.

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.

Predicting pain after standard pain therapy for knee osteoarthritis - the first steps towards personalized mechanistic-based pain medicine in osteoarthritis.

OBJECTIVES: The prevalence of osteoarthritis (OA) is rising, and pain is the hallmark symptom of OA. Pain in OA is complicated and can be influenced by multiple joint-related factors and factors related to, e.g., physiological, epigenetic, and pain sensory profiles. Increasing evidence suggests that a subset of patients with OA are pain sensitive. This can be assessed using quantitative sensory testing (QST). Common treatments of OA are total knee arthroplasty (TKA) and administration of 3-weeks of non-steroidal anti-inflammatory drugs (NSAIDs), which provide pain relief to many patients with OA. However, approx. 20% of patients experience chronic postoperative pain after TKA, whereas NSAIDs provide an average pain relief of approx. 25%. The current topical review focuses on the emerging evidence linking pretreatment QST to the treatment response of TKA and NSAID treatments. CONTENT: MEDLINE was systematically searched for all studies from 2000 to 2022 on pretreatment QST, TKA, and NSAIDs. Pre-clinical studies, reviews, and meta-analyses were excluded. SUMMARY: Currently, 14 studies on TKA and four studies on NSAIDs have been published with the aim to attempt prediction of the treatment response. The QST methodologies in the studies are inconsistent, but 11/14 (79%) studies on TKA and 4/4 (100%) studies on NSAIDs report statistically significant associations between pretreatment QST and chronic postoperative pain after TKA or analgesic effect after NSAID treatment. The strength of the associations remains low-to-moderate. The most consistent pretreatment QST predictors are pressure pain thresholds, temporal summation of pain, and conditioned pain modulation. OUTLOOK: The use of QST as predictors of standard OA treatment is interesting, but the predictive strength remains low-to-moderate. A transition of QST from a research-based setting and into the clinic is not advised until the predictive strength has been improved and the methodology has been standardized.

Quantitative sensory testing as an assessment tool to predict the response to standard pain treatment in knee osteoarthritis: a systematic review and meta-analysis.

Emerging evidence suggest that quantitative sensory testing (QST) may predict the treatment response to pain-relieving therapies. This systematic review and meta-analysis focus on the predictive value of QST for pain management of knee osteoarthritis (OA). MEDLINE and EMBASE were systematically searched for all studies from year 2000 to 2023 on pretreatment QST and treatment of OA including surgical, pharmaceutical, and nonsurgical and nonpharmaceutical therapies. Preclinical studies and reviews were excluded. The systematic review followed the PRISMA guidelines and was pre-registered on the Open Science Framework website (link: https://osf.io/4FETK/, Identifier: DOI 10.17605/OSF.IO/4FETK). Meta-analysis were conducted to demonstrate the strength of the pre-treatment QST predictions on pain outcomes after OA treatments. Sixteen surgical (all on total knee arthroplasty [TKA], N = 1967), 5 pharmaceutical (4 on non-steroidal anti-inflammatory drugs [NSAIDs], N = 271), and 4 exercise-based therapy studies (N = 232) were identified. Pretreatment QST parameters predicted pain-relieving treatment outcomes in 81% of surgical, 100% of pharmaceutical, and 50% of exercise-based therapy studies. Meta-analyses found pretreatment QST profiles to predicted pain outcomes after TKA (random effects: 0.309, 95% confidence interval [CI]: 0.206-0.405, P < 0.001), NSAIDs (random effects: 0.323, 95% CI: 0.194-0.441, P < 0.001), and exercise-based therapies (random effects: 0.417, 95% CI: 0.138-0.635, P = 0.004). The overall risk of bias for the included studies was low to moderate. This systematic review and meta-analysis demonstrate weak-to-moderate associations between pretreatment QST and pain outcomes after standard OA pain treatments. Based on this work, it is hypothesized that a subset of specific pain sensitive patients with OA exist and that these patients do not respond adequately to standard OA pain treatments.

Chronic postoperative pain after total knee arthroplasty: The potential contributions of synovitis, pain sensitization and pain catastrophizing-An explorative study.

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.

The effect of duloxetine on mechanistic pain profiles, cognitive factors and clinical pain in patients with painful knee osteoarthritis-A randomized, double-blind, placebo-controlled, crossover study.

BACKGROUND: Duloxetine is indicated in the management of pain in osteoarthritis. Evidence suggests that duloxetine modulates central pain mechanisms and cognitive factors, and these factors are assumed contributing to the analgesic effect. This proof-of-mechanism, randomized, placebo-controlled, crossover, double-blinded trial evaluated the effect of duloxetine on quantitative sensory testing (QST), cognitive factors and clinical pain in patients with osteoarthritis and to predict the analgesic effect. METHODS: Twenty-five patients completed this cross-over study with either 18-week duloxetine (maximum 60 mg/daily) followed by placebo or vice-versa. Pressure pain thresholds, temporal summation of pain and conditioned pain modulation were assessed using cuff algometry. The Hospital Anxiety and Depression Scale and the Pain Catastrophizing Scale evaluated cognitive factors. Clinical pain was assessed using Brief Pain Inventory and Western Ontario and McMaster Universities Osteoarthritis Index. Linear regression models were used to predict the analgesic effect of duloxetine. RESULTS: Depending on the clinical pain outcome, 40%-68% of patients were classified as responders to duloxetine. Linear regression models predicted the analgesic effect (predictive value of 45%-75% depending on clinical pain outcome parameter) using a combination of pretreatment QST parameters, cognitive factors and clinical pain. No significant changes were found for QST, cognitive factors or clinical pain on a group level when comparing duloxetine to placebo. CONCLUSION: A combination of pretreatment QST, cognitive factors and clinical pain was able to predict the analgesic response of duloxetine. However, in this relatively small study, duloxetine did not selectively modulate QST, cognitive factors or clinical pain intensity when compared with placebo. SIGNIFICANCE: Duloxetine is proposed as a treatment for chronic pain. Pre-clinical trials suggest that duloxetine provides analgesia through modulation of descending pain inhibitory pathways or through improvements in cognitive factors. The current study demonstrates that pretreatment mechanistic pain profiling, cognitive factors and clinical pain can predict the analgesic effect of duloxetine and that only a subset of patients might benefit from duloxetine treatment.