The Role of Nuclear Medicine Imaging with 18F-FDG PET/CT, Combined 111In-WBC/99mTc-Nanocoll, and 99mTc-HDP SPECT/CT in the Evaluation of Patients with Chronic Problems after TKA or THA in a Prospective Study.

BACKGROUND: The aim of this prospective study was to assess the diagnostic value of nuclear imaging with 18F-FDG PET/CT (FDG PET/CT), combined 111In-WBC/99mTc-Nanocoll, and 99mTc-HDP SPECT/CT (dual-isotope WBC/bone marrow scan) for patients with chronic problems related to knee or hip prostheses (TKA or THA) scheduled by a structured multidisciplinary algorithm. MATERIALS AND METHODS: Fifty-five patients underwent imaging with 99mTc-HDP SPECT/CT (bone scan), dual-isotope WBC/bone marrow scan, and FDG PET/CT. The final diagnosis of prosthetic joint infection (PJI) and/or loosening was based on the intraoperative findings and microbiological culture results and the clinical follow-up. RESULTS: The diagnostic performance of dual-isotope WBC/bone marrow SPECT/CT for PJI showed a sensitivity of 100% (CI 0.74-1.00), a specificity of 97% (CI 0.82-1.00), and an accuracy of 98% (CI 0.88-1.00); for PET/CT, the sensitivity, specificity, and accuracy were 100% (CI 0.74-1.00), 71% (CI 0.56-0.90), and 79% (CI 0.68-0.93), respectively. CONCLUSIONS: In a standardized prospectively scheduled patient group, the results showed highly specific performance of combined dual-isotope WBC/bone marrow SPECT/CT in confirming chronic PJI. FDG PET/CT has an appropriate accuracy, but the utility of its use in the clinical diagnostic algorithm of suspected PJI needs further evidence.

The association between sleep quality, preoperative risk factors for chronic postoperative pain and postoperative pain intensity 12 months after knee and hip arthroplasty.

BACKGROUND: Chronic postoperative pain following total joint replacement (TJA) is a substantial clinical problem, and poor sleep may affect predictive factors for postoperative pain, such as pain catastrophizing. However, the magnitude of these associations is currently unknown. This exploratory study investigated (1) the relationship between preoperative sleep quality, clinical pain intensity, pain catastrophizing, anxiety, and depression and (2) their associations with chronic postoperative pain following TJA. METHODS: This secondary analysis from a larger randomized controlled trial included rest pain intensity (preoperative and 12 months postoperative; visual analogue scale, VAS), preoperative Pittsburgh Sleep Quality Index (PSQI), Pain Catastrophizing Scale (PCS), Hospital Anxiety and Depression Scale (HADS) data from 74 knee and 89 hip osteoarthritis (OA) patients scheduled for TJA. Poor sleepers were identified based on preoperative PSQI scores higher than 5. RESULTS: Poor sleepers demonstrated higher preoperative VAS, pain catastrophizing, anxiety, and depression compared with good sleepers (all p < 0.003). Preoperative PSQI (ß = 0.23, p = 0.006), PCS (ß = 0.44, p < 0.005), and anxiety (ß = 0.18, p = 0.036) were independent factors for preoperative VAS. Preoperative VAS (ß = 0.32, p < 0.005), but not preoperative sleep quality (ß = -0.06, p = 0.5), was an independent factor for postoperative VAS. CONCLUSION: The OA patients reporting poor preoperative sleep quality show higher preoperative pain, pain catastrophizing, anxiety, and depression. High preoperative pain intensity, but not poor sleep quality, was associated with higher chronic postoperative pain intensity. Future studies are encouraged to explore associations between sleep and chronic postoperative pain.

Circulating long non-coding RNA signature in knee osteoarthritis patients with postoperative pain one-year after total knee replacement.

OBJECTIVES: The incidence of chronic postoperative pain after total knee replacement (TKR) is approx. 20%, and hence preoperative risk factors are important to identify. Recent studies have indicated that preoperative inflammatory markers might hold prognostic information for the development of chronic postoperative pain. Long non-coding RNA (lncRNA) regulates the expression of genes related to e.g. inflammatory processes. The current study aimed to investigate the preoperative lncRNA signature as possible preoperative predictive markers for chronic postoperative pain following TKR. METHODS: Serum samples, collected preoperatively from 20 knee osteoarthritis (KOA) patients, were analyzed for 84 validated circulatory lncRNA. Pain intensity was assessed using a visual analog scale (VAS) before and one-year after TKR. Differences for the lncRNA expression were analyzed between patients with chronic postoperative pain (VAS≥3) and those with a normal postoperative recovery (VAS<3). RESULTS: LncRNA Myeloid Zinc Finger 1 Antisense RNA 1 (MZF1-AS1) (fold change -3.99; p-value: 0.038) (shown to be involved neuropathic pain) Metastasis associated lung adenocarcinoma transcript 1 (MALAT1) (fold change -3.39; p-value: 0.044) (shown to be involved neuropathic pain); Patched 1 pseudogene (LOC100287846) (fold change -6.99; p-value: 0.029) (unknown in pain) were down-regulated preoperatively in the group with chronic postoperative pain compared to the group normal postoperative pain recovery. CONCLUSIONS: These findings suggest, that TKR patients with chronic postoperative pain present preoperative downregulations of three specific lncRNA detectable at the systemic level. The presented study might give new insights into the complexity of chronic postoperative pain development and show how non-coding RNA plays a role in the underlying molecular mechanisms of pain.

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.

Patients With High Chronic Postoperative Knee Pain 5 Years After Total Knee Replacement Demonstrate Low-grad Inflammation, Impairment of Function, and High Levels of Pain Catastrophizing.

OBJECTIVES: Total knee replacement (TKR) normally provides improvements of physical function and reduces pain. However, ∼20% of the patients report chronic postoperative knee pain. The aims of the present study were to assess the pain, physical function, and physiological characteristics 5 years after TKR surgery. MATERIALS AND METHODS: Eighty patients were recruited 5 years after TKR and divided into 2 groups based on their average 24-hour knee pain intensity assessed on a visual analog scale (VAS 0 to 10) ("high pain group": VAS≥3; "low pain group": VAS<3). The patients completed the PainDETECT Questionnaire (PDQ), Oxford Knee Score (OKS), Pain Catastrophizing Scale, and Forgotten Joint Score-12. Furthermore, the patients underwent a clinical examination of the knees and high-sensitivity serum C-reactive protein was measured as an inflammatory marker. RESULTS: A total of 53% of the patients in the high pain group were not satisfied with the outcome, while only 11% of the patients in the low pain group was not satisfied, and the pain intensities in the 2 groups were 5.1 (4.6 to 5 to 6) and 1.1 (0.6 to 1.5) (P<0.001), respectively. Furthermore, the high pain group demonstrates worse scores in: Forgotten Joint Score-12 (P=0.001), OKS function (P<0.001), OKS pain (P<0.001), and Pain Catastrophizing Scale (P<0.001).The high pain group demonstrated increased level of high-sensitivity serum C-reactive protein (4.3 mg/L [3.2 to 5.5] vs. 1.7 mg/L [1.2 to 2.2], P<0.001), and decreased range of motion in the knee (110 vs. 119-degree range of motion, P=0.013). DISCUSSION: Patients with high chronic postoperative knee pain 5 years after TKR demonstrate decreased physical function, higher levels of catastrophizing thoughts, and increased levels of inflammation.

Pain, sensitization and physical performances in patients with chronic painful knee osteoarthritis or chronic pain following total knee arthroplasty: An explorative study.

BACKGROUND: The aim of this study was to assess clinical pain, pain sensitization and physical performances to profile patients with chronic painful knee osteoarthritis (OA) or pain after total knee arthroplasty (TKA). Examining the interactions between pain mechanisms and physical performances would enable us to investigate the underlying explanatory relationships between these parameters. METHODS: In this explorative study, 70 patients with chronic painful knee OA (N = 46) or chronic pain after TKA (N = 24) were assessed for clinical pain, quantitative sensory profiling (mechanical pinprick pain sensitivity, temporal summation (TS) and conditioned pain modulation), physical performances (chair stand, walk and stair climb tests) and self-reported outcomes. Between-group comparisons were made using ANCOVA tests and associations between outcomes were analysed using multivariate linear regression models. RESULTS: Overall, no differences between groups regarding clinical pain and quantitative sensory profiling outcomes were observed. Physical performances were lower in the TKA group compared with the OA group with moderate-to-large effect sizes, and a tendency towards better scores in self-reported outcomes for the OA group was observed with small-to-moderate effect sizes. Self-reported function seems to be associated with physical performances in the TKA group. Sensitization (TS) appears to be associated with poorer physical performances in the OA group. CONCLUSIONS: Similar profiles for pain intensity, signs of sensitization and conditioned pain modulation were observed. Patients with TKA seems to have impaired physical performances compared with the OA group, underlining the importance of targeting physical performances. Only the OA patients showed an association between sensitization (TS) and physical performance. SIGNIFICANCE: Quantitative pain profiling assessment was used to assess pain intensities and pain mechanisms. We observed associations between physical performances and temporal summation in the OA group underlining the importance of assessing motor functions and pain mechanisms in the same trial. We observed lower levels of physical performances in the TKA group compared with the OA group, suggesting that examination and rehabilitation of physical performances is essential for TKA patients with chronic pain.

Novel Method for Osmotic Conductance to Glucose in Peritoneal Dialysis.

INTRODUCTION: The osmotic conductance to glucose (OCG) is a crucial determinant of ultrafiltration (UF) in peritoneal dialysis (PD) patients and can be used to monitor membrane integrity in patients on long-term PD. It has been proposed that OCG can be assessed based on drained volumes in 2 consecutive 1-hour glucose dwells, usually 1.5% and 4.25% glucose, in a so-called double mini-peritoneal equilibration test (dm-PET). However, recent data indicated that the dm-PET provides a poor estimate of OCG unless the residual volume (RV) is taken into account. We introduce an easy, robust, and accurate method to measure OCG and compare it with conventional methods. METHODS: In a prospective cohort of 21 PD patients, a modified version of the dm-PET was performed, along with the determination of RV before, between, and after dwells. Based on computer simulations derived from the 3-pore model (TPM) for membrane permeability, we developed and validated a novel single-dwell method to estimate OCG. We next validated the equation in an independent cohort consisting of 32 PD patients. RESULTS: Single-dwell OCG correlated more closely with actual UF (r = 0.94 vs. r = 0.07 for conventional dm-PET), sodium sieving, and free water transport (FWT) compared with other methods. These findings were replicated in the validation cohort in which OCG calculated using the single-dwell method closely correlated with parameters of osmotic water transport, even when RV was not taken into account, using only drained volumes. CONCLUSION: We propose a novel, easy, and robust single-dwell method to determine OCG in individual patients and to monitor membrane integrity over time on PD.

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).

Development of an individualized asynchronous sensor-based telerehabilitation program for patients undergoing total knee replacement: Participatory design.

Telerehabilitation programs can be employed to establish communication between patients and healthcare professionals and empower patients performing their training remotely. This study aimed to identify patients' requirements after a total knee replacement following a self-training rehabilitation program, leading to the design and development of a telerehabilitation program that can meet the stakeholders' actual needs. System design, development, and testing were conducted in five iterations based on a participatory design approach. Data collection was performed using interviews, observations, prototyping, and questionnaires. It was found that the main barriers facing the existing rehabilitation program were a lack of clear communication, lack of relevant information, and healthcare professional's feedback. The participants emphasized the main themes of communication, information, training, and motivation in the process of design and development. In using the telerehabilitation program, the patients reported a high level of user-friendliness, flexibility, and a sense of security. This study has identified obstacles in the current rehabilitation program and revealed the potential effectiveness of using asynchronous communication and sensor-based technologies by employing participatory design and development. A higher level of portability and flexibility were observed. However, future studies and development are required to investigate the overall usability and reliability of the telerehabilitation program.

Neuromuscular exercise and pain neuroscience education compared with pain neuroscience education alone in patients with chronic pain after primary total knee arthroplasty: study protocol for the NEPNEP randomized controlled trial.

BACKGROUND: Total knee arthroplasty (TKA) is considered an effective treatment for pain relief and improved physical performances in end-stage knee osteoarthritis. However, several studies have reported less favorable outcomes after TKA with chronic pain rates of approximately 20%. Exercise might be an effective treatment strategy for chronic pain following TKA, but no randomized controlled trials have evaluated its effect. Therefore, the purpose of this randomized controlled trial is to investigate whether a 12-week neuromuscular exercise (NEuroMuscular EXercise training program for patients with knee or hip osteoarthritis assigned for total joint replacement; NEMEX-TJR) program combined with pain neuroscience education (PNE) provides greater pain relief and improvement in physical performances than PNE alone at 12 months follow-up in a population of patients with chronic pain after primary TKA. METHODS: For this randomized controlled superiority trial, 120 patients with moderate-to-severe chronic pain after TKA are recruited from Aalborg University Hospital, Denmark. Patients are randomly assigned in a 1:1 ratio to one of two interventions: (a) NEMEX-TJR twice weekly for 12 weeks combined with two sessions of PNE or (b) two sessions of PNE given over 6 weeks. Assessment is performed at baseline before intervention and at 3, 6, and 12 months after initiation of the intervention. Outcome assessors are blinded toward group allocation. The primary outcome is the change in the Knee Injury and Osteoarthritis Outcome Score4 (KOOS4), defined as the mean score for the KOOS subscales pain, symptoms, activities of daily living, and quality of life. Secondary outcomes include all KOOS subscale scores and scores for PainDETECT, the Fear-Avoidance Beliefs Questionnaire, Global Perceived Effect, the Pain Catastrophizing Scale, pain intensities, temporal summation, conditioned pain modulation, and pressure pain thresholds. Physical performances are measured with walking, stair climbing, and chair standing tests as well as tests of muscle strength and power. DISCUSSION: The findings will be useful in establishing effective treatment strategies for chronic pain after TKA. The randomized controlled trial involves rigorous scientific methods and uses clinically applicable interventions. The study interventions are conducted in clinical settings, thereby enhancing the possibility of future implementation of the treatments in the health care systems. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03886259. Registered 22 March 2019. Ethics committee registration: N-20180046.

Multidisciplinary Diagnostic Algorithm for Evaluation of Patients Presenting with a Prosthetic Problem in the Hip or Knee: A Prospective Study.

The predominant indications for revision surgery after total hip (THA) or knee arthroplasty (TKA) are an aseptic failure (AF) and prosthetic joint infection (PJI). Accurate diagnosis is crucial. Therefore, we evaluated prospectively a multidisciplinary diagnostic algorithm including multi-modal radionucleid imaging (RNI) and extended microbiological diagnostics. If the surgeon suspected PJI or AF, revision surgery was performed with multiple samples obtained in parallel for special culture procedures and later molecular analyses. Alternatively, if the underlying cause was not evident, RNI was scheduled comprising 99Tc - HDP SPECT/CT, 111In-labeled white blood cells combined with 99Tc-nanocoll bone marrow SPECT/CT, and 18F-FDG PET/CT. A multidisciplinary clinical team made a recommendation on the indication for a diagnostic procedure guided by RNI images or revision surgery. A total of 156 patients with 163 arthroplasties were included. Fifty-five patients underwent RNI. In all, 118 revision surgeries were performed in 112 patients: 71 on the indication of AF and 41 revision of PJI. Thirty-four patients were concluded with chronic pain, and revision surgery refrained. The effective median follow-up period was 13 months. A structured approach offered by the algorithm was useful for the clinician in the evaluation of patients with a failing TKA or THA. Surgical revision was possibly obviated in approximately 20% of patients where an explanation or cause of failure was not found. The algorithm served as an effective tool.

Cost-effectiveness of total knee replacement in addition to non-surgical treatment: a 2-year outcome from a randomised trial in secondary care in Denmark.

OBJECTIVE: To assess the 24-month cost-effectiveness of total knee replacement (TKR) plus non-surgical treatment compared with non-surgical treatment with the option of later TKR if needed. METHODS: 100 adults with moderate-to-severe knee osteoarthritis found eligible for TKR by an orthopaedic surgeon in secondary care were randomised to TKR plus 12 weeks of supervised non-surgical treatment (exercise, education, diet, insoles and pain medication) or to supervised non-surgical treatment alone. Including quality-adjusted life years (QALYs) data from baseline, 3, 6, 12 and 24 months, effectiveness was measured as change at 24 months. Healthcare costs and transfer payments were derived from national registries. Incremental healthcare costs, and incremental cost-effectiveness ratios (ICERs) were calculated. A probabilistic sensitivity analysis was conducted and the probability of cost-effectiveness was estimated at the 22 665 Euros/QALY threshold defined by the National Institute for Health and Care Excellence. RESULTS: TKR plus non-surgical treatment was more expensive (mean of 23 076 vs 14 514 Euros) but also more effective than non-surgical treatment (mean 24-month improvement in QALY of 0.195 vs 0.056). While cost-effective in the unadjusted scenario (ICER of 18 497 Euros/QALY), TKR plus non-surgical treatment was not cost-effective compared with non-surgical treatment with the option of later TKR if needed in the adjusted (age, sex and baseline values), base-case scenario (ICER of 32 611 Euros/QALY) with a probability of cost-effectiveness of 23.2%. Including deaths, TKR plus non-surgical treatment was still not cost-effective (ICERs of 46 277 to 64 208 Euros/QALY). CONCLUSIONS: From a 24-month perspective, TKR plus non-surgical treatment does not appear to be cost-effective compared with non-surgical treatment with the option of later TKR if needed in patients with moderate-to-severe knee osteoarthritis and moderate intensity pain in secondary care in Denmark. Results were sensitive to changes, highlighting the need for further confirmatory research also assessing the long-term cost-effectiveness of TKR. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov (NCT01410409).

Investigating the Effect of Perioperative Chlorzoxazone on Acute Postoperative Pain After Total Hip and Knee Replacement Surgery.

BACKGROUND AND AIMS: Severe preoperative and acute postoperative pain have been associated with the development of chronic postoperative pain. Chlorzoxazone (a muscle relaxant) has been suggested to enhance acute postoperative pain recovery, but the lack of larger randomized controlled trials has, however, questioned the continued use. Despite this, chlorzoxazone is still used for acute postoperative pain management following total knee replacement (TKR) or total hip replacement (THR). The current randomized, double-blinded, placebo-controlled, parallel-group, clinical trial aimed to assess the effect of chlorzoxazone for postoperative pain management following TKR or THR. METHODS: A total of 393 patients scheduled for TKR or THR were included in the trial. Patients were assigned to 250 mg chlorzoxazone 3 times daily for the first 7 days postoperatively or to placebo. The primary outcome was pain after 5 m walk assessed 24 hours postoperatively. Secondary outcomes included changes in preoperative pain at rest, worst pain in the last 24 hours, and Oxford Knee or Hip Score compared with 12 months' follow-up. In addition, adverse events were assessed in the perioperative period. RESULTS: No significant differences were found for any of the outcome parameters after TKR or THR. As regards TKR or THR, no effects were demonstrated for pain after 5 m walk 24 hours after surgery (P>0.313), or for any of the secondary outcomes (P>0.288) or adverse events (P>0.112) in the group receiving chlorzoxazone compared with placebo. CONCLUSION: The current study demonstrated no analgesic effects of postoperative chlorzoxazone administration compared with placebo on acute or chronic postoperative pain 12 months following TKR and THR.

Serum Inflammatory Markers in Patients With Knee Osteoarthritis: A Proteomic Approach.

OBJECTIVES: Osteoarthritis (OA) is known to be a slowly progressive disease that alters all tissue compartments of the joint involved with a characteristic degradation of the cartilage, bone remodeling, and inflammation. One of the prominent symptoms in OA patients is pain, but a few radiologic, inflammatory, or structurally related biomarkers have shown few if any associations with pain. This study aimed to assess serum levels of 92 markers involved in inflammatory pathways in patients with knee osteoarthritis (KOA) and evaluate their possible associations with the clinical pain intensity. MATERIALS AND METHODS: Serum samples were collected from 127 KOA patients and 39 healthy participants with no knee pain. Each serum sample was analyzed for 92 inflammatory markers using the Proximity Extension Array (PEA) technology. Clinical pain intensity was assessed using a Visual Analog Scale, and patients completed the Knee Injury and Osteoarthritis Outcome Score (KOOS) questionnaire. RESULTS: Fifteen markers were significantly different when comparing KOA patients and healthy participants. Two markers, fibroblast growth factor-21 and Eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1), correlated positively with pain intensity (R=0.235, P=0.008; R=0.233, P=0.008). Moreover, a linear regression model showed interleukin-6, macrophage colony-stimulating factor 1, fibroblast growth factor-21, and tumor necrosis factor superfamily member 12 (TWEAK) as significant independent parameters for pain intensity. DISCUSSION: The associations between specific cytokines and KOA pain intensities provide new insights into the understanding of the underlying factors driving the pain in OA.

Less Severe Preoperative Synovitis is Associated With Higher Self-reported Pain Intensity 12 Months After Total Knee Arthroplasty-An Exploratory Prospective Observational Study.

OBJECTIVES: Synovitis is one of the possible pain generators in osteoarthritis (OA) and is associated with upregulation of proinflammatory cytokines, which can lead to worsening of the postoperative pain. This exploratory study aimed to investigate the association between perioperative synovitis and self-reported pain 12 months after total knee arthroplasty (TKA) in patients with OA. MATERIALS AND METHODS: Twenty-six knee OA patients were included in this analysis. The perioperative volume of synovitis in predefined locations was assessed by contrast-enhanced magnetic resonance imaging (CE-MRI) and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Perioperative synovitis was assessed histologically from biopsies of the synovium. Highest pain intensity within the last 24 hours (Visual Analog Scale, VAS, 0 to 100) was assessed before and 12 months after TKA. Patients were divided into a low-pain intensity (VAS≤30) and a high-pain intensity (VAS>30) group on the basis of 12 months postoperative VAS. RESULTS: The high-pain intensity group had significantly lower perioperative contrast-enhanced-synovitis (P=0.025), DCE-synovitis (P<0.04), and a trend toward lower histologically assessed synovitis (P=0.077) compared with the low-pain intensity group. Perioperative synovitis scores were inversely correlated with pain intensity 12 months after TKA (P<0.05), indicating that more severe perioperative synovitis is associated with less severe pain intensity at 12 months. DISCUSSION: Higher degrees of perioperative synovitis scores are found to be associated with less postoperative pain 12 months after TKA. Further, correlation analysis revealed that less severe perioperative CE-MRI and DCE-MRI synovitis was associated with higher pain intensity 12 months after TKA, suggesting that CE-MRI and DCE-MRI synovitis grades could be used as imaging markers for prediction of chronic postoperative pain after TKA.

Pain inhibitory mechanisms and response to weak analgesics in patients with knee osteoarthritis.

BACKGROUND: Conditioned pain modulation (CPM) and offset analgesia are different features of descending pain inhibition. This study investigated CPM, offset analgesia and clinical pain measures in patients with knee osteoarthritis (KOA) before and after treatment with the combination of a non-steroidal anti-inflammatory drug (NSAIDs) plus acetaminophen. METHODS: Forty-two patients with KOA received Ibuprofen 1.2 g/daily and acetaminophen 3.0 g/daily for three weeks. Before administration, CPM magnitude was assessed as the difference between cuff pain detection (cPDT) with and without a conditioning stimulus (evoked by tourniquet pain). Offset analgesia was assessed as the pain intensities evoked by a constant 46°C for 30-s stimulus compared to an offset analgesia paradigm of 46°C for 5-s, 47°C for 5-s and 46°C for 20-s. The worst pain within the last 24-hr and pain during activity were assessed before and after treatment. RESULTS: Clinical pain significantly decreased after treatment (p < 0.001) and less efficient CPM before treatment was associated with weaker analgesic effect (R = 0.354, p = 0.043). No significant modulation of CPM or offset analgesia was found for the treatment. CONCLUSION: This study found that less efficient CPM is associated with reduced analgesic effect of NSAIDs plus acetaminophen in patients with KOA whereas the treatment did not modulate CPM nor offset analgesia magnitude. SIGNIFICANCE: This study demonstrated that conditioned pain modulation is correlated with the response to a standard pharmaceutical interventions treating osteoarthritis pain. Furthermore, we demonstrated that a decrease in clinical pain intensity is not associated with a normalization of conditioned pain modulation or offset analgesia, which questions if restoring these descending pain inhibitory mechanisms are pain intensity driven.

Developing a telerehabilitation programme for postoperative recovery from knee surgery: specifications and requirements.

INTRODUCTION: Telerehabilitation programmes have been attracting increasing attention as a potential alternative to conventional rehabilitation. Video conferencing can facilitate communication between healthcare professionals and patients. However, in certain cases, video conferencing may face practical limitations. As an alternative to real-time conferencing, sensor-based technologies can transmit the acquired data to healthcare providers. This study aimed to design and develop a sensor-based telerehabilitation programme and to outline the corresponding requirements for such a system. DEVELOPMENT: The development of the sensor-based telerehabilitation programme was carried out based on user needs. The programme includes a portable platform for the patient as well as a web-based platform for the healthcare professional, thus allowing for an individualised rehabilitation programme. Communication, training, reporting, and information services were provided for the patients. Moreover, the portability and usability of the programme were enhanced by utilising the system in offline mode as well. APPLICATION: The programme is currently being tested in the North Denmark Region to assess the feasibility and acceptance of a telerehabilitation programme as an alternative solution to the self-training programme for patients who have been discharged from knee surgery. The preliminary results of our assessment showed a high level of acceptance among the users. DISCUSSION: In this study, a semi-online sensor-based telerehabilitation programme was tested. It is argued that a similar sensor-based telerehabilitation programme can be utilised as an alternative solution for self-training rehabilitation in the future; however; further studies and development are required to ensure the quality and reliability of sensor-based services.

Presurgical Comorbidities as Risk Factors For Chronic Postsurgical Pain Following Total Knee Replacement.

OBJECTIVES: Chronic postsurgical knee pain (CPSP) is a burden for ∼20% of the patients following total knee replacement (TKR). Presurgical pain intensities have consistently been found associated with CPSP, and it is suggested that comorbidities are likewise important for the development of CPSP. This study aimed to identify presurgical risk factors for the development of CPSP 5 years after TKR on the basis of medical records containing information with regard to comorbidities. MATERIALS AND METHODS: Patients undergoing primary TKR surgery were contacted 5 years after TKR. Presurgical Knee Society Score and comorbidities were evaluated. Postsurgical knee pain at 5 years of follow-up was assessed on a Numeric Rating Scale (NRS, 0 to 10). Logistic regression models were utilized to identify patients with moderate-to-severe (NRS≥3) and mild-to-no (NRS<3) CPSP at 5-year follow-up. Odds ratio (OR) for significant factors was calculated. RESULTS: A total of 604 patients were contacted, 493 patients responded, 352 patients provided a completed questionnaire. A total of 107 patients reported NRS≥3 at follow-up. Significant presurgical factors associated with CPSP were fibromyalgia (OR=20.66; P=0.024), chronic pain in body parts other than the knee (OR=6.70; P=0.033), previous diagnosis of cancer (OR=3.06; P=0.001), knee instability (OR=2.16; P=0.021), younger age (OR=2.15; P=0.007), and presurgical knee pain (OR=1.61; P=0.044). Regression analysis identified 36 of 107 (33.6%) patients with CPSP on the basis of presurgical factors, and 231 patients (94.3%) without CPSP were classified correctly. DISCUSSION: The current study found that a variety of presurgical clinical factors can correctly classify 33.6% of patients at risk for developing CPSP 5 years following TKR.

Mechanistic pain profiling as a tool to predict the efficacy of 3-week nonsteroidal anti-inflammatory drugs plus paracetamol in patients with painful knee osteoarthritis.

Joint inflammation is present in a subpopulation of knee osteoarthritis (OA) patients. Proinflammatory cytokines are known to sensitize the peripheral and central pain pathways. This can be mechanistically assessed by pressure pain thresholds and temporal summation of pain (TSP). Nonsteroidal anti-inflammatory drugs (NSAIDs) combined with paracetamol are recommended as OA treatment. The current study hypothesized that evidence of central sensitization would predict poor responses to peripherally directed therapies in knee OA and therefore aimed to investigate the value of mechanistic pain profiling for predicting pain outcome of treatment with NSAIDs plus paracetamol. One hundred thirty-two patients received ibuprofen 1200 mg/daily, paracetamol 3 g/daily, and pantoprazole 20 mg/daily for 3 weeks. Before administration, cuff pain detection, tolerance threshold, and TSP were assessed. Worst pain within the last 24 hours and pain during activity (visual analogue scales) were assessed before and after treatment. Facilitated TSP was found at baseline in the nonresponders to the 3-weeks treatment as compared to responders for both the 30% and 50% pain alleviation criteria (P < 0.02). Linear regression models identified facilitated TSP (P < 0.01) and low clinical pain scores (P < 0.001) as independent factors for prediction of poor pain alleviation by the treatment. In conclusion, this study found that mechanistic pain profiling can predict pain alleviation of NSAIDs and paracetamol. Facilitated TSP and low clinical pain scores before treatment are independent predictors of poor pain alleviation after NSAIDs and paracetamol. This study adds to the growing evidence that a subgroup of knee OA patients with manifested central sensitization may require special management attention.

A Novel High Sensitivity Type II Collagen Blood-Based Biomarker, PRO-C2, for Assessment of Cartilage Formation.

N-terminal propeptide of type II collagen (PIINP) is a biomarker reflecting cartilage formation. PIINP exists in two main splice variants termed as type IIA and type IIB collagen NH2-propeptide (PIIANP, PIIBNP). PIIANP has been widely recognized as a cartilage formation biomarker. However, the utility of PIIBNP as a marker in preclinical and clinical settings has not been fully investigated yet. In this study, we aimed to characterize an antibody targeting human PIIBNP and to develop an immunoassay assessing type II collagen synthesis in human blood samples. A high sensitivity electrochemiluminescence immunoassay, hsPRO-C2, was developed using a well-characterized antibody against human PIIBNP. Human cartilage explants from replaced osteoarthritis knees were cultured for ten weeks in the presence of growth factors, insulin-like growth factor 1 (IGF-1) or recombinant human fibroblast growth factor 18 (rhFGF-18). The culture medium was changed every seven days, and levels of PIIBNP, PIIANP, and matrix metalloproteinase 9-mediated degradation of type II collagen (C2M) were analyzed herein. Serum samples from a cross-sectional knee osteoarthritis cohort, as well as pediatric and rheumatoid arthritis samples, were assayed for PIIBNP and PIIANP. Western blot showed that the antibody recognized PIIBNP either as a free fragment or attached to the main molecule. Immunohistochemistry demonstrated that PIIBNP was predominately located in the extracellular matrix of the superficial and deep zones and chondrocytes in both normal and osteoarthritic articular cartilage. In addition, the hsPRO-C2 immunoassay exhibits acceptable technical performances. In the human cartilage explants model, levels of PIIBNP, but not PIIANP and C2M, were increased (2 to 7-fold) time-dependently in response to IGF-1. Moreover, there was no significant correlation between PIIBNP and PIIANP levels when measured in knee osteoarthritis, rheumatoid arthritis, and pediatric serum samples. Serum PIIBNP was significantly higher in controls (KL0/1) compared to OA groups (KL2/3/4, p = 0.012). The hsPRO-C2 assay shows completely different biological and clinical patterns than PIIANP ELISA, suggesting that it may be a promising biomarker of cartilage formation.