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).

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.

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).

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.

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.

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.

Mechanical hyperalgesia and neuropathic pain qualities impart risk for chronic postoperative pain after total knee replacement.

Total knee replacement (TKR) is the gold-standard treatment for end-stage chronic osteoarthritis pain, yet many patients report chronic postoperative pain after TKR. The search for preoperative predictors for chronic postoperative pain following TKR has been studied with inconsistent findings. This study investigates the predictive value of quantitative sensory testing (QST) and PainDETECT for postoperative pain 3, 6, and 12 months post-TKR. We assessed baseline and postoperative (3- and 6-months) QST measures in 77 patients with knee OA (KOA) and 41 healthy controls, along with neuropathic pain scores in patients (PainDETECT). QST parameters included pressure pain pressure threshold (PPT), pain tolerance threshold (PTT), conditioned pain modulation (CPM), and temporal summation (TS) using cuff algometry, alongside mechanical hyperalgesia, and mechanical temporal summation to repeated pinprick stimulation. Compared to healthy controls, KOA patients at baseline demonstrated hyperalgesia to pinprick stimulation at the medial OA-affected knee and cuff pressure on the ipsilateral calf. Lower cuff algometry PTT and mechanical pinprick hyperalgesia were associated with baseline KOA pain intensity. Moreover, baseline pinprick pain hyperalgesia explained 25% of variance in pain intensity 12 months post-TKR and preoperative neuropathic pain scores also captured 30% and 20% of the variance in postoperative pain at 6- and 12-months, respectively. A decrease in mechanical pinprick hyperalgesia from before surgery to 3 months after TKR was associated with lower postoperative pain at the 12 months post-TKR follow-up, and vice-versa. Our findings suggest that preoperative pinprick hyperalgesia and PainDETECT neuropathic-like pain symptoms show predictive value for the development of chronic post-TKR pain.

Prognostic value of preoperative mechanical hyperalgesia and neuropathic pain qualities for postoperative pain after total knee replacement.

BACKGROUND: Total knee replacement (TKR) is the gold standard treatment for end-stage chronic osteoarthritis pain, yet many patients report chronic postoperative pain after TKR. The search for preoperative predictors for chronic postoperative pain following TKR has been studied with inconsistent findings. METHODS: This study investigates the predictive value of quantitative sensory testing (QST) and PainDETECT for postoperative pain 3, 6 and 12 months post-TKR. We assessed preoperative and postoperative (3 and 6 months) QST measures in 77 patients with knee OA (KOA) and 41 healthy controls, along with neuropathic pain scores in patients (PainDETECT). QST parameters included pressure pain pressure threshold (PPT), pain tolerance threshold (PTT), conditioned pain modulation (CPM) and temporal summation (TS) using cuff algometry, alongside mechanical hyperalgesia and temporal summation to repeated pinprick stimulation. RESULTS: Compared to healthy controls, KOA patients at baseline demonstrated hyperalgesia to pinprick stimulation at the medial knee undergoing TKR, and cuff pressure at the calf. Lower cuff algometry PTT and mechanical pinprick hyperalgesia were associated with preoperative KOA pain intensity. Moreover, preoperative pinprick pain hyperalgesia explained 25% of variance in pain intensity 12 months post-TKR and preoperative neuropathic pain scores also captured 30% and 20% of the variance in postoperative pain at 6 and 12 months respectively. A decrease in mechanical pinprick hyperalgesia from before surgery to 3 months after TKR was associated with lower postoperative pain at the 12 months post-TKR follow-up. CONCLUSION: Our findings suggest that preoperative pinprick hyperalgesia and neuropathic-like pain symptoms show predictive value for the development of chronic post-TKR pain. SIGNIFICANCE STATEMENT: This study's findings hold significant implications for chronic pain management in knee osteoarthritis patients, particularly those undergoing total knee replacement surgery (TKR). Mechanical hyperalgesia and neuropathic pain-like characteristics predict postoperative pain 1 year after TKR, emphasizing the importance of understanding pain phenotypes in OA for selecting appropriate pain management strategies. The normalization of hyperalgesia after surgery correlates with better long-term outcomes, further highlighting the therapeutic potential of addressing abnormal pain processing mechanisms pre- and post-TKR.

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.

Preoperatively assessed offset analgesia predicts acute postoperative pain following orthognathic surgery.

OBJECTIVES: High intensity and longer duration of acute postoperative pain are generally associated with a higher risk of developing chronic postoperative pain. Therefore, it is important to identify the preoperative predictors for acute postoperative pain. Preoperative evaluation of offset analgesia (OA) and the Pain Catastrophising Scale (PCS) may be potential predictors for acute postoperative pain. This study aimed to investigate the relationship between preoperative OA, PCS, and acute postoperative pain following orthognathic surgery. METHODS: Thirty patients (19 females) scheduled to undergo orthognathic surgery were included in this study. OA and PCS were evaluated preoperatively, and the patients reported their postoperative pain intensity using the visual analogue scale [0-100 mm] until it reached zero (number of days with pain). OA was induced on the dominant forearm via three consecutive painful heat pulses delivered for 5 s (T1=46 °C), 5 s (T2=47 °C), and 20 s (T3=46 °C). Subsequently, the associations between OA, PCS, and the number of days with pain were analysed. RESULTS: The median duration of postoperative pain was 10.3 days. Multiple linear regression analysis showed a significant (p=0.0019) predictive value of OA (p=0.008) for the number of days with pain. The PCS-magnification component was positively correlated with the number of days with pain (R=0.369, p=0.045), with no predictive values of PCS-total and PCS-subscale scores observed. CONCLUSIONS: Preoperative evaluation of OA may be a new individualised, predictive tool for the number of days with acute postoperative pain following orthognathic surgery; hence, a possible biomarker for the patient's vulnerability to developing chronic postoperative pain. ETHICAL COMMITTEE NUMBER: The study was approved by the Ethics Committee of Meikai University (A1624, A2113). TRIAL REGISTRY NUMBER: This study was registered in the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) Clinical Trial (Unique ID: UMIN000026719, UMIN000046957).

A simple, bed-side tool to assess evoked pressure pain intensity.

OBJECTIVES: Existing equipment for quantitative sensory testing is generally expensive and not easily applicable in a clinical setting thus simple bed-side devices are warranted. Pressure hyperalgesia is a common finding in patients with musculoskeletal pain and an experimental model is delayed-onset muscle soreness (DOMS). DOMS is characterised by muscle hyperalgesia and some studies report facilitation of temporal summation of pain. This study aimed to detect DOMS induced muscle hyperalgesia and temporal summation of pain using a newly developed bed-side quantitative sensory testing device to deliver standardised pressure. METHODS: Twenty-two healthy participants participated in two sessions with the second session approximately 48 h after baseline. Pressure pain intensities were assessed from the gastrocnemius muscle with four probes calibrated to apply 2, 4, 6 and 8 kg, respectively. Temporal summation of pain (10 stimuli delivered at 0.5 Hz using the 6 kg probe) intensities were assessed from the same location. DOMS was evoked in the gastrocnemius muscle by an eccentric exercise. Sleepiness and physical activity were measured with the Epworth Sleepiness Scale and the Global Physical Activity Questionnaire to investigate if they were associated with the quantitative sensory testing measures. RESULTS: Pressure pain intensity was significantly increased 48 h after induction of DOMS when compared to baseline for all four probes (p<0.05). Temporal summation of pain was not statistically significant affected by DOMS and sleep quality and physical activity did not associate with any of the measures. CONCLUSIONS: This study introduces a simple, bed-side assessment tool for the assessment of pressure pain intensity and hence hyperalgesia and temporal summation of pain.

Modulation of offset analgesia in patients with chronic pain and healthy subjects - a systematic review and meta-analysis.

OBJECTIVES: Offset analgesia (OA) induces a brief pain inhibition and studies suggest OA impairment in patients with chronic pain when compared to healthy subjects. Conditioned pain modulation remains the most studied descending pain inhibitory control mechanism and is modulated by centrally-acting analgesics. Since OA may be mediated by similar neural substrates as conditioned pain modulation, understanding if OA is a peripheral or central proxy of pain modulation is important. The modulatory effect of centrally-acting drugs on OA in healthy and chronic pain populations has not yet been systematically reviewed and meta-analyzed, and this systematic review and meta-analysis aimed to identify studies employing interventions for modulating OA magnitude. METHODS: A systematic search of PubMed, Embase, Web of Science, and the Cochrane Library yielded 146 records of which 11 (172 healthy pain-free subjects, 106 chronic pain patients) were eligible for qualitative synthesis, and 10 for meta-analysis on overall modulatory effect of interventions on OA, and subgroup analysis of patients and healthy pain-free subjects. RESULTS: Risk of bias was evident for study participation and study confounding in the included studies. Several different methods for assessing and calculating OA magnitude were identified, which may affect interpretability of findings and warrants standardization. The meta-analysis showed no modulatory effects on OA overall (standardized mean difference (SMD) [95%CI]: 0.04 [-0.22, 0.30], Z=0.29, p=0.77), or in the subgroup analysis for patients (SMD [95%CI]: -0.04 [-0.63, 0.71], Z=0.13, p=0.90) or healthy pain-free subjects (SMD [95%CI]: 0.01 [-0.21, 0.24], Z=0.11, p=0.91). Moderate to substantial heterogeneity was found for the overall analysis (I2=47%, p=0.03) and patient subgroup analysis (I2=75%, p=0.003). CONCLUSIONS: The current systematic review and meta-analysis conclude that centrally-acting drugs and exercise do not influence OA. Evidence on the peripheral contribution to OA response requires further investigations. Preclinical models of OA should be established to identify the neurophysiology and -biology behind OA.

Detection of altered pain facilitatory and inhibitory mechanisms in patients with knee osteoarthritis by using a simple bedside tool kit (QuantiPain).

Purpose: Altered pain facilitatory and inhibitory mechanisms have been recognized as an important manifestation in patients with chronic pain, and quantitative sensory testing (QST) can act as a proxy for this process. We have recently developed a simple bedside QST tool kit (QuantiPain) for more clinical use. The purpose of this study was to investigate its test-retest reliability and to evaluate its validity compared with the laboratory-based QST protocols in patients with knee osteoarthritis (OA). Methods: QuantiPain consists of 3 items: "pressure algometer" (for pressure pain thresholds [PPTs]), "pinprick" (for temporal summation of pain [TSP]), and "conditioning clamp" (for conditioned pain modulation [CPM]). In experiment-A, intrarater and interrater test-retest reliabilities were investigated in 21 young healthy subjects by using interclass correlation coefficient (ICC). In experiment-B, 40 unilateral painful patients with OA and 40 age-matched, healthy control subjects were included to compare the bedside tool kit against the computerized pressure algometry. Results: In experiment-A, excellent to moderate intrarater and interrater reliabilities were achieved in PPT and TSP (ICC: 0.60-0.92) while the agreements of CPM were good to poor (ICC: 0.37-0.80). In experiment-B, localized and widespread decrease of PPT, facilitated TSP, and impaired CPM was found by using the bedside tool kit in patients with OA compared with controls (P < 0.05). The data were significantly correlated with the established laboratory-based tools (R = 0.281-0.848, P < 0.05). Conclusion: QuantiPain demonstrated acceptable test-retest reliability and assessment validity with the sensitivity to separate patients with painful OA from controls, which has a potential to create more practical approach for quantifying altered pain mechanisms in clinical settings.

Human assumed central sensitisation (HACS) in patients with chronic low back pain radiating to the leg (CLaSSICO study).

INTRODUCTION: Patients with chronic low back pain radiating to the leg (CLBPr) are sometimes referred to a specialised pain clinic for a precise diagnosis based, for example, on a diagnostic selective nerve root block. Possible interventions are therapeutic selective nerve root block or pulsed radiofrequency. Central pain sensitisation is not directly assessable in humans and therefore the term 'human assumed central sensitisation' (HACS) is proposed. The possible existence and degree of sensitisation associated with pain mechanisms assumed present in the human central nervous system, its role in the chronification of pain and its interaction with diagnostic and therapeutic interventions are largely unknown in patients with CLBPr. The aim of quantitative sensory testing (QST) is to estimate quantitatively the presence of HACS and accumulating evidence suggest that a subset of patients with CLBPr have facilitated responses to a range of QST tests.The aims of this study are to identify HACS in patients with CLBPr, to determine associations with the effect of selective nerve root blocks and compare outcomes of HACS in patients to healthy volunteers. METHODS AND ANALYSIS: A prospective observational study including 50 patients with CLBPr. Measurements are performed before diagnostic and therapeutic nerve root block interventions and at 4 weeks follow-up. Data from patients will be compared with those of 50 sex-matched and age-matched healthy volunteers. The primary study parameters are the outcomes of QST and the Central Sensitisation Inventory. Statistical analyses to be performed will be analysis of variance. ETHICS AND DISSEMINATION: The Medical Research Ethics Committee of the University Medical Center Groningen, Groningen, the Netherlands, approved this study (dossier NL60439.042.17). The results will be disseminated via publications in peer-reviewed journals and at conferences. TRIAL REGISTRATION NUMBER: NTR NL6765.

Cannabidiol treatment in hand osteoarthritis and psoriatic arthritis: a randomized, double-blind, placebo-controlled trial.

ABSTRACT: Cannabidiol (CBD) is increasingly used as analgesic medication although the recent International Association for the Study of Pain Presidential Task Force on cannabis and cannabinoid analgesia found a lack of trials examining CBD for pain management. This trial examines CBD as add-on analgesic therapy in patients with hand osteoarthritis or psoriatic arthritis experiencing moderate pain intensity despite therapy. Using a randomized, double-blind, placebo-controlled design, patients received synthetic CBD 20 to 30 mg or placebo daily for 12 weeks. The primary outcome was pain intensity during the past 24 hours (0-100 mm); safety outcomes were percentage of patients experiencing adverse events and a characterization of serious adverse events. Explorative outcomes included change in Pittsburgh Sleep Quality Index, Hospital Anxiety and Depression Scale, Pain Catastrophizing Scale (PCS), and Health Assessment Questionnaire Disability Index. One hundred thirty-six patients were randomized, of which 129 were included in the primary analysis. Between-group difference in pain intensity at 12 weeks was 0.23 mm (95% confidence interval -9.41 to 9.90; P = 0.96). Twenty-two percent patients receiving CBD and 21% receiving placebo experienced a reduction in pain intensity of more than 30 mm. We found neither clinically nor statistically significant effects of CBD for pain intensity in patients with hand osteoarthritis and psoriatic arthritis when compared with placebo. In addition, no statistically significant effects were found on sleep quality, depression, anxiety, or pain catastrophizing scores.