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).

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.

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.

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).

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.

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.

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 influence of exercise on clinical pain and pain mechanisms in patients with subacromial pain syndrome.

BACKGROUND: Few studies have investigated the underlying mechanisms for unilateral subacromial pain syndrome (SAPS). Therefore, this study examined (1) if 8-weeks of exercise could modulate clinical pain or temporal summation of pain (TSP), conditioned pain modulation (CPM), and exercise-induced hypoalgesia (EIH) and (2) if any of these parameters could predict the effect of 8-weeks of exercise in patients with unilateral SAPS. METHODS: Thirty-seven patients completed a progressive abduction exercise program every other day for 8-weeks. Worst shoulder pain in full abduction was rated on a numeric rating scale (NRS). Pain pressure thresholds (PPTs), TSP, CPM, EIH, Shoulder Pain and Disability Index (SPADI), Pain Catastrophizing Scale (PCS), PainDETECT questionnaire (PD-Q), Pain Self-Efficacy Questionnaire (PSE-Q) and Pittsburgh Sleep Quality Index (PSQI) were assessed before and after intervention. RESULTS: The intervention improved worst pain intensity (p < 0.001), increased the CPM (p < 0.001), improved the sleep scores (p < 0.005) and reduced the PainDETECT ratings (p < 0.001). No changes were observed in PPT, TSP, EIH, SPADI, PCS and PSE-Q (all p > 0.05). In a linear regression, the combination of all baseline parameters predicted 23.2% variance in absolute change in pain after 8 weeks. Applying backwards elimination to the linear regression yielded that baseline pain intensity combined with TSP predicted 33.8% variance. CONCLUSION: This explorative study suggested reduction in pain, improved sleep quality and increased CPM after 8-weeks of exercise. Furthermore, the results suggests that low pain intensity and high TSP scores (indicative for pain sensitisation) may predict a lack of pain improvement after exercise.

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.

Long-term biopsychosocial issues and health-related quality of life in young adolescents and adults treated for childhood Complex Regional Pain Syndrome, type 1.

OBJECTIVES: Treatment for childhood Complex Regional Pain Syndrome (CRPS) is associated with long-term recovery. The present study aimed to investigate the long-term biopsychosocial status and quality of life in young adolescents and adults after the treatment of childhood CRPS. METHODS: A 4 year follow-up of individuals with childhood-CRPS, type 1 (n=22; age:12 years (years) [median] at treatment and 17 years at follow-up) was completed. Biopsychosocial status and quality of life were assessed with structured interviews, using the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), the Strengths and Difficulties Questionnaire (SDQ), the Pediatric Pain Coping Inventory (PPCI), and the Pediatric Quality of Life Inventory (PedsQL). Comparisons were made with normative samples of age-matched controls. RESULTS: CRPS at follow-up was still present in seven out of 22, and non-CRPS pain symptoms were found in 12 out of 22 individuals. Signs of mental health pain-related problems, including phobias and obsessive-compulsive disorder, were observed in ten out of 19 individuals. Mental well-being, social functioning, and quality of life (SDQ and PedsQL) were independent of pain status (p>0.05). Adaptive pain coping strategies were utilized regardless of pain status (PPCI). Social functioning (p<0.01) and the quality of life (p=0.01) were attenuated and statistically significantly poorer than healthy age-matched young adults but better than for fibromyalgia subjects. CONCLUSIONS: A subset of individuals treated for childhood-CRPS, type 1 experiences long-term consequences of persistent pain, a decrease in quality of life indicators, and demonstrates significant psychosocial issues. Childhood-CRPS is suggested to be associated with long-term psychosocial consequences and poorer quality of life than found in age-related healthy peers. Subjects treated for childhood CRPS may need a longer clinical follow-up attempting to preclude relapse of CRPS and non-CRPS pain.

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.

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.

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.

Obstructive sleep apnea is common in patients with high-impact chronic pain - an exploratory study from an interdisciplinary pain center.

OBJECTIVES: Sleep disturbances are increasingly recognized as a major part of chronic pain pathology. Obstructive sleep apnea (OSA) is a common occurrence in patients with chronic pain attending specialized pain clinics, yet its prevalence remains unclear. Using screening tools such as the Berlin and STOP-BANG questionnaires may aid in early identification of OSA and improve clinical care. This study i) examined the frequency of OSA based on objective sleep monitoring in patients with high-impact chronic pain, ii) explored potential differences in self-reported pain and sleep characteristics between patients with and without OSA, and iii) tested the agreement between OSA classification based on objective assessment and two OSA screening questionnaires. METHODS: A consecutive cohort of 90 patients (71 women and 19 men; mean age: 47.1 ± 11.0 years) referred for interdisciplinary pain treatment, underwent one night of sleep monitoring using portable respiratory polygraphy (RP), and suspected OSA was confirmed with polysomnography (PSG). Self-reported data on clinical pain (severity, pain drawings and health-related quality of life), sleep characteristics (sleep quality insomnia, sleepiness), and risk of OSA (Berlin and STOP-BANG questionnaires) were collected the day before RP assessment. RESULTS: Forty-six (51.1%) patients were classified with OSA according to RP and verified with PSG. Twenty-eight patients (31.1%) had moderate or severe OSA (apnea-hypopnea index [AHI] >15). Patients with OSA reported lower sleep quality compared with patients without OSA. Scores on pain severity, disability, quality of life, insomnia and sleepiness were comparable between patients with and without OSA. Sensitivity and specificity were 78.6 and 45.2% respectively for the Berlin questionnaire, and 71.4 and 58.1% respectively for the STOP-BANG questionnaire. The agreement for both questionnaires with objective assessment was poor-to-fair. Both questionnaires had acceptable negative predictive values but low positive predictive values reducing the clinical utility to identify patients with low OSA-risk in this sample. CONCLUSIONS: The current study demonstrates a high prevalence of OSA in patients with high-impact chronic pain referred to specialized pain treatment, however the clinical pain profiles were similar in patients with and without OSA. The Berlin and STOP-BANG questionnaires have poor specificity and low-to-fair agreement with RP/PSG questioning their clinical utility in identifying OSA in this sample.

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.

Hypoalgesia after exercises with painful vs. non-painful muscles in healthy subjects - a randomized cross-over study.

OBJECTIVES: Exercise-induced hypoalgesia (EIH) is a decrease in the pain sensitivity after exercise. Individuals with chronic pain show less EIH after one exercise session compared with pain-free individuals possibly due to pain in exercising muscles. The primary aim of this randomized controlled cross-over study was to compare the EIH response at the exercising thigh muscle following exercises performed with painful vs. non-painful muscles. Secondary aims were to explore if a reduced EIH response was confined to the painful muscle, and whether the muscle pain intensity and the EIH responses were negatively associated. METHODS: In two sessions, 34 pain-free participants received a painful (hypertonic saline, 5.8%) injection and a control (isotonic saline, 0.9%) injection in the right thigh muscle before performing a 3 min isometric wall squat exercise. Pressure pain thresholds (PPTs) were assessed at both thighs and the left neck/shoulder at baseline, after injections and after exercise. Pain intensities in the thighs were rated on numerical rating scales (NRS: 0-10). RESULTS: Hypertonic saline induced moderate thigh pain at rest (NRS: 4.6 ± 2.1) compared to the control injection (NRS: 0.3 ± 0.4; p<0.001). EIH at the thighs and neck/shoulder were not different between sessions (Injected thigh: 0 kPa; 95% CI: -51 to 52; Contralateral thigh: -6 kPa; 95% CI: -42 to 30; neck/shoulder: 19 kPa; 95% CI: -6 to 44). No significant associations between pain intensity ratings immediately after the Painful injection and EIH responses at any assessment sites were found (right thigh: ß=0.08, 95% CI: -12.95 to 20.64, p=0.64, left thigh: ß=-0.33, 95% CI: -27.86 to 0.44, p=0.06; neck/shoulder: ß=-0.18, 95% CI: -15.11 to 4.96, p=0.31). CONCLUSIONS: Pain in the area of an exercising muscle did not reduce local or systemic EIH responses. TRIAL REGISTRATION NUMBER: NCT04354948.

A mechanism-based proof of concept study on the effects of duloxetine in patients with painful knee osteoarthritis.

BACKGROUND: The global burden of osteoarthritis (OA) is steadily increasing due to demographic and lifestyle changes. The nervous system can undergo peripheral and central neuroplastic changes (sensitization) in patients with OA impacting the options to manage the pain adequately. As a result of sensitization, patients with OA show lower pressure pain thresholds (PPTs), facilitated temporal summation of pain (TSP), and impaired conditioned pain modulation (CPM). As traditional analgesics (acetaminophen and non-steroidal anti-inflammatory drugs) are not recommended for long-term use in OA, more fundamental knowledge related to other possible management regimes are needed. Duloxetine is a serotonin-noradrenalin reuptake inhibitor, and analgesic effects are documented in patients with OA although the underlying fundamental mechanisms remain unclear. The descending pain inhibitory control system is believed to be dependent on serotonin and noradrenalin. We hypothesized that the analgesic effect of duloxetine could act through these pathways and consequently indirectly reduce pain and sensitization. The aim of this mechanistic study is to investigate if PPTs, TSP, CPM, and clinical pain parameters are modulated by duloxetine. METHODS: This proof of concept study is a randomized, placebo-controlled, double-blinded, crossover trial, which compares PPTs, TSP, and CPM before and after 18 weeks of duloxetine and placebo in forty patients with knee OA. The intervention periods include a titration period (2 weeks), treatment period (60 mg daily for 14 weeks), and a discontinuation period (2 weeks). Intervention periods are separated by 2 weeks. DISCUSSION: Duloxetine is recommended for the treatment of chronic pain, but the underlying mechanisms of the analgesic effects are currently unknown. This study will investigate if duloxetine can modify central pain mechanisms and thereby provide insights into the underlying mechanisms of the analgesic effect. TRIAL REGISTRATION: ClinicalTrials.gov NCT04224584 . Registered on January 6, 2020. EudraCT 2019-003437-42 . Registered on October 22, 2019. The North Denmark Region Committee on Health Research Ethics N-20190055. Registered on October 31, 2019.

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.

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.